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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[4]

Overview

Heartburn is the feeling of burning or pressure inside the chest, normally located behind the breastbone, which can last for several hours and may worsen after food ingestion. Some patients may also have a peculiar acid taste in the back of the throat accompanied with excessive salivation, regurgitating gas and bloating. The most common cause of heartburn is gastroesophageal reflux disease (GERD), in which the lower esophageal sphincter allows for gastric content to reflux into the esophagus. This may cause atypical symptoms which includes: coughing, wheezing or asthma-like symptoms, hoarseness, sore throat, dental erosions or gum disease, discomfort in the ears and nose. Heartburn is a symptom though, and it can have other causes besides GERD, such as esophagitis (infections, eosinophilic) and esophageal cancer. It can also be mistaken by chest pain and presented in life-threatening diseases such as acute coronary syndromes, aortic dissection and pericarditis.

Causes

Life Threatening Causes

Heartburn can be expressed by the patient as a type of chest pain. While evaluating heartburn, it is mandatory to differentiate it from cardiac chest pain.

Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated.

• Acute coronary syndromes
• Aortic dissection
• Pulmonary embolism

Differentiating heartburn from angina

Heartburn (GERD)	Angina or Heart Attack
Burning chest pain, begins at the breastbone	Tightness, pressure, squeezing, stabbing or dull pain, most often in the center
Pain that radiates towards the throat	Pain radiates to the shoulders, neck or arms
Sensation of food coming back to the mouth	Irregular or rapid heartbeat
Acid taste in the back of the throat	Cold sweat or clammy skin
Pain worsens when patient lie down or bend over	Lightheadedness, weakness, dizziness, nausea, indigestion or vomiting
Appears after large or spicy meal	Shortness of breath
	Symptoms appears with physical exertion or extreme stress

Common Causes

• Gastroesophageal reflux disease (GERD)
• Eosinophillic esophagitis
• Malignancy
• Achalasia
• Peptic ulcer disease

Diagnosis

Below is shown a compendium of information summarizing the diagnosis of gastroesophageal reflux disease (GERD) according the the American Journal of Gastroenterology guidelines.

The diagnosis of GERD is made based on:

• Symptom presentation;
• Response to antisecretory therapy;
• Objective testing with endoscopy;
• Ambulatory reflux monitoring.

Classic symptoms of GERD (heartburn and regurgitation)

If there are warning signs*: upper endoscopy during the initial evaluation

PPI 8-week trial

If better: GERD probable

If refractory, proceed to refractory GERD algorithm

* Dysphagia, bleeding, anemia, weight loss and recurrent vomiting are considered warning signs and should be investigated with upper endoscopy.

Shown below is an algorithm summarizing the treatment of refractory GERD according the the American Journal of Gastroenterology guidelines.

Treat GERD: Start a 8-week course of PPI

If there are warning signs*: upper endoscopy during the initial evaluation

Refractory GERD

Optimize PPI therapy

No response: Exclude other etiologies

Typical symptoms: Upper endoscopy

Atypical symptoms: Referral to ENT, pulmonary, allergy

Abnormal: (eosinophilic esophagitis, erosive esophagitis, other) Specific treatment

NORMAL

Abnormal: (ENT, pulmonary, or allergic disorder) Specific treatment

REFLUX MONITORING

Low pre test probability of GERD

High pre test probability of GERD

Test off medication with pH or impedance-pH

Test on medication with impedance-pH

• High Risk: Men >50 years with chronic gastroesophageal reflux disease symptoms (>5 years), AND:
  • Nocturnal reflux symptoms,
  • Hiatal hernia,
  • Elevated body mass index,
  • Tobacco use,
  • Intra-abdominal distribution of fat.

Perform upper endoscopy to detect esophageal adenocarcinoma and Barret’s esophagus. Surveillance examinations should occur not more frequently than once every 3 to 5 years. If the patient presents with Barret's esophagus or dysplasia, more frequent intervals are indicated.

Screening for H. Pylori is not recommended routinely on GERD.

Diagnostic Testing for GERD

Test	Indication	Recommendation
Proton Pump Inhibitor (PPI) trial	Classic symptoms, no warning/alarm symptoms	If negative does not rule out GERD
Barium swallow	Use for evaluating dysphagia	Only useful for complications (stricture, ring)
Endoscopy	Use if alarm symptoms, chest pain or high risk* patients	Consider early for elderly, high risk for Barret’s, non-cardiac chest pain, patients unresponsive to PPI
Esophageal biopsy	Exclude non-GERD causes
Esophageal manometry	Pre operative evaluation for surgery	Rule out achalasia/scleroderma-like esophagus pre-op
Ambulatory reflux monitoring	Preoperatively for non-erosive disease, refractory GERD symptoms or GERD diagnosis in question	Correlate symptoms with reflux, document abnormal acid exposure or reflux frequency

Treatment

Shown below is an algorithm summarizing the treatment of refractory GERD according the the American Journal of Gastroenterology guidelines.

Lifestyle modifications are indicated for all patients and include:

• Dietary changes (reduce ingestion of chocolate, caffeine, alcohol, acidic and/or spicy foods - low degree of evidence, but there are reports of improvements with elimination);
• Weight loss for overweight patients or patients that have had recent weight gain;
• Head of bed elevation and avoidance of meals 2–3 h before bedtime if nocturnal symptoms.

Medications used in GERD

Medication	Indication	Recommendation
PPI therapy	All patients without contraindications	Use the lowest effective dose, safe during pregnancy
H2-receptor antagonist	May be used as a complement to PPIs or as maintenance option in patients without erosive disease	Beware tachyphylaxis after several weeks of usage
Prokinetic therapy and/or baclofen	Used if symptoms do not improve	Undergo diagnostic evaluation first
Sucralfate	Pregnant women	No role in non-pregnant patients

Do's

• Differentiate heartburn from cardiac chest pain;
• Consider a twice daily dosing in patients with night-time symptoms, variable schedules, and/or sleep disturbance;
• Advise the patient to cease eating chocolate, caffeine, spicy foods, citrus or carbonated beverages;
• Strongly recommend weight loss if patient's BMI is >25 or recent weight gain;
• Recommend head of bed elevation if nocturnal GERD;
• Advise against late evening meals;
• Promote alcohol and tobacco cessation.
• If there is an alarm symptom such as dysphagia
• If there's no response with such measures and initial 8-week PPI treatment, refer patient to a specialist.

Don'ts

• Do not request an upper endoscopy for every patient complaining of GERD;
• Do not request manometry or ambulatory reflux monitoring routinely.

References

Template:WikiDoc Sources

Overview

Claudication is the description of cramping muscle pain that occurs after a certain degree of exercise and is relieved by rest. Claudication is classically caused by peripheral arterial disease, in which an obstruction in artery of the lower limbs can lead to an insufficient blood flow which is not enough to supply the demands from the muscles of that region, but there are other conditions that can mimic its symptoms such as nerve root compression, spinal stenosis, hip arthritis, symptomatic Baker's cyst, venous claudication and chronic compartment syndrome.

Causes

Life Threatening Causes

There are no life-threatening causes, which include conditions which may result in death or permanent disability within 24 hours if left untreated.

Common Causes

• Peripheral arterial disease
• Venous claudication
• Arterial thromboembolism
• Cholesterol embolism
• Vasculitis
• Nerve root compression (radiculopathy, plexopathy)
• Peripheral neuropathy
• Lumbar canal stenosis (pseudoclaudication)
• Spinal stenosis
• Arthritis/Connective tissue disease
• Baker's cyst
• Muscle strain
• Ligament/tendon injury
• Chronic compartment syndrome

Diagnosis

Shown below is a flowchart for diagnostic testing for suspected peripheral arterial disease according to the 2016 AHA/ACC guidelines:

Suspected PAD

Symptoms: ❑ Leg pain at rest ❑ Reduced or absent pulses ❑ Leg pain during exertion ❑ Gangrene ❑ Pale extremity ❑ Non healing wound ❑ Calf or foot cramping ❑ Paresthesias

Suspected critical limb ischemia

Order Ankle brachial index

≤ 0.90

Normal 1.00-1.40 Borderline 0.91-0.99

> 1.40

Order Exercise ankle-brachial index if exertion non-joint related leg symptoms If absent - search for alternative diagnosis

Order Toe-Brachial Index

Exercise ankle-brachial index

Does the patient have > 20% decrease in Postexercise ABI?

Is TBI < 0.7?

Yes

No

No

Yes

PAD confirmed

No PAD - search for alternative diagnosis

PAD confirmed

Lifestyle-limited claudication despite guideline-directed management and therapy, revascularization considered

Yes

No? Continue guideline-directed management and therapy

Anatomic assessment: (Class I) ❑ Duplex ultrasound ❑ Computed tomography angiography ❑ Magnetic resonance angiography

Anatomic assessment: (Class IIa) ❑ Invasive angiography

Shown below is a table summarizing the differential diagnosis of claudication according the age and clinical presentation:

Differential Diagnosis of Intermittent Claudication and Lower Limb Pain

In younger patients:
Diagnosis	Clinical Features	Diagnostic Method of Choice	Treatment
Buerger's Disease	Rare vasculitis mostly seen in young Asians males who are smokers. Causes inflammation and thrombosis of the arteries of the legs, feet, forearms, and hands.	Conventional angiography - multilevel occlusions and segmental narrowing of the lower extremity arteries with extensive collateral flow showing a corkscrew or “tree root” appearance	Smoking cessation
Extrinsic Compression by Bone Lesions	Not a common cause, 40% of osteochondromas arise from the posterior aspect of distal femur compressing the femoral artery.	MRI, limb x-ray or CT scan	Excision of the lesion and repair of the affected artery
Popliteal Artery Entrapment Syndrome	Common in young patients with claudication, especially athletes - compression of the popliteal artery by the medial head of the gastrocnemius muscle.	Stress angiography	Surgery
Fibromuscular Dysplasia	Affects young women of childbearing age, affects mostly renal, cerebral and visceral arteries but may affect limbs as well.	Angiography - string-of-beads appearance	Angioplasty
Takayasu's Arteritis	Rare vasculitis mostly seen on Asian and South American women. Stenosis of the abdominal aorta and iliac arteries are present in 17% of the patients and may cause claudication.	Conventional angiography	Corticosteroids, methotrexate, azathioprine, and cyclophosphamide
Cystic Adventitial Disease	1 in 1200 cases of claudication, most common in men, 20-50 years without risk factors for atherosclerosis. It is caused by repetitive trauma, which causes the formation of a mucin-containing cystic structure in the wall of the popliteal artery.	Conventional angiography, MRI	Complete excision of the cyst with prosthetic and vein replacement, as well as bypass
In older patients:
Spinal Stenosis	Motor weakness is the most important symptom, which may be accompanied by pain. It starts soon after standing up, and may be relieved by sitting or bending (lumbar spine flexion)	MRI	Analgesic drugs, physical therapy, acupuncture or surgery (gold standard)
Peripheral Arterial Disease	May present with absent or reduced peripheral pulses, and audible bruits but some patients may not present with these symptoms. A low ankle-brachial pressure index (<0.9) is suggestive of the disease but if normal it does not exclude it. An exercise ankle-brachial pressure index can be done on patients that doesn't present with these signs. Other clinical features include: decreased skin temperature, shiny, hairless skin over the lower extremities, pallor on elevation of the extremity, dystrophic toenails, and rubor when the limb is dependent.	Handheld Doppler, conventional angiography	Smoking cessation, antiplatelet drugs, statins, diabetes and blood pressure control, exercise, percutaneous transluminal angioplasty.
Nerve Root Compression	Caused by compression of the nerve root by other structure, such as an herniated disc. The pain usually radiates down the back of the leg and is described as sharp lancinating pain. It may be relieved by adjusting the position of the back (leaning forward).	MRI	Surgery
Hip Arthritis	Pain starts when the patient undergoes weight bearing and is worsened by activity. The pain is continuous and intensified by weight bearing, with inflammatory signs such as tenderness, swelling, and hyperthermia.	MRI	Surgery
Baker's Cyst	Pain is worsened with activity, not relieved by resting, and may have tenderness and swelling behind the knee.	Ultrasound, MRI	Surgery

Treatment

Shown below is an algorithm summarizing the diagnosis of claudication due to peripheral arterial disease according the the British Medical Journal guidelines.

Evaluate affected limb - check for color and trophic changes, early ulcerations, skin temperature, capillary refill time, pulses at the groin and popliteal fossa, and the pedal pulses.

If peripheral arterial disease is suspected: Screening test: ankle-brachial index (systolic blood pressure of the dorsalis pedis, posterior tibialis, or fibularis artery is obtained with a handheld Doppler and divided by the higher of the two brachial pressures) - if <0.9 confirms peripheral arterial disease.

Secondary prevention for coronary arterial disease: start aspirin 75mg daily and statins

Control cardiovascular risk factors (hyperglycemia, obesity, dyslipidemia, smoking)

Advise the patient to exercise for 30 minutes twice daily to increase pain-free walking and total walking distance by stimulating collateral blood flow)

Cilostazol may be used for improving symptoms

Be aware of the 5 Ps—pain, pale, pulseless, paraesthesia, paralysis—indicating an acute limb ischemia

Do's

• Assess for peripheral arterial disease, as it is the most common cause for intermittent claudication, but do consider other causes depending on the age;
• Confirm the diagnosis by measuring the ankle-brachial pressure indices;
• Assess the risk factors for atherosclerosis and control them. Encourage patients to cease smoking, to control the blood glucose, prescribe antiplatelet drugs, optimize antihypertensive medication doses, start statins and encourage exercise;
• If there's no improvement, symptoms are disabling or diagnosis is uncertain, refer to a specialist.
• Best treatment options for peripheral arterial disease are: open surgery, endovascular therapy, and exercise therapy. These were superior to medical management in achieve higher walking distance and managing claudication.
• Antiplatelet drugs with either aspirin or clopidogrel alone is recommended to reduce myocardial infarction, stroke, and vascular death in patients with symptomatic PAD.
• In patients with claudication, supervised exercise programs increases functional status and reduce leg symptoms.
• Patients with diabetes mellitus should be oriented to perform self-foot examination and healthy foot behaviors. Quick diagnosis and treatment of foot infections can prevent amputation.

Don'ts

• Symptomatic treatment of the claudication and leg pain must not overshadow the reduction of cardiovascular risk, as these patients have a significantly increased risk of death.
• When treating peripheral arterial disease, always attempt reducing symptoms with less invasive treatment options such as exercising, do not immediately refer patients to more invasive treatment options;
• Don't forget to address other causes of claudication if the patient is presenting it at a younger age, or if the treatment doesn't improve the symptoms.
• Do not perform invasive or non-invasive anatomic assessments for asymptomatic patients.
• In patients not at increased risk of peripheral arterial disease, and without history of physical examination findings suggestive of PAD, the ankle-brachial index is not recommended.
• Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD.
• Pentoxifylline is not effective for treatment of claudication.

References

Template:WikiDoc Sources

Overview

COVID-19-associated multisystem inflammatory syndrome (also known as PIMS-TS - pediatric inflammatory multisystem syndrome temporally with SARS-CoV2 infection or MIS-C - multisystem inflammatory syndrome in children) is an uncommon clinical entity caused by SARS-CoV2 and seen mostly on children. It presents with: fever > 3 days and elevated markers of inflammation and 2 of the following 5 criteria: rash or conjunctivitis; hypotension or shock; myocardial dysfunction, pericarditis, valvulitis or coronary abnormalities; evidence of coagulopathy and/or acute gastrointestinal problems along with evidence of COVID-19. It seems to be a severe form of COVID-19 in children presenting with symptoms that can be challenging to differentiate from other pediatric infectious diseases such as toxic shock syndrome and Kawasaki disease. The pathophysiology of this form of SARS-CoV2 infection remains unknown.

Historical Perspective

• Reports of a new febrile pediatric entity began to appear in late April 2020 during the COVID-19 pandemic in the Western Europe, characterized by systemic hyperinflammation, abdominal pain with gastrointestinal symptoms and multiorgan involvement affecting especially the myocardium causing cardiogenic shock which reminded the physicians of Kawasaki disease;
• Cases of children with such symptoms were quickly identified in the New York City area, which was then the most heavily affected city in the U.S. by the COVID-19 pandemic;
• A report of 8 cases from Evelina London Children's Hospital was published on 6 May 2020, showing very prominent markers of inflammation such as ferritin, D-dimers, triglycerides, elevated cardiac enzymes, high NT-pro-BNP levels and troponin, being empirically treated with IVIG;
• In 22 May, an article from the Journal of Pediatric Infectious Diseases Society addressed some of the similarities and differences of this new entity with Kawasaki's disease, noting that the demographics affected was significantly different, as it was not seen in Asia despite the pandemic also affecting such countries, but it was affecting mostly children of African ethnicity. The author also differentiated some of the laboratory findings, resembling the macrophage activation syndrome and not Kawasaki's disease.

Classification of Disease Severity of COVID-19-associated multisystem inflammatory syndrome

• There is no established system for the classification of COVID-19-associated multisystem inflammatory syndrome.

Pathophysiology

• The exact pathophysiological mechanism of COVID-19-associated multisystem inflammatory syndrome is unclear.
• Since there is a lag time between COVID-19-associated multisystem inflammatory syndrome appearance and COVID-19 infection (median time: 25 days) it is suspected to be a post-infectious phenomenon related to IgG antibody-mediated enhancement of disease. There are two arguments that support this theory: the presence of IgG antibodies against SARS-CoV2 and the presence of the lag time between COVID-19 symptoms and COVID-19-associated multisystem inflammatory syndrome.
• There is, however, another theory that states that it is still an acute viral presentation of the disease due to the fact that children presenting with such symptoms undergone exploratory laparotomy which found mesenteric adenitis, supporting GI infection. SARS-CoV2 is also known to easily infect enterocytes. Another interesting point to consider is that the worsening of illness has not been seen in patients with COVID-19 who are treated with convalescent plasma, which could have occurred if it was an antibody-mediated enhancement.
• There is another hypothesis for the cytokine storm seen on children with COVID-19-associated multisystem inflammatory syndrome is originated from the known ability of coronaviruses to block type I and type III interferon responses, delaying the cytokine storm in patients that could not control the viral replication on earlier phases of the disease.

Differentiating Any Disease from other disease

• Children who met criteria for COVID-19-associated multisystem inflammatory syndrome presented features that overlapped with the ones seen on Kawasaki's disease and toxic shock syndrome, such as conjunctival injection, oropharyngeal findings (red and/or cracked lips, strawberry tongue), rash, swollen and/or erythematous hands and feet, and cervical lymphadenopathy.
• PCR tests for SARS-CoV-2 were positive in the minority of cases (26%), while the IgG antibody was positive in most patients (87%) and it remains as the preferred laboratory test for differentiating such diseases;
• The first cases of COVID-19-associated multisystem inflammatory syndrome presented with: unrelenting fever (38–40°C), conjunctivitis, cutaneous rash, peripheral edema, extremity pain and remarkable gastrointestinal symptoms. Most didn't have any respiratory symptoms, and all progressed to warm vasoplegic shock, refractory to volume resuscitation demanding vasopressors for hemodynamic support.
• Serum IL-6 level was elevated in most patients. IL-2R, IL-18, and CXCL 9 levels were elevated in all patients of a cohort and mildly increased IFN-γ and IL-8 levels in some.
• TNF-α, IL-1b, IL-2, IL-4, IL-5, and IL-13 levels remained normal in one in a series of cases from New York City.

Summary of laboratory parameters of a COVID-19-associated multisystem inflammatory syndrome cohort compared with the historic cohorts of Kawasaki Disease, Kawasaki Disease Shock Syndrome and Toxic Shock Syndrome

Parameters	COVID-19-associated multisystem inflammatory syndrome (PIMS-TS)	Kawasaki Disease (KD)	Kawasaki Disease Shock (KDS)	Toxic Shock Syndrome (TSS)
Age (median, IQR)	9 (5.7-14)	2.7 (1.4-4.7)	3.8 (0.2-18)	7.38 (2.4-15.4)
Total white cell count (*10^9/L)	17 (12-22)	13.4 (10.5-17.3)	12.1 (7.9-15.5)	15.6 (7.5-20)
Neutrophil count (*10^9/L)	13 (10-19)	7.2 (5.1-9.9)	5.5 (3.2-10.3)	16.4 (12-22)
Lymphocyte count (*10^9/L)	0.8 (0.5-1.5)	2.8 (1.5-4.4)	1.6 (1-2.5)	0.63 (0.41, 1.13)
Hemoglobin (g/L)	92 (83-103)	111.0 (105-119)	107 (98-115)	114 (98-130)
Platelet number (10^9/L)	151 (104-210)	365.0 (288-462)	235 (138-352)	155 (92- 255)
C-reactive protein (mg/L)	229 (156-338)	67.0(40-150)	193 (83-237)	201 (122, 317)
ALT (IU/L)	42 (26-95)	42.0 (24-112)	73 (34-107)	30.00 (22.10, 49.25)
Albumin (g/L)	24 (21-27)	38.0 (35-41)	30 (27-35)	27.00 (21.00, 31.00)
Ferritin (ug/L)	610 (359-1280)	200 (143-243)	301 (228-337)	-
NT-Pro-BNP (pg/ml)	788 (174-10548)	41 (12-102)	396 (57-1520)	-
Troponin (ng/L)	45 (8-294)	10.0 (10-20)	10 (10-30)	-
D-dimer (ng/ml)	3578 (2085- 8235)	1650 (970-2660)	2580 (1460- 2990)	-

• Most patients presented with the following findings: elevated erythrocyte sedimentation rate or C-reactive protein level, elevated ferritin level, lymphocytopenia, hypoalbuminemia, neutrophilia, elevated alanine aminotransferase level, anemia, thrombocytopenia prolonged INR, elevated d-dimer level, or elevated fibrinogen level.

Epidemiology and Demographics

• Poor prognostic factors include age over 5 years and ferritin larger than 1400 µg/L.

Age

• Children aged age over 5 years seem to have a worse prognosis than younger ones.
• The median age found out in a study published by JAMA was 9 years.

Gender

• Most of the cases, estimated in two thirds, seem to happen in boys.

Race

• It seems to affect predominantly blacks and asians.

Comorbidities

• Clinical evidence of association with underlying diseases is still scarce since it is a rare presentation of COVID-19 in children and teenagers.

Overview

Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition that causes inflammation of some parts of the body like heart, blood vessels, kidneys, digestive system, brain, skin, or eyes. According to recent evidence, it is suggested that children with MIS-C had antibodies against COVID-19 suggesting children had COVID-19 infection in the past. This syndrome appears to be similar in presentation to Kawasaki disease, hence also called Kawasaki -like a disease. It also shares features with staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes.

Classification of Disease Severity of MIS-C

• Mild Disease
• Children with MIS-C fall under this category who-
  • require minimal to no respiratory support.
  • minimal to no organ injury
  • normotensive
  • Do not meet the criteria for ICU admission.
• Severe Disease
• Children with MIS-C fall under this category who-
  • have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
  • have a mild-severe organ injury and ventricular dysfunction.
  • have a vasoactive requirement.
  • meet the criteria for ICU admissions

Pathophysiology

• The excat pathophysiological mechanism of MIS-C is unclear. Since there is a lag time between MIS-C appearance and COVID-19 infection it is suspected to be causing by antibody dependent enhancement.
• Another hypothesis is that since coronavirus block type1 and type III interferons, it results in delayed cytokine response in children with initially high viral load or whose immune response is unable to control infections causing MIS-C. Therefore, IFN responses result in viral clearance when the viral load is low resulting in mild infection. However, when the viral load is high and /or immune system is not able to clear the virus, the cytokine storm result in multisystem inflammatory syndrome in children (MIS-C).
• It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.

Differentiating Any Disease from other disease

It should be differentiated from following diseases

• Bacterial sepsis
• Staphylococcal and streptococcal toxic shock syndrome
• Kawasaki disease.
• More information about the differential diagnosis could be found here.

Epidemiology and Demographics

• According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12% between March 16 and April 15 and 88% between April 16 and May 20.
• 80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.
• 4% of the children required extracorporeal membrane oxygenation.
• The mortality rate among 186 children with MIS-C was 2%.

Age

• Among the 186 children with MIS-C distribution of age group was
  • <1yr-7%
  • 1-4yr-28%
  • 5-9yr-25%
  • 10-14yr-24%
  • 15-20yr-16%.

Gender

• Among the 186 children with MIS-C

Comorbidities

• Children with MIS-C had following underlying comorbidities.
  • Clinically diagnosed Obesity-8%
  • BMI-Based Obesity-29%
  • Cardiovascular diasease-3%
  • Respiratory disease-18%
  • Autoimmune disease or immunocompromising condition-5%

Organ System Involved

• 71% of children had involvement of at least four organ systems.

The most common organ system involved in MIS-C children among a total of 186 children were.

