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'''For patient information click [[{{PAGENAME}} (patient information)|here]]'''
__NOTOC__
{{Taxobox
{{Streptococcus pneumoniae infection}}
| color = lightgrey <!-- Please read [[WP:Taxobox_usage#Color]] before making any changes to the taxobox color. -->
| name = ''Streptococcus pneumoniae''
| image = Streptococcus pneumoniae.jpg
| image_width = 240px
| image_caption = [[Scanning electron microscopy|SEM]] [[micrograph]] of ''S. pneumoniae''.
| domain = [[Bacteria]]
| phylum = [[Firmicutes]]
| classis = [[Diplococci]]
| ordo = [[Lactobacillales]]
| familia = [[Streptococcaceae]]
| genus = ''[[Streptococcus]]''
| species = '''''S. pneumoniae'''''
| binomial = ''Streptococcus pneumoniae''
| binomial_authority = (Klein 1884)<br>Chester 1901
}}
{{CMG}}


==Overview==
{{About1|Streptococcus pneumoniae}}
'''''Streptococcus pneumoniae''''', or '''pneumococcus''', is a [[Gram-positive]], [[Hemolysis (microbiology)|alpha-hemolytic]] diplococcus [[bacterium]] and a member of the [[genus]] ''[[Streptococcus]]''.<ref name=Sherris>{{cite book | author = Ryan KJ; Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | publisher = McGraw Hill | year = 2004 | id = ISBN 0-8385-8529-9 }}</ref> A significant human [[pathogen]], ''S. pneumoniae'' was recognized as a major cause of [[pneumonia]] in the late 19th century and is the subject of many [[humoral immunity]] studies.


Despite the name, the organism causes many types of infection other than [[pneumonia]], including [[acute sinusitis]], [[otitis media]], [[meningitis]], [[osteomyelitis]], [[septic arthritis]], [[endocarditis]], [[peritonitis]], [[pericarditis]], [[cellulitis]], and [[brain abscess]].
'''For patient information click [[{{PAGENAME}} (patient information)|here]].'''


''S. pneumoniae'' is the most common cause of bacterial meningitis in adults and children, and is one of the top two isolates found in otitis media.<ref>{{cite journal |author=Dagan R |title=Treatment of acute otitis media - challenges in the era of antibiotic resistance |journal=Vaccine |volume=19 Suppl 1 |issue= |pages=S9-S16 |year= |pmid=11163457}}</ref> Pneumococcal pneumonia is more common in the very young and the very old.
{{CMG}}; {{AE}} {{USAMA}}


''S. pneumoniae'' can be differentiated from ''[[Streptococcus viridans]]'', which is also alpha hemolytic, using an [[optochin]] test, as ''S. pneumoniae'' is optochin sensitive. The encapsulated, gram-positive coccoid bacteria have a distinctive morphology on gram stain, the so-called, "lancet shape." It has a polysaccharide capsule that acts as a virulence factor for the organism; 91 different capsular types are known, and these types differ in virulence, prevalence, and extent of drug resistance.
{{SK}} Strep pnumoniae; Strep pneumoniae infection


==History==
==Overview==
In 1881, the organism, then known as the pneumococcus for its role as an etiologic agent of pneumonia, was first isolated simultaneously and independently by the U.S Army physician [[George Sternberg]] and the French chemist [[Louis Pasteur]]
'''''Streptococcus pneumoniae''''', or '''pneumococcus''', is a [[Gram-positive]] bacterium. It is a diplococcus, [[Hemolysis (microbiology)|alpha-hemolytic]] member of the ''[[Streptococcus]]'' [[genus]].<ref name="Sherris">{{cite book | author = Ryan KJ; Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | publisher = McGraw Hill | year = 2004 | id = ISBN 0-8385-8529-9 }}</ref>  During the 19th century pneumonia was heavily associated with this pathogen. ''[[S. pneumoniae]]'' is known to be the cause of various different infections apart from [[pneumonia]] including [[endocarditis]], [[meningitis]], [[pericarditis]], [[brain abscess]], [[otitis media]], [[osteomyelitis]], [[acute sinusitis]], [[septic arthritis]], [[peritonitis]], and [[cellulitis]]. In children as well as adults,  ''[[Streptococcus pneumoniae|S. pneumoniae]]'' is the most common cause of [[otitis media]] as well as [[Bacterial meningitis|bacterial meningiti]]<nowiki/>s.<ref>{{cite journal |author=Dagan R |title=Treatment of acute otitis media - challenges in the era of antibiotic resistance |journal=Vaccine |volume=19 Suppl 1 |issue= |pages=S9-S16 |year= |pmid=11163457}}</ref> [[Pneumonia]] caused by ''[[S. pneumoniae]]'' is usually found at the extremes of the age (in old or very young individuals). ''[[Streptococcus viridans]]'' also belongs to the family of alpha hemolytic bacteria but can e distinguished from ''[[Streptococcus pneumoniae|S. pneumoniae]]'' by an [[optochin]] test. ''[[Streptococcus viridans]]'' are found to be insensitive to [[optochin]] where as ''[[S. pneumoniae]]'' are found to be [[Optochin|optochin sensitive]]. The most potent [[virulence factor]] of ''[[Streptococcus pneumoniae|S. pneumoniae]]''  is its [[Polysaccharide encapsulated bacteria|polysaccharide capsule]]. Up to 91 various types of capsules have been discovered; each of these differ in [[virulence]], drug resistance, [[prevalence|prevalence,]] and distribution.
 
The organism was termed ''Diplococcus pneumoniae'' from 1926 because of its characteristic appearance in [[Gram stain|Gram-stained]] [[sputum]]. It was renamed ''Streptococcus pneumoniae'' in [[1974]] because of its growth in chains in liquid media.
 
