Proposal to include antibacterial drugs for treating upper and lower respiratory infections in Children

Index Summarystatement Publichealthrelevance Amoxicillin/Ampicillin Penicillin Cloxacillin

Amoxicillin+Clavulanicacid Erythromycin/Azithromycin Chloramphenicol Cotrimoxazole Gentamicin Ceftriaxone/Cefotaxime References

Table1Communityacquiredpneumonia Table2OralvsParenteraltherapyforCAP Table3Otitismedia Table4Sorethroat

1.

Summarystatement

Communityacquiredacuteupperandlowerrespiratoryinfections(LRI)arecommon in children. Although viruses cause a proportion of these infections, bacterial infections of the respiratory tract are important preventable causes of mortality and morbidity among children. In childrenaged 1m to5yrs, pneumonia is responsible for 19% of deathsand is the single most common cause of mortality. Evidence shows that prompt therapy with appropriate antimicrobials can significantly reduce mortality associated with community acquired pneumonia (CAP). Reducing mortality among children is on of the Millennium DevelopmentGoals. Acute streptococcal tonsillo pharyngitis and bacterial otitis media are other common infections in children with possibility of serious complications. Penicillin therapy can prevent development of long term complications following streptococcal infections. Treatment of acute otitis media can reduce complications like mastoiditis, chronic otitis mediaanddeafnessespeciallyinchildrenfrompoorercommunities. Since majority of these infections are caused by S pneumoniae and H influenzae, empiricaltherapyofcommunityacquiredrespiratoryinfectionsinchildrenismainlyaimed at these two bacteria. However, resistance has appeared among these bacteria to several commonlyusedantimicrobialsandsothereisaneedforalternativechoices.Otherbacteria, requiring different drugs, can also be responsible for community and hospital acquired respiratoryinfections.Henceseveralantimicrobialshavetobeavailableontheessentialdrug listforeffectivemanagementofrespiratoryinfectionsinchildhood.Mostoften,therapyfor respiratory infections are initiated based on clinical findings, especially at primary care facilities. Drugs being requested include those for use at community level and also those requiredfortreatmentofseverecommunityandhospitalacquiredrespiratoryinfections. 2. 3. 4. Internationalnonproprietyname(INNgenericname)ofthemedicines Namesoforganizationsconsultedandorsupportingtheapplication NameofthefocalpointinWHOsubmittingorsupportingapplication