• Gastrointestinal(92%)
• Cardiovascular(80%)
• Hematologic(76%)
• Mucocutaneous(74%)
• Pulmonary(70%)
• Historical perspective

External links

Classification	[[d: |D]] ICD-10: Q85.1 ICD-9-CM: 759.5 OMIM: 191100 613254 DiseasesDB: 13433
External resources	MedlinePlus: 000787 eMedicine: neuro/386 derm/438 ped/2796 radio/723 Patient UK: Sandbox Jose NCI: Sandbox Jose GeneReviews: Tuberous Sclerosis Complex Orphanet: 805

• tuberous-sclerosis at NIH/UW GeneTests
• GeneReview/NCBI/NIH/UW entry on Tuberous Sclerosis Complex

Tuberous sclerosis skin lesion - Angiofibromas - image taken from: www.atlasdermatologico.com.br

Tuberous sclerosis skin lesion - Ash-leaf spot - image taken from: www.atlasdermatologico.com.br

Tuberous sclerosis skin lesion - Ungual fibroma - image taken from: www.atlasdermatologico.com.br

Overview

Tuberous sclerosis complex (TSC), is a rare autosomal dominant congenital disorder that affects multiple organ systems and is characterized by an abnormal growth of ectodermal and mesodermal cells that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs, and skin.

A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, and lung and kidney disease. TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.

The disease presents with a myriad of symptoms, having been described by multiple doctors throughtout the 19th century and called by many different names, but it is now called tuberous sclerosis complex, and the relationship between benign brain tumors and the symptoms of the disease was first described by Désiré-Magloire Bourneville in 1880.

Historical Perspective

Tuberous Sclerosis was described as a specific disease in the 19th century, being initially referred to adenoma sebaceum, epiloia, Pringle's disease or Bourneville's disease. Rayer, a French dermatologist, was the one to first describe the disease and the fibrovascular papules that characterize it, making illustrations of it. He described two cases of tuberous sclerosis in patients who had the nasolabial papular eruption with telangiectasias at the base. In 1850 the first written report of tuberous sclerosis appeared in "Vitiligoidea", published by Addison and Gull. It was not recognized as a distinct disease but was classified as "vitiligoidea tuberosa". In 1862, von Recklinghausen reported a tumor of the heart found in a newborn during autopsy, and by that he is credited to be the first that described the microscopic appearance of tuberous sclerosis. Bourneville in 1880, a French neurologist, described the case of a girl who presented at the age of 3 with facial eruption and died at 15 years of age due to epilepsy, which complicated with pneumonia and inanition. He found brain and kidney tumors on the autopsy which were correctly believed to be the cause of her seizures and mental retardation. In 1911, E. B. Sherlock, superintendent of Belmont Asylum of Idiots, London, coined the word "epiloia" that indicated a clinical triad of epilepsy, low intelligence and adenoma sebaceum.

In 2002, treatment with rapamycin was found to be effective at shrinking tumours in animals. This has led to human trials of rapamycin as a drug to treat several of the tumors associated with TSC.

Classification

There is no established system for the classification of tuberous sclerosis.

Pathophysiology

Patients with tuberous sclerosis have loss-of-function germline mutations in both alleles of the following tumor suppressor genes: TSC1 or TSC2. One third of the mutations is inherited, two thirds are de novo mutations. The mutations causes the loss of one allele, but as long as the second one remains intact, the cell won't present any metabolic change. When there is a second TSC1 or TSC2 mutation, which typically occurs in multiple cells over a person's lifetime, then the disease starts to manifest (fitting the "two-hit" tumor-suppressor gene model, with the germline mutation inactivating one gene and then a somatic event inactivating the remaining other one). TSC1 codes for a protein called hamartin, and TSC2 codes for a protein called tuberin. They belong to a protein complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 via RAS homologue enriched in brain (RHEB) which regulates cell growth. In a normal patient, RHEB activates mTORC1 when bound to GTP, but in TSC there is a hyperactivarion of RHEB and consequently of mTORC1. mTOR regulates cellular proliferation, autophagy, growth and protein and lipid synthesis and it enhances protein translation when activated, reprograming the cell metabolism, which increases cell proliferation but also may make it vulnerable to death in nutrient-restricted media. Besides the TSC-RHEB-mTORC1 pathway, there is evidence of alternate pathways also having a role in the disease that are mTORC1 independent, but they are currently under investigation.

Causes

Loss of function mutation of the genes TSC1 and TSC2 which are responsible for the production of hamartin and tuberin. These proteins regulate the cell cycle. Damage to this pathway leads to a very variable presentation of benign tumors in multiple systems. TSC1 and TSC2 are both tumor suppressor genes that function according to Knudson's "two hit" hypothesis. That is, a second random mutation must occur before a tumor can develop. This explains why, despite its high penetrance, TSC has wide expressivity.

Differentiating Tuberous Sclerosis from other Diseases

Tuberous sclerosis must be differentiated from other diseases that cause myxoma or other benign tumors and/or seizures, such as Sturge Weber, hypomelanosis of Ito, Birt-Hogg-Dube syndrome, multiple endocrine neoplasia and various seizures disorders.

Epidemiology and Demographics

Tuberous sclerosis complex affects about 1 in 6,000 people, occurring in all races and ethnic groups, and in both genders. Prior to the invention of CT scanning to identify the nodules and tubers in the brain, the prevalence was thought to be much lower and the disease associated with those people diagnosed clinically with learning disability, seizures, and facial angiofibroma. Whilst still regarded as a rare disease, TSC is common when compared to many other genetic diseases, with at least 1 million individuals worldwide.

Risk Factors

There are no established environmental risk factors for tuberous sclerosis. One third of the cases are familial, so family history can be a risk factor for the disease.

Screening

As it is a rare disease, screening is not recommended.

Natural History, Complications, and Prognosis

Skin

Symptoms develop in almost all patients with TSC and include ungual fibromas, facial angiofibromas (may demand treatment and may worsen with UV exposure), shagreen patches (oval-shaped lesions, generally skin-colored but can be sometimes pigmented, may be crinkled or smooth), focal hypopigmented macules (ash-leaf spots), dental enamel pits (present in 100% of the patients), oral fibromas, retinal astrocytic hamartomas (tumors of the retinal nerve), retinal achromic patches (light or dark spots on the eye).

Renal

TSC leads to the formation of renal angiomyolipomas (present in 60-80% of the TSC patients), benign tumors composed of abnormal vessels, smooth-muscle cells and fat cells which may cause hematuria. These tumors can be detectable in early childhood by MRI, CT or ultrasound. Although benign, in TSC they are commonly multiple and bilateral. Angiomyolipomas larger than 4 cm are at risk for potentially catastrophic hemorrhage either spontaneously or with minimal trauma. Patients may also develop epithelial cysts, polycystic kidney disease (as 2-3% of the patients carries a deletion that affects both TSC2 gene and one of the genes that lead to autosomal dominant polycystic kidney disease) and renal-cell carcinomas that may be diagnosed at a younger age (mean 28 years). Patients ≥18 years may have higher rates of chronic kidney disease, hematuria, kidney failure, embolization (EMB), and partial and complete nephrectomy compared to patients <18 years.

Pulmonary

Lymphangiomyomatosis affects mostly women and is a proliferation of smooth-muscle cells that may result in cystic changes in the lungs. Recent genetic analysis has shown that the proliferative bronchiolar smooth muscle in TSC-related lymphangioleiomyomatosis is monoclonal metastasis from a coexisting renal angiomyolipoma. Cases of TSC-related lymphangioleiomyomatosis recurring following lung transplant have been reported. Diagnosed mostly during early adulthood, may cause pneumothorax. Multifocal micronodular pneumocyte hyperplasia can occur in both men and women and are mostly asymptomatic.

In 2020 a paper showed that epilepsy remission by appropriate treatment in early life can possibly prevent autism and intellectual disability.

Neurologic

These manifestations are one of the major causes of morbidity in patients with TSC. TSC may cause epilepsy, which is the most common neurological presentation occurring in 70-80% of patients and may complicate with infantile spasms, a severe form of epileptic syndrome. If epilepsy presents with an early onset t is associated with cognitive disabilities, which are also very prevalent in such patients. Neuropsychiatric disorders are present in two-thirds of the patients and anxiety is one of the most common presentations. Autism is one possible manifestation and is especially associated with cerebral cortical tubers. It consists of neurologic tissue that grows in a different pattern, losing the normal six-layered cortical structure, with dysmorphic neurons, large astrocytes and giant cells. Some patients may also present with subependymal giant cell astrocytomas, which may cause obstructive hydrocephalus. Risk of such benign tumors decreases after age of 20.

Cardiovascular

Rhabdomyomas may be present, being intramural or intracavitary in its distribution along the myocardium. May be detected in utero on fetuses and is associated with cardiac failure. Often disappear spontaneously in later life. 80% of children under two-years-old with TSC have at least one rhabdomyoma, and about 90% of those will have several.

Diagnosis

Tuberous sclerosis complex is diagnosed if a set of diagnostic criteria are met. These criteria include major and minor features. If a case meets the clinical diagnostic criteria, then it is performed a genetic molecular testing which is seem mostly as corroborative. Most of the patients seek medical assistance due to their dermatologic lesions or seizures but for making this diagnosis an evaluation that assesses all the clinical features of the tuberous sclerosis complex is necessary, as these manifestations have variable penetrance. The latest diagnostic criteria was developed by the 2012 International Tuberous Sclerosis Complex Consensus Conference, and it is showed at the table below:

Diagnostic Criteria for Tuberous Sclerosis Complex

Major Features
	Location	Sign	Onset	Note
1	Skin	Hypomelanotic macules	Infant – child	At least three, at least 5 mm in diameter.
2	Head	Facial angiofibromas or fibrous cephalic plaque	Infant – adult	At least three angiofibromas
3	Fingers and toes	Ungual fibroma	Adolescent – adult	At least two
4	Skin	Shagreen patch (connective tissue nevus)	Child
5	Eyes	Multiple retinal nodular hamartomas	Infant
6	Brain	Cortical dysplasias (includes tubers and cerebral white matter radial migration lines)	Fetus
7	Brain	Subependymal nodule	Child – adolescent
8	Brain	Subependymal giant cell astrocytoma	Child – adolescent
9	Heart	Cardiac rhabdomyoma	Fetus
10	Lungs	Lymphangioleiomyomatosis	Adolescent – adult
11	Kidneys	Renal angiomyolipoma	Child – adult	At least two. Together, 10 and 11 count as one major feature.
Minor Features
	Location	Sign	Note
1	Skin	"Confetti" skin lesions
2	Teeth	Dental enamel pits	At least three
3	Gums	Intraoral fibromas	At least two
4	Eyes	Retinal achromic patch
5	Kidneys	Multiple renal cysts
6	Liver, spleen and other organs	Nonrenal hamartoma

TSC can be first diagnosed at any stage of life. Prenatal diagnosis is possible by chance if heart tumours are discovered during routine ultrasound. In infancy, white patches on the skin may be noticed, or the child may present with epilepsy, particularly infantile spasms, or developmental delay may lead to neurological tests. In childhood, behavioural problems and autism spectrum disorder may also lead to a clinical investigation and a diagnosis. During adolescence it is usually that skin problems appear while in adulthood, kidney and lung problems may become evident. An individual may also be diagnosed at any time as a result of genetic testing of family members of another affected person.

History and Symptoms

The most common symptoms of tuberous sclerosis are due to the growth of the already disclosed benign tumors. Tumors in the CSN may cause epilepsy, autism and children may also present with cognitive disabilities. Tumors in the kidneys may compromise renal function and metastasize to the lungs, which in most cases is asymptomatic. Tumors in the heart may compromise heart function, but they tend to spontaneously disappear later in life.

Physical Examination

Physical examination of patients with tuberous sclerosis is a very rich one due to the different skin lesions that the disease can cause and it is usually remarkable for dental enamel pits (present in 100% of the patients),hypomelanotic macules, shagreen patches, and forehead plaques.

Laboratory Findings

There are no typical diagnostic laboratory findings associated with tuberous sclerosis. Patients may present with elevated BUN or creatinine if their renal angiomyolipomas compromise renal function or if they also present with autosomal dominant polycystic kidney disease.

Electrocardiogram

There are no ECG findings associated with tuberous sclerosis.

X-ray

There are no typical x-ray findings associated with tuberous sclerosis, but patients may present with pneumothorax and/or chylous pleural effusions due if they develop lymphangioleiomyomatosis.

Echocardiography or Ultrasound

Echocardiography/ultrasound may be helpful raising the suspicion of tuberous sclerosis. Echocardiographs can detect cardiac rhabdomyomas, present in more than 80% of the children with TSC. Ultrasound can detect hepatic angiomyolipomas, renal angiomyolipomas (present in 55-75% of patients) and renal cysts (present in 18-55% of the patients).

CT scan

CT scan may be helpful in the diagnosis of tuberous sclerosis. It can diagnose cortical or subependymal tubers and white matter abnormalities, subependymal hamartomas, subependymal giant cell astrocytomas, renal angiomyolipomas, renal cysts, renal cell carcinoma (associated with tuberous sclerosis), retroperitoneal lymphangiomyomatosis, gastrointestinal polyps, pancreatic neuroendocrine tumors, lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia and cardiac rhabdomyomas.

MRI

MRI may be helpful in the diagnosis of tuberous sclerosis as it can find the same abnormalities found on CT scan which are described above, some of them with much more detail, but it is especially useful for evaluating white matter changes seen in the disease.

Other Imaging Findings

There are no other imaging findings associated with tuberous sclerosis.

Other Diagnostic Studies

Genetic testing may be helpful in the diagnosis of tuberous sclerosis but some patients may not have detectable genetic mutations on the test and still have the disease. It is considered to be a corroborative test.

Treatment

Tuberous sclerosis complex affects multiple organ systems so a multidisciplinary team of medical professionals is required.

Screening of complications:

In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.

• Take a personal and family history covering three generations. Genetic counselling and tests determine if other individuals are at risk.
• A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).
• Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.
• Assess children for behavioural issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.
• Scan the abdomen for tumours in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.
• In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.
• Examine the skin under a Wood's lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).
• In infants under three, perform an echocardiogram to spot rhabdomyomas, and electrocardiogram (ECG) for any arrhythmia.
• Use a fundoscope to spot retinal hamartomas or achromic patches.

Treatment:

The various symptoms and complications from TSC may appear throughout life, requiring continued surveillance and adjustment to treatments. The following ongoing tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference:

• In children and adults younger than 25 years, a magnetic resonance imaging (MRI) of the brain is performed every one to three years to monitor for subependymal giant cell astrocytoma (SEGA). If a SEGA is large, growing or interfering with ventricles, the MRI is performed more frequently. After 25 years, if there are no SEGAs then periodic scans may no longer be required. A SEGA causing acute symptoms are removed with surgery, otherwise either surgery or drug treatment with an mTOR inhibitor may be indicated.
• Repeat screening for TSC-associated neuropsychiatric disorders (TAND) at least annually. Sudden behavioural changes may indicate a new physical problem (for example with the kidneys, epilepsy or a SEGA).
• Routine EEG determined by clinical need.
• Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).
• Repeat MRI of abdomen every one to three years throughout life. Check renal (kidney) function annually. Should angiomyolipoma bleed, this is best treated with embolisation and then corticosteroids. Removal of the kidney (nephrectomy) is strongly to be avoided. An asymptomatic angiomyolipoma that is growing larger than 3cm is best treated with an mTOR inhibitor drug. Other renal complications spotted by imaging include polycystic kidney disease and renal cell carcinoma.
• Repeat chest HRCT in adult women every five to 10 years. Evidence of lymphangioleiomyomatosis (LAM) indicates more frequent testing. An mTOR inhibitor drug can help, though a lung transplant may be required.
• A 12-lead ECG should be performed every three to five years.

The mTOR inhibitor everolimus was approved in the US for treatment of TSC-related tumors in the brain (subependymal giant cell astrocytoma) in 2010 and in the kidneys (renal angiomyolipoma) in 2012.  Everolimus also showed evidence of effectiveness at treating epilepsy in some people with TSC. In 2017, the European Commission approved everolimus for treatment of refractory partial-onset seizures associated with TSC.

Neurosurgical intervention may reduce the severity and frequency of seizures in TSC patients. Embolization and other surgical interventions can be used to treat renal angiomyolipoma with acute hemorrhage. Surgical treatments for symptoms of lymphangioleiomyomatosis (LAM) in adult TSC patients include pleurodesis to prevent pneumothorax and lung transplantation in the case of irreversible lung failure.

Other treatments that have been used to treat TSC manifestations and symptoms include a ketogenic diet for intractable epilepsy and pulmonary rehabilitation for LAM. Facial angiofibromas can be reduced with laser treatment and the effectiveness of mTOR inhibitor topical treatment is being investigated. Laser therapy is painful, requires anaesthesia, and has risks of scarring and dyspigmentation.

External links

Classification	[[d: |D]] ICD-10: Q85.1 ICD-9-CM: 759.5 OMIM: 191100 613254 DiseasesDB: 13433
External resources	MedlinePlus: 000787 eMedicine: neuro/386 derm/438 ped/2796 radio/723 Patient UK: Sandbox Jose NCI: Sandbox Jose GeneReviews: Tuberous Sclerosis Complex Orphanet: 805

• tuberous-sclerosis at NIH/UW GeneTests
• GeneReview/NCBI/NIH/UW entry on Tuberous Sclerosis Complex

Case courtesy of Dr Ian Bickle, Radiopaedia.org, rID: 76157

Syncope classification

Vasovagal

Micturation

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Case courtesy of Dr Vinay V Belaval, Radiopaedia.org, rID: 66974

Disease	Type	Sign		Symptom

Syncope is classified into three categories:

• Neurally mediated
• Cardiac
• Vasovagal

Disease Name	Age of Onset	Gender Preponderance	Signs/Symptoms	Imaging Feature(s)	Macroscopic Feature(s)	Microscopic Feature(s)	Laboratory Findings(s)	Other Feature(s)	ECG view

end of Tuberous Sclerosis

Resident Survival Guide

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Atherosclerotic Aneurysm: Gross, an excellent example, natural color, external view of typical thoracic aortic aneurysms Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

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For patient information on Thoracic aortic aneurysm, click here

For patient information on Abdominal aortic aneurysm, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5], Associate Editor(s)-in-Chief: Lina Ya'qoub, MD Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [6]

Overview

An aortic aneurysm is a dilation of the aorta in which the aortic diameter is ≥ 3.0 cm if abdominal or >4 cm if thoracic, usually representing an underlying weakness in the wall of the aorta at that location. While the stretched vessel may occasionally cause discomfort, a greater concern is the risk of rupture which causes severe pain, massive internal hemorrhage which are often fatal. Aneurysms often are a source of blood clots (emboli) stemming from the most common etiology of atherosclerosis.

Classification

There are 2 types of aortic aneurysms: thoracic and abdominal. These can be further classified according to the respective part of the vessel that's been affected:

• Thoracic aortic aneurysm, which occur in the thoracic aorta (runs through the chest);
• Abdominal aortic aneurysm, which occur in the abdominal aorta, are the most common.
  • Suprarenal - not as common, often more difficult to repair surgically due to the presence of many aortic branches;
  • Infrarenal - often more easily surgically repaired and more common;
  • Pararenal - aortic aneurysm is infrarenal but affects renal arteries;
  • Juxtarenal - infrarenal aortic aneurysm that affects the aorta just below the renal arteries.

Aortic aneurysms may also be classified according to Crawford classification into 5 subtypes/groups:

• Type 1: from the origin of left subclavian artery in descending thoracic aorta to the supra-renal abdominal aorta.
• Type 2: from the left subclavian to the aorto-iliac bifurcation.
• Type 3: from distal thoracic aorta to the aorto-iliac bifurcation
• Type 4: limited to abdominal aorta below the diaphragm
• Type 5: from distal thoracic aorta to celiac and superior mesenteric origins, but not the renal arteries.

Historical Perspective

Aortic aneurysm was first recorded by Antyllus, a Greek surgeon, in the second century AD. In the Renaissaince era, in 1555, Vesalius first diagnosed an abdominal aortic aneurysm. The first publication on the pathology with case studies was published by Lancisi in 1728. Finally, in 1817, Astley Cooper was the first surgeon to ligate the abdominal aorta to treat a ruptured iliac aneurysm. In 1888, Rudoff Matas came up with the concept of endoaneurysmorrhaphy.

Pathophysiology

The aortic aneurysms are a multifactorial disease associated with genetic and environmental risk factors. Marfan's syndrome and Ehlers-Danlos syndrome are associated with the disease, but there are also rarer syndromes like the Loeys-Dietz syndrome that are associated as well. Even in patients that do not have genetic syndromes, it has been observed that genetics can also play a role on aortic aneurysms' development. There has been evidence of genetic heterogeneity as there has already been documented in intracranial aneurysms. The genetic alterations associated with these genetic syndromes are the following:

Genetic diseases associated with aortic aneurysms

Disease	Involved Cellular Pathway	Mutated Gene(s)	Affected Protein(s)
Ehlers-Danlos type IV syndrome	Extracellular Matrix Proteins	COL3A1	Collagen type III
Marfan's Syndrome	Extracellular Matrix Proteins	FBN1	Fibrillin-1
Loeys-Dietz syndrome	TGF-β Pathway	TGFBR1/TGFBR2
Aneurysm-Osteoarthritis Syndrome		SMAD3	SMAD3
Autosomal Dominant Polycystic Kidney Disease	Ciliopathy	PKD1/PKD2	Polycystin 1 Polycystin 2
Turner Syndrome	Meiotic Error with Monosomy, Mosaicism, or De Novo Germ Cell Mutation	45X 45XO	Partial or Complete Absence of X Chromosome
Bicuspid Aortic Valve with TAA	Neural Crest Migration	NOTCH1	Notch 1
Familial TAA	Smooth Muscle Contraction Proteins	ACTA2	α-Smooth Muscle Actin
Familial TAA with Patent Ductus Arteriosus	Smooth Muscle Contraction Proteins	MYH11	Smooth Muscle Myosin
Familial TAA	Smooth Muscle Contraction Proteins	MYLK	Myosin Light Chain Kinase
Familial TAA	Smooth Muscle Contraction Proteins	PRKG1	Protein Kinase c-GMP Dependent, type I
Loeys-Dietz Syndrome variants	TGF-β Pathway	TGF-βR1 TGF-βR2 SMAD3 TGF-β2 TGF-β3

These genetic diseases mostly affect either the synthesis of extracellular matrix protein or damage the smooth muscle cells both important component's of the aortic wall. Injury to any of these components lead to weakening of the aortic wall and dilation - resulting in aneurysm formation.

The aorta is the largest vessel of the body, but it is not homogenous. Its upper segment is composed by a larger proportion of elastin in comparison to collagen, therefore being more distensible. The lower segment has a larger proportion of collagen, therefore it is less distensible. It is also where most of the atherosclerotic plaques of the aorta are located. Historically it was thought that abdominal and thoracic aortic aneurysms were caused by the same etiology: atherosclerotic degeneration of the aortic wall, but recently it has been theorized that they are indeed different diseases.

The aortic arch mostly derives from the neural crest cell which differentiate into smooth muscle cells. These smooth muscle cells are probably more adapted to remodel the thoracic aorta and manage the higher pulse pressure and ejection volume due to increased production of elastic lamellae during development and growth. The abdominal aorta remains with cells of mesodermal origin, which are more similar to that of the original primitive arterial. That difference results in the neural crest cell precursors of the thoracic aorta being able to respond differently to various cytokines and growth factors than the mesodermal precursors of the abdominal aorta, such as homocysteine and angiotensin II.

When neural crest vascular smooth muscle cells are treated with TGF-β they demonstrate increased collagen production, while mesodermal vascular smooth muscle cell did not. Not coincidently, mutations of the TGF-β receptor can cause thoracic aortic aneurysm but do not cause abdominal aortic ones.

The thoracic and abdominal aorta are very structurally different. While they both have three layers: intimal, medial and adventitia, the media of the thoracic aorta is comprised of approximately 60 units divided into vascular and avascular regions. The abdominal aorta consists of about 30 units and is entirely avascular, being dependent on trans-intimal diffusion of nutrients for its smooth muscle cells to survive. It is believed that both differences explain why the abdominal aorta is more likely to form aneurysms.

The development of aortic aneurysms is defined by: inflammation: infiltration of the vessel wall by lymphocytes and macrophage; extracellular matrix damage: destruction of elastin and collagen by proteases (also metalloproteinases) in the media and adventitia; cellular damage: loss of smooth muscle cells with thinning of the media; and insufficient repair: neovascularization.

Clinical Features

Thoracic aortic aneurysms: The aneurysms tend to grow slowly and most of them will never rupture. As they grow, however, their symptoms become more evident and present with mass effects over surrounding structures and pain. They may present with thoracic symptoms: interscapular or central pain, ripping chest pain and dyspnea. Atypical presentations include hoarseness, dizziness and dysphagia, due to esophageal compression. Aneurysm rupture lead to massive internal bleeding, hypovolemic shock and it is usually fatal.

Abdominal aortic aneurysms: as the thoracic aneurysms, they begin asymptomatic but may cause symptoms as they grow and compress surrounding structures.Even though they usually remain asymptomatic, when they rupture they present with an ensuing mortality of 85 to 90%., and symptomatic patients require urgent surgical repair.