''S. pneumoniae'' played a central role in demonstrating that genetic material consists of [[DNA]]. In 1928, [[Frederick Griffith]] demonstrated [[transformation (genetics)|transformation]] of live, harmless pneumococcus into a lethal form by co-inoculating the live pneumococci into a mouse along with heat-killed, [[virulent]] pneumococci.  In 1944, [[Oswald Avery]], [[Colin MacLeod]], and [[Maclyn McCarty]] demonstrated that the transforming factor in [[Griffith's experiment]] was DNA, not protein as was widely believed at the time.<ref>Avery OT, MacLeod CM, and McCarty M (1944).  "Studies on the chemical nature of the substance inducing transformation of pneumococcal types." ''J Exp Med'' '''79''':137-158.</ref> Avery's work marked the birth of the molecular era of genetics.<ref>{{cite journal |author=Lederberg J |title=The transformation of genetics by DNA: an anniversary celebration of Avery, MacLeod and McCarty (1944) |journal=Genetics |volume=136 |issue=2 |pages=423-6 |year=1994 |pmid=8150273}}</ref>


== Pathogenesis ==
==Classification==
''S. pneumoniae'' is normally found in the [[nasopharynx]] of 5-10% of healthy adults, and 20-40% of healthy children.<ref name=Sherris/> It can be found in higher amounts in certain environments, especially those where people are spending a great deal of time in close proximity to each other (day cares, army barracks).  It attaches to nasopharyngeal cells through interaction of bacterial surface [[adhesin]]s. This normal colonization can become infectious if the organisms are carried into areas such as the [[Eustachian tube]] or [[nasal sinus]]es where it can cause [[otitis media]] and [[sinusitis]], respectively. Pneumonia occurs if the organisms are inhaled into the lungs and not cleared (again, viral infection, or [[Tobacco smoking|smoking]]-induced ciliary paralysis might be contributing factors). Once the organism makes its way to a site where it is not normally found, it activates the [[Complement system|complement]] protein group, stimulates [[cytokine]] production, and attracts [[white blood cell]]s (specifically [[neutrophil granulocyte|neutrophil]]s). The organism's [[polysaccharide]] capsule makes it resistant to [[phagocytosis]], and if there is no pre-existing anticapsular antibody, alveolar [[macrophage]]s cannot adequately kill the pneumococci. The organism spreads to the blood stream (where it can cause [[bacteremia]]) and is carried to the [[meninges]], joint spaces, [[bone]]s, and [[peritoneal cavity]], and may result in [[meningitis]], [[brain abscess]], [[septic arthritis]], or [[osteomyelitis]].
Streptococcus pneumoniae infections may be classified as follows:


''S. pneumoniae'' has several virulence factors, including the polysaccharide capsule mentioned earlier, that help it evade a host's immune system.  It has pneumococcal surface proteins that inhibit complement-mediated opsonization, and it secretes IgA1 protease that will destroy secretory IgA produced by the body.
*[[Community-acquired pneumonia|Community Acquired Pneumonia]]
*[[Endocarditis]]
*[[Sinusitis]]
*[[Bronchitis]]
*[[Meningitis]]


The risk of pneumococcal infection is much increased in persons with impaired IgG synthesis, impaired phagocytosis, or defective clearance of pneumococci. In particular, the absence of a functional [[spleen]], through [[congenital asplenia]], [[splenectomy]], or [[sickle-cell disease]] predisposes one to a more severe course of infection ([[Overwhelming post-splenectomy infection]]) and prevention measures are indicated (see [[asplenia]]).
{{familytree/start}}
{{familytree | | | | | | | | | A01 | | | | | | | | | | | | | | | |A01=Streptococcus Pneumoniae Infection}}
{{familytree | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | }}
{{familytree | | | |,|-|-|-|v|-|^|-|v|-|-|-|v|-|-|-|.| | | | | | | | | | | | }}
{{familytree | | | |!| | | |!| | | |!| | | |!| | | |!| | | | | | | | | | | }}
{{familytree | | | B01 | | B02 | | B03 | | B04 | | B05 | | | | | | |B01=[[Community-acquired pneumonia|Community Acquired Pneumonia]]|B02=[[Endocarditis]]|B03=[[Sinusitis]]|B04=[[Bronchitis]]|B05=[[Meningitis]]}}
{{familytree/end}}


==Virulence Factors==
==Laboratory Findings==  
''S. pneumoniae'' expresses different virulence factors on its cell surface and inside the organism.  These virulence factors contribute to some of the clinical manifestations during infection with ''S. pneumoniae''.
Depending on the nature of infection, an appropriate sample is collected from the infected area for laboratory identification. Commonly found
*'''Polysaccharide capsule''' -prevents phagocytosis by host immune cells by inhibiting C3b opsonization of the bacterial cells
* [[Pneumococci]] are gram positive, cocci, seen in pairs or chains.
*'''Pneumolysin''' (Ply) -a 53-kDa protein that can cause lysis of host cells and activate complement
*When cultured on [[blood agar]] plates with added [[optochin]] antibiotic disk, [[pneumococci]] show [[hemolysis (microbiology)|alpha-hemolytic]] colonies and a clear zone of inhibition around the disk meaning [[pneumococci]] are sensitive to the [[antibiotic]].  
*'''Autolysin''' (LytA) -activation of this protein lyses the bacteria releasing its internal contents (i.e. pneumolysin)
*[[Pneumococci]] are also [[bile]] soluble.  
*'''[[Hydrogen peroxide]]''' - causes damage to host cells (can cause apoptosis in neuronal cells during meningitis) and has bactericidal effects against competing bacteria ([[Staphylococcus aureus]])<ref>{{cite journal |author=Pericone, Christopher D., Overweg, Karin, Hermans, Peter W. M., Weiser, Jeffrey N. |title=Inhibitory and Bactericidal Effects of Hydrogen Peroxide Production by Streptococcus pneumoniae on Other Inhabitants of the Upper Respiratory Tract |journal=Infect Immun |volume=68 |issue=7 |pages=3990-3997 |year=2000 |id=PMID 10858213}}</ref>
*Similar to other [[streptococci]], [[pneumococci]] are [[catalase]] negative.
*'''[[Pilus|Pili]]''' - hair-like structures that extend from the surface of many strains of ''S. pneumoniae''. They contribute to colonization of upper respiratory tract and increase the formation of large amounts of [[tumor necrosis factors|TNF]] by the immune system during [[sepsis]], raising the possibility of [[septic shock]]<ref>{{cite journal |author=Barocchi M, Ries J, Zogaj X, Hemsley C, Albiger B, Kanth A, Dahlberg S, Fernebro J, Moschioni M, Masignani V, Hultenby K, Taddei A, Beiter K, Wartha F, von Euler A, Covacci A, Holden D, Normark S, Rappuoli R, Henriques-Normark B |title=A pneumococcal pilus influences virulence and host inflammatory responses |journal=Proc Natl Acad Sci U S A |volume=103 |issue=8 |pages=2857-2862 |year=2006 |id=PMID 16481624}}</ref>
*[[Quellung]] test to identify specific capsular [[polysaccharides]] may also be done.
*'''Choline binding protein A''' (CbpA) -an adhesin that can interact with carbohydrates on the cell surface of pulmonary epithelial cells
*'''Protective Antigen''' (PspA) -can inhibit complement-mediated opsonization of pneumococci


