Fanconi anemia medical therapy
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Overview
- Treatments for fanconi anemia include red blood cell transfusions, and marrow stem cell transplants, and medicines.
- The Allogenic HSCT is curative therapy in Bone marrow failure.
- Androgen and G-CSF and RBC transfusion are useful to increase blood count.
- People who have mild or moderate bone marrow failure may need supportive treatment as symptoms will resolve.
- Fanconi anemia management is challenging because SCT is curative for bone marrow failure and haematological neoplasms but not for non haematological features.
- Patient also need increased surveillance for both hematologic and non hematologic features and reduced intensity therapy is typically used for HCT and cancer treatment.
- Blood transfusions and medicine help relieve the symptoms of fancon ianemia, but they're not curative treatment
Management of patients with FA is challenging because hematopoietic stem cell transplantation (HCT) is curative for bone marrow failure and hematologic neoplasms but not for the non-hematologic features.
Patients also require increased surveillance for both hematologic and non-hematologic malignancies, and reduced-intensity therapy is typically used for HCT and cancer treatment.
Androgen therapy may be a reasonable option to improve blood counts for some patients including those with moderate bone marrow failure for whom no donor is available, those who do not meet medical eligibility criteria for HCT due to pre-existing organ dysfunction or ongoing infection, and those who decline HCT
Bone Marrow Failure:
Allogenic HSCT is the only curative therapy for bone marrow failure and hematological malignancies (myelodysplastic syndrome (MDS) and acute leukaemia) in falcon anaemia patients.
Outcome of HCT in FA improved drastically in 2000, when a trend has started by development of FA-specific reduced intensity approaches to conditioning and improvement in the understanding and supportive care for these patients.
All patients who have evidence of bone marrow failure with FA we refer to specialised HCT centre to discuss the risk and benefits of HCT and evaluation of HCT donor.
It is also applicable to refer individuals of FA without bona more failure to HCT centre to discuss these issues.
However, We do not recommend individuals performing HCT who have adequate bone marrow function, with rationale of aplastic anemia, those with mild cytopenia, will not develop bone marrow failure.
Furthermore, HCT earlier to the onset of bone marrow failure may require increased conditioning intensity and thus carries risk of increased toxicity.
Monitoring bone marrow function:
Initial approach of monitoring bone marrow function is classified according to the severity of bone marrow failure and the presence or absence of clonal hematopoietic neoplasms.
● For those with mild bone marrow failure: described as absolute neutrophil count (ANC) between 1000 and 1500/microL, platelet count between 50,000 and 150,000/microL, and hemoglobin ≥10 g/dL, and we should monitor CBC with differential every 3-4 months as the blood count remain stable, and we also perform a bone marrow examination with cytogenetics annually.
If there are any changes in blood count without an apparent cause (e.g: infection) we should increase the frequency of CBC monitoring and the bone marrow studies repeated regardless of the date of last study.
● For those with moderate bone marrow failure (ANC between 500 and 1000/microL, platelet count between 30,000 and 50,000/microL, hemoglobin between 8 and 10 g/dL) whose counts continue to decrease, we initiate HCT planning with an HLA-matched related donor (first choice) or closely matched unrelated donor.
Androgen therapy may be an alternate option to improve blood counts for some patients including those with moderate bone marrow failure for whom no donor is available, those who do not meet medical eligibility criteria for HCT due to pre-existing organ dysfunction or ongoing infection, and those who decline HCT.
Alternatively, If the individual is asymptomatic with stable cell counts and no clonal abnormality, it may be reasonable to monitor the CBC every three to four months and perform a bone marrow examination annually as done for mild bone marrow failure.
If cytogenetic abnormality is associated with poor risk-MDS in absence of other MDS defining feature, CBC and bone marrow should be monitored more frequently (eg, CBC every 1-2months, Bone marrow every 1-6months), and should be proceed with the best available donor.