When symptomatic, abdominal aortic aneurysms present with:

• Pain: in the chest, abdomen, lower back, or flanks. It may radiate to the groin, buttocks, or legs. The pain characteristics vary and may be deep, aching, gnawing, or throbbing It may also last for hours or days, not affected by movement. Occasionally, certain positions can be more comfortable and alleviate the symptoms;
• Pulsating abdominal mass;
• Ischemia: "cold foot" or a black or blue painful toe. This is usually the presentation when an aneurysm forms a blood cloth and it releases emboli to the lower extremities;
• Fever or weight loss if caused by inflammatory states such as vasculitis.

If ruptured, the abdominal aortic aneurysm can present with sharp abdominal pain, often radiating to the back, discoloration of the skin and mucosa, tachycardia and low blood pressure due to hypovolemic shock.

Differentiating Aortic Aneurysm from other Diseases

Thoracic aortic aneurysms: differential diagnosis include other causes of chest pain: acute aortic dissection, acute pericarditis, aortic regurgitation, heart failure, hypertensive emergencies, infective endocarditis, myocardial Infarction, pulmonary embolism, superior vena cava syndrome.

Abdominal aortic aneurysms: differential diagnosis include causes of pulsatile abdominal mass and/or abdominal pain such as ruptured viscus, strangulated hernia, ruptured visceral artery aneurysms, mesenteric ischemia, acute cholecystitis, ruptured hepatobiliary cancer, acute pancreatitis, lymphomas, and diverticular abscess.

These conditions can be easily differentiated using abdominal or thoracic imaging.

Epidemiology and Demographics

In the United States alone 15,000 people die yearly due to aortic aneurysms and it is the 13th leading cause of death. 1-2% of the population may have aortic aneurysms and prevalence rises up to 10% in older age groups. The disease varies according to where it takes place. In the thorax, the aortic arch is the less affected segment (10%) and the most common is the ascending aorta (50%). Regarding abdominal aneurysms, the infrarenal segment aortic aneurysms are three times more prevalent than the aortic aneurysms and dissections.

Regarding other factors as age, abdominal aortic aneurysms usually present 10 years later than thoracic aortic aneurysms. Both lesions are more present in men, but the proportion is much higher regarding abdominal aortic aneurysms (6:1 male:female ratio) in comparison to thoracic ones.

Abdominal aortic aneurysms also affect patients differently regarding race, as they are more prevalent among whites than blacks, asians and hispanics. It also seems to be declining in prevalence as evidenced by a Swedish study that found out a 2% prevalence of abdominal aortic aneurysms in comparison to earlier studies which reported 4-8%, probably due to risk-factor modification.

Risk Factors

Many risk factors are common between both forms of aortic aneurysms, but some are specific for each presentation:

• Abdominal aortic aneurysm: smoking, male gender, age (>65 years), race (white), family history, other aneurysms.
• Thoracic aortic aneurysm: smoking, age (>65 years), hypertension, atherosclerosis, family history, Marfan's syndrome, bicuspid aortic valve.

Natural History, Complications and Prognosis

Even though the majority of the aortic aneurysms remain asymptomatic for years, their natural history is dissection or rupture. According to Laplace's law, as the aneurysms grow larger they have a higher rate of expansion. Due to that, the frequency of monitoring changes with the diameter of the abdominal aortic aneurysm, being every 3 years for aneurysms with a 3-3.4cm diameter, yearly for diameters of 3.5-4.4cm, and every 6 months for larger than 4.5cm. For the thoracic one, up to 80% of the aneurysms will eventually rupture, and patients present with a 10-20% five-year survival rate if they remain untreated. Risk of rupture doubles every 1cm in growth over the 5cm diameter in descending thoracic aorta.

Besides rupturing and dissection of the aorta, aortic aneurysms can also present with systemic embolization and aortic regurgitation (if the thoracic aortic aneurysm is located in the ascending aorta). The altered blood flow in the aneurysm can also lead to the formation of blood cloths and embolization.

Diagnosis

Diagnostic Criteria:

Thoracic aortic aneurysm: considered an aneurysm when the diameter is >4 cm.

Abdominal aortic aneurysm: considered an aneurysm when the diameter is >3 cm.

Symptoms:

Thoracic aortic aneurysm: as discussed above: most are asymptomatic. As they grow, they may cause: chest pain, dyspnea, hoarseness, dizziness, dysphagia and when they rupture: hypovolemic shock

Abdominal aortic aneurysm: begin asymptomatic but may cause pain, pulsating abdominal mass, peripheral ischemia, fever or weight loss. When they rupture, they cause acute abdominal pain and hypovolemic shock.

Laboratory Findings

• There are no specific laboratory findings associated withaortic aneurysms.
• Anemia can be seen in ruptured aortic aneurysms.

Imaging Findings

• An abdominal ultrasound can be diagnostic of abdominal aortic aneurysms and is the imaging tool used to screen for aortic aortic aneurysms.
• CTA/MRA can accurately demonstrate aortic aneurysms extent.

Other Diagnostic Studies

• Conventional angiogram can be used to diagnose aortic aneurysms.

Treatment

Medical Therapy

Focus is to reduce systemic blood pressure, inhibit MMP (zinc endopeptidases that degrade the extracellular matrix in aortic aneurysms), and contain the progression of atherosclerosis.

• Beta-blockers may help in reducing the rate of expansion of the aortic aneurysm, reducing shear stress - studies have been mostly on Marfan patients and they found a low compliance with propranolol due to a significant effect on quality of life;
• Tetracyclines inhibit the MMP endopeptidases, and has been used in conditions in which MMP are overexpressed such as rheumatoid arthritis. There are studies in humans showing that doxycycline reduced the rate of expansion of aortic aneurysms. Roxithromycin, a macrolide has been also show to reduce the expansion of the aortic aneurysms.
• Statins may also be helpful due to their pleiotropic effecs, reducing the oxidative stress by blocking the reactive oxygen species on aneurysms, suppressing the NADH/NADPH oxidase system.
• Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers promotes vascular hypertrophy, cell proliferation and production of extracellular matrix. It also activates the NADH/NADPH oxidase system, both stimulating and inhibiting MMPs and degradation of extracellular matrix. There is a controversy of which class is more effective, and ongoing trials are being run to further clarify these questions.

There are no established guidelines for this matter, treatment is still controversial and should be individualized.

Surgery

Decision to perform elective surgery to prevent aneurysm rupture is complicated as there must be an appropriate patient selection and timing for repair of the aneurysm which demands selecting patients at the greatest risk of aneurysm rupture. Once rupture occurs, mortality is extremely high. Fatality rates of emergency surgical repair is 50% if the patient manages to reach the hospital, in comparison to 1-5% fatality rate in elective surgical repair.

According to the 2005 AHA/ACC guidelines - it is recommended surgical repair of abdominal aortic aneurysms:

• 5.5 cm in diameter or greater in asymptomatic patients;
• Increase by 0.5 cm or greater in diameter in 6 months;
• Symptomatic aneurysms.

Endovascular repair may be performed with better short-term morbidity and mortality rates but with failed long-term benefits over surgical repair. Endovascular is preferred in high-risk patients while surgical repair is generally indicated for low/average-risk patients.

In thoracic aortic aneurysms, surgery is indicated in Marfan's syndrome when the aortic diameter reaches 5.0cm, or the rate of increase of the aortic root diameter approaches 1.0 cm per year, or progressive and severe aortic regurgitation. If family history is positive for aortic aneurysms, aggressive therapy may be indicated in individuals with Marfan and Loeys Dietz syndrome. Surgery consists in replacing the affected portion of the aorta.

Prevention

Smoking cessation is an important measure to prevent aortic aneurysm progression and rupture, as is control of the other cardiovascular risks, such as hypertension, sedentarism and dyslipidemia.

Related Chapters

• Aortic Dissection
• Thoracic Aortic Aneurysm
• Abdominal Aortic Aneurysm
• Aneurysm

Short QT Syndrome Overview

Short QT syndrome is a rare autosomal dominant inherited disease of the electrical conduction system of the heart. It is defined by short QT intervals (≤ 360 ms) that increases an individual propensity to atrial and ventricular tachyarrhythmias. It occurs due to gain-of-function mutations in genes encoding for cardiac potassium channels KCNH2, KCNQ1 and KCNJ2. The shortened QT interval does not significantly change with heart rate, and there are tall and peaked T waves in the right precordium. It is associated with an increased risk of atrial fibrillation, syncope and sudden death.

Historical Perspective

The syndrome was first described by Dr. Prebe Bjerregaard MD, DMSc in 1999, who wrote the first clinical report of three members of one family who presented with persistently short QT interval.

Classification

• Short QT syndrome type 1 (SQT1): This variant is due to a gain-of-function mutation of the rapid component of the delayed rectifier potassium current HERG (KCNH2) channel(IKr). The variant is a result of missense mutations which increase IKr. It is associated with sudden death and sudden infant death syndrome.
• Short QT syndrome type 2 (SQT2): Caused by a mutation in the KCNQ1 gene. In the first patient, a g919c substitution in the KCNQ1 gene encoding for the K+ channel KvLQT1 was identified. The mutation led to a gain of function in in the KvLQT1 (I(Ks)) channel. This variant is associated with ventricular fibrillation.
• Short QT syndrome type 3 (SQT3): This variant results from a G514A substitution in the KCNJ2 gene ( a change from aspartic acid to asparagine at position 172 (D172N)). This causes a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel. The ECG shows asymmetrical T waves. These patients have an increased risk for re-entry arrhythmias.
• Short QT syndrome type 4 (SQT4): A loss of function mutation in the CACNA1C gene alters the encoding for the α1- and β2b-subunits of the L-type calcium channel. The phenotype is similar to Brugada syndrome combined with a short QT interval. There is an increased risk of sudden cardiac death.
• Short QT syndrome type 5 (SQT5): A loss of function mutation in the CACNB2B gene alters the encoding for the α1- and β2b-subunits of the L-type calcium channel. The phenotype is similar to Brugada syndrome combined with a short QT interval. There is an increased risk of sudden cardiac death.
• Short QT syndrome type 6 (SQT6): A loss of function mutation in the CACNAD2D1 coding for the Cavα2δ-1 subunit of the L-type calcium channel.

Pathophysiology

Short QT syndrome types 1-3 are due to increased activity of outward potassium currents in phase 2 and 3 of the cardiac action potential due to mutations in potassium channels. This causes a shortening of the plateau phase of the action potential (phase 2), causing a shortening of the overall action potential, leading to an overall shortening of refractory periods and the QT interval. In the families afflicted by short QT syndrome, two different missense mutations have been described in the human ether-a-go-go gene (HERG). These mutations result in expression of the same amino acid change in the cardiac I_Kr ion channel. This mutated I_Kr has increased activity compared to the normal ion channel, and would theoretically explain the above hypothesis. Short QT syndrome types 4 and 5 and 6 are due to mutations in the calcium channel and consequent reduction in L-type Ca-channel current.

Genetics

In the families afflicted by short QT syndrome, mutations have been described in three genes, KvLQT1, the human ether-a-go-go gene (HERG), and KCNJ2. Mutations in the KCNH2, KCNJ2, and KCNQ1 genes cause short QT syndrome. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged atoms (ions) of potassium into and out of cells. In cardiac muscle, these ion channels play critical roles in maintaining the heart's normal rhythm. Mutations in the KCNH2, KCNJ2, or KCNQ1 gene increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heart beats, leading to the abnormal heart rhythm characteristic of short QT syndrome. Short QT syndrome appears to have an autosomal dominant pattern of inheritance.

Due to the autosomal dominant inheritance pattern, individuals may have family members with a history of unexplained or sudden death at a young age (even in infancy), palpitations, or atrial fibrillation. The penetrance of symptoms is high in affected family members. It is also interesting to note that while mutations involving potassium channel genes associated with the long QT syndrome are loss-of-function mutations, the mutations that cause short QT syndrome are gain-of-function mutations.

The calcium channels' dysfunction are mostly due to CACNA1C and CACNB2b genes mutation which caused Brugada-like ECG changes with short QT interval. Lastly, a novel mutation of the CACNA2D1 gene was reported in a 17-year-old female who presented with short QT interval and ventricular fibrillation.

Causes

The causes of shortening of the QT interval can be divided into primary causes (Short QT syndrome types 1-5) and secondary causes such as drugs and electrolyte disturbances.

Common Causes

• Hypercalcemia
• Digoxin

Causes in Alphabetical Order

• Acidosis
• Altered autonomic tone
• Digoxin
• Hypercalcaemia
• Hyperkalemia
• Hyperthermia
• Lanatoside C
• Rufinamide
• Short QT syndrome type 1
• Short QT syndrome type 2
• Short QT syndrome type 3
• Short QT syndrome type 4
• Short QT syndrome type 5
• Short QT syndrome type 6

Differentiating Short QT Syndrome from other Disorders

Short QT may have secondary causes that must be ruled out, since the short QT syndrome is by definition a primary, congenital disease of the heart. Such causes include: hyperkalemia, hypercalcemia, acidosis, hyperthermia - caused by the use of drugs like digitalis, effect of acetylcholine or catecholamine and activation of Katp or Kach current. Only after ruling out such causes is that the diagnosis of short QT syndrome may be made.

Epidemiology and Demographics

European studies have estimated a prevalence of 0.02% to 0.1% among adults. A paper from 2015 which tried to assess the prevalence among pediatric population in the U.S. estimated a prevalence of 0.05% at this population. Sudden cardiac arrest has a peak incidence between the second and fourth decades of life, which might indicate an association with testosterone levels in males.

Natural History, Complications, Prognosis

The disease can have clinical manifestations from the first year of life until as late as 80 years old, and most cases are symptomatic. Its most frequent symptoms include cardiac arrest (which was the first symptom in 28% of the patients), followed by palpitations, and syncope. Patients may also present with atrial fibrillation and ventricular extrasystoles. They remain at high risk for sudden death during their lifetime and may present with a strong family history for this occurence. Sudden cardiac death presents with two high-risk peaks, one in the first year of life, and another one from 20 to 40 years old. Even though familial association is present in the majority of patients, the yields for genetic tests is low.

Screening

Since the disease is so rare, no screening for the general population is advised. Individuals with short QT interval detected on the ECG must first rule out other causes. Genetic screening is performed if a patient presents with: sudden cardiac arrest, history of polymorphic ventricular tachycardia or ventricular fibrillation without a known cause, history of unexplained syncope, young individuals with atrial fibrillation, family members diagnosed with short QT syndrome, family members who died from sudden cardiac arrest.

Diagnosis

The first step for diagnosing short QT syndrome is ruling out secondary causes, such as the ones cited above. Once them are ruled out, there are two suggested diagnostic approaches in the medical literature: one proposed by GOLLOB, and another one proposed by PRIORI:

- Scoring type of diagnostic criteria, as proposed by the Arrhythmia Research Laboratory at the University of Ottawa Heart Institute from Drs. Michael H Gollob and Jason D Roberts.

Diagnostic Criteria for Short QT Syndrome from UoO Heart Institute

QTc in milliseconds <370 = 1 point <350 = 2 points <330 = 3 points

J point - T peak interval in milliseconds <120 = 1 point

Clinical History Sudden cardiac arrest = 2 points Polymorphic VT or VF = 2 points Unexplained syncope = 1 point Atrial fibrillation = 1 point

Family History 1st or 2nd degree relative with SQTS = 2 points 1st or 2nd degree relative with sudden death = 1 point Sudden infant death syndrome = 1 point

Genotype Genotype positive = 2 points Mutation of undetermined significance in a culprit gene = 1 point

The points are summed and interpreted as follows:

• > or equal to 4 points: High-probability of SQTS
• 3 Points: Intermediate probability of SQTS
• 2 points or less: Low probability of SQTS

- Diagnostic criteria suggested by PRIORI, 2015 for the European Society of Cardiology:

• QTc <340ms or QTc <360ms and one or more of the following:
  • Confirmed pathogenic mutation;
  • Family history of SQTS;
  • Family history of sudden death at 40 years of age;
  • Survival from a VT/VF episode at the absence of heart diseases.
    

Electrocardiogam

Duration of the QT Interval

Tall peaked T wave and short QT in the right precordial lead V2

While the QT interval is generally short, the QT interval alone cannot be used to distinguish the patient with short QT syndrome from a normal patient (similar to long QT syndrome). In general though, if the QTc is < 330 msec in a male, and <340 msec in a female, then short QT syndrome can be diagnosed even in the absence of symptoms as these QT intervals are much shorter than in the rest of the population. On the other hand, if the QTc is moderately shortened to < 360 msec in a male or < 370 msec in a female, the short QT syndrome should only be diagnosed in the presence of symptoms or a family history according to the guidelines above.

SQTS 1,2,3

The QTc is usually < 300-320 msec.

SQTS 4,5,6

The QTc is usually just under 360 msec

Variability of the QT Interval with Heart Rate

The short QT interval does not vary significantly with the heart rate. Normally the QT will become longer at slow heart rates and this does not occur among patients with short QT syndrome. The Bazett formula may overcorrect (i.e. shorten) the QT interval in the patient with bradycardia, and it is therefore important to use treadmill testing to increase the heart rate and confirm the absence of QT interval variation.

Other ECG findings:

• There is a high prevalence of early depolarization patterns on SQTS.
• QRS complex is followed by T wave without any ST segment.

• Prominent U wave separated by isoelectric T-U segment.
• Longer Tpeak - Tend interval.
• Prolongation of the QT interval at slower heart rates is suppressed, remaining below the lower limit.
• Depressed PQ segment commonly observed in the inferior and anterior leads.

• In a very limited number of patients it has been observed that early repolarization (which is present in 65% of patients with SQTS) and a longer T wave peak to T wave end period is associated with the occurrence of arrhythmic events.

70% of patients with short QT have a history of either paroxysmal atrial fibrillation or permanent atrial fibrillation, and atrial fibrillation is the first sign of short QT syndrome in 50% of patients. In young patients with lone atrial fibrillation, the patient should be screened for short QT syndrome.

Electrophysiologic Studies

Among patients with SQTS, the atrial and ventricular refractory periods are shortened (ranging from 120 to 180 ms). Ventricular fibrillation can be induced on programmed stimulation in 90% of patients with short QT syndrome. Despite the high rate of VF inducibility, the risk of sudden death in an individual patient is difficult to predict given the genetic and clinical heterogeneity of short QT syndrome and the limited number of patients with short follow-up to date. The limitations of electrophysiologic testing are highlighted by a study of Giustetto et al in which the sensitivity of electrophysiologic testing in relation to the clinical occurrence of ventricular fibrillation was only 50% (3 of 6 cases). Importantly, lack of inducibility does not exclude a future episode of ventricular fibrillation. Thus, the role of electrophysiologic testing in risk stratification of the patient with SQTS is not clear at present.

Genetic Testing

Because new genetic variants of SQTS are still being identified, a negative genetic test for existing variants does not exclude the presence of SQTS. A negative genetic test for existing variants could mean that a patient with a short QT interval does not have a heretofore unidentified variant of SQTS.

However, among family members of an affected patient, genetic testing may identify the syndrome in an asymptomatic patient, and may also rule out the presence of the syndrome in asymptomatic patients.

Mutations in the KCNH2, KCNJ2, and KCNQ1 genes cause short QT syndrome. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged atoms (ions) of potassium into and out of cells. In cardiac muscle, these ion channels play critical roles in maintaining the heart's normal rhythm. Mutations in the KCNH2, KCNJ2, or KCNQ1 gene increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heart beats, leading to the abnormal heart rhythm characteristic of short QT syndrome. Short QT syndrome appears to have an autosomal dominant pattern of inheritance.

Centers Performing Genetic Testing for Short QT Syndrome

• Gene Tests: Short QT Syndrome 1
• Gene Tests: Short QT Syndrome 2
• Gene Tests: Short QT Syndrome 3

Treatment

Device Based Therapy

An implantable cardioverter-defibrillator (ICD) is indicated in symptomatic patients who have either survived a sudden cardiac arrest and/or have had documented episodes of spontaneous sustained ventricular tachyarrhythmias with or without syncope. There's a problem with ICD in such patients though, because the tall and peaked T wave can be interpreted as a short R-R interval provoking inappropriate shock.

Generally accepted criteria for implantation of an AICD also include:

• Inducibility on electrophysiologic testing;
• Positive genetic test, although a negative result does not exclude the presence of a previously unreported mutation or the occurrence of a future arrhythmic event.

Complications of AICD Placement

Inappropriate shocks may be delivered due to:

• The occurence of tachycardias such as sinus tachycardia and atrial fibrillation.
• Oversensing of the tall, narrow peaked T wave.

Pharmacologic Therapy

Short QT Syndrome 1 (SQT1)

The efficacy of pharmacotherapy in preventing ventricular fibrillation has only been studies in patients with SQT1. Given the limited number of patients studied, and the limited duration of follow-up, pharmacotherapy as primary or secondary preventive therapy for patients with SQT1 cannot be recommended at this time. AICD implantation remains the mainstay of therapy in these patients. Pharmacotherapy may play an adjunctive role in reducing the risk of events in patients with an AICD as described below in the indications section.

Patients with Short QT Syndrome 1 (SQT1) have a mutation in KCNH2 (HERG). Class IC and III antiarrhythmic drugs do not produce any significant QT interval prolongation . Flecainide has not been shown to consistently reduce the inducibility of ventricular fibrillation. Although it does not prolong the QT interval in SQT1 patients, propafenone reduces the risk of recurrent atrial fibrillation in SQT1 patients.

Quinidine in contrast may be effective in patients with SQT1 in so far as it blocks both potassium channels (IKr, IKs, Ito, IKATP and IK1) and the inward sodium and calcium channels. In four out of four patients, Quinidine prolonged the QT interval from 263 +/- 12 msec to 362 +/-25 msec, most likely due to its effects on prolonging the action potential and by virtue of its action on the I_K channels. Although Quinidine was successful in preventing the inducibility of ventricular fibrillation in 4 out of 4 patients, it is unclear if the prolongation of the QT interval by quinidine would reduce the risk of sudden cardiac death. It also prolonged the ST interval and T wave durations, restored the heart rate dependent variability in the QT interval and decreased depolarization dispersion in patients with SQT1.

There is a report which states that disopyramide was also effectively used in two patients with SQT-1, increasing their QT interval and ventricular refractory period while also abbreviating the Tpeak-Tend interval.

As atrial fibrillation is also very commonly found on those patients propafenone has also been successfully used to prevent its paroxysms, without having any effect on QT interval.

Although pharmacotherapy can be used to suppress the occurrence of atrial fibrillation in patients with SQT1, AICD implantation is the mainstay of therapy, and pharmacotherapy to prevent sudden death should is only indicated if AICD implantation is not possible.

Indications for Pharmacologic Therapy

The following are indications for pharmacologic therapy of SQTS:

• In children as an alternate to AICD implantation;
• In patients with a contraindications AICD implantation;
• In patients who decline AICD implantation;
• In patients with appropriate AICD discharges to reduce the frequency of discharges;
• In patients with atrial fibrillation to reduce the frequency of symptomatic episodes.

Yersinia pseudotuberculosis

• 1. Enterocolitis treatment

• Preferred regimen: There is also no evidence that early antimicrobial therapy reduces the frequency or severity of chronic sequelae for either Y. enterocolitica or Y. pseudotuberculosis
• Note: Susceptible to Ampicillin, third generation cephalosporins, aminoglycosides, tetracyclines, and chloramphenicol

• 2. Septicemia treatment

• Preferred regimen: Ceftriaxone 1 g IM/IV q12h
• Note: Pediatric dose: Ceftriaxone 100 mg/kg/day (up to 2 g/day) IM/IV q12h
• Note: There is no duration of treatment established but some Yersinia spp infections have been treat for at least 3 weeks.

Yersinia pestis

• 1. Plague treatment

• Preferred regimen (1): Streptomycin 2 g/day IM q12h for at least 10 days

• Note: Pediatric dose: Streptomycin 30 mg/kg/day (up to 2 g/day) IM q6-12h for at least 10 days

• Preferred regimen (2): Gentamicin 3 mg/kg/day IM or IV q8h for at least 10 days

• Note: Pediatric dose: Gentamicin 6-7.5 mg/kg/day IM or IV q8h for at least 10 days - if neonates/infants use 7.5 mg/kg/day.

• Alternative regimen (1): Chloramphenicol 50 mg/kg/day IV or PO q6h for 10 days
• Alternative regimen (2): Tetracycline 2 g/day PO qid for 10 days

• Note: Pediatric dose: Tetracycline 15 mg/kg of loading dose THEN 25-50 mg/kg/day (up to 2 g/day) PO qid for 10 days

• Alternative regimen (3): Sulfadiazine 2-4 g loading dose THEN 1 g PO q4-6h
• Alternative regimen (4): Doxycycline 200 mg/day PO q12-24h
• Note (1): Fluoroquinolones have good effect against Y. pestis in both in vitro and animal studies, but no studies have been published on its use in treating human plague.
• Note (2): Other antibiotics have been shown ineffective against plague.