5. Information supporting public health relevance (epidemiological information on diseaseburden,assessmentofcurrentuse,targetpopulation) Lowerrespiratoryinfections In children aged 1m to 5yrs, pneumonia is responsible for 19% of deaths and is the single most common cause of mortality [1]. About 26% of neonatal deaths are caused by severe bacterial infections, a large proportion of which is pneumonia/sepsis. The burden of acute respiratory infections and the mortality due to this is significantly more in developing countries. 150 million episodes of pneumonia occur per year among children below five yearsindevelopingcountries,accountingfor95%ofnewcases.Pneumoniarelatedmortality is2%indevelopedcountriescomparedto21%eachinSouthAsiaandSubSaharanAfrica. Riskofinfectionismoreforundernourishedchildren,childrensufferingfrominfectionslike AIDS,measlesetcandforthoselivinginovercrowdedsituations. Effective interventions are available but reach too few children. Less than 20% of children with pneumonia receive antibiotics. Main reason is the health seeking behaviour. If treatmentforpneumoniaisuniversallydelivered,600,000livescanbesavedeveryyearata cost of $600 million [1]. Reducing mortality among children is one of the millennium developmentgoals. Simple guidelines based on respiratory rates and chest in drawing while breathing are availableandpopularisedforclinicaldiagnosisofpneumoniaandforassessingseverityof infection. A metaanalyses of 9 studies on community based management of pneumonia usingtheseguidelinesshowedthatoverallmortalitycouldbereducedby27%,20%and24% respectively among neonates, infants and children up to 4yrs of age [2]. The larger than expectedbenefitinthesestudiesunderscoretheneedfortreatingchildrenwithpneumonia effectivelyataprimaryhealthcarelevel. Choice of therapy depends on the aetiology of infection. Data on relative frequencies of pathogens causing LRI including pneumonia in children in different parts of the world is limited. Streptococcus pneumoniae is responsible for more than 50% cases of pneumonia and proportionately more of fatal cases in most developing countries. In developed countries incidence of this infection has fallen after introduction of pneumococcal vaccines, but still continues to be the most important cause [3]. This is followed by Haemophilus influenzae whichcausesabout20%ofcases.[1].OtherbacteriaincludeStaphylococcusaureus,Klebsiella pneumoniae, Mycoplasma pneumoniae and others. A recent Cochrane review [4] on therapies forCAP,report10studieswereaetiologicalagentswereidentified.Only324/4009(8%)had bacteria isolated from blood cultures 169 (52%) S. pneumoniae, 102 (32%) H. influenzae, 11 (3%) S. aureus and 42 (13%) other pathogens. Most bacteria isolated were susceptible to commonlyusedantimicrobials,butthestudiesweredoneover10yrsago.Sincemajorityof infectionsarecausedbySpneumoniaeandHinfluenzae,empiricaltherapyshouldcoverthese twopathogens.Atypicalpathogenswerealsoidentifiedinsomestudies213/885(24%)were positiveforM.pneumoniae(underfiveyears57/388(15%))and151/825(18%)forChlamydia spp (under five years 41/ 388 (11%)). Viruses also cause LRI in children. In neonates Gram negativebacilliarecommoncausesofpneumonia. Immediate antimicrobial therapy is recommended for children diagnosed to have pneumonia [1]. The drugs recommended for use at primary care level are Cotrimoxazole andamoxicillin.However,withincreasingprevalenceofresistance,otherdrugsmayneedto beusedincertainsituations.Similarly,inchildrenwithsevereinfectionsandinthosewith 3

underlying disorders like severe malnutrition or HIV infections, the choice of antibacterial therapymaydiffer.Antibacterialdrugsthatareshowntobeeffectiveandrecommendedfor use in these alternative regimes include macrolides, cloxacillin, penicillin, gentamicin, chloramphenicolandsecondandthirdgenerationcephalosporins[5]. Prophylactic use of cotrimoxazole, in HIV infected children and in infants born to HIV positive mothers, is shown to prevent pneumonia and significantly reduce mortality [1]. Routineantibacterialtherapyisnotrecommendedforacutebronchitis,bronchiolitis[68], cough associated with viral upper respiratory infections and wheeze [9]. 90% of croup has viralaetiologyandantibacterialtherapyisofnouse.However,epiglottitismostlyduetoH influenzaerequireantimicrobials[10]. Some of these drugs should be available at the community level. With this comes the responsibility to prevent misuse of antimicrobials. Training of health workers to diagnose infections requiring antibacterial therapy, guidelines for clinical management of acute respiratoryinfectionsindifferentsettingsandsupervisionwillhelpinthisregard. Sorethroat Sorethroatoracutetonsillopharyngitisisaverycommonconditioninthecommunityand manyseektreatmenteventhoughitisselfcuring.Majorityofthroatinfectionsarecausedby viruses and so require no antibiotics. Those caused by Group A haemolytic streptococci can lead onto complications like Rheumatic fever and heart disease (RF/RHFD) and glomerulonephritis. It is however, difficult to clinically differentiate streptococcal tonsillo pharyngitisfromviralinfectionsandguidelineshavelowsensitivity(<15%)forspecifically diagnosing this infection [9]. A recent Cochrane review on antibiotic therapy for clinically diagnosed sore throat showed that therapy reduces incidence of rheumatic fever by two thirdsandthatincidenceofsuppurativecomplicationslikeotitismediaandquinsyarealso reduced[11].Althoughtherewasatrendtowardsreductioninglomerulonephritis,numbers werenotsufficient.Therewasnotmuchdifferenceintimetorecoveryfromsorethroatitself between treated and untreated patients. Therefore treatment of sore throat is basically to prevent complications especially RF/RHD. Where facilities exist, diagnosis of streptococcal pharyngitis is to be made based on antigen detection tests or culture[12, 13]. Since specific clinical diagnosis of streptococcal sore throat is very difficult, physicians in settings where facilitiesforcultureorrapiddiagnostictestsdonotexist,candecidetotreatsorethroatwith antibioticsbasedontheprevalenceofRF/RHDinthecommunity[9].Thistendstobehigher indevelopingcountries.Penicillinhasthemostevidenceforthiseffect. Otitismedia Acuteotitismedia(AOM)isanothercommoninfectioninchildrenforwhichantibioticsare prescribed. Most cases occur in children between 6 months to 36 months[10]. Upto 71% of childrensufferatleastoneattack.BacteriaresponsibleareSpneumoniae,HinfluenzaeandM catarrhalis.About40%ofcasesareduetoviruses[14].Inabout80%ofchildrentheinfection resolveswithoutantibioticsinafewdaystime[14].Areview[15]ofeightplacebocontrolled trials in developed countries showed that antibiotics do not significantly affect out comes like pain or incidence of complications like mastoiditis. However there are geographic differences in the incidence of mastoiditis. While in the US it is only 0.4%[14] the complication is common in developing countries[16]. The authors of the Cochrane review statethatantibiotictreatmentmayplayanimportantroleinreducingtheriskofmastoiditis in populations where it is common. Acute infections can also lead to chronic otitis media 4