- For severe bone marrow failure (ANC ≤500/microL, platelet count ≤30,000/microL, hemoglobin <8 g/dL), and/or transfusion dependence, We pursue HCT with the best available donor, An HLA_matched sibling/family member who has been determined not to have FA would be preferable, second choice should be closely matched unrelated donor. If neither of above options available then we should start trial of androgen therapy while pursuing other alternative donor such as cord blood or haploidentical HCT, with attempt to avoid transfusion exposure and opportunistic infection during the androgen trial. For individuals who do not have access to HCT for whatever reason (eg, medically ineligible, lack of donor, cost), androgen therapy or investigational approaches such as gene therapy may be good options.
- This monitoring T schedule and management approach is consistent with the 2014 Fanconi Anemia Guidelines for Diagnosis and Managementfrom the Fanconi Anemia Research Fund [1].
Allogeneic hematopoietic stem cell transplantation (HCT): Allogenic HSCT is the only accepted curative therapy for fanconi anaemia with severe bone marrow failue, MDS or AML, transfusion dependent anaemia or thrombocytopenia,
We immediately refer these patients for HCT. The recommended approach is to use bone marrow (rather than peripheral blood stem cells) from an eligible sibling who is HLA matched at 8 of 8 alleles of the four most commonly tested HLA genes (HLA -A, -B, -C, and DRB1) or a closely matched unrelated donor.
It is essential that all sibling or other related donors must go through chromosomal breakage testing or genetic testing to confirm that they do not also have FA.
This testing is very important because family donors those are apparently asymptomatic and healthy may have FA but lack classic findings due to mosaicism, incomplete penetrance of FA-associated abnormalities, or young age/late onset of disease manifestations.
HCT performed with a family donor who also turns out to have FA, even if mosaic and/or asymptomatic, would possess a very high risk of graft failure. Alternatively, siblings who are only carriers of one heterozygous mutation in an autosomal recessive FA-associated gene are eligible as donors.
Options for patients with FA who lack a closely matched related or unrelated donor but still require HCT for bone marrow failure include the following:
- Those parents who are interested in having additional children, in vitro fertilization (IVF) with pre-implantation genetic diagnosis (PGD) approaches are an established method that not only ensures that future children will not have FA, but also can select for an HLA-matched sibling that can be used as a donor.
- While not always effective and its also associated with challenging ethical and emotional dimensions that must be addressed, this method has facilitated successful matched sibling donor HCT in a number of patients with FA dating back to 2001. This approach is not optimal for somebody with FA who have an urgent need for HCT (eg, those who require transfusions or have severe neutropenia despite optimal supportive care), since it may take one to two years before a healthy sibling donor is available.
●Unrelated cord blood transplantation (CBT) seems to be less effective than matched unrelated donor bone marrow for patients with FA. This was demonstrated in a 2007 series of 93 patients with FA who underwent CBT, in which overall survival was 40 percent [3]. Use of cord blood units with higher stem cell doses and incorporation of fludarabine into CBT conditioning regimens may improve outcomes in the future.
- Haploidentical HCT using a parental or other related donor is still under investigation at several centers. This approach shows promise, although outcomes are not as good as those seen with closely matched unrelated donors.
Based on the above conclusion, CBT or haploidentical HCT should only be performed for patients with FA in the context of active clinical trials.
Patients with FA are at risk for significant toxicity from standard chemotherapy doses which used for HCT conditioning. Strategies revised at the Minnesota university and other centre that incorporate reduced dose of cyclophosphamide (20-60mg/kg) representing 50-90% reduction compared with conventional cyclophosphamide doses, also combination with immunosuppressive but low toxicity agents such as fludarabine and anti thymocyte globulin, have been extremely effective in matched sibling donor HCT for FA.
Rates of engraftment associated with these approaches are >90 percent, and overall post-HCT survival is >95 percent in most series reported since 2005 [6].