• 2. Plague prophylaxis

• Preferred regimen: Tetracycline 1-2 g/day PO bid-qid

• Note: Pediatric dose: Tetracycline 25-50 mg/kg/day (up to 2 g/day) PO qid for 10 days

• Alternative regimen (1): Doxycycline 100-200 mg/day PO q12-24h
• Alternative regimen (2): Sulfamethoxazole-Trimethoprim 1.6 g/day PO bid

• Note: Pediatric dose: Sulfamethoxazole-Trimethoprim 40 mg/kg/day PO bid

Neutropenic fever

• 1. Empiric initial treatment

• 1.1 Low-risk (anticipated neutropenia for less than 7 days, clinically stable and no medical comorbidities, MASCC score ≥21)

• Preferred regimen: Ciprofloxacin PLUS Amoxicillin-clavulanate

• 1.2 High-risk (anticipated neutropenia for more than 7 days, clinically unstable or any medical comorbidities, MASCC score <21)

• Preferred regimen (1): Piperacillin-tazobactam 4.5 g IV q6-8h
• Preferred regimen (2): Imipenem 500 mg IV q6h
• Preferred regimen (3): Meropenem 1 g IV q8h
• Preferred regimen (4): Cefepime 2 g IV q8h
• Preferred regimen (5): Ceftazidime 2 g IV q8h
• Alternative regimen (1): (for penicillin allergic patients) (Ciprofloxacin PLUS Clindamycin)

• Alternative regimen (2): Aztreonam PLUS Vancomycin
• Note (1): monotherapy is preferred since no study has shown superiority for combination therapy.
• Note (2): add Vancomycin to the regimen if patient has signs of severe sepsis, hemodynamic instability, pneumonia, positive blood cultures for gram-positive bacteria while awaiting susceptibility results, suspected central venous catheter related infection, skin or soft tissue infection, severe mucositis in patients receiving prophylaxis with a fluoroquinolone lacking acitvity against streptococci and in whom ceftazidime is being used as empiric therapy (addition of gram-positive coverage is recommended in this situation because of the increased risk of Streptococcus viridans infections, which can result in sepsis and the acute respiratory distress syndrome).
• Note (3): modify the initial regimen if patient is at risk of infection with the following antibiotic-resistant organisms:

• MRSA: consider early addition of Vancomycin OR Linezolid OR Daptomycin
• VRE: consider early addition of Linezolid OR Daptomycin
• ESBLs: consider early use of a Carbapenem
• KPCs: consider early use of Polymyxin-colistin OR Tigecycline

• Note (4): the initial regimen should not be changed because of unexplained persistent fever if the patient is stable. However, if an infection is identified, the patient must be treated accordingly.
• Note (5): if Vancomycin or other gram-positive coverage was started initially, it may be stopped after two to three days if there is no evidence of a gram-positive infection.
• Note (6): empiric antifungal coverage should be considered in high-risk neutropenic patients who are expected to have a total duration of neutropenia >7 days and have persistent fever after four to seven days of a broad-spectrum antibacterial regimen and no identified source of fever. Clinically unstable patients with suspected fungal infection should be considered for antifungal therapy even earlier than what is recommended for empiric therapy.Candida spp are the most likely cause of invasive fungal infection in patients who are not receiving prophylaxis. In patients receiving fluconazole prophylaxis, fluconazole-resistant Candida spp and invasive mold infections, particularly Aspergillus spp, are the most likely causes. Recommended antifungal regimen:

• Caspofungin 70 mg IV on day one THEN 50 mg IV qd
• Voriconazole 6 mg/kg IV q12h on day one THEN 4 mg/kg IV q12h
• Amphotericin B lipid complex 5 mg/kg IV qd
• Liposomal amphotericin B 3 to 5 mg/kg IV qd

• 2. Prophylaxis

• 2.1 Antifungal prophylaxis
• Indications:

• Prophylaxis against Candida infections is recommended in patient groups in whom the risk of invasive candidal infections is substantial, such as allogeneic HSCT recipients or those undergoing intensive remission-induction or salvage induction chemotherapy for acute leukemia.
• Prophylaxis against invasive Aspergillus infections with Posaconazole should be considered for selected patients >13 years of age who are undergoing intensive chemotherapy for AML/MDS in whom the risk of invasive aspergillosis without prophylaxis is substantial.
• Prophylaxis against Aspergillus infection in pre- engraftment allogeneic or autologous transplant recipients has not been shown to be efficacious. However, a mold-active agent is recommended in patients with prior invasive aspergillosis, anticipated prolonged neutropenic periods of at least 2 weeks, or a prolonged period of neutropenia immediately prior to HSCT.

• Recommended drugs:

• Preferred regimen: Fluconazole
• Alternative regimen (1): Posaconazole
• Alternative regimen (2): Voriconazole
• Alternative regimen (3): Caspofungin
• Alternative regimen (4): Micafungin

• 2.2 Antiviral prophylaxis

• There is usually no indication for the prophylactic use of antiviral drugs in patients with neutropenia. However, if skin or mucous membrane lesions due to herpes simplex or varicella-zoster viruses are present, even if they are not the cause of fever, prophylaxis with Acyclovir can be considered.

• Recommended drugs:

• Preferred regimen: Acyclovir

• 2.3 Antibacterial prophylxis

• Fluoroquinolone prophylaxis should be considered for high-risk patients with expected durations of prolonged and profound neutropenia (ANC <100 cells/mm3 for >7 days)

• Recommended drugs:

• Preferred regimen (1): Levofloxacin
• Preferred regimen (2): Ciprofloxacin

Sporotrichosis

• Sporotrichosis Return to Top

• Lymphocutaneous/cutaneous

• Preferred regimen: Itraconazole 200mg PO qd
• Alternative regimen: Itraconazole 200 mg PO bid OR Terbinafine 500 mg PO bid OR Saturated solution potassium iodide with increasing doses OR Fluconazole 400–800 mg PO qd OR local hyperthermia
• Note (1): Treat for 2–4 weeks after lesions resolved
• Note (2): SSKI initiated at a dosage of 5 drops (using a standard eyedropper) q8h, increasing as tolerated to 40–50 drops q8h

• Osteoarticular

• Preferred regimen: Itraconazole 200mg PO bid for 12 months
• Alternative regimen: Lipid amphotericin B (Lipid AmB) 3–5 mg/kg/day IV OR Amphotericin B deoxycholate 0.7–1 mg/kg/day IV
• Note (1): Switch to Itraconazole after favorable response if AmB used
• Note (2): Treat for a total of at least 12 months

• Pulmonary

• Preferred regimen(1): Lipid amphotericin B (Lipid AmB) 3–5 mg/kg/day IV for severe or life-threatening pulmonary sporotrichosis, then Itraconazole 200 mg PO bid
• Preferred regimen(2): Itraconazole 200 mg PO bid for 12 months for less severe disease
• Alternative regimen: Amphotericin B deoxycholate 0.7–1 mg/kg/d IV THEN Itraconazole 200 mg PO bid OR surgical removal
• Note (1): Treat severe disease with an AmB formulation followed by Itraconazole
• Note (2): Treat less severe disease with Itraconazole
• Note (3): Treat for a total of at least 12 monthsSurgery combined with amphotericin B therapy is rec- ommended for localized pulmonary disease

• Meningitis

• Preferred regimen: Lipid amphotericin B (Lipid AmB) 5 mg/kg daily for 4–6 weeks, then Itraconazole 200 mg PO bid
• Alternative regimen: Amphotericin B deoxycholate 0.7–1 mg/kg/d, then Itraconazole 200 mg PO bid
• Note (1): Length of therapy with AmB not established, but therapy for at least 4–6 weeks is recommended.
• Note (2): Treat for a total of at least 12 months.
• Note (3): May require long-term suppression with Itraconazole.

• Disseminated

• Preferred regimen: Lipid amphotericin B (Lipid AmB) 3–5 mg/kg/day, then Itraconazole 200 mg PO bid
• Alternative regimen: Amphotericin B deoxycholate 0.7–1 mg/kg/day, then Itraconazole 200 mg PO bid
• Note(1): Therapy with AmB should be continued until the patient shows objective evidence of improvement.
• Note(2): Treat for a total of at least 12 months.
• Note(3): May require long-term suppression with Itraconazole.

• Pregnant women

• Preferred regimen(1): Lipid amphotericin B (Lipid AmB) 3–5 mg/kg/day IV OR Amphotericin B deoxycholate 0.7–1 mg/kg/day IV for severe sporotrichosis
• Preferred regimen(2): Local hyperthermia for cutaneous disease.
• Note (1): It is preferable to wait until after delivery to treat non–life-threatening forms of sporotrichosis.
• Note (2): Azoles should be avoided.

• Children

• Preferred regimen:

• Mild disease: Itraconazole 6–10 mg/kg/day PO (400 mg/day maximum)
• Severe disease: Amphotericin B deoxycholate 0.7 mg/kg/day IV followed by Itraconazole 6–10 mg/kg PO up to a maximum of 400 mg PO daily, as step-down therapy::* Alternative regimen: Saturated solution potassium iodide with increasing doses for mild disease initiated at a dosage of 1 drop (using a standard eyedropper) q8h and increased as tolerated up to a maximum of 1 drop/kg or 40–50 drops q8h, whichever is lowest

MERS

• Middle East Respiratory Syndrome

• Preferred regimen: supportive care. There is no antiviral recommended for this infection at this moment, even though experimental therapies are at research (IFNs, Ribavirin, Lopinavir, Mycophenolic acid, Cyclosporine, Chloroquine, Chlorpromazine, Loperamide, 6-mercaptopurine and 6-thioguanine). Supportive care include: administer oxygen to patients with severe acute pulmonary infection with signs of respiratory distress, hypoxaemia or shock; use conservative fluids management, avoid administering high-dose systemic glucocorticoids, use non-invasive ventilation, but, if its nor effective, do not delay endotracheal intubation; use lung-protective strategy for intubated patients, recognize sepsis as early as possible and treat it accordingly.

Penicilliosis

• Penicilliosis treatment

• 1. Mild disease

• Preferred regimen: Itraconazole 200 mg PO bid for 8 to 12 weeks without amphotericin B induction therapy
• Alternative regimen: Voriconazole 400 mg PO bid on day 1 THEN 200 mg PO bid for 12 weeks

• 2. Moderate-severe disease

• Preferred regimen: Liposomal Amphotericin B 3-5 mg/kg/day IV qd OR Amphotericin B lipid complex 5 mg/kg/day IV qd for 2 weeks THEN Itraconazole 200 mg PO bid for 10 weeks
• Alternative regimen: Voriconazole 6 mg/kg IV q12h on day 1 THEN 4 mg/kg q12h for at least 3 days THEN Voriconazole 200 mg PO bid for a total of 12 weeks

• 3. Maintenance therapy

• Preferred regimen Itraconazole 200 mg PO qd
• Alternative regimen: Voriconazole 200 mg PO bid

• Note: Voriconazole and Itraconazole use require serum levels to be monitored to ensure adequate absorption.

Mucormycosis

• Mucormycosis Return to Top
• Mucormycosis

• Treatment include surgical debridement of involved tissues, antifungal therapy, use of growth factors to accelerate recovery from neutropenia, provision of granulocyte transfusions with sustained circulating neutrophils until the patient recovers from neutropenia, and discontinuation or reduction in the dose of glucocorticoids, correction of metabolic acidosis and hyperglycemia.
• Preferred regimen (1): Amphotericin B Deoxycholate 1.0-1.5 mg/kg/day IV q24h
• Preferred regimen (2): Lipid Amphotericin B 5-10 mg/kg/day IV q24h
• Preferred regimen (3): Amphotericin B lipid complex 5-7.5 mg/kg/day IV q24h
• Alternative regimen (1):Caspofungin 70 mg IV load dose, 50 mg/day for >2 weeks PLUS Lipid Amphotericin B 5-10 mg/kg/day IV q24h

• Pediatric dose: Caspofungin 50 mg/m² IV q24h PLUS Lipid Amphotericin B 5-10 mg/kg/day IV q24h

• Alternative regimen (2): Micafungin OR Anidulafungin 100 mg/day for 2 weeks PLUS Lipid Amphotericin B 5-10 mg/kg/day IV q24h

• Pediatric dose: Micafungin 4 mg/kg/day; Micafungin 10mg/kg/day for low-birth weight infants; Anidulafungin 1.5 mg/kg/day

• Alternative regimen (3): Deferasirox 20 mg/kg PO qd for 2–4 weeks PLUS Lipid Amphotericin B 5-10 mg/kg/day IV q24h
• Alternative regimen (4): Posaconazole 800 mg/day PO qid or bid
• Alternative regimen (5): Initial: Isavuconazole 200 mg PO/IV q8h for 6 doses; maintenance: 200 mg PO/IV qd
• Note (1): start maintenance dose 12 to 24 hours after the last loading dose.
• Note (2): For salvage therapy: (Posaconazole 800 mg/day PO qid or bid ± Lipid Amphotericin B 5-10 mg/kg/day IV q24h) OR (Deferasirox 20 mg/kg PO qd for 2–4 weeks PLUS Lipid Amphotericin B 5-10 mg/kg/day IV q24h) OR Granulocyte transfusions (for persistently neutropenic patients) ∼10ˆ9 cells/kg OR Recombinant cytokines G-CSF 5 μg/kg/day, GM-CSF 100–250 μg/m², or IFN-g at 50 μg/m² for those with body surface area ≥ 0.5 m² and 1.5 μg/kg for those with body surface area <0.5 m²

Herpes Virus

• Human herpesvirus 6 Return to Top

• Human herpesvirus 6 treatment

• Preferred regimen: supportive therapy
• Note: If patient is immunocompromised, there are no antiviral regimens stablished as there are no clinical trials to validate their use on these cases. Consider administering Ganciclovir, Acyclovir, Foscarnet OR Cidofovir.

• Roseola Return to Top

• Human herpesvirus 7 (roseola virus) treatment

• Preferred regimen: Supportive therapy
• Note (1): Immunocompetent hosts with uncomplicated skin manifestations associated with HHV-7, particularly roseola infantum and pityriasis rosea, need only symptomatic management
• Note (2): For HIV-positive patients, antiretroviral therapy may be advisable
• Note (3): The most active antiviral compounds against HHV-7 are Cidofovir and Foscarnet

Hepatitis E

• Hepatitis E virus Return to Top
• Hepatitis E treatment

• Preferred regimen: supportive therapy. There is no specific treatment available.

• Note (1): Hepatitis E is usually self-limiting, hospitalization is generally not required.
• Note (2): Hospitalization is required for people with fulminant hepatitis and should also be considered for symptomatic pregnant women.

Enterovirus D68

• Enterovirus D68 Return to Top

• Enterovirus treatment

• Preferred regimen: supportive therapy
• Note: A new drug Pleconaril designed to affect Rhinovirus is being suggested to be effective against Enterovirus D68 but further investigation is required

Adenovirus

• Adenovirus Return to Top

• Adenovirus

• 1. In severe cases of pneumonia or post hematopoietic stem cell transplantation

• Preferred regimen (1): Cidofovir 5 mg/kg/week IV for 2 weeks, then every 2 weeks AND Probenecid 1.25 g/M² PO given 3 hours before Cidofovir and 3 & 9 hours after each infusion
• Preferred regimen (2): Cidofovir 1 mg/kg IV 3 times per week
• Note: Ganciclovir, Foscarnet and Ribavirin are not recommended for use on adenovirus infection.

• 2. For hemorrhagic cystitis

• Preferred regimen: Cidofovir (5 mg/kg in 100 mL saline instilled into bladder) intravesical

• 3. Pink eye (viral conjunctivitis)

• Preferred regimen: No specific treatment available. If symptomatic, cold artificial tears may help.

• 4.Bronchitis

• Preferred regimen: No specific therapy recommended, treatment is symptomatic.

SARS

• SARS Return to Top
• Severe acute respiratory distress syndrome- coronavirus

• Preferred regimen: supportive therapy
• Note: New therapies were studied for SARS during the last outbreaks which concluded:

• Ribavirin ineffective and probably harmful due to haemolytic anaemia
• Lopinavir PLUS Ritonavir is still controversial and need further investigation
• Interferon has no benefit and its studies are inconclusive
• Corticosteroids increases risk of fungal infections, some studies showed a higher incidence of psychosis, diabetes, avascular necrosis and osteoporosis
• Inhaled Nitric oxide potent mediator of airway inflammation, its has improved oxygenation in some studies

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CMV

• Cytomegalovirus Return to Top

• Cytomegalovirus treatment

• 1. Immunocompetent patients

• 1.1 Mononucleosis syndrome

• Preferred regimen: supportive therapy

• 1.2 CMV in pregnancy

• Preferred regimen: Hyperimmune 200 IU/kg of maternal weight as single-dose during pregnancy

• 2. Immunocompromised patients

• 2.1 Retinitis

• Preferred regimen (1): Ganciclovir intraocular implant PLUS Valganciclovir 900 mg PO bid for 14-21 days THEN Valganciclovir 900mg PO qq for maintenance therapy - for immediate sight-threatening lesions
• Preferred regimen (2): Valganciclovir 900 mg PO bid for 14-21 days THEN Valganciclovir 900 mg PO qq for maintenance therapy - for peripheral lesions
• Alternative regimen (1): Foscarnet 60 mg/kg IV q8h OR Foscarnet 90 mg/kg IV q12h for 14-21 days THEN Foscarnet 90-120 mg/kg IV q24h
• Alternative regimen (2): Cidofovir 5 mg/kg IV for 2 weeks THEN Cidofovir 5 mg/kg IV every other week - each dose should be admnistered with IV saline hydration and probenecid
• Alternative regimen (3): Ganciclovir 5 mg/kg IV q12h for 14-21 days THEN Valganciclovir 900 mg PO bid
• Alternative regimen (4): Fomivirsen intravitreal injection - for relapses
• Note: keep a maintenance dose of Valganciclovir 900 mg PO qd until CD4 >100/mm³

• 2.2 Transplant patients

• Preferred regimen: Valganciclovir 900 mg PO bid OR Ganciclovir 5 mg/kg IV q12h for at least 2-3 weeek
• Note: Use Valganciclovir 900 mg PO qd for 1-3 months if high dose of immunosuppression.

• 2.3 Colitis, esophagitis, gastritis

• Preferred regimen: Ganciclovir 5 mg/kg/dose IV q12h for 3-6 weeks weeks for induction. There is no agreement on the use of maintenance.
• Alternative regimen: Cidofovir 5 mg/kg IV for 2 weeks, then 5 mg/kg every other week; each dose should be administered with IV saline hydration and oral probenecid 2 g PO 3h before each dose and further 1 g doses after 2h and 8h.
• Note: Switch to oral Valganciclovir when PO tolerated & when symptoms not severe enough to interfere with absorption.

• 2.4 Pneumonia

• Preferred regimen: Valganciclovir 900 mg PO bid for 14–21 days, then 900 mg PO qd for maintenance therapy
• Alternative regimen for retinitis: Ganciclovir 5 mg/kg IV q12h for 14–21 days, then Valganciclovir 900 mg PO qd
• Note: In bone marrow transplant patients, combine therapy with CMV immune globulin.

• 2.5 Encephalitis, ventriculitis

• Note: Treatment not defined, but should be considered the same as retinitis. Disease may develop while taking Ganciclovir as suppressive therapy.

• 2.6 Lumbosacral polyradiculopathy

• Preferred regimen: Ganciclovir, as with retinitis
• Alternative regimen: Foscarnet 40 mg/kg IV q12h another option
• Alternative regimen: Cidofovir 5 mg/kg IV for 2 weeks, then 5 mg/kg every other week; each dose should be administered with IV saline hydration and oral probenecid 2 g PO 3h before each dose and further 1 g doses after 2h and 8h.
• Note (1): Switch to Valganciclovir when possible.
• Note (2): Suppression continued until CD4 remains >100/mm³ for 6 months.

• 2.7 Peri/postnatal severe CMV infection in very low birth weight infants

• Preferred regimen: Ganciclovir 6 mg/kg/dose IV q12h for 3 weeks

Ebola

• Ebola virus Return to Top

• Ebola virus treatment

• Preferred regimen: supportive therapy. There is no specific antiviral drug available for Ebola thus far. For information of investigational therapies including Favipiravir, Brincidofovir, ZMapp, TKM-Ebola, AVI-6002, and BCX4430, see here.

• Isolate patient
• Provide intravenous fluids (IV) (patients need large volumes in some cases) and maintain electrolytes at normal levels
• Maintain oxygen saturation and blood pressure
• Administer blood products if coagulopathy or bleeding, antiemetics if vomiting , antipyretics if fever, analgesics, anti-motility if severe diarrhea, total parenteral nutrition if patient has poor oral intake and dialysis if there's renal failure
• Treat other infections if they occur. Provide adequate Gram-negative coverage and gram-positive if the patient has any catheter or hospital-acquired pneumonia.
• If there's respiratory failure, invasive mechanical ventilation may be the best option to offer respiratory support

• Note (1): Recovery from Ebola depends on good supportive care and the patient’s immune response.
• Note (2): While there is no proven treatment available for Ebola virus disease, human convalescent whole blood has been used as an empirical treatment with promising results in a small group of EVD cases.
• Note (3): People who recover from Ebola infection develop antibodies that last for at least 10 years, possibly longer. It is not known if people who recover are immune for life or if they can become infected with a different species of Ebola.
• Note (4): Some people who have recovered from Ebola have developed long-term complications, such as joint and vision problems.

Marburg

• Marburg virus Return to Top

• Marburg virus treatment

• Preferred regimen: supportive therapy including maintenance of blood volume and electrolyte balance, as well as analgesics and standard nursing care

Hantavirus

• Hantavirus Return to Top

• Hantavirus cardiopulmonary syndrome treatment

• Preferred regimen: Supportive therapy, there is no specific treatment for hantavirus cardiopulmonary syndrome
• Note (1): ICU management should include careful assessment, monitoring and adjustment of volume status and cardiac function, including inotropic and vasopressor support if needed
• Note (2): Fluids should be administered carefully due to the potential for capillary leakage
• Note (3): Supplemental oxygen should be administered if patients become hypoxic
• Note (4): Equipment and materials for intubation and mechanical ventilation should be readily available since onset of respiratory failure may be precipitous
• Note (5): Extracorporeal membrane oxygenation was used with survival rates of 50% in some studies in patients with cardiac index output <2.5L/min/m²

Streptococcus pyogenes

• Streptococcus pyogenes Return to Top
• 1. Streptococcus pyogenes tonsilitis

• Preferred regimen (1): Penicillin V 250 mg PO bid or tid (for children) 250 mg PO qid or 500 mg PO bid (for adults) for 10 days
• Preferred regimen (2): Benzathine penicillin G if <27kg: 600,000 U, if >27kg 1,200,000 U IM single-dose
• Alternative regimen (1): Amoxicillin 50 mg/kg/day PO qd for 10 days OR 25 mg/kg/day PO bid for 10 days. Its oral suspension is more tolerable to children and it is better absorbed by the GI tract
• Alternative regimen (2): first generation Cephalosporins are acceptable for treating recurrent group A streptococcus infection but not as first-line therapy
• Alternative regimen (3): Clarithromycin 250 mg PO bid for 10 days OR Azithromycin 12 mg/kg maximum 500 mg PO on day 1 THEN 6 mg/kg maximum 250 mg PO qd on days 2 through 5 OR Erythromycin 20 mg/kg/day PO or 40 mg/kg/day (ethylsuccinate) PO bid for 10 days.
• Alternative regimen (4): Clindamycin for penicillin-intolerant patients with erythromycin-resistant strains.
• Note: Intramuscular penicillin is the only therapy that has been shown to prevent initial attacks of rheumatic fever in controlled studies

• 2. Recurrent Streptococcus pyogenes tonsilitis

• Preferred regimen (1): Clindamycin 20-30 mg/kg/day PO tid (for children), 600 mg/day bid, tid or qid (for adults) for 10 days
• Preferred regimen (2): Amoxicillin-clavulanic acid 40 mg/kg/day PO tid (for children), 500 mg bid (for adults) for 10 days
• Alternative regimen: Benzathine penicillin G if <27kg: 600,000 U, if >27kg 1,200,000 U IM single-dose ± Rifampin 20 mg/kg/day PO bid for 4 days

• 3. Secondary prophylaxis for rheumatic fever

• Preferred regimen (1): Benzathine penicillin G if <27kg: 600,000 U, if >27kg 1,200,000 U IM every 4 weeks
• Alternative regimen (1): Penicillin V potassium 250 mg PO bid
• Alternative regimen (2): Sulfadiazine if <27kg 0.5 g PO qd, if >27kg 1 g PO qd
• Duration of treatment: if residual cardiac disease, keep treatment until 40 patient is 40 years old or for 10 years (whichever is longer); if there's no residual cardiac disease keep treatment for 10 years or until age 21 years (whichever is longer); if there's rheumatic fever without carditis keep it for 5 years or until age 21 years (whichever is longer).
• Note: For patients allergic to penicillin and sulfadiazine, consider a macrolide or azalide antibiotic

• 4. Streptococcus pyogenes bacteremia

• Preferred regimen: Penicillin G 4 million units IV q4h AND Clindamycin 900 mg IV q8h for at least 14 days
• Penicillin is added to the regimen to cover any other group A streptococcus which might be resistant to Clindamycin.
• Alternative regimen (1): Erythromycin
• Alternative regimen (2): Azithromycin
• Alternative regimen (3): Clarithromycin
• Alternative regimen (4): any other β-lactam
• Note (1): Macrolide resistance is increasing.
• Note (2): Consider using intravenous immune globulin in patients with invasive infection and signs of shock. Immunoglobulin-G IV 1 g/kg day 1, then 0.5 g/kg days 2 & 3.
• Note (3): If shock, administer massive IV fluids (10-20 L/day), Albumin if <2 g/dL, debridement of necrotic tissue.