(COM) which is a preventable cause of deafness. COM is a public health problem and is more common in developing countries and in poor communities. Early diagnosis and management of AOM helps to prevent COM. So in developing countries antibiotics are usuallyrecommendedforAOMtopreventcomplicationslikemastoiditisandCOM[17,18]. Children below 2 yrs and those with severe infections are more likely to benefit from antibiotic therapy[14]. In countries where mastoiditis is rare, children over 2 without high fever or vomiting could generally be treated with analgesia, and antibiotic use can be delayedtothoserequiringit[15]. TherearealsoissuesrelatedtodiagnosisofAOM[9].Theseincludeconsensusonguidelines (clinicalanduseofotoscope),feasibilityetc. For children at risk of future episodes of AOM, the available evidence suggests that antibioticsgivenonceortwicedailywillreducetheprobabilityofAOMwhilethechildison treatment[19].InmostcasesofCOMsystemicantibiotictherapyisnotrequired[20,21],but maybeofbenefitinsomecases[18]. Sinusitis Sinusitis develops in about 510% of children with Upper respiratory infections[22]. The condition is usually diagnosed clinically by the presence of purulent nasal discharge especially from middle meatus, pain on pressure over sinuses etc. Thebacteria responsible are similar to that causing otitis media S. pneumoniae and H influenzae. M. catarrhalis, S aureusandanaerobesarealsocausativeagents.Hereagain,thereisnoconclusiveevidenceto recommendroutineantibiotictherapy.However,antibiotictherapyisrecommendedinsome cases[22,23]. Theantibacterialdrugsrequiredfortreatingcommonupperandlowerrespiratoryinfections arediscussedindetailbelow. Amoxicillin Ampicillin Penicillin Amoxicillinplus Clavulanicacid Cloxacillin Cotrimoxazole Erythromycin Azithromycin Chloramphenicol Gentamicin Ceftriaxone/ Cefotaxime Firstlinetherapyforcommunityacquiredpneumonia,otitis media Forseverepneumoniaincludingthoseinneonates, streptococcalsorethroat ForpenicillinaseproducingHinfluenzaeinfectionsLRI andotitismedia Forstaphylococcallunginfection Alternativetherapyforcommunityacquiredpneumoniain resourcepoorsettings Alternativeinthosewithpenicillinhypersensitivityandfor LRIcausedbyorganismslikemycoplasma,otitismedia ForepiglottitiscausedbyHinfluenzae,severecommunity acquiredpneumonia Forseverepneumoniasofunknownaetiologyinnewborn andchildren,tobeusedtogetherwithpenicillin Severecommunityacquiredpneumonia,hospitalacquired pneumonia 5