== Humoral immunity ==
===Laboratory Diagnosis===
In the [[19th century]], it was demonstrated that immunization of [[rabbit]]s with killed pneumococci protected them against subsequent challenge with viable pneumococci. [[blood plasma|Serum]] from immunized rabbits or from humans who had recovered from pneumococcal pneumonia also conferred protection. In the [[20th century]], the efficacy of immunization was demonstrated in [[South Africa]]n miners.  
[[Medical diagnosis|Diagnosis]] of [[streptococcus pneumoniae]] infection is generally made based on clinical suspicion along with a positive culture from a sample from virtually any place in the body.  
*An [[Antistreptolysin O titer|ASO titre]] of >200 units is significant.<ref name="Siemieniuk 2011">{{cite journal|last=Siemieniuk|first=Reed A.C.|coauthors= Gregson, Dan B.; Gill, M. John |title=The persisting burden of invasive pneumococcal disease in HIV patients: an observational cohort study|journal=BMC Infectious Diseases|date=Nov 2011|volume=11|doi=10.1186/1471-2334-11-314|pmid=22078162|url=http://www.biomedcentral.com/content/pdf/1471-2334-11-314.pdf|pages=314|pmc=3226630}}</ref> 
*''[[S. pneumoniae]]'' is, in general, [[optochin]] sensitive, although [[optochin]] resistance has been observed.<ref>{{Cite journal |title=Optochin resistance in ''Streptococcus pneumoniae'': mechanism, significance, and clinical implications |journal=Journal of Infectious Diseases |url=http://www.journals.uchicago.edu/doi/pdf/10.1086/322803?cookieSet=1 |volume=184 |issue=5 |pages=582–590 |year=2001 |pmid=11474432 |doi=10.1086/322803 |author8=Pikis A, Campos JM, Rodriguez WJ, Keith JM |last1=Pikis |first1=A |last2=Campos |first2=JM |last3=Rodriguez |first3=WJ |last4=Keith |first4=JM}}</ref>
*Atromentin and leucomelone possess antibacterial activity, inhibiting the [[enzyme]] [[enoyl-acyl carrier protein reductase]], (essential for the [[fatty acid metabolism#Synthesis|biosynthesis]] of [[fatty acid]]s) in ''[[S. pneumoniae]]''.<ref name="Zheng2006">{{cite journal |author=Zheng CJ, Sohn MJ, Kim WG. |year=2006 |title=Atromentin and [[leucomelone]], the first inhibitors specific to enoyl-ACP reductase (FabK) of ''Streptococcus pneumoniae'' |journal=Journal of Antibiotics |volume=59 |issue=12 |pages=808–12 |doi=10.1038/ja.2006.108 |pmid=17323650}}</ref>


It was discovered that the pneumococcus's capsule made it resistant to phagocytosis, and in the [[1920s]] it was shown that an antibody specific for capsular polysaccharide aided the killing of ''S. pneumoniae''. In [[1936]], a pneumococcal capsular polysaccharide vaccine was used to abort an epidemic of pneumococcal pneumonia. In the [[1940s]], experiments on capsular transformation by pneumococci first identified [[DNA]] as the material that carries genetic information.
==Treatment==
:* Streptococcus pneumonia treatment
::* 1. '''Lung (Community-acquired pneumonia)'''<ref name="pmid17278083">{{cite journal| author=Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC et al.| title=Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. | journal=Clin Infect Dis | year= 2007 | volume= 44 Suppl 2 | issue=  | pages= S27-72 | pmid=17278083 | doi=10.1086/511159 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17278083  }} </ref>
:::* 1.1 '''[[Penicillin]] sensitive (minimum inhibitory concentration < 2 mcg/ml)'''
::::* Preferred regimen: [[Penicillin G]] 5-24 MU IV in equally divided doses q4-6h, [[Amoxicillin]] 1 g PO tid (+/- macrolide)
::::* Alternative regimen:  Macrolides ([[Azithromycin]] (IV) 500 mg IV qd for at least 2 days followed by 500 mg PO qd 7-10 days or [[Clarithromycin]] extended-release tablets 1000 mg PO qd for 7 days) and oral [[Cephalosporins]]-[[Cefpodoxime]] 200 mg PO bd, ([[Cefprozil]] 500 mg PO bd, [[Cefditoren]] 400 mg PO bd, [[Cefdinir]] 300 mg PO bd), {{or}} parenteral Cephalosporins-[[Ceftriaxone]] 2 g IV q24h (or [[Cefotaxime]] 1-2 g IV q6-8h), [[Clindamycin]] 600-1200 mg IV/IM q6-12h, do not give single IM doses > 600 mg; IV infusion rates should not exceed 30 mg/min , [[Doxycycline]] 100 mg PO bd, respiratory [[Quinolones|flouroquniolones]].
:::* 1.2 '''[[Penicillin]]-resistant ([[Penicillin]] minimum inhibitory concentration ≥ 2 mcg/ml)'''
::::* Preferred regimen: [[Ceftriaxone]] 2 g IV q24h (or [[Cefotaxime]] 1-2 g IV q6-8h), respiratory [[Flouroquniolones]] [[Levofloxacin]] (Levaquin) 500 mg IV/PO q24h for 7-14 days or 750 mg IV/PO q24h for 5 days  (or [[Moxifloxacin]] (Avelox) 400 mg PO/IV over 60 minutes q24h for 7-14 days)
::::* Alternative regimen: [[Vancomycin]] 2 g/day IV q6-12h over at least 60 minutes, [[Linezolid]] 600 mg IV/PO q12h for 7-21 days , high-dose [[Amoxicillin]] (3 g qd with [[Penicillin]] minimum concentration of inhibitory <4 mcg/mL).