• 5. Streptococcus pyogenes celulitis

• Preferred regimen: treat as Streptococcus pyogenes bacteremia

• 6 Epiglottitis in childern

• Preferred regimen (1): Cefotaxime 50 mg/kg IV q8h
• Preferred regimen (2): Ceftriaxone 50 mg/kg IV q24h
• Alternative regimen (1): Amoxicillin-SB 100–200 mg/kg qd q6h
• Alternative regimen (2): Trimethoprim-Sulfamethoxazole 8–12 mg/kg bid
• Note: Have tracheostomy set “at bedside.” Chloro is effective, but potentially less toxic alternative agents available.

• 7 Burn wound sepsis

• Preferred regimen: Vancomycin 1 gm IV q12h AND (Amikacin 10 mg/kg IV loading dose then 7.5 mg/kg IV q12h) AND [ Piperacillin 4 g IV q4h (give ½ q24h dose of Piperacillin into subeschar tissues with surgical eschar removal within 12 hours]. Can use Piperacillin-Tazobactam if Piperacillin not available.

• 8. Soft tissue

• Note: For necrotizing fasciitis, surgical consultation for emergent fasciotomy and debridement; repeat debridements usually necessary.

• 9. Muscle

• Note: For myositis-debirdement is recommended.

• 10. Eye

• 10.1 Keratitis

• 10.1.1 Acute bacterial keratitis

• Preferred regimen: Moxifloxacin eye gtts. 1 gtt tid for 7 days
• Alternative therapy: Gatifloxacin eye gtts. 1-2 gtts q2h while awake for 2 days, then q4h for 3-7 days.
• Note: Prefer Moxifloxacin due to enhanced lipophilicity and penetration into aqueous humor (1 gtt = 1 drop).

• 10.1.2 Keratitis due to dry cornea, diabetes, immunosuppression

• Preferred regimen: Cefazolin (50 mg/mL) AND (Gentamicin OR Tobramycin (14 mg/mL) q15–60 min around clock for 24–72 hrs, then slow reduction)
• Alternative therapy: Vancomycin (50 mg/mL) AND Ceftazidime (50 mg/mL) q15–60 min around clock for 24–72 hrs, then slow reduction.
• Note: Specific therapy guided by results of alginate swab culture and sensitivity. Ciprofloxacin 0.3% found clinically equivalent to CefazolinAND Tobramycin; only concern was efficacy of Ciprofloxacin vs S. pneumoniae

• 10.2 Dacryocystitis (lacrimal sac)

• Preferred regimen: Moxifloxacin 1 gtt tid for 7 days OR Cefazolin (50 mg/mL) (1 gtt = 1 drop)

• 11. Suppurative phlebitis

• Preferred regimen: Vancomycin 15 mg/kg IV q12h (normal weight)
• Alternative regimen: Daptomycin 6 mg/kg IV q12h
• Note: Retrospective study for suppurative phlebitis recommends 2-3 weeks IV therapy and 2 weeks PO therapy.

• 12. Infected prosthetic joint

• Preferred regimen: Penicillin G 2 million units IV q4h OR Ceftriaxone 2 g IV q24h for 4 weeks
• Note: Debridement & prosthesis retention with intravenous antibiotics.

• 13. “Hot” tender parotid swelling

• Preferred regimen: Nafcillin OR Oxacillin 2 g IV q4h
• Note: Predisposing factors are stone(s) in Stensen’s duct, dehydration. Therapy depends on ID of specific etiologic organism.

• 14. Diabetic foot ulcer (ulcer with <2 cm of superficial inflammation)

• Preferred regimen: (Trimethoprim-Sulfamethoxazole 800/160 mg 1-2 tabs PO bid OR Minocycline 100 mg PO bid) AND (Penicillin VK 500 mg PO qid OR selected Cephalosporins 2nd, 3rd generation - cefprozil 500 mg PO bid OR cefuroxime axetil 500 mg PO bid OR cefdinir 300 mg PO bid or 600 mg PO qd OR cefpodoxime 200 mg PO bid OR Fluoroquinolones Levofloxacin 750 mg PO qd).

• 15. Recurrent cellulitis, chronic lymphedema prophylaxis

• Preferred regimen: Clindamycin 150 mg PO qd OR Trimethoprim-Sulfamethoxazole 800/160 mg 1 tablet PO qd OR “stand-by therapy” immediate treatment with Penicillin V OR Amoxicillin 500-750 mg PO bd at onset of symptoms.

Staphylococcus epidermidis

• Staphylococcus epidermidis Return to Top
• Staphylococcus epidermidis

• 1. Methicillin-sensitive Staphylococcus epidermidis

• Preferred regimen (1): Oxacillin 1-2 g IV q4h
• Preferred regimen (2): Nafcillin 1-2 g IV q4h
• Preferred regimen (3): Cephalothin
• Alternative regimen: Rifampin 600 mg/day PO qd PLUS Sulfamethoxazole and Trimethoprim OR Fluoroquinolones AND Daptomycin 600 mg PO/IV q12h
• Note: 75% of the S. epidermidis are methicillin-resistant.

• 2. Methicillin-resistant Staphylococcus epidermidis

• Preferred regimen: Vancomycin 1 g IV q12h ± Rifampin 600 mg/day PO qd

• Note: For deep-seated infections consider adding Gentamicin AND/OR Rifampin 600 mg/day PO qd to the regimen
• 3. Prosthetic device infections

• Preferred regimen: Oxacillin 1-2 g IV q4h OR Vancomycin 1 g IV q12h PLUS Rifampin 600 mg/day PO qd AND Gentamicin 3 mg/kg/day IV/IM q8-24h is appropriate

• Note: Duration depends on site of infection and severity.

Actinomycosis

• Actinomycosis Return to Top
• Actinomyces species including A. israeli

• Preferred regimen: Penicillin 3-4 million units IV q4h for 2-6 weeks THEN Penicillin V 2-4 g/day PO qid for 6-12 months
• Alternative regimen (1): Erythromycin 500-1000 mg IV q6h OR 500 mg PO qid
• Alternative regimen (2): Tetracyclin 500 mg PO qid
• Alternative regimen (3): Doxycycline 100 mg IV q12h OR 100 mg PO bid
• Alternative regimen (4): Clindamycin 900 mg IV q8h OR 300-450 mg PO qd
• Alternative regimen (5): Minocycline 100 mg IV q12h OR 100 mg PO bid

Sparganosis

• Sparganosis Return to Top

• Sparganosis (Spirometra mansonoides) treatment

• Preferred treatment: Surgical resection or ethanol injection of subcutaneous masses
• Note: Praziquantel 75 mg/kg/day PO qd for 3 days is controversial. It's been innefective in some cases, but has had some results in patients when surgical therapy wasn't an option.

Filariasis

• Filariasis Return to Top

• Filariasis

• 1. Lymphatic filariasis - Wuchereria bancrofti, Brugia malayi Brugia timori

• Preferred regimen: Diethylcarbamazine 6 mg/day PO qd for 12 days (single dose if patient will continue to live in endemic area or is younger than 9 years old) ± Albendazole 400 mg PO qd
• Alternative regimen: Doxycycline 200 mg/day for 4 weeks ± Ivermectin 150 μg/kg single dose (do not administer Ivermectin if there's a risk of serious adverse effects in areas where L loa is coendemic)
• Note: Do not administer Diethylcarbamazine where onchocerciasis is endemic due to the risk of causing severe local inflammation in patients with ocular microfilariae.

• 2. Cutaneous filariasis - Onchocercia volvulus, Loa loa

• Preferred regimen: Doxycycline 150 μg/kg single dose
• Preferred regimen: (Doxycyclin 100 mg PO qd for 6 weeks OR 200 mg PO qd for 4 weeks) THEN Ivermectin after 4-6 months 150 μg/kg single dose; OR Doxycyclin 200 mg PO qd for 6 weeks THEN Ivermectin after 4-6 months 150 μg/kg single dose

Echinococcosis

• Echinococcus Return to Top

• 1.1 Echinococcus granulosus (hydatid disease) treatment

• Preferred regimen: Albendazole ≥60 kg 400 mg PO bid or <60 kg 10-15 mg/kg/day PO bid with meals for 3-6 months
• Alternative regimen: Mebendazole 40-50mg/kg/day PO tid for 3-6 months
• Note: Percutaneous aspiration-injection-reaspiration (PAIR). Puncture & needle aspirate cyst content. Instill hypertonic saline (15–30%) or absolute alcohol, wait 20–30 min, then re-aspirate with final irrigation. Administer Albendazole at least 4 hours before PAIR.
• Note: If surgery is needed, make sure to administer Albendazole for at least a week before the surgery, and to keep the medication for at least 4 weeks after the procedure.

• 1.2 Echinococcus multilocularis (alveolar cyst disease) treatment

• Preferred regimen: Albendazole ≥60 kg 400 mg PO bid or <60 kg 15 mg/kg/day PO bid with meals for at least 2 years. Long-term follow up needed to evaluate progression of the lesions.

Note: Wide surgical resection only reliable treatment; technique evolving.

Parvovirus B19

• Parvovirus B19 Return to Top

• Parvovirus B19

• 1. Erythema infectiosum

• Supportive therapy: Symptomatic treatment only

• 2. Arthritis/arthalgia

• Preferred regimen: Nonsteroidal anti-inflammatory drugs (NSAID)

• 3.Transient aplastic crisis

• Supportive therapy: Transfusions and oxygen

• 4. Fetal hydrops

• Supportive therapy: Intrauterine blood transfusion

• 5. Chronic infection with anemia

• Preferred regimen: transfusion and IVIG (there are different IVIG regimens such as 400 mg/kg of commercial IVIG for 5 or 10 days or 1000 mg/kg for 3 days both with good results). Relapses have been treated with maintenance IVIG at doses of 0.4 grams/kg/day every four weeks.

• 6.Chronic infection without anemia

• Preferred regimen: IVIG is controversial. Further studies needed.

JC virus

• JC virus Return to Top

• Progressive Multifocal Leukoencephalopathy (PML) caused by JC Virus ( John Cunningham virus) infections

• There is no specific antiviral therapy for JC virus infection. The main treatment approach is to reverse the immunosuppression caused by HIV.
• Initiate anti retroviral therapy (ART) immediately in ART-naive patients, and optimize ART in patients who develop Progressive Multifocal Leukoencephalopathy in phase of HIV viremia on ART .
• Corticosteroids may be used for Progressive Multifocal Leukoencephalopathy- immune reconstitution inflammatory syndrome (IRIS) characterized by contrast enhancement, edema or mass effect, and with clinical deterioration

RSV

• Respiratory Syncytial Virus Return to Top

• Preferred regimen: Supportive therapy

• Hydration and supplemental oxygen.
• Routine use of Ribavirin not recommended. Ribavirin therapy associated with small increases in O2 saturation.
• No consistent decrease in need for mechanical ventilation or ICU stays. High cost, aerosol administration and potential toxicity
• Note (1): Its is FDA-approved for RSV infection in children, but not for RSV infection in adults. Dose: Ribavirin 20mg/dl 6 g inhaled continuosly for 12-18h.
• Note (2): Respiratory Syncytial Virus major cause of morbidity in neonates/infants.

• Prevention of Respiratory syncytial virus

• 1. In children <24 months old with chronic lung disease of prematurity (formerly broncho-pulmonary dysplasia) requiring supplemental oxygen or
• 2. In premature infants (<32 wks gestation) and <6 months old at start of Respiratory syncytial virus season or
• 3. In children with selected congenital heart diseases.

• Preferred regimen for prevention of Respiratory syncytial virus: Palivizumab (Synagis) 15 mg per kg IM q month Nov.-April

• Note: Significant reduction in Respiratory syncytial virus hospitalization among children with congenital heart disease

Rhinovirus

• Rhinovirus Return to Top
• Rhinovirus treatment (commom cold)

• Supportive therapy

• Preferred regimen: An association of antihistamines and decongestants (such as brompheniramine and sustained-release pseudoephedrine) can be used to treat acute cough.
• Alternative regimen: Naproxen - no dose established yet, maximum 1g/day

Rotavirus

• Rotavirus Return to Top
• Rotavirus treatment

• Treatment of diarrhea caused by rotavirus

• Preferred regimen: Suportive therapy. No specific antiviral available.

• Rehydration with oral rehydration salts (ORS) solution.
• Rehydration with intravenous fluids in case of severe dehydration or shock.

Clostridium

• Clostridium botulinum Return to Top
• 1. Antibiotics

• Antibiotics are not recommended in gastrointestinal botulism due to the risk of worsening of neurological symptoms caused by the lysis of the bacteria. For wound botulism antibiotics are indicated with surgical treatment as followed:

• Preferred regimen: Metronidazole 500 mg IV q8h
• Alternative regimen: Penicillin G 3 million units IV q4h

• 2. Antitoxin

• Preferred regimen: Trivalent antitoxin (A 7,500 IU, B 5,000 IU, and E 5,000 IU) 1 vial diluted 1:10, IV infusion over 30 min
• Alternative regimen: Equine antitoxin

• 3. General Therapy

• Preferred regimen: Mechanical ventilation; IV hydration; tube feedings

• Clostridium perfringens Return to Top

• Clostridium perfringens
• Gas gangrene

• Preferred regimen: Penicillin G 3-4 million units IV q4h AND (Clindamycin 900 mg IV q8h OR Tetracycline 500 mg IV q6h)

• Clostridium tetani Return to Top

• 1. General measures

• Preferred regimen: Patients should be placed in a quiet shaded area and protected from tactile and auditory stimulation as much as possible; All wounds should be cleaned and debrided as indicated

• 2. Immunotherapy

• Preferred regimen: Human TIG 500 units IV/IM as soon as possible AND Age-appropriate TT-containing vaccine, 0.5 cc IM at a separate site
• Note: patients without a history of primary TT vaccination should receive a second dose 1–2 months after the first dose and a third dose 6–12 months later

• 3. Antibiotic treatment

• Preferred regimen: Metronidazole 500 mg IV/PO q6h OR Penicillin G 100,000–200,000 IU/kg/day IV, administered in 2–4 divided doses
• Alternative regimen: Tetracyclines OR Macrolides OR Clindamycin OR Cephalosporins OR Chloramphenicol

• 4. Muscle spasm control

• Preferred regimen: Diazepam 5 mg IV OR Lorazepam 2 mg IV titrating to achieve spasm control without excessive sedation and hypoventilation
• Alternative regimen (1): Magnesium sulphate 5 g (or 75mg/kg) IV loading dose, then 2–3 g per hour until spasm control is achieved ± Benzodiazepines
• Note: Monitor patellar reflex as areflexia (absence of patellar reflex) occurs at the upper end of the therapeutic range (4mmol/L). If areflexia develops, dose should be decreased
• Alternative regimen (2): Baclofen OR Dantrolene 1–2 mg/kg IV/PO q4h
• Alternative regimen (3): Barbiturates 100–150 mg q1-4h by any route
• Alternative regimen (4): Chlorpromazine 50–150 mg IM q4–8h
• Pediatric regimen: Lorazepam 0.1–0.2 mg/kg IV q2–6h, titrating upward as needed; Barbiturates 6–10 mg/kg in children by any route; Chlorpromazine 4–12 mg IM every q4–8h
• Note: As for Benzodiazepines, large amounts may be required (up to 600 mg/day); Oral preparations could be used but must be accompanied by careful monitoring to avoid respiratory depression or arrest

• 5. Autonomic dysfunction control

• Preferred regimen: Magnesium sulphate OR Morphine OR Esmolol

• 6. Airway/respiratory control

• Note: Drugs used to control spasm and provide sedation can result in respiratory depression. If spasm, including laryngeal spasm, is impeding or threatening adequate ventilation, mechanical ventilation is recommended when possible. Early tracheostomy is preferred as endotracheal tubes can provoke spasm and exacerbate airway compromise.

• Clostridium difficile Return to Top

• 1. Pseudomembranous colitis - mild to moderate

• Preferred regimen:Metronidazole 500 mg PO tid for 10-14 days
• Alternative regimen: Vancomycin 125 mg PO qid for 10-14 days
• Note: If significant risk of recurrence: Vancomycin 125 mg PO qid for 10-14 days OR Fidaxomicin 200 mg PO bid for 10 days

• 2. Pseudomembranous colitis - severe

• Preferred regimen: Vancomycin 125 mg PO qid for 10-14 days
• Note: If significant risk of recurrence: Vancomycin 125 mg PO qid for 10-14 days OR Fidaxomicin 200 mg PO bid for 10 days

• 3 . Pseudomembranous colitis - severe, complicated

• Preferred regimen: Vancomycin 125-500 mg PO qid for 10-14 days AND Vancomycin 500 mg diluted in 500 ml of saline as enema per rectum q6h AND Metronidazole 500 mg IV q8h
• Note: Consider urgent surgical consult

• 4. Recurrent pseudomembranous colitis

• First recurrence treatment

• Preferred regimen: same as first episode or [Fidaxomicin]] 200 mg PO bid for 10 days

• Second or more recurrence treatment

• Preferred regimen: Vancomycin 125 mg PO qid for 14 days THEN Vancomycin 125 mg PO tid for 7 days THEN Vancomycin 125 mg PO bid for 7 days THEN Vancomycin 125 mg PO qd for 7 days THEN Vancomycin 125 mg PO q48h for 7 days THEN Vancomycin 125 mg PO q72h for 7 days OR Fidaxomicin 200 mg PO bid for 10 days
• Note: Consider expert consult for fecal microbiota transplantation

Plasmodium

• Plasmodium Return to Top
• 1. Plasmodium falciparum

• 1.1 Treatment of uncomplicated P. falciparum malaria

• 1.1.1 Treat children and adults with uncomplicated P. falciparum malaria (except pregnant women in their first trimester) with one of the following recommended ACT (artemisinin-based combination therapy)

• Preferred regimen (1): Artemether 5–24 mg/kg/day PO bid AND Lumefantrine 29–144 mg/kg/day PO bid for 3 days.
• Note: The first two doses should, ideally, be given 8 h apart.

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 15- Artemether 20 mg PO bid AND Lumefantrine 120 mg PO bid for 3 days
• Body weight (kg)-15 to < 25- Artemether 40 mg PO bid AND Lumefantrine 240 mg PO bid for 3 days
• Body weight (kg)-25 to < 35- Artemether 60 mg PO bid AND Lumefantrine 360 mg PO bid for 3 days
• Body weight (kg) ≥ 35- Artemether 80 mg PO bid AND Lumefantrine 480 mg PO bid for 3 days

• Preferred regimen (2): Artesunate 2–10 mg/kg/day PO qd AND Amodiaquine 7.5–15 mg/kg/day PO qd for 3 days
• Note: A total therapeutic dose range of 6–30 mg/kg/day artesunate and 22.5–45 mg/kg/day per dose amodiaquine is recommended.

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-4.5 to < 9- Artesunate 25 mg PO qd AND Amodiaquine 67.5 mg PO qd for 3 days
• Body weight (kg)-9 to < 18 - Artesunate 50 mg PO qd AND Amodiaquine 135 mg PO qd for 3 days
• Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Amodiaquine 270 mg PO qd for 3 days
• Body weight (kg) ≥ 36 - Artesunate 200 mg PO qd AND Amodiaquine 540 mg PO qd for 3 days

• Preferred regimen (3): Artesunate 2–10 mg/kg/day PO qd AND Mefloquine 2–10 mg/kg/day PO qd for 3 days

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 9- Artesunate 25 mg PO qd AND Mefloquine 55 mg PO qd for 3 days
• Body weight (kg)-9to < 18- Artesunate 50 mg PO qd AND Mefloquine 110 mg PO qd for 3 days
• Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Mefloquine 220 mg PO qd for 3 days
• Body weight (kg)- ≥ 36 - Artesunate 200 mg PO qd AND Mefloquine 440 mg PO qd for 3 days

• Preferred regimen (4): Artesunate 2–10 mg/kg/day PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1.25 (25–70 / 1.25–3.5) mg/kg/day PO given as a single dose on day 1

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 10- Artesunate 25 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 250/12 mg PO given as a single dose on day 1
• Body weight (kg)-10 to < 25- Artesunate 50 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 500/25 mg PO given as a single dose on day 1
• Body weight (kg)-25 to < 50- Artesunate 100 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1000/50 mg PO given as a single dose on day 1
• Body weight (kg)- ≥50- Artesunate 200 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1500/75 mg PO given as a single dose on day 1

• Preferred regimen (5): Dihydroartemisinin 2–10 mg/kg/day PO qd AND Piperaquine16–27 mg/kg/day PO qd for 3 days

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 8- Dihydroartemisinin 20 mg PO qd AND Piperaquine 160 mg PO qd for 3 days
• Body weight (kg)-8 to < 11- Dihydroartemisinin 30 mg PO qd AND Piperaquine 240 mg PO qd for 3 days
• Body weight (kg)-11 to < 17 - Dihydroartemisinin 40 mg PO qd AND Piperaquine 320 mg PO qd for 3 days
• Body weight (kg)-17 to < 25- Dihydroartemisinin 60 mg PO qd AND Piperaquine 480 mg PO qd for 3 days
• Body weight (kg)-25 to < 36- Dihydroartemisinin 80 mg PO qd AND Piperaquine 640 mg PO qd for 3 days
• Body weight (kg)-36 to < 60- Dihydroartemisinin 120 mg PO qd AND Piperaquine 960 mg PO qd for 3 days
• Body weight (kg)-60 < 80 - Dihydroartemisinin 160 mg PO qd AND Piperaquine 1280 mg PO qd for 3 days
• Body weight (kg)- >80- Dose of Dihydroartemisinin 200 mg PO qd AND Piperaquine 1600 mg PO qd for 3 days

• 1.1.2 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)

• Preferred regimen: Single dose of 0.25 mg/kg Primaquine with ACT

• 1.2 Recurrent Falciparum Malaria

• 1.2.1 Failure within 28 days

• Note:The recommended second-line treatment is an alternative ACT known to be effective in the region. Adherence to 7-day treatment regimens (with artesunate or quinine both of which should be co-administered with + tetracycline, or doxycycline or clindamycin) is likely to be poor if treatment is not directly observed; these regimens are no longer generally recommended.

• 1.2.2 Failure after 28 days

• Note: all presumed treatment failures after 4 weeks of initial treatment should, from an operational standpoint, be considered new infections and be treated with the first-line ACT. However, reuse of mefloquine within 60 days of first treatment is associated with an increased risk for neuropsychiatric reactions, and an alternative ACT should be used.

• 1.3 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)

• Note: Single dose of 0.25 mg/kg bw Primaquine with ACT

• 1.4 Treating uncomplicated P. falciparum malaria in special risk groups

• 1.4.1 Pregnancy

• First trimester of pregnancy : Quinine AND Clindamycin 10mg/kg/day PO bid for 7 days
• Second and third trimesters : Mefloquine is considered safe for the treatment of malaria during the second and third trimesters; however, it should be given only in combination with an artemisinin derivative.
• Note (1): Quinine is associated with an increased risk for hypoglycaemia in late pregnancy, and it should be used (with clindamycin) only if effective alternatives are not available.
• Note (2): Primaquine and tetracyclines should not be used in pregnancy.

• 1.4.2 Infants less than 5kg body weight : with an ACT at the same mg/kg bw target dose as for children weighing 5 kg.
• 1.4.3 Patients co-infected with HIV: should avoid Artesunate + SP if they are also receiving Co-trimoxazole, and avoid Artesunate AND Amodiaquine if they are also receiving efavirenz or zidovudine.
• 1.4.4 Large and Obese adults: For obese patients, less drug is often distributed to fat than to other tissues; therefore, they should be dosed on the basis of an estimate of lean body weight, ideal body weight. Patients who are heavy but not obese require the same mg/kg bw doses as lighter patients.
• 1.4.5 Patients co-infected with TB: Rifamycins, in particular rifampicin, are potent CYP3A4 inducers with weak antimalarial activity. Concomitant administration of rifampicin during quinine treatment of adults with malaria was associated with a significant decrease in exposure to quinine and a five-fold higher recrudescence rate
• 1.4.6 Non-immune travellers : Treat travellers with uncomplicated P. falciparum malaria returning to nonendemic settings with an ACT.
• 1.4.7 Uncomplicated hyperparasitaemia: People with P. falciparum hyperparasitaemia are at increased risk of treatment failure, severe malaria and death so should be closely monitored, in addition to receiving an ACT.

• 2. Treatment of uncomplicated malaria caused by P. vivax, P. ovale, P. malariae or P. knowlesi

• 2.1 Blood Stage infection

• 2.1.1. Uncomplicated malaria caused by P. vivax

• 2.1.1.1 In areas with chloroquine-sensitive P. vivax

• Preferred regimen: Chloroquine total dose of 25 mg/kg PO. Chloroquine is given at an initial dose of 10 mg/kg, followed by 10 mg/kg on the second day and 5 mg/kg on the third day.

• 2.1.1.2 In areas with chloroquine-resistant P. vivax

• Note: ACTs containing Piperaquine, Mefloquine OR Lumefantrine are the recommended treatment, although Artesunate + Amodiaquine may also be effective in some areas. In the systematic review of ACTs for treating P. vivax malaria, Dihydroartemisinin + Piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (Artemether + Lumefantrine, Artesunate + Amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up.