Additional developments have also improved outcomes from unrelated donors, including matching with high-resolution HLA genotyping, T cell depletion, and conditioning regimens with lower toxicity. Thus, even though unrelated donor HCT may carry a higher risk of long-term toxicity, it is likely to be essential to delaying HCT while attempting to use non-curative supportive care approaches to increasing blood counts.
Although HCT is curative for bone marrow failure and potentially for hematopoietic neoplasms, it does not cure other manifestations of FA. As noted above, HCT appears to increase the risk of squamous cell cancers, especially in individuals with severe graft-versus-host disease. Additionally, insulin resistance, bone health disorders, and other endocrinopathies may be worsened by HCT, and require close lifelong monitoring [7].
Androgens — Androgen therapy is not curative but it may be a good option for those who lack a closely matched related donor for HCT, or for whom HCT is not pursued due to family preference or medically eligible [8,9]. Androgen therapy is used to increase blood count for a period of weeks to month while parents attempt to IVF with PGD and until resulting HLA-matched related donor is available.
Only half of patents with FA will respond to androgen therapy [10]. Patients with severe bone marrow aplasia are less likely to respond than those with residual bone marrow function, and response can take weeks to months. Thus, the recommended time to initiate a trial of androgen therapy when a patient has developed moderate to severe bone marrow failure but is not consistently transfusion dependent. Androgen therapy has the most dramatic effect on the erythroid lineage and can improve hemoglobin within a few weeks of initiation. Responses in the platelet count are generally slower and less complete, and neutropenia may not completely resolve.
Oxymetholone is the most commonly used androgen in FA (starting dose 2 to 5 mg/kg/day); danazol and oxandrolone have also been used [13-15]. If the blood counts stabilize or improve, the daily dose may be tapered to the minimum effective dose to avoid non-hematologic toxicity. If no response is seen after three months, oxymetholone should be discontinued.
Androgen therapy can be associated with a number of side effects, including virilization, growth abnormalities, behavioral changes, and hypertension. The most concerning side effects of androgens in patients with FA involve the liver, and include transaminitis, cholestasis, peliosis hepatis, and liver tumors.
A 2014 study was the first to report outcomes of FA patients treated with low-dose oxandrolone, an anabolic steroid with a potentially favorable toxicity profile compared to oxymetholone. Of nine patients with a median follow-up of nearly two years, 78 percent had a hematologic response, none had clinical virilization, and none developed liver tumors [15]. More experience with this agent is needed.
Transfusions and growth factors — Transfusion and growth factor support may be essential due to progressive bone marrow failure and associated complications in patients with FA. However, increasing evidence supports a judicious approach, as extensive transfusions may be associated with worse outcomes with HCT, and extensive use and high doses of growth factors such as G-CSF and thrombopoietin mimetics in patients with other bone marrow failure syndromes have been associated with increased risks of developing MDS and AML.
●
RBCs – Red blood cell (RBC) transfusion is indicated for any patient with symptomatic anemia (eg, decreased activity level, excessive fatigue, shortness of breath, and poor growth) or anemia with hemodynamic instability. Only leukoreduced, irradiated units of RBCs should be used, to minimize the risk of cytomegalovirus transmission, alloimmunization, and transfusion-associated graft-versus host disease (ta-GVHD). Directed donations by family members should be avoided to reduce the risk of graft rejection due to alloimmunization in patients who subsequently undergo HCT.
Chronic RBC transfusions can lead to iron overload, which, if not treated, can lead to significant morbidity and mortality. An approach to assessing and treating transfusional iron overload (eg, with phlebotomy or chelation therapy) is presented separately
● Platelets – Platelet transfusion is indicated in patients with platelet counts <10,000/microL and in any patient with severe bruising, bleeding, or invasive procedures. The use of single donor pheresis platelets minimizes exposure to multiple donors, and all products should be irradiated to prevent ta-GVHD. As with RBCs, directed platelet donations from family members should be avoided.