In [[1900]], it was recognized that different [[serovar]]s of pneumococci exist, and that immunization with a given serovar did not protect against infection with other serovars. Since then over ninety serovars have been discovered, each with a unique polysaccharide capsule which can be identified by the [[quellung reaction]]. Because some of these serovars cause disease more commonly than others, it is possible to provide reasonable protection by immunizing with less than 90 serovars; the current vaccine contains 23 serovars (i.e., it is "23-valent").  
::* 2.'''Endocarditis'''<ref name="pmid15956145">{{cite journal| author=Baddour LM, Wilson WR, Bayer AS, Fowler VG, Bolger AF, Levison ME et al.| title=Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. | journal=Circulation | year= 2005 | volume= 111 | issue= 23 | pages= e394-434 | pmid=15956145 | doi=10.1161/CIRCULATIONAHA.105.165564 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15956145 }}</ref>
:::* Preferred regimen (1):  Aqueous crystalline [[Penicillin G|Penicillin-G]] 6 MU q4-6h IV  for 4 weeks
:::* Preferred regimen (2) (who are unable to tolerate beta lactams therapy): [[Vancomycin]] 15 mg/kg IV q12h (target trough concentration, 10-15 mcg/mL); for troughs of 15-20 mcg/mL (MIC, 1 mcg/mL or less), 15-20 mg/kg (actual body weight) IV q8-12h for most patients with normal renal function
:::* Preferred regimen (3) (If the isolate is resistant (MIC 2 g/mL) to cefotaxime): [[Cefotaxime]] 1-2 g q8-12h IV/IM (max dose: 12 g/24 hr) {{and}} [[Vancomycin]] 15 mg/kg/day IV q12h {{and}} [[Rifampin]] 300 mg IV/PO q8h for 6 weeks, in combination with appropriate antimicrobial therapy
:::* Alternative regimen (1): [[Cefazolin]]  0.5-2 g q8h IV/IM (max dose: 12 g/24 hr)
:::* Alternative regimen (2): [[Ceftriaxone]] 2 g IV q12h
::::* Note : Streptococcus pneumoniae with intermediate doses minimum inhibitory concentration (MIC) 0.12 g/mL–0.5 g/mL [[Penicillin]] resistance (MIC 0.1 to 1.0 g/mL) or high [[Penicillin]] resistance (MIC 2.0 g/mL) is being recovered from patients with bacteremia.  


The serovars are numbered according to two systems: the American system, which numbers them in the order in which they were discovered, and the Danish system which groups them according to antigenic similarities.
::* 3. '''Sinuses (sinusitis)'''<ref name="pmid22438350">{{cite journal| author=Chow AW, Benninger MS, Brook I, Brozek JL, Goldstein EJ, Hicks LA et al.| title=IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. | journal=Clin Infect Dis | year= 2012 | volume= 54 | issue= 8 | pages= e72-e112 | pmid=22438350 | doi=10.1093/cid/cir1043 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22438350  }} </ref>
:::* Empiric therapy
::::* 3.1 '''For initial empiric treatment of acute bacterial rhinosinusitis in adults'''
:::::* Preferred regimen: [[Amoxicillin]] 500 mg/[[Clavulanate]] 125 mg PO tid or [[Amoxicillin]] 875 mg/[[Clavulanate]] 125 mg PO bid for 5 to 7 days recommended by the Infectious Disease Society of America (IDSA)
:::::* Alternative regimen (1): [[Doxycycline]] 100 mg PO q12h
::::::* Note: [[Doxycycline]] can be used in patients with [[Penicillin]] allergy.
:::::* Alternative regimen (2): A respiratory [[Fluoroquinolone]] ([[Levofloxacin]] or [[Moxifloxacin]]) is another recommended drug for [[Penicillin]]-allergic patients.
::::* 3.2 '''For second-line high-dose therapy for acute bacterial rhinosinusitis in adults'''
:::::* Preferred regimen: [[Amoxicillin]] 2 g/[[Clavulanate]] 125 mg PO bid recommended by the Infectious Disease Society of America (IDSA).
:::::* Note: The second line high dose therapy  is recommended in adults who have failed initial therapy, in regions of high endemic rates (10% or greater) of invasive [[Penicillin]]-nonsusceptible Streptococcus pneumoniae, severe infection.


==Diagnosis==
::* 4. '''Bronchi (acute exacerbation of chronic bronchitis)'''<ref>{{cite book | last = Bartlett | first = John | title = Johns Hopkins ABX guide : diagnosis and treatment of infectious diseases | publisher = Jones and Bartlett Learning | location = Burlington, MA | year = 2012 | isbn = 978-1449625580 }}</ref>
Depending on the nature of infection, an appropriate sample is collected for laboratory identification. Pneumococci are typically gram positive, cocci, seen in pairs or chains. When cultured on [[blood agar]] plates with added [[optochin]] antibiotic disk, they show [[hemolysis (microbiology)|alpha-hemolytic]] colonies and a clear zone of inhibition around the disk meaning they're sensitive to the antibiotic. Pneumococci are also bile soluble. Just like other [[streptococci]], it's [[catalase]] negative. [[Quellung]] test to identify specific capsular polysaccharides may also be done.
:::* Preferred regimen (1): [[Amoxicillin]] 875 mg PO q12h or 500 mg PO q8h
:::* Preferred regimen (2): [[Doxycycline]] 100 mg PO q12h