Amoxicillinandampicillin Trialssummarizedintables Amoxicillin

AddoYobo2004 Catchup,2002 Harris,1998 Jibril,1989 Kogan,2003 Strauss,1998 Tsarouhas,1998 APPISgroup2004 Campbell,1988 Deivanayagam,1996 Campbell,1988 1. Formulationproposedforinclusion Appleman,1991 Burke,1991 Damoiseaux,2000 Kaleida,1991 VanBuchem,1981(a) VanBuchem,1981(b) Leelarasamee,2000 Taylor,1977

Ampicillin
Halsted,1968 Howie,1972 Laxdal,1970

Amoxicillin250mgtabcapforperoraluse Amoxicillin125mg/5mlsuspensionforperoraluse

OnWHOessentialdrugliststrengthmaybedifferent Ampicillin250mg/vialor500mg/vialforinjection

Whenparenteraltherapyisindicated,ampicillinisusedandisonWHOEDL 2. Internationalavailability(sources) Amoxicillin TabcapUNFPA,MISSION,IMRES,JMS,MEDS,IDA,DURBIN,ORBI,ACTION Powder for suspension UNFPA, MEDS, MISSION, IDA, IMRES, JMS, DURBIN, ACTION, ORBI Ampicillin 250mg/vialMEDS 500mg/vialACTION,IDA,IMRES,MEDS,UNFPA,JMS,ORBI,MISSION,DURBIN

3. Whether listing is requested as individual drug or as an example of a therapeutic group Individualdrugs 4. Treatment details(dosage, regimen, duration, references to existing WHO or other guidelines,needforspecialdiagnosticortreatmentfacilitiesandskills) Amoxicillin and ampicillin[24, 25] are amino penicillins and act by inhibiting synthesis of cell walls in bacteria. They are penicillinase susceptible and have similar antibacterial spectrum. They are active against most bacteria causing respiratory infections like Streptococcus pneumoniae, Streptocccus pyogenes and Haemophilus influenzae which do not 6

producelactamase.Sotheyareusedforavarietyofrespiratorytractinfections.Thedrug also has activity against a few aerobic Gram negative bacilli and enterococci and so is also usedforotherinfectionsincludingurinaryinfections. Amoxicillin is acid stable and is absorbed rapidly and completely from GIT. Peak plasma concentrations are reached at 2 hours. Food does not interfere with absorption. Perhaps because of more complete absorption, incidence of diarrhea is less than that following administration of ampicillin. Effective concentrations of orally administered amoxicillinaredetectableintheplasmafortwiceaslongaswithampicillinandsorequire only less frequent dosing. Therefore this is the preferred oral agent[25]. Ampicillin is preferred for parenteral use IM or IV. These drugs are distributed well in tissues and reaches therapeutic levels in pleural fluid and middle ear fluid. Drug entry into CSF is minimalwhenthemeningesisnormal.Mostoftheantibioticisexcretedinanactiveformin theurine. Bacterialresistancetotheseantibioticsarealreadyhighinmostareas.Resistancemay beduetoproductionof lactamasesthatdestroytheantibioticsorduetoalterationsinor acquisition of novel penicillinbinding proteins (PBP). Decreased drug entry into the bacteriumand/oractiveeffluxoftheantibiotic,asseenmostlyinGramnegativebacteria,can alsocauseresistance. lactamasemediatedresistance,foundinHinfluenzaecanbeovercome using a combination of amoxicillin and clavulanic acid which is a lactamase inhibitor . Prevalenceofthisresistancevariesandcanbeapproximately215%[2628].ResistanceinS. pneumoniae,isPBPmediatedandsocannotbeovercomeusingclavulanicacidcombination. Uptoabout35%ofS.pneumoniaeisolatedfromcommunityacquiredpneumoniasintheUS show resistance to penicillins[3]. The prevalence varies in different areas[2931]. In vitro resistance however, does not have a consistent relationship with clinical treatment failures[9]. Infections due to penicillin resistant pneumococci, especially the ones with intermediate resistance may respond to amoxicillin or ampicillin therapy but dosage may needtobeincreased[3,25]. Mycoplasmapneumoniae,anotheragentofLRIinchildrendoesnothavecellwallsand soarenaturallyresistantto lactamantibiotics.Amoxicillinmaybeofuseintreatinglung infectionswhereanaerobesmaybeinvolved. Therapeuticusesinrespiratoryinfections 1. Communityacquiredpneumonia.Forsevereinfectionsalsooralamoxicillinisfound tobeeffective 2. Otitismediawhereantibioticsareindicated[14,32] 3. Sinusitiswhereantibioticsarerequired[22,33] 4. Streptococcaltonsillopharyngitisasanalternativetopenicillin 5. Cysticfibrosisforbacterialinfection It is also used for prophylaxis during oral and respiratory procedures to prevent endocarditisinthoseatrisk.