- G-CSF – Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) raises the neutrophil count in most neutropenic patients [17-19]. However, we reserve the use of G-CSF for patients with FA to those with an ANC <200/microL, or those with known active invasive bacterial or fungal infections and an ANC <1000/microL, due to concerns that G-CSF or GM-CSF may increase the risk of MDS and AML in patients with bone marrow failure syndromes.
- For those who require growth factor support, experience is greater with G-CSF than with GM-CSF. The starting dose of G-CSF is 5 mcg/kg daily, and the dose is adjusted towards a target goal of ANC 1500 to 2000/microL. If possible, the administration of G-CSF is adjusted to every other day to minimize the frequency of administration. If GM-CSF is used, the starting dose is 250 mcg/m2/day. There are no clinical trials comparing G-CSF with GM-CSF. If there is no improvement in the neutrophil count after eight weeks, treatment should be discontinued.
- Importantly, patients with neutropenia and fever should be evaluated urgently, cultures obtained, and broad spectrum antibiotics administered until the fever resolves or cultures are negative, to reduce the risk of life-threatening infections. However, we do not give routine prophylactic antibiotics to patients with FA, as there are no studies to indicate clinical benefit from this practice, and it may potentially increase the risk of fungal infections and antibiotic resistance.
Therapies under development
● Gene therapy – Gene therapy has the potential to improve bone marrow function in individuals with FA since the origin of bone marrow failure is deficiency of an FA gene function. Gene-corrected CD34+ stem cells from FA patients have been engrafted in immune-deficient mice, but successful clinical applications of gene therapy for FA have not yet been demonstrated [20,21].
● Metformin – In a mouse model of FA (FANCD2 gene knockout), metformin produced modest increases in white blood cell (WBC) counts, hemoglobin levels, and platelet counts [22]. There was also reduced p53-dependent tumor formation and a suggestion of decreased susceptibility to DNA damage. Metformin has not been evaluated in patients with FA.
HEMATOLOGIC NEOPLASMS— Clonal hematopoiesis is very common in patients with FA. For newly diagnosed patients who have not had a bone marrow evaluation, we obtain a unilateral bone marrow aspirate and biopsy (>1 cm) for morphologic review. Flow cytometry analysis should be performed if dysplasia or increased myeloblasts are seen. Cytogenetic analysis should also should be performed, and at minimum should include G-banding analysis of at least 20 metaphases to assess for acquired chromosomal aberrations. Fluorescence in situ hybridization (FISH) analysis for specific aberrations associated with transformation to myelodysplastic syndrome (MDS) (eg, +1q, +3q, -7, -7q) and whole genome single nucleotide polymorphism (SNP) array with copy number analysis may increase sensitivity and the ability to detect subtle chromosome aberrations. If adequate cytogenetic analysis was not done on a bone marrow performed prior to the diagnosis of FA, we repeat the bone marrow to obtain cytogenetics.
Greater intensity monitoring and other interventions are generally based on the presence of dysplasia, blast count, and specific cytogenetic findings. Our approach is as follows:
●As noted above, an initial bone marrow aspirate and biopsy with cytogenetics is done in all patients diagnosed with FA. This is usually repeated annually as long as no concerning features are noted.
●Patients with morphologic features concerning for hematologic neoplasm, including multilineage dysplasia and/or excess blasts, or those with poor-risk cytogenetic features (eg, -7, +3q) even in the absence of dysmorphology, should be referred for urgent hematopoietic cell transplantation (HCT) with the best available donor. Pre-HCT chemotherapy cycles are not advised in these patients, because of the risk of prolonged aplasia and the lack of evidence for a survival benefit, even in young patients without FA who develop MDS [23]. Regardless of the pre-HCT cytoreduction approach, it is critical to identify the HCT donor prior to initiating chemotherapy for MDS or AML in patients with FA because of the risk of chemotherapy-induced aplasia.