== Treatment ==
::* 5. '''CNS (meningitis)'''<ref name="pmid15494903">{{cite journal| author=Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM et al.| title=Practice guidelines for the management of bacterial meningitis. | journal=Clin Infect Dis | year= 2004 | volume= 39 | issue= 9 | pages= 1267-84 | pmid=15494903 | doi=10.1086/425368 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15494903  }} </ref>
Historically, treatment relied primarily on β-lactam antibiotics. In the [[1960s]], nearly all strains of ''S. pneumoniae'' were susceptible to [[penicillin]], but since that time, there has been an increasing prevalence of penicillin [[antibiotic resistance|resistance]], especially in areas of high [[antibiotic]] use. A varying proportion of strains may also be resistant to [[cephalosporin]]s, [[macrolide]]s (such as erythromycin), [[tetracycline]], [[clindamycin]] and the [[quinolone]]s.  Penicillin-resistant strains are more likely to be resistant to other antibiotics. Most isolates remain susceptible to [[vancomycin]], though its use in a β-lactam-susceptible isolate is less desirable because of tissue distribution of the drug and concerns of development of vancomycin resistance. More advanced beta-lactam antibiotics ([[cephalosporins]]) are commonly used in combination with other drugs to treat meningitis and community-acquired pneumonia. In adults, recently developed fluoroquinolones such as [[levofloxacin]] and [[moxifloxacin]] are often used to provide empiric coverage for patients with pneumonia. [[Susceptibility testing]] should be routine, with empiric antibiotic treatment guided by resistance patterns in the community in which the organism was acquired, pending the results.  There is currently debate as to how relevant the results of susceptibility testing are to clinical outcome.<ref name="ClinInfectDis2006-Peterson">{{cite journal | author=Peterson LR | title=Penicillins for treatment of pneumococcal pneumonia: does in vitro resistance really matter? | journal=Clin Infect Dis | year=2006 | pages=224-33 | volume=42 | issue=2 | id={{PMID|16355333}} }}</ref><ref name="ClinInfectDis2006-Tleyjeh">{{cite journal | author=Tleyjeh IM, Tlaygeh HM, Hejal R, Montori VM, Baddour LM | title=The impact of penicillin resistance on short-term mortality in hospitalized adults with pneumococcal pneumonia: a systematic review and meta-analysis | journal=Clin Infect Dis | year=2006 | pages=788-97 | volume=42 | issue=6 | id={{PMID|16477555}} }}</ref> There is slight clinical evidence that penicillins may act synergistically with macrolides to improve outcomes.<ref>{{cite journal | title=Addition of a Macrolide to a β-Lactam based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia | author=Martínez JA, Horcajada JP, Almela M, ''et al.'' | journal=Clin Infect Dis | volume=36 | year=2003 | pages=389–395 | DOI=10.1086/367541 | id=PMID 12567294 }}</ref>
:::* Empiric therapy
::::* Preferred regimen: [[Vancomycin]] 15 mg/kg/day IV q12h {{and}} a third-generation cephalosporin ([[Ceftriaxone]] 2 g IV q12h {{or}} [[Cefotaxime]] 2 g IV q4h or 3 g q6h) {{and}} [[Rifampin]] 600 mg IV qd in combination with [[Vancomycin]]
::::* Alternative regimen: [[Meropenem]], fluoroquinolones 
::::: Note: Middle ear infections ([[otitis media]]), peritoneum infections ([[spontaneous bacterial peritonitis]]), pericardium infections (purulent [[pericarditis]]), skin infections ([[cellulitis]]) and eye infections ([[conjunctivitis]]) caused by ''[[Streptococcus pneumonia]]''.


== Prevention ==
==Prevention==
* '''General principles'''
:::* 1. Pneumovax (23-valent) prevents bacteremia; impact on rates of CAP are modest or nil.
:::* 2. [[Prevnar]] vaccine for children <2 yrs age prevents invasive pneumococcal infection in adults by herd effect. Impact is impressive with rates of invasive pneumococcal infection down 80% in peds and 20-40% in adults.
:::* 3. Risk for [[bacteremia]] in [[splenectomy]], [[Human Immunodeficiency Virus (HIV)|HIV]], smokers, black race, [[multiple myeloma]], [[asthma]].
===Vaccination in the USA===
===Vaccination in the USA===
In the USA, a heptavalent pneumococcal [[conjugate vaccine]] vaccine (PCV 7) (e.g. [[Prevnar]]) is recommended since 2000 for all children aged 2-23 months and for at-risk children aged 24-59 months. The normally 4-doses series is given at 2, 4, 6 &  12 - 14 months of age. Protection is good against deep pneumococcal infections (especially septicemia and meningitis). Similar 9- and 13-valent vaccines are being tested. Yet, if the child is exposed to a serotype of pneumococcus that is not contained in the vaccine, he/she is not afforded any protectionThis limitation, and the ability of capsular-polysaccharide conjugate vaccines to promote the spread of non-covered serotypes, has led to research into vaccines that would provide species-wide protection.
*A heptavalent pneumococcal [[conjugate vaccine]] vaccine (PCV 7) (e.g. [[Prevnar]]) is recommended in the USA since 2000 for all children between 2 to 23 months of age. PCV 7 is also recommended for children between 24 to 59 months of age if they are at risk of getting the infection.  
*The vaccination is generally given as a 4-doses series at 2, 4, 6 &  12 - 14 months of age.  
*The PCV 7 provides a good protection is good against deep pneumococcal infections (especially septicemia and meningitis). Some new vaccines being tested are 9- and 13-valent. No protection is offered if the child is infected by a pneumococcus serotype that is not a component of the current vaccine.  The ability of capsular-polysaccharide conjugate vaccines to promote the spread of non-covered serotypes and the limitation has led to research into vaccines that would provide species-wide protection.