• 2.1.2 Uncomplicated malaria caused by P. ovale, P. malariae or P. knowlesi malaria

• Note: Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. In only one study, conducted in Indonesia, was resistance to chloroquine reported in P. malariae. The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or Chloroquine, as for vivax malaria.

• 2.1.3 Mixed malaria infections

• Note: ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.

• 2.2 Liver stages (hypnozoites) of P. vivax and P. ovale

• Note: To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants < 6 months, women breastfeeding older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with a 14-day course of primaquine in all transmission settings. Strong recommendation, high-quality evidence In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.]
• 2.2.1 Primaquine for preventive relapse

• Preferred regimen: Primaquine 0.25–0.5 mg/kg/day PO qd for 14 days

• 2.2.2 Primaquine and glucose-6-phosphate dehydrogenase deficiency

• Preferred regimen: Primaquine 0.75 mg base/kg/day PO once a week for 8 weeks.
• Note: The decision to give or withhold Primaquine should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services.

• 2.2.3 Prevention of relapse in pregnant or lacating women and infants

• Note: Primaquine is contraindicated in pregnant women, infants < 6 months of age and in lactating women (unless the infant is known not to be G6PD deficient).

• 3. Treatment of severe malaria

• 3.1 Treatment of severe falciparum infection with Artesunate

• 3.1.1 Adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women):-

• Preferred regimen: Artesunate IV/IM for at least 24 h and until they can tolerate oral medication. Once a patient has received at least 24 h of parenteral therapy and can tolerate oral therapy, complete treatment with 3 days of an ACT (add single dose Primaquine in areas of low transmission).

• 3.1.2 Young children weighing < 20 kg

• Preferred regimen: Artesunate 3 mg/kg per dose IV/IM q24h
• Alternatives regimen: use Artemether in preference to quinine for treating children and adults with severe malaria

• 3.2.Treating cases of suspected severe malaria pending transfer to a higher-level facility (pre-referral treatment)

• 3.2.1 Adults and children

• Preferred regimen: Artesunate IM qd
• Alternative regimen: Artemether IM OR Quinine IM

• 3.2.2 Children < 6 years

• Preferred regimen: Where intramuscular injections of artesunate are not available, treat with a single rectal dose (10 mg/kg) of Artesunate, and refer immediately to an appropriate facility for further care.
• Note: Do not use rectal artesunate in older children and adults.

• 3.3 Pregancy

• Note: Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed.

• 3.4 Treatment of severe P. Vivax infection

• Note: parenteral artesunate, treatment can be completed with a full treatment course of oral ACT or chloroquine (in countries where chloroquine is the treatment of choice). A full course of radical treatment with primaquine should be given after recovery.

• 3.5 Additional aspects of management in severe malaria

• Fluid therapy: It is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit.
• Blood Transfusion :In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL(haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin, 7 g/100 mL) is recommended.
• Exchange blood transfusion: Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion.

Bartonella

• Bartonella Return to Top

• 1. Bartonella quintana

• 1.1 Acute or chronic infections without endocarditis

• Preferred regimen: Doxycycline 200 mg PO qd or 100 mg bid for 4 weeks PLUS Gentamicin 3 mg/kg IV q24h for the first 2 weeks

• 1.2 Endocarditis

• Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g/day IV for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks

• 2. Bartonella elizabethae

• 2.2 Endocarditis

• Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g/day IV for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks

• 3. Bartonella bacilliformis

• 3.1 Oroya fever

• Preferred regimen: Ciprofloxacin 500 mg PO bid for 14 days
• Note: if severe disease, associate Ceftriaxone 1 g IV q24h for 14 days

• 3.2 Verruga peruana

• Preferred regimen: Azithromycin 500 mg PO qd for 7 days
• Alternative regimen (1): Rifampin 600 mg PO qd for 14-21 days
• Alternative regimen (2): Ciprofloxacin 500 mg bid for 7-10 days

• 4. Bartonella hansealae

• 4.1 Cat scratch disease

• If extensive adenopathy

• Preferred regimen: Azithromycin 500 mg PO at day 1 THEN 250 mg PO for 4 days for patients weighting less than 45kg, 1 g PO at day 1 THEN 500 mg PO for 4 days for patients weighting more than 45 kg

• Alternative regimen (1): Clarithromycin 500 mg PO bid
• Note: Pediatric dose: 15-20 mg/kg/day PO bid (maximum dose 500 mg bid)
• Alternative regimen (2): Rifampin 300 mg PO bid
• Note Pediatric dose: Rifampin 10 mg/kg bid (maximum dose 600 mg daily)
• Alternative regimen (3): Ciprofloxacin 500 mg PO bid for patients >17 years of age for 7-10 days
• Alternative regimen (4): Trimethoprim-sulfamethoxazole one double strength tablet bid for 7-10 days
• Note: Pediatric dose: trimethoprim 8 mg/kg per day, sulfamethoxazole 40 mg/kg per day bid for 7-10 days

• 4.2 Endocarditis

• Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g/day IV for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks

• 4.3 Retinitis

• Preferred regimen: Doxycycline 100 mg bid AND Rifampin 300 mg bid PO for 4-6 weeks

• 4.4 Bacillary angiomatosis

• Preferred regimen (1): Erythromycin 500 mg PO qid for 2 months at least
• Preferred regimen (2): Doxycycline 100mg PO bid for 2 months at least

• 4.5 Bacillary Pelliosis

• Preferred regimen (1): Erythromycin 500 mg PO qid for 4 months at least
• Preferred regimen (2): Doxycycline 100 mg PO bid for 4 months at least

Blastomycosis

• Blastomycosis Return to Top
• Blastomycosis

• 1. Mild to moderate pulmonary blastomycosis

• Preferred regimen: Itraconazole 200 mg PO qd or bid for 6–12 months
• Note: Oral Itraconazole, 200 mg tid PO for 3 days and THEN 200 mg PO qd or bid for 6–12 months

• 2. Moderately severe to severe pulmonary blastomycosis

• Preferred regimen (1): Lipid Amphotericin B 3–5 mg/kg IV q24h for 1–2 weeks AND Itraconazole 200 mg PO bid for 6–12 months
• Preferred regimen (2): Amphotericin B deoxycholate 0.7–1 mg/kg IV q24h for 1–2 weeks AND Itraconazole 200 mg PO bid for 6–12 months
• Note: Oral Itraconazole, 200 mg tid PO for 3 days THEN 200 mg PO bid, for a total of 6–12 months

• 3. Mild to moderate disseminated blastomycosis

• Preferred regimen: Itraconazole 200 mg PO qd or bid for 6–12 months
• Note (1): Treat osteoarticular disease for 12 months
• Note (2): Oral Itraconazole, 200 mg PO tid for 3 days THEN 200 mg PO bid, for 6–12 months

• 4. Moderately severe to severe disseminated blastomycosis

• Preferred regimen (1): Lipid Amphotericin B 3–5 mg/kg IV q24h, for 1–2 weeks AND Itraconazole 200 mg PO bid for 6–12 months
• Preferred regimen (2): Amphotericin B deoxycholate 0.7–1 mg/kg IV q24h, for 1–2 weeks AND Itraconazole 200 mg PO bid for 6–12 months
• Note: oral Itraconazole, 200 mg PO tid for 3 days THEN 200 mg PO bid, for 6–12 months

• 5. CNS disease

• Preferred regimen: Lipid Amphotericin B 5 mg/kg IV q24h for 4–6 weeks AND an oral azole for at least 1 year
• Note (1): Step-down therapy can be with Fluconazole, 800 mg/day PO qd or bid OR Itraconazole, 200 mg bid or tid OR voriconazole, 200–400 mg bid.
• Note (2): Longer treatment may be required for immunosuppressed patients.

• 6. Immunosuppressed patients

• Preferred regimen (1): Lipid Amphotericin B 3–5 mg/kg IV q24h, for 1–2 weeks, AND Itraconazole, 200 mg PO bid for 12 months
• Preferred regimen (2): Amphotericin B deoxycholate, 0.7–1 mg/kg IV q24h, for 1–2 weeks, AND Itraconazole, 200 mg PO bid for 12 months
• Note (1): Oral Itraconazole, 200 mg PO tid for 3 days THEN 200 mg PO bid, for 12 months
• Note (2): Life-long suppressive treatment may be required if immunosuppression cannot be reversed.

• 7. Pregnant women

• Preferred regimen: Lipid Amphotericin B 3–5 mg/kg IV q24h
• Note (1): Azoles should be avoided because of possible teratogenicity
• Note (2): If the newborn shows evidence of infection, treatment is recommended with Amphotericin B deoxycholate, 1.0 mg/kg IV q24h

• 8. Children with mild to moderate disease

• Preferred regimen: Itraconazole 10 mg/kg PO qd for 6–12 months
• Note: Maximum dose 400 mg/day

• 9. Children with moderately severe to severe disease

• Preferred regimen (1): Amphotericin B deoxycholate 0.7–1 mg/kg IV q24h for 1–2 weeks AND Itraconazole 10 mg/kg PO qd to a maximum of 400 mg/day for 6–12 months
• Preferred regimen (2): Lipid amphotericin B (Lipid AmB) 3–5 mg/kg IV q24h for 1–2 weeks AND Itraconazole 10 mg/kg PO qd to a maximum of 400 mg/day for 6–12 months
• Note: Children tolerate Amphotericin B deoxycholate better than adults do.

Chromoblastomycosis

• Chromoblastomycosis Return to Top

• Preferred regimen: Itraconazole 200-400 mg PO q24h OR 400 mg pulse therapy once daily for 1 week monthly for 6-12 months
• Note: Pulse therapy reduces cost but it is questionable if it produces resistance to the drug.
• Alternative regimen (1): Terbinafine 500-1000 mg PO qd for 6-12 months
• Alternative regimen (2): Posaconazole 800 mg PO qd for 6-12 months
• Alternative regimen (3): 5-fluorocytosine 100-150 mg/kg/day PO qd for 6-12 months
• Note: This disease has a low cure ratio and high relapse ratio. Physical treatment is needed to achieve better results:

• Cryosurgery with liquid nitrogen - most used physical therapy, it's used in localized lesions and it has a very good treatment response, probably achieved by immune mechanisms since fungi are eliminated from lesions as late as 1-2 weeks after the therapy.
• Thermotherapy - used in conjunction with systemic therapy, was developed by Japanese authors and consists in placing "pocket warmers" in the lesions for 24h/day for some months, as the fungi is sensible to heat.
• Laser vaporization - studied in Germany as an alternative therapy, reported to successfully treat relapsing lesions.

Hepatitis C

• Hepatitis C virus Return to Top

Chronic Hepatitis C

• 1. Treatment regimens for chronic hepatitis C virus genotype 1

• 1.1. Treatment regimens for genotype 1a:

• Preferred regimen (1): Ledipasvir 90 mg PO qd AND Sofosbuvir 400 mg PO qd for 12 weeks
• Preferred regimen (2): Paritaprevir 150 mg PO qd AND Ritonavir 100 mg PO qd AND Ombitasvir 25 mg PO qd AND Dasabuvir 250 mg PO bid AND weight-based Ribavirin PO qd ([1000 mg <75 kg] to [1200 mg >75 kg]) for 12 weeks (no cirrhosis) OR 24 weeks (cirrhosis)
• Preferred regimen (3): Sofosbuvir 400 mg PO qd AND Simeprevir 150 mg PO qd ± weight-based Ribavirin PO qd ([1000 mg <75 kg] to [1200 mg >75 kg]) for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis)
• Note: these regimens are recommended for treatment-naive patients with HCV genotype 1a infection.

• 1.2. Treatment regimens for genotype 1b:

• Preferred regimen (1): Ledipasvir 90 mg PO qd AND Sofosbuvir 400 mg PO qd for 12 weeks
• Preferred regimen (2): Paritaprevir PO 150 mg qd AND Ritonavir 100 mg PO qd AND Ombitasvir 25 mg PO qd AND Dasabuvir 250 mg PO bid for 12 weeks. The addition of weight-based Ribavirin PO qd (1000 mg [<75kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis
• Preferred regimen (3): Sofosbuvir 400 mg PO qd AND Simeprevir 150 mg PO qd for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis)
• Note: these regimens are recommended for treatment-naive patients with HCV genotype 1b infection.

• 2. Treatment regimens for chronic hepatitis C virus genotype 2

• Preferred regimen: Sofosbuvir 400 mg PO qd AND weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks
• Note (1): This regimen are recommended for treatment-naive patients with HCV genotype 2 infection.
• Note (2): Extending treatment to 16 weeks is recommended in patients with cirrhosis.

• 3. Treatment regimens for chronic hepatitis C virus genotype 3

• Preferred regimen: Sofosbuvir 400 mg PO qd and weight-based Ribavirin PO qd (1000 mg [<75 kg] to 1200 mg [>75 kg]) PO qd for 24 weeks
• Alternative regimen: Sofosbuvir 400 mg and weight-based Ribavirin PO qd (1000 mg [<75 kg] to 1200 mg [>75 kg]) PO qd AND weekly PEG-IFN for 12 weeks is an acceptable regimen for IFN-eligible, treatment-naive patients with HCV genotype 3 infection.
• Note: These regimens are recommended for treatment-naive patients with HCV genotype 3 infection.

• 4. Treatment regimens for chronic hepatitis C virus genotype 4

• Preferred regimen (1): Ledipasvir 90 mg PO qd AND Sofosbuvir 400 mg PO qd for 12 weeks
• Preferred regimen (2): Paritaprevir 150 mg PO qd AND Ritonavir 100 mg PO qd AND Ombitasvir 25 mg PO qd AND weight-based Ribavirin PO qd (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks
• Preferred regimen (3): Sofosbuvir 400 mg PO qd AND weight-based Ribavirin PO qd (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks
• Alternative regimen (1): Sofosbuvir 400 mg PO qd AND weight-based Ribavirin PO qd (1000 mg [<75 kg] to 1200 mg [>75 kg]) AND weekly PEG-IFN for 12 weeks
• Alternative regimen (2): Sofosbuvir 400 mg PO qd AND Simeprevir 150 mg PO qd ± weight-based Ribavirin PO qd (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks
• Note: These regimens are accpetable for treatment-naive patients with HCV genotype 3 infection.

• 5. Treatment regimens for chronic hepatitis C virus genotype 5

• Preferred regimen: Sofosbuvir 400 mg PO qd AND weight-based Ribavirin PO qd(1000 mg [<75 kg] to 1200 mg [>75 kg]) AND weekly PEG-IFN for 12 weeks is recommended for treatment-naive patients with HCV genotype 5 infection.
• Alternative regimen: Weekly PEG-IFN AND weight-based Ribavirin PO qd (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 48 weeks is an alternative regimen for IFN-eligible, treatment-naive patients with HCV genotype 5 infection.

• 6. Treatment regimens for chronic hepatitis C virus genotype 6

• Preferred regimen: Ledipasvir 90 mg PO qd AND Sofosbuvir PO qd 400 mg for 12 weeks is recommended for treatment-naive patients with HCV genotype 6 infection.
• Alternative regimen: Sofosbuvir 400 mg PO qd AND weight-based Ribavirin PO qd (1000 mg [<75 kg] to 1200 mg [>75 kg]) AND weekly PEG-IFN for 12 weeks is an alternative regimen for IFN-eligible, treatment-naive patients with HCV genotype 6 infection.

Toxocariasis

• Toxocariasis Return to Top

• 1.1.Visceral toxocariasis

• Preferred regimen: Albendazole 400 mg PO bid for five days (both adult and pediatric dosage)
• Alternative regimen: Mebendazole 100-200 mg PO bid for five days (both adult and pediatric dosage)
• Note: Treatment is indicated for moderate-severe cases. Patients with mild symptoms of toxocariasis may not require anthelminthic therapy as symptoms are limited.

• 1.2.Ocular toxocariasis

• Preferred regimen: Prednisone 0.5-1 mg/kg/day PO q24h AND Albendazole 400 mg PO bid for 2 to 4 weeks (pediatric dose: 400 mg PO qd)
• Note: Surgical therapy might be neeeded.

Hep B

• Hepatitis B virus Return to Top
• Acute Hepatitis B

• Chronic Hepatitis B

• 1. Patients with HBeAg-positive chronic hepatitis B

• 1.1. HBV DNA >20,000, ALT <2 times upper limit normal (ULN)

• Observe; consider treatment when ALT becomes elevated.
• Consider biopsy in persons 40 years, ALT persistently high normal >2 times upper limit normal (ULN), or with family history of HCC.
• Consider treatment if HBV DNA >20,000 IU/mL and biopsy shows moderate/severe inflammation or significant fibrosis.

• 1.2. HBV DNA >20,000, ALT >2 times upper limit normal (ULN)

• Preferred regimen (1): Pegylated IFN-alpha 180 mcg weekly SC for 48 weeks
• Preferred regimen (2): Tenofovir (TDF) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 300 mg q24 hrs
• If creatinine clearance 30–49 give 300 mg q48 hrs
• If creatinine clearance 10–29 give 300 mg q72-96 hrs
• If creatinine clearance <10 with dialysis give 300 mg once a week or after a total of approximately 12 hours of dialysis
• If creatinine clearance <10 without dialysis there is no recommendation
• Note: duration of treatment is minimum 1 year, continue for at least 6 months after HBeAg seroconversion

• Preferred regimen (3): Entecavir (ETV) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 give 0.5 mg PO daily for patients with no prior Lamivudine treatment, and 1 mg PO daily for patients who are refractory/resistant to lamivudine for minimum 1 year, continue for at least 6 months after HBeAg seroconversion.
• If creatinine clearance 30–49 give 0.25 mg PO qd OR 0.5 mg PO q48 hr for patients with no prior Lamivudine treatment, and 0.5 mg PO qd OR 1 mg PO q 48 hr for patients who are refractory/resistant to lamivudine for minimum 1 year, continue for at least 6 months after HBeAg seroconversion.
• If creatinine clearance 10–29 give 0.15 mg PO qd OR 0.5 mg PO q 72 hr for patients with no prior Lamivudine treatment, and 0.3 mg PO qd OR 1 mg PO q 72 hr for patients who are refractory/resistant to lamivudine for minimum 1 year, continue for at least 6 months after HBeAg seroconversion.
• If creatinine clearance <10 or hemodialysis or continuous ambulatory peritoneal dialysis give 0.05 mg PO qd OR 0.5 mg PO q7 days for patients with no prior Lamivudine treatment, and 0.1 mg PO qd OR 1 mg PO q 7 days for patients who are refractory/resistant to lamivudine for minimum 1 year, continue for at least 6 months after HBeAg seroconversion.
• Note: duration of treatment is minimum 1 year, continue for at least 6 months after HBeAg seroconversion

• Alternative regimen (1): Interferon alpha (IFNα) 5 MU daily or 10 MU thrice weekly SC for 16 weeks
• Alternative regimen (2): Lamivudine (LAM) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 100 mg PO qd
• If creatinine clearance 30–49 give 100 mg PO first dose, then 50 mg PO qd
• If creatinine clearance 15–29 give 100 mg PO first dose, then 25 mg PO qd
• If creatinine clearance 5-14 give 35 mg PO first dose, then 15 mg PO qd
• If creatinine clearance <5 give 35 mg PO first dose, then 10 mg PO qd
• The recommended dose of lamivudine for persons coinfected with HIV is 150mg PO twice daily.
• Note: duration of treatment is minimum 1 year, continue for at least 6 months after HBeAg seroconversion

• Alternative regimen (3): Adefovir (ADV) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 10 mg PO daily
• If creatinine clearance 30–49 give 10 mg PO every other day
• If creatinine clearance 10–19 10 mg PO every third day
• If hemodialysis patients give 10 mg PO every week following dialysis
• Note: duration of treatment is minimum 1 year, continue for at least 6 months after HBeAg seroconversion

• Alternative regimen (4): Telbivudine (LdT) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 600 mg PO once daily
• If creatinine clearance 30–49 600 give mg PO once every 48 hours
• If creatinine clearance <30 (not requiring dialysis) give 600 mg PO once every 72 hours
• If End-stage renal disease give 600 mg PO once every 96 hours after hemodialysis

• Note (1): duration of treatment is minimum 1 year, continue for at least 6 months after HBeAg seroconversion
• Note (2): Observe for 3-6 months and treat if no spontaneous HBeAg loss.
• Note (3): Consider liver biopsy prior to treatment if compensated.
• Note (4): Immediate treatment if icteric or clinical decompensation.
• Note (5): Interferon alpha (IFNα)/ pegylated interferon-alpha (peg-IFNα), Lamivudine (LAM), Adefovir (ADV), Entecavir (ETV), tenofovir disoproxil fumarate (TDF) or telbivudine (LdT) may be used as initial therapy.
• Note (6): Adefovir (ADV) not preferred due to weak antiviral activity and high rate of resistance after 1st year.
• Note (7): Lamivudine (LAM) and Telbivudine (LdT) not preferred due to high rate of drug resistance.
• Note (8): End-point of treatment – Seroconversion from HBeAg to anti-HBe.
• Note (9): Interferon alpha (IFNα) non-responders / contraindications to IFNα change to Tenofovir (TDF)/Entecavir (ETV).

• 1.3. Children with elevated ALT greater than 2 times normal

• Preferred regimen(1): Interferon alpha (IFNα) 6 MU/m2 SC thrice weekly with a maximum of 10 MU
• Preferred regimen(2): Lamivudine (LAM) 3 mg/kg/d PO with a maximum of 100 mg/d.

• 2. Patients with HBeAg-negative chronic hepatitis B

• 2.1. HBV DNA >2,000 IU/mL and elevated ALT >2 times normal

• Preferred regimen (1): Pegylated IFN-alpha 180 mcg weekly SC for 1 year
• Preferred regimen (2): Tenofovir (TDF) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 300 mg q24 hrs
• If creatinine clearance 30–49 give 300 mg q48 hrs
• If creatinine clearance 10–29 give 300 mg q72-96 hrs
• If creatinine clearance <10 with dialysis give 300 mg once a week or after a total of approximately 12 hours of dialysis
• If creatinine clearance <10 without dialysis there is no recommendation
• Note: duration of treatment is more than 1 year

• Preferred regimen (3): Entecavir (ETV) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 give 0.5 mg PO daily for patients with no prior Lamivudine treatment, and 1 mg PO daily for patients who are refractory/resistant to lamivudine
• If creatinine clearance 30–49 give 0.25 mg PO qd OR 0.5 mg PO q48 hr for patients with no prior Lamivudine treatment, and 0.5 mg PO qd OR 1 mg PO q 48 hr for patients who are refractory/resistant to lamivudine
• If creatinine clearance 10–29 give 0.15 mg PO qd OR 0.5 mg PO q 72 hr for patients with no prior Lamivudine treatment, and 0.3 mg PO qd OR 1 mg PO q 72 hr for patients who are refractory/resistant to lamivudine
• If creatinine clearance <10 or hemodialysis or continuous ambulatory peritoneal dialysis give 0.05 mg PO qd OR 0.5 mg PO q7 days for patients with no prior Lamivudine treatment, and 0.1 mg PO qd OR 1 mg PO q 7 days for patients who are refractory/resistant to lamivudine.
• Note: duration of treatment is more than 1 year

• Alternative regimen (1): Interferon alpha (IFNα) 5 MU daily or 10 MU thrice weekly SC for 1 year
• Alternative regimen (2): Lamivudine (LAM) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 100 mg PO qd
• If creatinine clearance 30–49 give 100 mg PO first dose, then 50 mg PO qd
• If creatinine clearance 15–29 give 100 mg PO first dose, then 25 mg PO qd
• If creatinine clearance 5-14 give 35 mg PO first dose, then 15 mg PO qd
• If creatinine clearance <5 give 35 mg PO first dose, then 10 mg PO qd
• The recommended dose of lamivudine for persons coinfected with HIV is 150mg PO twice daily.
• Note: duration of treatment is more than 1 year

• Alternative regimen (3): Adefovir (ADV) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 10 mg PO daily
• If creatinine clearance 30–49 give 10 mg PO every other day
• If creatinine clearance 10–19 10 mg PO every third day
• If hemodialysis patients give 10 mg PO every week following dialysis
• Note: duration of treatment is more than 1 year

• Alternative regimen (4): Telbivudine (LdT)Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 600 mg PO once daily
• If creatinine clearance 30–49 600 give mg PO once every 48 hours
• If creatinine clearance <30 (not requiring dialysis) give 600 mg PO once every 72 hours
• If End-stage renal disease give 600 mg PO once every 96 hours after hemodialysis

• Note (1): duration of treatment is more than 1 year
• Note (2): Interferon alpha (IFNα)/ pegylated interferon-alpha (peg-IFNα), Lamivudine (LAM), Adefovir (ADV), Entecavir (ETV), tenofovir disoproxil fumarate (TDF) or telbivudine (LdT) may be used as initial therapy.
• Note (3): Adefovir (ADV) not preferred due to weak antiviral activity and high rate of resistance after 1st year.
• Note (4): Lamivudine (LAM) and Telbivudine (LdT) not preferred due to high rate of drug resistance.
• Note (5): End-point of treatment – not defined
• Note (6): Interferon alpha (IFNα) non-responders / contraindications to IFNα change to Tenofovir (TDF)/Entecavir (ETV).