●Patients with advanced MDS (eg, bone marrow blast count >10 to 15 percent) or acute myeloid leukemia (AML) may be treated with a course of chemotherapy followed by HCT. One piloted strategy used a single cycle of reduced intensity FLAG (fludarabine, cytarabine, and G-CSF) three weeks prior to the initiation of HCT conditioning (without waiting for hematologic recovery from the FLAG regimen); this may be an effective approach, as all six patients in a study using this approach were alive and disease free at a follow-up of 28 months [24]. However, the use of pre-transplant cytoreduction remains highly controversial and is best discussed with experts in FA prior to initiation [25].
●Certain cytogenetic abnormalities such as +1q, del(20q), and del(5q) are not associated with poor-risk MDS for patients with FA. For patients with these findings who do not have another indication for HCT such as severe bone marrow failure, dysplasia, or acute leukemia, we monitor the complete blood count (CBC) closely (eg, once per month) and repeat the bone marrow every one to six months until the stability (or instability) of the clone is established.
●Patients with biallelic BRCA2 (FANCD1) mutations (and perhaps also those with FANCN mutations) present a special challenge, as these patients have a very high risk of presenting early in childhood with MDS or AML in the absence of bone marrow failure. A 2015 study using a theoretical survival analysis approach suggested that some patients with biallelic BRCA2 mutations might benefit from pre-emptive HCT because of the nearly 80 percent actuarial risk of leukemia by 10 years of age [26].
SOLID TUMORS — As noted above, individuals with FA are at increased risk for a number of types of solid tumors, and this risk is likely to be increased in those who have undergone hematopoietic cell transplantation (HCT). (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Solid tumors'.)
Screening and prevention — We screen for the following, with referrals as appropriate:
●Skin cancer – A full skin examination should be performed, and all concerning skin lesions should be evaluated by a dermatologist.
●Head and neck squamous cell carcinoma (HNSCC) – We advise patients with FA to avoid tobacco and alcohol, since these are known risk factors for HNSCC. We also advise good oral hygiene and regular dental care including thorough examination of the oral cavity every six months, since poor oral hygiene is also a risk factor for HNSCC in patients with FA. In addition, all patients older than 10 years of age and patients under 10 years who have undergone HCT and have a history of graft-versus-host disease (GVHD) should have laryngoscopic examination of the nasopharynx and oropharynx by an otolaryngologist at least annually.
Any lesions suspicious for oral leukoplakia should be evaluated by an oral surgeon. Patients with difficulty swallowing or similar complaints should undergo esophagoscopy.
●Liver tumors – Patients who are receiving androgen therapy or have received androgens in the past should be screened for liver tumors as outlined above. (See 'Androgens' above.)
●Gynecological and anogenital cancer – Human papilloma virus (HPV) vaccination should be given to all patients prior to the onset of puberty. Information on HPV vaccine administration is presented in detail separately. (See "Human papillomavirus vaccination".)
Adolescent girls should have a visual examination of the external genitalia beginning at menarche and a comprehensive gynecologic evaluation including PAP test once they become sexually active or by the age of 18 years, whichever comes first.
Routine anoscopy is indicated for patients with prior anogenital dysplasia due to increased risk of anal squamous cell carcinoma.
●Breast cancer – Breast self-examination should be performed monthly beginning in the early 20s, and routine physical examinations should include evaluation for breast masses. Screening mammography may be initiated as early as age 25, particularly if self-examination or physician examination identifies any concerning lesions.
●Gastrointestinal cancer – Stomach and colon cancers are not common in FA; however, any patient with FA who has abnormal upper or lower gastrointestinal bleeding, discomfort, pain, or other attributable symptom that is not explained by other evaluations should undergo upper and/or lower endoscopic evaluation.