[[Pneumococcal polysaccharide vaccine]] (Pneumovax™ is one brand) gives at least 85% protection in those under 55 years of age for five years or longer. Immunization is suggested for those at highest risk of infection, including those 65 years or older, and generally should be a single lifetime dose (high risk side effects if repeated).  The standard 23-valent vaccines are ineffective for children under two years old.  
*Pneumovax™  which is one trade name for the [[Pneumococcal polysaccharide vaccine]] which approximately provides 85% protection for 5 or more years in individuals younger than age 55.
*Individuals at a high risk of infection such as those who are 65 years or older are recommended to get the vaccine. 
*Generally it is a single once in a lifetime dose as it is associated with high risk of side effects with repitition.  The standard 23-valent vaccines are not effective for children who are less than two years old.  


The current guidelines of the [[American College of Physicians]] call for administration of the immunization between ages 2 and 65 when indicated, or at age 65. If someone received the immunization before age 60, the guidelines call for a one-time revaccination.  
*The [[American College of Physicians]] in its current guidelines recommends immunization administration between 2 to 65 years old in the presence of indications, or at age 65. If someone received the immunization before age 60, the guidelines call for a one-time revaccination.  


''Revaccination'' at periodic intervals is also indicated for those with other conditions such as [[asplenia]] or [[nephrotic syndrome]].
*''Periodic revaccination'' for those who have conditions like [[asplenia]] or [[nephrotic syndrome]] is indicated.


===Vaccination in the UK===
===Vaccination in the UK===
It was announced in February 2006 that the UK government would introduce vaccination with the conjugate vaccine in children aged 2, 4 and 13 months.<ref name="BBCVac">[http://news.bbc.co.uk/1/hi/health/4692908.stm "Children to be given new vaccine"] ''BBC News'', [[February 08]], [[2006]], retrieved [[August 25]], [[2006]]</ref><ref name="DoHPress">[http://www.dh.gov.uk/PublicationsAndStatistics/PressReleases/PressReleasesNotices/fs/en?CONTENT_ID=4128036&chk=PI8e57 "Pneumococcal vaccine added to the childhood immunisation programme"] [[February 08]], [[2006]]</ref> This is expected to start on [[September 4]],[[2006]] and is to include changes to the immunisation programme in general.<ref name="MRF">[http://www.meningitis.org/sect5/subsect12/page1 "Changes to the immunisation programme in the UK"] ''Meningitis Research Foundation'', retrieved [[August 25]], [[2006]]</ref>
*It was announced in February 2006 that the UK government would introduce vaccination with the conjugate vaccine in children aged 2, 4 and 13 months.<ref name="BBCVac">[http://news.bbc.co.uk/1/hi/health/4692908.stm "Children to be given new vaccine"] ''BBC News'', [[February 08]], [[2006]], retrieved [[August 25]], [[2006]]</ref><ref name="DoHPress">[http://www.dh.gov.uk/PublicationsAndStatistics/PressReleases/PressReleasesNotices/fs/en?CONTENT_ID=4128036&chk=PI8e57 "Pneumococcal vaccine added to the childhood immunisation programme"] [[February 08]], [[2006]]</ref> This is expected to start on [[September 4]], [[2006]] and is to include changes to the immunisation programme in general.<ref name="MRF">[http://www.meningitis.org/sect5/subsect12/page1 "Changes to the immunisation programme in the UK"] ''Meningitis Research Foundation'', retrieved [[August 25]], [[2006]]</ref>


===Vaccination Worldwide===
===Vaccination Worldwide===
[[PneumoADIP|Pneumococcal vaccines Accelerated Development and Introduction Plan (PnemoADIP)]] is a program to accelerate the evaluation and access to new pneumococcal vaccines in the developing world. PneumoADIP is funded by the [[Global Alliance for Vaccines and Immunization|Global Alliance for Vaccines and Immunization (GAVI)]]. Thirty GAVI countries have expressed interest in participating by 2010. PneumoADIP aims to save 5.4 million children by 2030.<ref name="PneumoADIP website">[http://www.pneumoadip.com "PneumoADIP website"]</ref>
*In the developing world a plan to accomplish the accelerated new pneumococcal vaccines evaluation and access is done according to the [[PneumoADIP|Pneumococcal vaccines Accelerated Development and Introduction Plan (PnemoADIP)]]. [[Global Alliance for Vaccines and Immunization|Global Alliance for Vaccines and Immunization (GAVI)]] funds this plan for new pneumococcal vaccines. Almost 30 countries in this list showed interest in participating by 2010. An estimated 5.4 million lives of the children can be saved by PneumoADIP by 2030.<ref name="PneumoADIP website">[http://www.pneumoadip.com "PneumoADIP website"]</ref>
 
===Vaccine research===
There is currently research into producing vaccines than can be given into the nose rather than by injection.<ref>{{cite journal | title=Mucosal delivery of a Pneumococcal vaccine using ''Lactococcus lactis'' affords protection against respiratory infection | author=Hanniffy SB, Carter AT, Hitchin E, Wellsa JM. | journal=J Infect Dis | year=2007 | volume=195 | pages=185-193 | url=http://www.journals.uchicago.edu/JID/journal/issues/v195n2/36706/brief/36706.abstract.html }}</ref>
<ref>{{cite journal | title=Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci.| author= Malley R. Lipsitch M, Stack A, Saladino R, Fleisher G, Pelton S, Thompson C, Briles D, Anderson P. | journal=Infect Immun | year=2001 | volume=69 | pages=4870-4873 | url=http://iai.asm.org/cgi/content/full/69/8/4870 }}</ref>  It is believed that this improves vaccine efficacy and also avoids the need for injection.
 