• 3. HBV DNA >2,000 IU/mL and elevated ALT 1->2 times normal

• Consider liver biopsy and treat if liver biopsy shows moderate/severe necroinflammation or significant fibrosis.

• 4. HBV DNA <2,000 IU/mL and ALT < upper limit normal (ULN)

• Observe, treat if HBV DNA or ALT becomes higher.

• 5. +/- HBeAg and detectable HBV DNA with Cirrhosis

• 5.1. Compensated Cirrhosis and HBV DNA >2,000

• Preferred regimen (1): Entecavir (ETV) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 give 0.5 mg PO daily for patients with no prior Lamivudine treatment, and 1 mg PO daily for patients who are refractory/resistant to lamivudine.
• If creatinine clearance 30–49 give 0.25 mg PO qd OR 0.5 mg PO q48 hr for patients with no prior Lamivudine treatment, and 0.5 mg PO qd OR 1 mg PO q 48 hr for patients who are refractory/resistant to lamivudine.
• If creatinine clearance 10–29 give 0.15 mg PO qd OR 0.5 mg PO q 72 hr for patients with no prior Lamivudine treatment, and 0.3 mg PO qd OR 1 mg PO q 72 hr for patients who are refractory/resistant to lamivudine.
• If creatinine clearance <10 or hemodialysis or continuous ambulatory peritoneal dialysis give 0.05 mg PO qd OR 0.5 mg PO q7 days for patients with no prior Lamivudine treatment, and 0.1 mg PO qd OR 1 mg PO q 7 days for patients who are refractory/resistant to lamivudine.

• Preferred regimen (2): Tenofovir (TDF) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 300 mg q24 hrs
• If creatinine clearance 30–49 give 300 mg q48 hrs
• If creatinine clearance 10–29 give 300 mg q72-96 hrs
• If creatinine clearance <10 with dialysis give 300 mg once a week or after a total of approximately 12 hours of dialysis
• If creatinine clearance <10 without dialysis there is no recommendation

• Alternative regimen (1): Lamivudine (LAM) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 100 mg PO qd
• If creatinine clearance 30–49 give 100 mg PO first dose, then 50 mg PO qd
• If creatinine clearance 15–29 give 100 mg PO first dose, then 25 mg PO qd
• If creatinine clearance 5-14 give 35 mg PO first dose, then 15 mg PO qd
• If creatinine clearance <5 give 35 mg PO first dose, then 10 mg PO qd
• The recommended dose of lamivudine for persons coinfected with HIV is 150mg PO twice daily.

• Alternative regimen (2): Adefovir (ADV) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 10 mg PO daily
• If creatinine clearance 30–49 give 10 mg PO every other day
• If creatinine clearance 10–19 give 10 mg PO every third day
• If hemodialysis patients give 10 mg PO every week following dialysis

• Alternative regimen (3): Telbivudine (LdT) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 600 mg PO once daily
• If creatinine clearance 30–49 600 give mg PO once every 48 hours
• If creatinine clearance <30 (not requiring dialysis) give 600 mg PO once every 72 hours
• If End-stage renal disease give 600 mg PO once every 96 hours after hemodialysis

• Note (1): LAM and LdT not preferred due to high rate of drug resistance.
• Note (2): ADV not preferred due to weak antiviral activity and high risk of resistance after 1st year.
• Note (3): These patients should receive long-term treatment. However, treatment may be stopped in HBeAg-positive patients if they have confirmed HBeAg seroconversion and have completed at least 6 months of consolidation therapy and in HBeAg-negative patients if they have confirmed HBsAg clearance.

• 5.2. Compensated Cirrhosis and HBV DNA <2,000

• Consider treatment if ALT elevated.

• 5.3. Decompensated Cirrhosis

• Preferred regimen (1): Tenofovir (TDF) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 300 mg q24 hrs
• If creatinine clearance 30–49 give 300 mg q48 hrs
• If creatinine clearance 10–29 give 300 mg q72-96 hrs
• If creatinine clearance <10 with dialysis give 300 mg once a week or after a total of approximately 12 hours of dialysis
• If creatinine clearance <10 without dialysis there is no recommendation

• Preferred regimen (2): Entecavir (ETV) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 give 0.5 mg PO daily for patients with no prior Lamivudine treatment, and 1 mg PO daily for patients who are refractory/resistant to lamivudine.
• If creatinine clearance 30–49 give 0.25 mg PO qd OR 0.5 mg PO q48 hr for patients with no prior Lamivudine treatment, and 0.5 mg PO qd OR 1 mg PO q 48 hr for patients who are refractory/resistant to lamivudine.
• If creatinine clearance 10–29 give 0.15 mg PO qd OR 0.5 mg PO q 72 hr for patients with no prior Lamivudine treatment, and 0.3 mg PO qd OR 1 mg PO q 72 hr for patients who are refractory/resistant to lamivudine.
• If creatinine clearance <10 or hemodialysis or continuous ambulatory peritoneal dialysis give 0.05 mg PO qd OR 0.5 mg PO q7 days for patients with no prior Lamivudine treatment, and 0.1 mg PO qd OR 1 mg PO q 7 days for patients who are refractory/resistant to lamivudine.

• Preferred regimen (3): Lamivudine (LAM) AND Adefovir (ADV)

• Lamivudine (LAM) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 100 mg PO qd
• If creatinine clearance 30–49 give 100 mg PO first dose, then 50 mg PO qd
• If creatinine clearance 15–29 give 100 mg PO first dose, then 25 mg PO qd
• If creatinine clearance 5-14 give 35 mg PO first dose, then 15 mg PO qd
• If creatinine clearance <5 give 35 mg PO first dose, then 10 mg PO qd
• The recommended dose of lamivudine for persons coinfected with HIV is 150mg PO twice daily.

• Adefovir (ADV) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 10 mg PO daily
• If creatinine clearance 30–49 give 10 mg PO every other day
• If creatinine clearance 10–19 give 10 mg PO every third day
• If hemodialysis patients give 10 mg PO every week following dialysis

• Preferred regimen (4): Telbivudine (LdT) AND Adefovir (ADV)

• Telbivudine (LdT) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 600 mg PO once daily
• If creatinine clearance 30–49 600 give mg PO once every 48 hours
• If creatinine clearance <30 (not requiring dialysis) give 600 mg PO once every 72 hours
• If End-stage renal disease give 600 mg PO once every 96 hours after hemodialysis

• Adefovir (ADV) Adjustment of Adult Dosage in Accordance with Creatinine Clearance:

• If creatinine clearance >50 or normal renal function give 10 mg PO daily
• If creatinine clearance 30–49 give 10 mg PO every other day
• If creatinine clearance 10–19 give 10 mg PO every third day
• If hemodialysis patients give 10 mg PO every week following dialysis

• Note: coordinate treatment with transplant center and refer for liver transplant.
• Life-long treatment is recommended.

• 6. +/- HBeAg and undetectable HBV DNA with Cirrhosis

• Compensated Cirrhosis: Observe
• Uncompensated Cirrhosis: Refer for liver transplant

Schistosomiasis

• Schistosomiasis Return to Top

• 1. Schistosoma mansoni, S. haematobium, S. intercalatum

• Preferred regimen: Praziquantel 40 mg/kg per day PO in qd or bid for one day
• Alternative regimen (1): Oxamniquine 20 mg/kg PO single dose
• Alternative regimen (2): Artemisinin no dose is established yet
• Alternative regimen (3): Mefloquine 250 mg PO single dose
• Note: There is no benefit in associating the alternative therapies to Praziquantel.
• Note: Praziquantel is not effective against larval/egg stages of the disease.

• 2. S. japonicum, S. mekongi

• Preferred regimen: Praziquantel 60 mg/kg per day PO bid for one day
• Alternative regimen (1): Artemisinin no dose is established yet
• Alternative regimen (2): Mefloquine 250 mg PO single dose
• Note: There is no benefit in associating the alternative therapies to Praziquantel.

• 3. Katayama Fever

• Preferred regimen: Prednisone 20-40 mg/day PO for 5 days, THEN Praziquantel
• Note: Praziquantel should be used after 4-6 weeks of exposure, because it cannot kill the larvae stages of the Schistosoma. Praziquantel should be used after acute schistosomiasis syndrome symptoms have resolved always together with corticosteroids, only when ova are detected in stool or urine samples.

• 4. Neuroschistosomiasis

• Preferred regimen: prednisone 1-2 mg/kg
• Note: Praziquantel should only be introduced after a few days of the initiation of corticosteroid therapy, due to the risk of increasing the inflammatory response.

Clonorchis sinensis

• Clonorchis sinensis Return to Top

• Preferred regimen: Praziquantel 75 mg/kg/day PO tid for 2 days
• Alternative regimen (1): Albendazole 10 mg/kg/day PO qd for 7 days
• Alternative regimen (2): Tribendimidine 400 mg PO single dose
• Note: This regimen is still under investigation, but it appears to be as effective as Praziquantel.
• Note: Urgent biliary decompression might be required for patients with acute cholangitis.

Dicrocoelium dendriticum

• Dicrocoelium dendriticum Return to Top

• Preferred regimen: Praziquantel 25 mg/kg PO tid for 2 days

• Note: Praziquantel is not approved for treatment of children less than 4 years old

• Alternative regimen (1): Myrrh (commiphora molmol) 12 mg/kg/day PO for 6 days
• Alternative regimen (2): Triclabendazole 10 mg/kg PO single dose

Fasciola hepatica

• Fasciola hepatica Return to Top

• Preferred regimen: Triclabendazole 10 mg/kg PO one dose
• Note: Two-dose (double-dose) triclabendazole therapy can be given to patients who have severe or heavy Fasciola infections (many parasites) or who did not respond to single-dose therapy.
• Alternative regimen: Nitazoxanide 500 mg PO bid for 7 days

Paragonimus westermani

• Paragonimus westermani Return to Top

• Preferred regimen (1): Praziquantel 25 mg/kg PO tid for 3 days
• Preferred regimen (2): Triclabendazole 10 mg/kg PO qd or bid
• Alternative regimen (1): Bithinol 30-50 mg/kg PO on alternate days for 10-15 doses
• Alternative regimen (2): Niclosamide 2 mg/kg PO single dose

Gnasthostoma spinigerum

• Gnathostoma spinigerum Return to Top

• Eosinophilic Meningitis
  • Preferred regimen: Supportive measures. Anthelminthic therapy might be deleterious by augmenting the inflammation due to the death of the larvae. The use of corticosteroids is generally favored for suppression of the inflammation but there are no clinical trials that prove its efficacy.
• Cutaneous disease:

• Preferred regimen: Albendazole 400 mg bid for 21 days OR Ivermectin 200 mcg/kg qd for 2 days
• Alternative regimen: Albendazole 400 mg qd for 21 days OR Ivermectin 200 mcg/kg qd single dose

Ancylostoma braziliense

• Ancylostoma braziliense Return to Top

• Preferred regimen

• Adult: Albendazole 400 mg PO qd for 3 to 7 days
• Pediatric: Albendazole > 2 years 400 mg PO qd for 3 days
• Note: This drug is contraindicated in children younger than 2 years age

• Alternative regimen

• Adult: Ivermectin 200 mcg/kg PO qd for one or two days
• Pediatric: Ivermectin >15 kg give 200 mcg/kg single dose

Angiostrongylus cantonensis

• Angiostrongylus cantonensis Return to Top

• Preferred: Symptomatic therapy, serial lumber puncture, corticosteroids (prednisone 60 mg qd for 2 weeks) and analgesics.
• Note: Albendazole and Mebendazole are generally not recommended due to the risk of exacerbation of neurological symptoms following anthelminthic therapy.

Ascaris lumbricoides

• Ascaris lumbricoides Return to Top

• Preferred regimen: Albendazole 400 mg PO qd OR Mebendazole 500 mg PO qd or 100 mg bid for 3 days

• Note: Albendazole dose for children of 1-2 years is 200 mg instead of 400 mg.

• Alternative regimen (1): Ivermectin 150 to 200 µg/kg PO single dose
• Alternative regimen (2): Nitazoxanide 500 mg bid for 3 days
• Alternative regimen (3): Levamisole 150 mg PO single dose
• Note: Pediatric dose: 2.5 mg/kg single dose
• Alternative regimen (4): Pyrantel Pamoate 11 mg/kg single dose PO - maximum 1.0 g
• Alternative regimen (5): Piperazine citrate 75 mg/kg qd for 2 days - maximum 3.5 g

Capillaria philippinensis

• Capillaria philippinensis Return to Top

• 1. Intestinal capillariasis

• Preferred regimen: Albendazole 400 mg/day PO for 10-30 days
• Alternative regimen: Mebendazole 200 mg PO bid for 20-30 days

Enterobius vermicularis

• Enterobius vermicularis Return to Top

• Preferred regimen (1): Albendazole 400 mg PO single dose - repeat in 2 weeks
• Preferred regimen (2): Mebendazole 100 mg PO single dose - repeat in 2 weeks
• Alternative regimen (1): Ivermectin 200 µg/kg PO single dose - repeat in 10 days
• Alternative regimen (2): Pyrantel pamoate 11 mg/kg up to 1.0 g PO single dose - repeat in 2 weeks

Necator americanus

• Necator americanus Return to Top

• Preferred regimen: Albendazole 400 mg PO single dose
• Alternative regimen (1): Mebendazole 100 mg PO bid or 500 mg daily for 3 days
• Alternative regimen (2): Pyrantel pamoate 11 mg/kg PO qd (maximum 1 g/day) for 3 days

Ancylostoma duodenale

• Ancylostoma duodenale Return to Top

• Preferred regimen: Albendazole 400 mg PO single dose
• Alternative regimen (1): Mebendazole 100 mg PO bid or 500 mg daily for 3 days
• Alternative regimen (2): Pyrantel pamoate 11 mg/kg PO qd (maximum 1 g/day) for 3 days

Strongyloides stercoralis

• Strongyloides stercoralis Return to Top

• Preferred regimen: Ivermectin 200 mcg/kg/day PO qd for 2 days or two doses 2 weeks apart from each other
• Alternative regimen: Albendazole 400 mg PO bid for 3-7 days

Trichuris trichiura

• Trichuris trichiura Return to Top

• Preferred regimen: Albendazole 400 mg PO qd for 3 days
• Alternatie regimen (1): Mebendazole 100 mg PO bid for 3 days
• Alternative regimen (2): Ivermectin 200 mcg/kg/day PO qd for 3 days

Entamoeba histolytica

• 1. Amebic Liver Abscess

• Preferred regimen: (Metronidazole 750 mg PO tid for 10 days OR Tinidazole 2 g PO qd for 5 days) AND (Paromomycin 30 mg/kg/day PO tid for 5-10 days OR Diloxanide furoate 500 mg PO tid for 10 days)
• Alternative regimen (1): Nitazoxanide 500 mg bid for 10 days AND (Paromomycin 30 mg/kg/day PO tid for 5-10 days OR Diloxanide furoate 500 mg PO tid for 10 days)
• Alternative regimen (2): Tinidazole 2 g PO qd for 5 days AND (Paromomycin 30 mg/kg/day PO tid for 5-10 days OR Diloxanide furoate 500 mg PO tid for 10 days)
• Alternative regimen (2): Tinidazole 2 g PO qd for 5 days

• 2. Amebic Colitis

• Preferred regimen: Metronidazole 500-750 mg PO tid for 7-10 days. Pediatric dose: 35-50 mg/kg per day tid AND (Paromomycin 30 mg/kg/day PO tid for 5-10 days OR Diloxanide furoate 500 mg PO tid for 10 days)
• Alternative regimen: Tinidazole 2 g PO qd for 5 days AND (Paromomycin 30 mg/kg/day PO tid for 5-10 days OR Diloxanide furoate 500 mg PO tid for 10 days)

• 3. Asymptomatic Intestinal Colonization

• Preferred regimen: Paromomycin 30 mg/kg/day PO tid for 5-10 days
• Alternative regimen (1): Diloxanide furoate 500 mg PO tid for 10 days
• Alternative regimen (2): Diiodohydroxyquin 650 mg PO tid for 20 days for adults and 30 to 40 mg/kg per day tid for 20 days for children

Paracoccidiodomycosis

• Preferred regimen (1):

• Adults: Itraconazole 200 mg/day PO
• Children: Itraconazole (<30/kg and >5 yr) 5-10 mg/kg/day PO
• Note: Treatment duration based on organ involvement:

• Mild involvement: 6-9 months
• Moderate involvement: 12-18 months

• Preferred regimen (2):

• Adults Trimethoprim/sulfamethoxazole (TMP/SMX) TMP: 160-240 mg/day PO/IV, SMX: 800-1200 mg/day PO/IV q12h
• Children Trimethoprim/sulfamethoxazole (TMP/SMX) TMP: 8-10 mg/kg PO/IV, SMX: 40-50 mg/kg PO/IV q12h
• Note (1): Treatment duration based on organ involvement:

• Minor involvement: 12 months
• Moderate involvement: 18-24 months

• Note (2): Preferred treatment in children due to larger experience.
• Note (3): Preferred in IV formulation in severe forms of the disease - 2 ampules IV q8h until patient condition improves so that oral medication can be given.

• Preferred regimen (3): Amphotericin B deoxycholate 1 mg/kg/day IV until patient improves and can be treated by the oral route.

• Note: Preferred in severe forms of the disease.

• Alternative regimen (4): Ketoconazole 200-400 mg/day PO for 9-12 months
• Alternative regimen (5): Voriconazole initial dose 400 mg PO/IV q12h for one day, then 200 mg q12h for 6 months

• Note: Diminish the dose to 50% if weight is <40 kg.

Aspergillosis

• Aspergillosis Return to Top
• 1. Invasive pulmonary aspergillosis

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.

• 2. Invasive sinus aspergillosis

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.

• 3. Tracheobronchial aspergillosis

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.

• 4. Chronic necrotizing pulmonary aspergillosis

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.

• 5. Aspergillosis of the CNS

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.

• Note: There are drug interactions with anticonvulsant therapy.

• 6. Aspergillus infections of the heart (endocarditis, pericarditis, and myocarditis)

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.
• Note: endocardial lesions generally require surgical treatment. Aspergillus pericarditis usually requires pericardiectomy.

• 7. Aspergillus osteomyelitis and septic arthritis

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.
• Note: Surgical resection of devitalized bone and cartilage is important for curative intent.

• 8. Aspergillus infections of the eye (endophthalmitis and keratitis)

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.
• Note: Topical therapy is indicated for keratitis, ophthalmologic intervention and management is recommended for all forms of ocular infection. Systemic therapy may be beneficial when treating aspergillus endophthalmitis.

• 9. Cutaneous aspergillosis

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.
• Note: Surgical resection is indicated when feasible.

• 10. Aspergillus peritonitis

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.

• 11. Prophylaxis against invasive aspergillosis

• Preferred regimen: Posaconazole PO 200 mg tid
• Alternative regimen: (1) Itraconazole 200 mg IV q12h for 2 days then 200 mg IV q24h OR Itraconazole PO 200mg bid
• Alternative regimen: (2) Micafungin 50 mg/day PO qd

• 12. Aspergilloma

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen: Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h

• 13. Chronic cavitary pulmonary aspergillosis

• Preferred regimen: Voriconazole 6 mg/kg IV q12h single dose, THEN 4 mg/kg IV q12h or PO 200 mg q12h
• Alternative regimen (1): Liposomal Amphotericin B (L-AMB) 3–5 mg/kg/day IV q24h
• Alternative regimen (2): Amphotericin B lipid complex (ABLC) 5 mg/ kg/day IV q24h
• Alternative regimen (3): Caspofungin 70 mg IV single dose THEN 50 mg/day IV q24h
• Alternative regimen (4): Posaconazole 200 mg PO qid if patient is critical, then 400 mg PO bid after stabilization of the disease.
• Alternative regimen (5): Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (6): Micafungin 100–150 mg/day PO qd
• Note: Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been established.

• Note: long-term therapy might be needed.

• 14. Allergic bronchopulmonary Itraconazole aspergillosis

• Preferred regimen: Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Alternative regimen (1): Voriconazole PO 200 mg bid
• Alternative regimen (2): Posaconazole PO 400 mg bid
• Note: Corticosteroids are a cornerstone of the therapy.

• 15. Allergic aspergillus sinusitis

• Preferred regimen: None or Itraconazole dosage depends upon formulation - 600 mg/day PO for 3 days, THEN 400 mg/day PO OR 200 mg q12h IV for 2 days, THEN 200 mg IV q24h
• Note: Few data available for other agents.

• 16. Relative indications for surgical treatment of invasive aspergillosis

• Pulmonary lesion in proximity to great vessels or pericardium;
• Pericardial infection;
• Invasion of chest wall from contiguous pulmonary lesion;
• Aspergillus empyema;
• Persistent hemoptysis from a single cavitary lesion;
• Infection of skin and soft tissues;
• Infected vascular catheters and prosthetic devices;
• Endocarditis;
• Osteomyelitis;
• Sinusitis;
• Cerebral lesions.

Yellow Fever Virus

• 1. Yellow fever

• 1.1. Summary

• Yellow fever was one of the most lethal diseases before the development of the vaccine. It is a major health concern for unvaccinated travellers to tropical regions in South America and Africa. It is transmitted by mosquitoes (Aedes aegypti) bites in a cycle which involve these mosquitoes biting also monkeys and human beings, which act as hosts for the virus. The yellow fever virus is a member of the Flaviviridae family, which comprises about 70 viruses, most of which are arthropod-borne.

• 1.2. Epidemiology

• Up to 5000 cases are reported annually in Africa and 300 annually in South America, although it is believed that numbers are underestimated. In Africa the human population is seasonally exposed in and around villages and small cities so the highest risk of disease are children without naturally acquired immunity. In South America the virus is transmitted in poorly populated forested areas and it occurs mainly with workers and farmers in the borders of the forested areas.

• 1.3. Clinical Manifestations

• Yellow fever can present itself in three forms: subclinical infection, nonspecific abortive febrile disease and fatal hemorrhagic fever. The incubation time for the disease is 3-6 days. After this period, the onset of fever, myalgia, lower back pain, irritability, nausea, malaise, headache, fotofobia and dizziness is oftenly abrupt. These findings are not specific to Yellow Fever and can be found in any acute infection. During this period the patient can be a source of virus for mosquitoes.
• On physical examination the liver can be enlarged with tenderness, Faget sign (slow pulse rate despite high fever) can be found. Skin might appear flushed with reddening of conjunctivae and gums. Between 48-72h after onset and before the jaundice, hepatic enzymes starts to rise. Laboratory studies may show leukopenia with relative neutropenia. This is called period of infection and may last for several days and may be THEN a remission period which last about 48h, with the disappearance of the fever and the symptoms. Patients with the abortive form of the disease recover at this stage.
• After the third to sixth day of the onset of the symptoms the patient may present return of the fever, vomiting, renal failure (oliguria), jaundice, epigastric pain and hemorrhagic diathesis. The viremia terminates during this stage and the antibodies appear in the blood. The patient may evolve with multiorgan failure during this phase. Also in this stage, AST concentrations might exceed ALT, probably due to myocardial and skeletal muscle damage. Serum creatinine and bilirubin levels also rise at this stage. Hemorrhagic manifestations may include petechiae, ecchymoses, epistaxis, melena, metrorrhagia, haematemesis. Laboratory studies may show thrombocytopenia, reduced fibrinogen levels, presence of fibrin split products, reduced factors II, V, VII, VIII, IX and X, which suggest a multifactorial cause for the bleeding with a consumption coagulopathy. Myocardial disfunction may be demonstrated by abnormalities in the ST-T segment in the electrocardiogram. Encephalitis is very rare.
• 20-50% of the patients with the hepatorenal disease die after 7-10 days of the onset.

• 1.4. Diagnosis

• Diagnosis can be made by serology, detection of viral genome by polymerase chain reaction, immunohistochemistry on postmortem tissues, viral isolation or histopathology. No commercial test is available and diagnostic capabilities are restricted to selected laboratories only. Serologic diagnosis is made by dosing IgM antibodies with ELISA. The virus might be isolated by inoculating it in mice, cell cultures or mosquitoes. PCR is generally used to detect viral genome in clinical samples that were negative by virus isolation or other method.

• 1.5. Treatment

• Preferred regimen: No specific treatment is available for yellow fever. In the toxic phase, supportive treatment includes therapies for treating dehydration and fever. Ribavirin has failed in several studies in the monkey model.

• Note: An international seminar held by WHO in 1984 recommended maintenance of nutrition, prevention of hypoglycemia, maintenance of the blood pressure with fluids and vasoactive drugs, prevention of bleeding with fresh-frozen plasma, dialysis if renal failure, correction of metabolic acidosis, administration of cimetidine IV to avoid gastric bleeding and oxygen if needed.

• 1.6. Prevention

• The Yellow fever 17D is highly effective, safe, attenuated vaccine that has been used for over 60 years. It should be taken my travellers who are going to endemic areas of the disease. Revaccination is needed after 10 years from the first dose. The side effects of the vaccines are rare but they include yellow fever associated viscerotropic disease and neurotropic disease. Immunization is contraindicated during pregnancy and in patients with immunodeficiency due to cancers, HIV/AIDS, or treatment with immunosuppressive agents.