Management with chemotherapy dose reductions -- For patients with FA who requires chemotherapy and/orradiation therapy, treatment is complicated by the extreme sensitivity to genotoxic agents, especially radiation and alkylating agents such as cyclophosphamide. Dose reduction of these agents or switching to alternative regimens may be necessary depending on the type of tumor and stage of disease. Chemotherapy regimens to treat solid tumors should be discussed with experts in the management of patients with FA prior to their initiation. Additionally, patients who have not undergone HCT who are treated with intensive chemotherapy or radiation therapy for solid tumors are at high risk for developing therapy-related bone marrow failure, and discussion with a center with both FA and HCT expertise is indicated before chemotherapy is initiated.
Medical Therapy[edit | edit source]
Androgen therapy is helpful in moderate bone marrow failure cases if no donor is available for HCT, or whom do not meet eligibility criteria for HCT due to pre existing organ dysfunction or ongoing infection, and those who decline HCT.
- Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].
- Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
- Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].
- Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].
Disease Name[edit | edit source]
- 1 Stage 1 - Name of stage
- 1.1 Specific Organ system involved 1
- 1.1.1 Adult
- Preferred regimen (1): drug name 100 mg PO q12h for 10-21 days (Contraindications/specific instructions)
- Preferred regimen (2): drug name 500 mg PO q8h for 14-21 days
- Preferred regimen (3): drug name 500 mg q12h for 14-21 days
- Alternative regimen (1): drug name 500 mg PO q6h for 7–10 days
- Alternative regimen (2): drug name 500 mg PO q12h for 14–21 days
- Alternative regimen (3): drug name 500 mg PO q6h for 14–21 days
- 1.1.2 Pediatric
- 1.1.2.1 (Specific population e.g. children < 8 years of age)
- Preferred regimen (1): drug KKJ 50 mg/kg PO per day q8h (maximum, 500 mg per dose)
- Preferred regimen (2): drug name 30 mg/kg PO per day in 2 divided doses (maximum, 500 mg per dose)
- Alternative regimen (1): drug name10 mg/kg PO q6h (maximum, 500 mg per day)
- Alternative regimen (2): drug name 7.5 mg/kg PO q12h (maximum, 500 mg per dose)
- Alternative regimen (3): drug name 12.5 mg/kg PO q6h (maximum, 500 mg per dose)
- 1.1.2.2 (Specific population e.g. 'children < 8 years of age')
- Preferred regimen (1): drug name 4 mg/kg/day PO q12h（maximum, 100 mg per dose）
- Alternative regimen (1): drug name 10 mg/kg PO q6h (maximum, 500 mg per day)
- Alternative regimen (2): drug name 7.5 mg/kg PO q12h (maximum, 500 mg per dose)
- Alternative regimen (3): drug name 12.5 mg/kg PO q6h (maximum, 500 mg per dose)
- 1.1.2.1 (Specific population e.g. children < 8 years of age)
- 1.1.1 Adult
- 1.2 Specific Organ system involved 2
- 1.2.1 Adult
- Preferred regimen (1): drug name 500 mg PO q8h
- 1.2.2 Pediatric
- Preferred regimen (1): drug name 50 mg/kg/day PO q8h (maximum, 500 mg per dose)
- 1.2.1 Adult
- 1.1 Specific Organ system involved 1
- 2 Stage 2 - Name of stage
- 2.1 Specific Organ system involved 1
- Note (1):
- Note (2):
- Note (3):
- 2.1.1 Adult
- Parenteral regimen
- Preferred regimen (1): drug name 2 g IV q24h for 14 (14–21) days
- Alternative regimen (1): drug name 2 g IV q8h for 14 (14–21) days