The development of serotype-specific anticapsular monoclonal antibodies has also been an area of vaccine research in recent years.  These antibodies have been shown to prolong survival in a mouse model of pneumococcal infection characterized by a reduction in bacterial loads and a suppression of the host inflammatory response.<ref>{{cite journal |author=Burns T, Abadi M, Pirofski L |title=Modulation of the lung inflammatory response to serotype 8 pneumococcal infection by a human immunoglobulin m monoclonal antibody to serotype 8 capsular polysaccharide |journal=Infect Immun |volume=73 |issue=8 |pages=4530-8 |year=2005 |pmid=16040964}}</ref><ref>{{cite journal |author=Fabrizio K, Groner A, Boes M, Pirofski L |title=A Human Monoclonal IgM Reduces Bacteremia and Inflammation in a Mouse Model of Systemic Pneumococcal Infection |journal=Clin Vaccine Immunol |volume= |issue= |pages= |year= |pmid=17301214}}</ref>
 
==Interaction with ''Haemophilus influenzae''==
Both ''[[Haemophilus influenzae|H. influenzae]]'' and ''S. pneumoniae'' can be found in the human upper respiratory system.  A study of competition in a laboratory revealed that, in a petrì dish, ''S. pneumoniae'' always overpowered ''H. influenzae'' by attacking it with a [[hydrogen peroxide]] and stripping off surface molecules that ''H. influenzae'' needs for survival.
 
When both bacteria are placed together into a nasal cavity, within 2 weeks, only ''H. influenzae'' survives.  When both are placed separately into a nasal cavity, each one survives.  Upon examining the upper respiratory tissue from mice exposed to both bacteria, an extraordinarily large number of [[neutrophils]] immune cells were found.  In mice exposed to only one bacteria, the cells were not present
 
Lab tests show that neutrophils that were exposed to already dead ''H. influenzae'' were more aggressive in attacking ''S. pneumoniae'' than unexposed neutrophils.  Exposure to killed ''H. influenzae'' had no effect on live ''H. influenzae''.
 
Two scenarios may be responsible for this response:
 
# When ''H. influenzae'' is attacked by ''S. pneumoniae'', it signals the immune system to attack the ''S. pneumoniae''
# The combination of the two species together sets off an immune system alarm that is not set off by either species individually.
 
It is unclear why ''H. influenzae'' is not affected by the immune system response.<ref name="PLosPathog2006-Lysenko">{{cite journal | author=Lysenko ES, Ratner AJ, Nelson AL, Weiser JN | title=The role of innate immune responses in the outcome of interspecies competition for colonization of mucosal surfaces | journal=PLoS Pathog | year=2005 | pages=e1 | volume=1 | issue=1 | id=PMID 16201010}} [http://pathogens.plosjournals.org/perlserv/?request=get-document&doi=#10.1371/journal.ppat.0010001 Full text]</ref>


==References==
==References==
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[[Category:Streptococcaceae]]
[[Category:Polysaccharide encapsulated bacteria]]
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Latest revision as of 18:41, 5 July 2017

Streptococcus pneumoniae infection Microchapters

Home

Patient Information

Overview

Classification

Community Acquired Pneumonia
Endocarditis
Sinusitis
Bronchitis
Meningitis

Cause

Laboratory Findings

Medical Therapy

Primary Prevention

This page is about clinical aspects of the disease.  For microbiologic aspects of the causative organism(s), see Streptococcus pneumoniae.

For patient information click here.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]

Synonyms and keywords: Strep pnumoniae; Strep pneumoniae infection

Overview

Streptococcus pneumoniae, or pneumococcus, is a Gram-positive bacterium. It is a diplococcus, alpha-hemolytic member of the Streptococcus genus.[1] During the 19th century pneumonia was heavily associated with this pathogen. S. pneumoniae is known to be the cause of various different infections apart from pneumonia including endocarditis, meningitis, pericarditis, brain abscess, otitis media, osteomyelitis, acute sinusitis, septic arthritis, peritonitis, and cellulitis. In children as well as adults, S. pneumoniae is the most common cause of otitis media as well as bacterial meningitis.[2] Pneumonia caused by S. pneumoniae is usually found at the extremes of the age (in old or very young individuals). Streptococcus viridans also belongs to the family of alpha hemolytic bacteria but can e distinguished from S. pneumoniae by an optochin test. Streptococcus viridans are found to be insensitive to optochin where as S. pneumoniae are found to be optochin sensitive. The most potent virulence factor of S. pneumoniae is its polysaccharide capsule. Up to 91 various types of capsules have been discovered; each of these differ in virulence, drug resistance, prevalence, and distribution.

Classification

Streptococcus pneumoniae infections may be classified as follows:

 
 
 
 
 
 
 
 
Streptococcus Pneumoniae Infection
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Community Acquired Pneumonia
 
Endocarditis
 
Sinusitis
 
Bronchitis
 
Meningitis
 
 
 
 
 
 

Laboratory Findings

Depending on the nature of infection, an appropriate sample is collected from the infected area for laboratory identification. Commonly found

Laboratory Diagnosis

Diagnosis of streptococcus pneumoniae infection is generally made based on clinical suspicion along with a positive culture from a sample from virtually any place in the body.

Treatment

  • Streptococcus pneumonia treatment
  • 1. Lung (Community-acquired pneumonia)[6]
  • 1.1 Penicillin sensitive (minimum inhibitory concentration < 2 mcg/ml)
  • 2.Endocarditis[7]
  • Preferred regimen (1): Aqueous crystalline Penicillin-G 6 MU q4-6h IV for 4 weeks
  • Preferred regimen (2) (who are unable to tolerate beta lactams therapy): Vancomycin 15 mg/kg IV q12h (target trough concentration, 10-15 mcg/mL); for troughs of 15-20 mcg/mL (MIC, 1 mcg/mL or less), 15-20 mg/kg (actual body weight) IV q8-12h for most patients with normal renal function
  • Preferred regimen (3) (If the isolate is resistant (MIC 2 g/mL) to cefotaxime): Cefotaxime 1-2 g q8-12h IV/IM (max dose: 12 g/24 hr) AND Vancomycin 15 mg/kg/day IV q12h AND Rifampin 300 mg IV/PO q8h for 6 weeks, in combination with appropriate antimicrobial therapy
  • Alternative regimen (1): Cefazolin 0.5-2 g q8h IV/IM (max dose: 12 g/24 hr)
  • Alternative regimen (2): Ceftriaxone 2 g IV q12h
  • Note : Streptococcus pneumoniae with intermediate doses minimum inhibitory concentration (MIC) 0.12 g/mL–0.5 g/mL Penicillin resistance (MIC 0.1 to 1.0 g/mL) or high Penicillin resistance (MIC 2.0 g/mL) is being recovered from patients with bacteremia.
  • 3. Sinuses (sinusitis)[8]
  • Empiric therapy
  • 3.1 For initial empiric treatment of acute bacterial rhinosinusitis in adults
  • 3.2 For second-line high-dose therapy for acute bacterial rhinosinusitis in adults
  • Preferred regimen: Amoxicillin 2 g/Clavulanate 125 mg PO bid recommended by the Infectious Disease Society of America (IDSA).
  • Note: The second line high dose therapy is recommended in adults who have failed initial therapy, in regions of high endemic rates (10% or greater) of invasive Penicillin-nonsusceptible Streptococcus pneumoniae, severe infection.
  • 4. Bronchi (acute exacerbation of chronic bronchitis)[9]
  • Preferred regimen (1): Amoxicillin 875 mg PO q12h or 500 mg PO q8h
  • Preferred regimen (2): Doxycycline 100 mg PO q12h
  • 5. CNS (meningitis)[10]
  • Empiric therapy
Note: Middle ear infections (otitis media), peritoneum infections (spontaneous bacterial peritonitis), pericardium infections (purulent pericarditis), skin infections (cellulitis) and eye infections (conjunctivitis) caused by Streptococcus pneumonia.