Chikungunya Fever

Chikungunya Fever

• Preferred regimen: no specific therapeutics agents are available and there are no licensed vaccines to prevent Chikungunya Fever.

• Note: Anti inflammatory drugs can be used to control joint swelling and arthritis.

Rabies

• Rabies

• Preferred regimen: no specific therapeutics agents are available once the disease is established.

• Note: There are vaccines and immune globulins available for postexposure prophylaxis:

• Postexposure Prophylaxis for non immunized individuals: Wound cleansing, human rabies immune globulin - administer full dose infiltrated around any wound. Administer any remaining volume IM at other site anatomically distant from the wound. Administer vaccine 1,0ml, IM at deltoid area one each on days 0, 3, 7 and 14.
• Postexposure Prophylaxis for immunized individuals: Wound cleansing, do not administer human rabies immune globulin. Administer vaccine 1,0ml, IM at deltoid area one each on days 0 and 3.

Cryptococcus

• Cryptococcus Return to Top

• 1. Cryptococcus neoformans

• 1.1 Cryptococcus neoformans meningitis in HIV infected patients

• Preferred regimen for induction and consolidation: (Amphotericin B deoxycholate 0.7-1.0 mg/kg IV q24h OR Liposomal AmB 3-4 mg/kg IV q24h OR Amphotericin B lipid complex 5 mg/kg IV q24h) AND Flucytosine 100 mg/kg/day PO/IV q6h for at least 2 weeks THEN Fluconazole 400 mg (6 mg/kg) PO qd for at least 8 weeks
• Alternative regimen for induction and consolidation (1): Amphotericin B deoxycholate 0.7-1.0 mg/kg IV q24h OR Liposomal AmB 3-4 mg/kg IV q24h OR AmB lipid complex 5 mg/kg IV q24h for 4-6 weeks
• Alternative regimen for induction and consolidation (2): Amphotericin B deoxycholate 0.7 mg/kg IV q24h AND Fluconazole 800 mg PO qd for 2 weeks, THEN Fluconazole 800 mg PO qd for at least 8 weeks
• Alternative regimen for induction and consolidation (3): Fluconazole 800-1200 mg PO qd AND Flucytosine 100 mg/kg/day PO qid for 6 weeks
• Alternative regimen for induction and consolidation (4): Fluconazole PO 800-2000 mg qd for 10-12 weeks
• Preferred regimen for maintenance and prophylactic therapy: Initiate HAART 2-10 weeks after commencing initial antifungal therapy AND Fluconazole 200 mg PO qd
• Alternative regimen for maintenance and prophylactic therapy: Itraconazole 200 mg PO bid - monitor drug-level (trough concentration must be higher than 0.5 μg/ml) OR Amphotericin B deoxycholate 1 mg/kg per week IV (should be used in azole-intolerant patients)
• Note (1): Consider discontinuing supressive therapy if CD4 count is higher than 100 cells/uL AND undetectable OR very low HIV RNA level for more than 3 months. Consider reinstitution of maintenance therapy if CD4 count <100 cels/uL.
• Note (2): Do not use acetazolamide OR mannitol OR corticosteroids to treat increased intracranial pressure, instead it should be used lombar puncture in the absence of focal neurologic signs or impaired mentation (which, if present, patient must be submitted to CT or MRI scan first).

1.2. Cerebral cryptococcomas

• Preferred regimen for induction and consolidation: (Amphotericin B deoxycholate 0.7-1.0 mg/kg IV q24h OR Liposomal AmB 3-4 mg/kg IV q24h OR Amphotericin B lipid complex 5 mg/kg IV q24h) AND Flucytosine 100 mg/kg/day PO/IV q6h for at least 2 weeks THEN Fluconazole 400 mg (6 mg/kg) PO qd for at least 8 weeks
• Note: Consider surgery if lesions are larger than 3 cm, accessible lesions with mass effect or lesions that are enlarging and not explained by IRIS.

1.3. Cryptococcus neoformans meningitis in HIV negative patients

• Preferred regimen: Amphotericin B deoxycholate 0.7-1.0 mg/kg IV q24h AND Flucytosine 100 mg/kg/day PO or IV q6h for at least 4 weeks (which may be extended to 6 weeks if there is any neurological complication) THEN Fluconazole 400 mg PO qd for 8 weeks.
• Note (1): If there's toxicity to Amphotericin B deoxycholate, consider changing to Liposomal AmB or Amphotericin B lipid complex in the second 2 weeks.
• Note (2): After induction and consolidation therapy, start Fluconazole 200 mg (3 mg/kg) PO qd for 6-12 months.
• Note (3): If Flucytosine is not given, consider lengthening the induction therapy for at least 2 weeks.

1.4. Cryptococcus neoformans pulmonary disease - immunosupressed

• Mild-moderate symptoms, without severe immunosupression and absence of diffuse pulmonary infiltrates:

• Preferred regimen: Fluconazole 400 mg PO qd for 6-12 months

• Severe pneumonia or disseminated disease or CNS infection:

• Preferred regimen: treat like CNS cryptococcosis.

• Note (1): In HIV- infected patients, treatment should be stopped after 1 year if CD4 count is >100 and a cryptococcal antigen titer is <1:512 and not increasing.
• Note (2): Consider corticosteroid if ARDS is present in a context which it might be attributed to IRIS.

1.5 Cryptococcus neoformans pulmonary disease - non-immunosupressed

• Mild-moderate symptoms, without severe immunosupression and absence of diffuse pulmonary infiltrates:

• Preferred regimen: Fluconazole 400 mg PO qd for 6-12 months
• Alternative regimen: if Fluconazole is unavailable or contraindicated, Itraconazole 200 mg PO bid, Voriconazole 200 mg PO bid, and Posaconazole 400 mg PO bid

• If there's severe pneumonia, disseminated disease or CNS infection:

• Preferred regimen: treat like CNS cryptococcosis for 6-12 months.

1.6 Cryptococcus neoformans non-lung, non-CNS infection

• Cryptococcemia or disseminated cryptococcic disease (involvement of at least 2 noncontiguous sites or cryptococcal antigen titer >1:512):

• Preferred regimen: treat like CNS infection.

• If infection occurs at a single site and no immunosupressive risk factors

• Preferred regimen: Fluconazole 400 mg PO qd for 6-12 months

1.7. Cryptococcosis in Children

• Preferred regimen for induction and consolidation: Amphotericin B deoxycholate 1.0 mg/kg qd IV AND Flucytosine 100 mg/kg PO or IV q6h for 2 weeks THEN Fluconazole 10-12 mg/kg PO qd for 8 weeks
• Alternative regimen: patients with renal dysfunction: change Amphotericin B deoxycholate by Liposomal AmB 5 mg/kg IV q24h or Amphotericin B lipid complex (ABLC) 5 mg/kg IV q24h
• Preferred regimen for maintenance: Fluconazole 6 mg/kg PO qd. Discontinuation of maintenance therapy is poorly studied and should be individualized.

• Cryptococcal pneumonia:

• Preferred regimen Fluconazole 6-12 mg/kg PO qd for 6-12 months

1.8. Cryptococcosis in Pregnant Women

• Preferred regimen for induction and consolidation: Amphotericin B deoxycholate 0.7-1.0 mg/kg IV q24h. Start Fluconazole after delivery. Avoid use during first trimester and consider use in the last 2 trimesters with the need for continuous antifungal therapy during pregnancy.
• Note (1): Consider using lipid formulations for patients with renal dysfunction - Liposomal AmB 3-4 mg/kg IV q24h OR Amphotericin B lipid complex (ABLC) 5 mg/kg IV q24h.
• Note (2): Consider using Flucytosine in relationship to benefit risk basis, since it is a Category C drug for pregnancy.
• Note (3): If pulmonary cryptococcosis: perform close follow-up and administer fluconazole after delivery.

2. Cryptococcus gatti

• Disseminated cryptococcosis or CNS disease:

• Preferred regimen: treatment is the same as C. neoformans

• Pulmonary disease: single and small cryptococcoma:

• Preferred regimen: Fluconazole 400 mg per day PO for 6-18 months

• Pulmonary disease: Very large or multiple cryptococcomas:

• Preferred regimen: administer Flucytosine AND AmB deocycholate for 4-6 weeks, THEN Fluconazole for 6-18 months
• Note: Surgery should be considered if there is compression of vital structures OR failure to reduce the size of the cryptococcoma after 4 weeks of therapy

Dermatophytosis

• Dermatophytosis

• 1. Tinea Cruris

• Preferred regimen (1): Interdigital: Topical cream/ointment: terbinafine, imidazoles (miconazole, econazole OR clotrimazole)
• Preferred regimen (2): Griseofulvin 250 mg PO tid for 14 days should be used in resistant to topic therapy cases

• 2. Tinea Corporis

• 2.1 Small, well-defined lesions:

• Preferred regimen: Topical cream/ointment: terbinafine, imidazoles (miconazole, econazole, clotrimazole).

• 2.2 Larger lesions:

• Preferred regimen: Larger lesions: terbinafine 250 mg/day PO for 2 weeks; itraconazole 200 mg/day PO for 1 week, fluconazole 250 mg PO weekly for 2-4 weeks

• 3. Tinea Pedis

• Preferred regimen: Interdigital: Topical cream/ointment: terbinafine, imidazoles (miconazole, econazole, clotrimazole), undecenoic acid, tolnaftate.
• Note (1): If "Dry type": Oral: terbinafine 250 mg/day PO for 2-4 weeks, itraconazole 400 mg/day PO for 1 week per month (repeat if necessary), fluconazole 200 mg PO weekly for 4-8 weeks

• 4. Tinea Capitis

• Preferred regimen: Griseofulvin 10-20 mg/kg/day PO qd for at least 6 weeks (Preferred for children).
• Alternative regimens: Terbinafine 62.5 mg/day if <20kg; 125 mg/day if 20-40kg; 250 mg/day if >40kg PO qd for 8 weeks OR Itraconazole 4-6 mg/kg/day (maximum 400 mg) PO for 4-6 weeks

• Note: Nistatin is not effective in the treatment of dermatophytosis.

• 5. Tinea Barbae

• Preferred regimen: Terbinafine 250 mg/day PO qd for 4 weeks
• Alternative regimen: Itraconazole 200 mg/day PO qd for 2 weeks

• 6. Tinea Incognito

• Preferred regimen: Stop topical steroids and treat with topical 1% terbinafine cream for 6 weeks

• 7. Tinea Manuum

• Preferred regimen: topical or systemic terbinafine 250 mg/day PO qd por 2-4 weeks

• 8.Tinea Versicolor

• Preferred regimen: Itraconazole 200 mg PO qd for a week
• Alternative regimen: Ketoconazole 200 mg PO qd for 4 weeks

• 9. Majocchi's Granuloma

• Preferred regimen: Terbinafine 250 mg/day PO for 2-4 weeks or Itraconazole 200 mg PO bid for 1 week, per month for 2 months

Onychomycosis

• 10. Onychomycosis

• 10.1 Fingernails

• Preferred regimen: Terbinafine 250 mg/day PO for 6 weeks OR Itraconazole 200 mg PO bid for one week per month for 2 months (European guidelines)

• 10.2 Toenails

• Preferred regimen: Toenails Terbinafine 250 mg/day PO for 12 weeks OR Itraconazole 200 mg/day PO for 12 weeks (U.S. guidelines) OR Itraconazole 200 mg PO bid for one week per month for 3 months (European guidelines)

• Note: There is no evidence that combining systemic and topic treatments has any benefit to the patient.

Antimicrobial Prophylaxis

Procedure	Causative etiologies	Recommended antimicrobials	Usual adult dosage	Comments
Cardiovascular
	Staphylococcus aureus, Staphylococcus epidermidis	Cefazolin	1-2 g IV	Antibiotic prophylaxis has been proved beneficial in the following patients: reconstruction of abdominal aorta, procedures on the leg that involve a groin incision, any vascular procedure that inserts prosthesis/foreign body, lower extremity amputation for ischemia, cardiac surgery, permanent pacemakers, heart transplant. The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses. Some experts recommend an additional dose when patients are removed from bypass during open-heart surgery.
		Cefuroxime	1.5 g IV	Some experts recommend an additional dose when patients are removed from bypass during open-heart surgery.
		Vancomycin	1 g IV	Vancomycin is preferable in hospitals with high frequency of MRSA, high risk patients, those colonized with MRSA or for pen-allergic patients. Clindamycin 900 mg IV is another alternative for pen-allergic or vanco-allergic patients. Vancomycin can be used in hospitals in which methicillin-resistant S. aureus and S. epidermidis are a frequent cause of postoperative wound infection, in patients previously colonized with MRSA, or for those who are allergic to penicillins or cephalosporins. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anesthesia. Even when the drug is given over 60 minutes, hypotension may occur; treatment with Diphenhydramine (Benadryl, and others) and further slowing of the infusion rate may be helpful. Some experts would give 15 mg/kg of Vancomycin to patients weighing more than 751<g, up to a maximum of 1.5 g, with a slower infusion rate (90 minutes for 1.5 g). For procedures in which enteric gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside (Gentamicin, Tobramycin or Amikacin), Aztreonam or a fluoroquinolone.
		Mupirocine		Consider intranasal Mupirocine evening before, day of surgery and bid for 5 days post-op in patients with positive nasal culture for S. aureus. Mupirocine resistance has been encountered.
Gastrointestinal
Esophageal, gastroduodenal (includes percutaneous endoscopic gastrostomy - high risk only)	Enteric gram-negative bacilli, gram-positive cocci	High-risk only: Cefazolin, Cefoxitin, Ceftriaxone	Single-dose: 2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses. PEG placement: high-risk is marked obesity, obstruction, reduced gastric acid or reduced motility.
Biliary tract	Enteric gram-negative bacilli, enterococci, clostridia	High-risk only: Cefazolin, Cefoxitin or Cefotetan	1-2 g IV	High risk: age >70, acute cholecystitis, non-functioning gallbladder, obstructive jaundice or common duct stones. With cholangitis, treat as infection, not prophylaxis. The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses. Low-risk, laparoscopic: no prophylaxis.
		OR Ampicillin/Sulbactam	3 g IV
Endoscopic retrograde cholangiopancreatography		Ciprofloxacin	500 - 750 mg PO OR 400 mg IV 2 hours before procedure	Only needed if there is obstruction. Greatest benefit of prophylaxis occurs when complete drainage cannot be achieved.
		OR Piperaciline-Tazobactam	4.5 g IV 1 hour before procedure	Only needed if there is obstruction.
Colorectal	Enteric gram-negative bacilli, anaerobes, enterococci	Oral: Neomycin PLUS Erythromycin bases OR Metronidazole		In addition to mechanical bowel preparation, 1 g of Neomycin PLUS 1 g of Erythromycin at 1 PM, 2 PM and 11 PM or 2 g of Neomycin PLUS 2 g of Metronidazole at 7 PM and 11 PM the day before an 8 AM operation.
		Parenteral: Cefoxitin or Cefotetan	1-2 g IV
		OR Cefazolin	1-2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses.
		PLUS Metronidazole	0.5 g IV
		Ampicillin/Sulbactam	3 g IV
		Ertapenem	1 g IV	Ertapenem can be used if there is beta-lactam allergy. Other regimens include: Clindamycin 900 mg IV PLUS Gentamycin 5mg/kg OR Aztreonam 2 g IV OR Ciprofloxacin 400 mg IV.
Appendectomy, non-perforated	Same as for colorectal	Cefoxitin OR Cefotetan	1-2 g IV	For patients allergic to penicillins and cephalosporins, Clindamycin OR Vancomycin with either Gentamicin, Ciprofloxacin, Levofloxacin or Aztreonam is a reasonable alternative. Fluoroquinolones should not be used for prophylaxis in cesarean section.
		OR Cefazolin	1-2 g IV
		PLUS Metronidazole	0.5 g IV
Genitourinary
Cystoscopy alone	Enteric gram-negative bacilli, enterococci	High-risk only: Ciprofloxacin	500 mg PO OR 400 mg IV	Due to increasing resistance of E. coli to fluoroquinolones and Ampicillin/Sulbactam, local sensitivity profiles should be reviewed prior to use. AUA recommends prophylaxis for those with several potentially adverse host factors (e.g. advanced age, immunocompromised state, anatomic abnormalities, etc.).
		OR Trimethoprim-Sulfamethoxazole	1 DS tablet
Cystoscopy with manipulation or upper tract instrumentation	Enteric gram-negative bacilli, enterococci	Ciprofloxacin	500 mg PO OR 400 mg IV	Due to increasing resistance of E. coli to fluoroquinolones and Ampicillin/Sulbactam, local sensitivity profiles should be reviewed prior to use.
		OR Trimethoprim-Sulfamethoxazole	1 DS tablet	Viable alternative in populations with low rates of resistance.
Transrectal prostate biopsy	Enteric gram-negative bacilli, enterococci	Ciprofloxacin	500 mg PO 12 hours before biopsy and 12 hours after first dose.
Open or laparoscopic surgery	Enteric gram-negative bacilli, enterococci	Cefazolin	1-2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses.
Gynecologic and Obstetric
Vaginal, abdominal or laparoscopic hysterectomy	Enteric gram-negative bacilli, anaerobes, Gp B strep, enterococci	Cefazolin OR Cefoxitin OR Cefotetan	1-2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses. For patients allergic to penicillins and cephalosporins, Clindamycin OR Vancomycin with either Gentamicin, Ciprofloxacin, Levofloxacin or Aztreonam is a reasonable alternative. Fluoroquinolones should not be used for prophylaxis in cesarean section. Due to increasing resistance of E. coli to fluoroquinolones and Ampicillin/Sulbactam, local sensitivity profiles should be reviewed prior to use.
		OR Ampicillin/Sulbactam	3 g IV	For patients allergic to penicillins and cephalosporins, Clindamycin OR Vancomycin with either Gentamicin, Ciprofloxacin, Levofloxacin or Aztreonam is a reasonable alternative. Fluoroquinolones should not be used for prophylaxis in cesarean section. Due to increasing resistance of E. coli to fluoroquinolones and Ampicillin/Sulbactam, local sensitivity profiles should be reviewed prior to use.
Cesarean section	Same as for hysterectomy	Cefazolin	1-2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses. For patients allergic to penicillins and cephalosporins, Clindamycin OR Vancomycin with either Gentamicin, Ciprofloxacin, Levofloxacin or Aztreonam is a reasonable alternative. Fluoroquinolones should not be used for prophylaxis in cesarean section. Due to increasing resistance of E. coli to fluoroquinolones and Ampicillin/Sulbactam, local sensitivity profiles should be reviewed prior to use.
		Clindamycin	900 mg IV	Use as alternative method to Cefazolin and associated with Gentamicin 5 mg/kg IV OR Tobramycin 5 mg/kg IV single dose.
Abortion, surgical	Same as for hysterectomy	Doxycycline	300 mg PO	Divided into 100 mg before the procedure and 200 mg after.
Head and Neck Surgery
Incisions through oral or pharyngeal mucosa	Anaerobes, enteric gram-negative bacilli, S. aureus	Clindamycin	600 mg - 900 mg IV	Clean, uncontaminated head and neck surgery does not require prophylaxis. If using Clindamycin, consider associating Gentamicin 5 mg/kg IV single dose.
		OR Cefazolin	2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses.
		PLUS Metronidazole	0.5 g IV
		OR Ampicillin/Sulbactam	3 g IV
Neurosurgery
	S. aureus, S. epidermidis	Cefazolin	1-2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses.
		OR Vancomycin	1 g IV	Vancomycin can be used in hospitals in which methicillin-resistant S. aureus and S. epidermidis are a frequent cause of postoperative wound infection, in patients previously colonized with MRSA, or for those who are allergic to penicillins or cephalosporins. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anesthesia. Even when the drug is given over 60 minutes, hypotension may occur; treatment with Diphenhydramine (Benadryl, and others) and further slowing of the infusion rate may be helpful. Some experts would give 15 mg/kg of Vancomycin to patients weighing more than 751<g, up to a maximum of 1.5 g, with a slower infusion rate (90 minutes for 1.5 g). For procedures in which enteric gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside (Gentamicin, Tobramycin or Amikacin), Aztreonam or a fluoroquinolone.
		Clindamycin	900 mg IV	Clindamycin can be used in clean, contaminated surgeries (cross sinuses, or naso/oropharynx). British recommend Amoxicilin-clavulanate 1.2 g IV OR Cefuroxime 1.5 g IV PLUS Metronidazole 0.5 mg g IV.
Ophthalmic
	S. aureus, S. epidermidis, streptococci, enteric gram-negative bacilli, Pseudomonas spp.	Gentamicin, Tobramycin, Ciprofloxacin, Gatifloxacin, Levofloxacin, Moxifloxacin, Ofloxacin OR Neomycin-gramicidin-polymyxin B	Multiple drops topically over 2 to 24 hours
		OR Cefazolin	100 mg subconjunctivally
Orthopedic
Hip arthroplasty, spinal fusion	S. aureus, S. epidermidis	Same as cardiac surgery
Total joint replacement (other than hip)	S. aureus, S. epidermidis	Cefazolin	1-2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses.
		OR Vancomycin	1 g IV	Vancomycin can be used in hospitals in which methicillin-resistant S. aureus and S. epidermidis are a frequent cause of postoperative wound infection, in patients previously colonized with MRSA, or for those who are allergic to penicillins or cephalosporins. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anesthesia. Even when the drug is given over 60 minutes, hypotension may occur; treatment with Diphenhydramine (Benadryl, and others) and further slowing of the infusion rate may be helpful. Some experts would give 15 mg/kg of Vancomycin to patients weighing more than 751<g, up to a maximum of 1.5 g, with a slower infusion rate (90 minutes for 1.5 g). For procedures in which enteric gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside (Gentamicin, Tobramycin or Amikacin), Aztreonam or a fluoroquinolone. If a tourniquet is to be used in the procedure, the entire dose of antibiotic must be infused prior to its inflation. For patients weighing >90 kg use Vancomycin 1.5 g IV as single dose OR Clindamycin 900 mg IV.
Open reduction of closed fracture with internal fixation	S. aureus, S. epidermidis	Ceftriaxone	2 g IV single dose
Thoracic (non-cardiac)
	S. aureus, S. epidermidis, enteric gram-negative bacilli, streptococci	Cefazolin	1-2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses.
		OR Vancomycin	1 g IV	Vancomycin can be used in hospitals in which methicillin-resistant S. aureus and S. epidermidis are a frequent cause of postoperative wound infection, in patients previously colonized with MRSA, or for those who are allergic to penicillins or cephalosporins. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anesthesia. Even when the drug is given over 60 minutes, hypotension may occur; treatment with Diphenhydramine (Benadryl, and others) and further slowing of the infusion rate may be helpful. Some experts would give 15 mg/kg of Vancomycin to patients weighing more than 751<g, up to a maximum of 1.5 g, with a slower infusion rate (90 minutes for 1.5 g). For procedures in which enteric gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside (Gentamicin, Tobramycin or Amikacin), Aztreonam or a fluoroquinolone.
		OR Ampicillin/Sulbactam	3 g IV	Due to increasing resistance of E. coli to fluoroquinolones and Ampicillin/Sulbactam, local sensitivity profiles should be reviewed prior to use.
Vascular
Arterial surgery involving· a prosthesis, the abdominal aorta, or a groin incision	S. aureus, S. epidermidis, enteric gram-negative bacilli	Cefazolin	1-2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses.
		OR Vancomycin	1 g IV	Vancomycin can be used in hospitals in which methicillin-resistant S. aureus and S. epidermidis are a frequent cause of postoperative wound infection, in patients previously colonized with MRSA, or for those who are allergic to penicillins or cephalosporins. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anesthesia. Even when the drug is given over 60 minutes, hypotension may occur; treatment with Diphenhydramine (Benadryl, and others) and further slowing of the infusion rate may be helpful. Some experts would give 15 mg/kg of Vancomycin to patients weighing more than 751<g, up to a maximum of 1.5 g, with a slower infusion rate (90 minutes for 1.5 g). For procedures in which enteric gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside (Gentamicin, Tobramycin or Amikacin), Aztreonam or a fluoroquinolone.
Lower extremity amputation for ischemia	S. aureus, S. epidermidis, enteric gram-negative bacilli, clostridia	Cefazolin	1-2 g IV	The recommended dose of Cefazolin is 1 g for patients who weigh <80 kg and 2 g for those ~80 kg. Morbidly obese patients may need higher doses.
		OR Vancomycin	1 g IV	Vancomycin can be used in hospitals in which methicillin-resistant S. aureus and S. epidermidis are a frequent cause of postoperative wound infection, in patients previously colonized with MRSA, or for those who are allergic to penicillins or cephalosporins. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anesthesia. Even when the drug is given over 60 minutes, hypotension may occur; treatment with Diphenhydramine (Benadryl, and others) and further slowing of the infusion rate may be helpful. Some experts would give 15 mg/kg of Vancomycin to patients weighing more than 751<g, up to a maximum of 1.5 g, with a slower infusion rate (90 minutes for 1.5 g). For procedures in which enteric gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside (Gentamicin, Tobramycin or Amikacin), Aztreonam or a fluoroquinolone.