- Alternative regimen (2): drug name 18–24 MU/day IV q4h for 14 (14–21) days
- Oral regimen
- Preferred regimen (1): drug name 500 mg PO q8h for 14 (14–21) days
- Preferred regimen (2): drug name 100 mg PO q12h for 14 (14–21) days
- Preferred regimen (3): drug name 500 mg PO q12h for 14 (14–21) days
- Alternative regimen (1): drug name 500 mg PO q6h for 7–10 days
- Alternative regimen (2): drug name 500 mg PO q12h for 14–21 days
- Alternative regimen (3):drug name 500 mg PO q6h for 14–21 days
- Parenteral regimen
- 2.1.2 Pediatric
- Parenteral regimen
- Preferred regimen (1): drug name 50–75 mg/kg IV q24h for 14 (14–21) days (maximum, 2 g)
- Alternative regimen (1): drug name 150–200 mg/kg/day IV q6–8h for 14 (14–21) days (maximum, 6 g per day)
- Alternative regimen (2): drug name 200,000–400,000 U/kg/day IV q4h for 14 (14–21) days (maximum, 18–24 million U per day) '(Contraindications/specific instructions)'
- Oral regimen
- Preferred regimen (1): drug name 50 mg/kg/day PO q8h for 14 (14–21) days (maximum, 500 mg per dose)
- Preferred regimen (2): drug name (for children aged ≥ 8 years) 4 mg/kg/day PO q12h for 14 (14–21) days (maximum, 100 mg per dose)
- Preferred regimen (3): drug name 30 mg/kg/day PO q12h for 14 (14–21) days (maximum, 500 mg per dose)
- Alternative regimen (1): drug name 10 mg/kg PO q6h 7–10 days (maximum, 500 mg per day)
- Alternative regimen (2): drug name 7.5 mg/kg PO q12h for 14–21 days (maximum, 500 mg per dose)
- Alternative regimen (3): drug name 12.5 mg/kg PO q6h for 14–21 days (maximum,500 mg per dose)
- Parenteral regimen
- 2.2 'Other Organ system involved 2'
- Note (1):
- Note (2):
- Note (3):
- 2.2.1 Adult
- Parenteral regimen
- Preferred regimen (1): drug name 2 g IV q24h for 14 (14–21) days
- Alternative regimen (1): drug name 2 g IV q8h for 14 (14–21) days
- Alternative regimen (2): drug name 18–24 MU/day IV q4h for 14 (14–21) days
- Oral regimen
- Preferred regimen (1): drug name 500 mg PO q8h for 14 (14–21) days
- Preferred regimen (2): drug name 100 mg PO q12h for 14 (14–21) days
- Preferred regimen (3): drug name 500 mg PO q12h for 14 (14–21) days
- Alternative regimen (1): drug name 500 mg PO q6h for 7–10 days
- Alternative regimen (2): drug name 500 mg PO q12h for 14–21 days
- Alternative regimen (3):drug name 500 mg PO q6h for 14–21 days
- Parenteral regimen
- 2.2.2 Pediatric
- Parenteral regimen
- Preferred regimen (1): drug name 50–75 mg/kg IV q24h for 14 (14–21) days (maximum, 2 g)
- Alternative regimen (1): drug name 150–200 mg/kg/day IV q6–8h for 14 (14–21) days (maximum, 6 g per day)
- Alternative regimen (2): drug name 200,000–400,000 U/kg/day IV q4h for 14 (14–21) days (maximum, 18–24 million U per day)
- Oral regimen
- Preferred regimen (1): drug name 50 mg/kg/day PO q8h for 14 (14–21) days (maximum, 500 mg per dose)
- Preferred regimen (2): drug name 4 mg/kg/day PO q12h for 14 (14–21) days (maximum, 100 mg per dose)
- Preferred regimen (3): drug name 30 mg/kg/day PO q12h for 14 (14–21) days (maximum, 500 mg per dose)
- Alternative regimen (1): drug name 10 mg/kg PO q6h 7–10 days (maximum, 500 mg per day)
- Alternative regimen (2): drug name 7.5 mg/kg PO q12h for 14–21 days (maximum, 500 mg per dose)
- Alternative regimen (3): drug name 12.5 mg/kg PO q6h for 14–21 days (maximum,500 mg per dose)
- Parenteral regimen
- 2.1 Specific Organ system involved 1