Prevention

  • General principles
  • 1. Pneumovax (23-valent) prevents bacteremia; impact on rates of CAP are modest or nil.
  • 2. Prevnar vaccine for children <2 yrs age prevents invasive pneumococcal infection in adults by herd effect. Impact is impressive with rates of invasive pneumococcal infection down 80% in peds and 20-40% in adults.
  • 3. Risk for bacteremia in splenectomy, HIV, smokers, black race, multiple myeloma, asthma.

Vaccination in the USA

  • A heptavalent pneumococcal conjugate vaccine vaccine (PCV 7) (e.g. Prevnar) is recommended in the USA since 2000 for all children between 2 to 23 months of age. PCV 7 is also recommended for children between 24 to 59 months of age if they are at risk of getting the infection.
  • The vaccination is generally given as a 4-doses series at 2, 4, 6 & 12 - 14 months of age.
  • The PCV 7 provides a good protection is good against deep pneumococcal infections (especially septicemia and meningitis). Some new vaccines being tested are 9- and 13-valent. No protection is offered if the child is infected by a pneumococcus serotype that is not a component of the current vaccine. The ability of capsular-polysaccharide conjugate vaccines to promote the spread of non-covered serotypes and the limitation has led to research into vaccines that would provide species-wide protection.
  • Pneumovax™ which is one trade name for the Pneumococcal polysaccharide vaccine which approximately provides 85% protection for 5 or more years in individuals younger than age 55.
  • Individuals at a high risk of infection such as those who are 65 years or older are recommended to get the vaccine.
  • Generally it is a single once in a lifetime dose as it is associated with high risk of side effects with repitition. The standard 23-valent vaccines are not effective for children who are less than two years old.
  • The American College of Physicians in its current guidelines recommends immunization administration between 2 to 65 years old in the presence of indications, or at age 65. If someone received the immunization before age 60, the guidelines call for a one-time revaccination.

Vaccination in the UK

  • It was announced in February 2006 that the UK government would introduce vaccination with the conjugate vaccine in children aged 2, 4 and 13 months.[11][12] This is expected to start on September 4, 2006 and is to include changes to the immunisation programme in general.[13]

Vaccination Worldwide

References

  1. Ryan KJ; Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed. ed.). McGraw Hill. ISBN 0-8385-8529-9.
  2. Dagan R. "Treatment of acute otitis media - challenges in the era of antibiotic resistance". Vaccine. 19 Suppl 1: S9–S16. PMID 11163457.
  3. Siemieniuk, Reed A.C. (Nov 2011). "The persisting burden of invasive pneumococcal disease in HIV patients: an observational cohort study" (PDF). BMC Infectious Diseases. 11: 314. doi:10.1186/1471-2334-11-314. PMC 3226630. PMID 22078162. Unknown parameter |coauthors= ignored (help)
  4. Pikis, A; Campos, JM; Rodriguez, WJ; Keith, JM (2001). "Optochin resistance in Streptococcus pneumoniae: mechanism, significance, and clinical implications". Journal of Infectious Diseases. 184 (5): 582–590. doi:10.1086/322803. PMID 11474432.
  5. Zheng CJ, Sohn MJ, Kim WG. (2006). "Atromentin and leucomelone, the first inhibitors specific to enoyl-ACP reductase (FabK) of Streptococcus pneumoniae". Journal of Antibiotics. 59 (12): 808–12. doi:10.1038/ja.2006.108. PMID 17323650.
  6. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC; et al. (2007). "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults". Clin Infect Dis. 44 Suppl 2: S27–72. doi:10.1086/511159. PMID 17278083.
  7. Baddour LM, Wilson WR, Bayer AS, Fowler VG, Bolger AF, Levison ME; et al. (2005). "Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America". Circulation. 111 (23): e394–434. doi:10.1161/CIRCULATIONAHA.105.165564. PMID 15956145.
  8. Chow AW, Benninger MS, Brook I, Brozek JL, Goldstein EJ, Hicks LA; et al. (2012). "IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults". Clin Infect Dis. 54 (8): e72–e112. doi:10.1093/cid/cir1043. PMID 22438350.
  9. Bartlett, John (2012). Johns Hopkins ABX guide : diagnosis and treatment of infectious diseases. Burlington, MA: Jones and Bartlett Learning. ISBN 978-1449625580.
  10. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM; et al. (2004). "Practice guidelines for the management of bacterial meningitis". Clin Infect Dis. 39 (9): 1267–84. doi:10.1086/425368. PMID 15494903.
  11. "Children to be given new vaccine" BBC News, February 08, 2006, retrieved August 25, 2006
  12. "Pneumococcal vaccine added to the childhood immunisation programme" February 08, 2006
  13. "Changes to the immunisation programme in the UK" Meningitis Research Foundation, retrieved August 25, 2006
  14. "PneumoADIP website"