Dosage Amoxicillin4590mg/kgperdaydependingonsiteofinfection,severityofinfectionand possibilityofpenicillinresistantpneumococci[22,25]as23divideddoses.Maximumdose is2gmperday.ForCAP,IMCIrecommends5days[21].Recentdatashowsthatthreedays maybesufficient[9] AmpicillinIMorIV25mg/kgfourtimesdaily(threetimesdailyforneonates) When there is severe renal impairment (creatinine clearance < 10ml/min/1.73m2) dose or frequencyistobereduced.Canchangetoamoxicillinafterclinicalresponse. Therapy for pneumonia, otitis media, sinusitis and sore throat can be initiated based on clinical diagnosis. Chest xray will help in confirming diagnoses and assessing severity of LRI.Fordocumentingspecificmicrobialpathogenandresistancepatternslaboratoryfacility forcultureandsusceptibilitytestingisrequired. Amoxicillin is recommended as an alternative for CAP and ear infections in WHO IMCI guidelines[21, 34]. Amoxicillin is also recommended for secondary bacterial infections followingbronchiolitis[34].ItisrecommendedforAOMandsinusitis[10].Otherguidelines [3, 5, 14]also recommend this drug for these indications. Parenteral ampicillin is recommended for neonatal sepsis and in serious bacterial infections in malnourished children along with gentamicin[34]. Amoxicillin can be used for acute streptococcal pharyngitis[12] 5.Summaryofcomparativeeffectivenessinavarietyofclinicalsettings:Identificationof clinicalevidence(searchstrategies,systematicreviewsidentified,reasonsforselection, /exclusionofparticulardata) A recent Cochrane review has found amoxicillin [4] to be better than co trimoxazole for community acquired pneumonia in two multicenter studies published in 2002 and 1998 respectively and involving 2054 children (1132 in the cotrimoxazole group and 922 in the amoxicillin group) between 2 months and 59 months of age. The diagnosis of pneumonia wasbasedonclinicalevidence.Boththestudiesweredoubleblindedandscoredfivepoints on the Jadad scale. The failure rate was significantly higher in the cotrimoxazole group compared to the amoxicillin group (OR 1.33; 95% CI 1.05 to 1.671). In one study involving 170childrenaged6monthsto18yearsandcomparingAmoxicillinwithprocainepenicillin (threeonJadadscale)failureratesweresimilarinthetwogroups(OR0.75;95%CI0.17to 3.25). On comparing amoxicillin with coamoxiclavulanic acid, one openlabel study involving100childrenbetween2and12yearsofage(twoonJadadscale)foundthatcure ratewasbetterwithcoamoxiclavulanicacid(OR10.44;95%CI2.85to38.21).Inatrial(2on Jadadscale)involving47childrenagedbetween1mand14yearswithclassicalpneumonia comparing azithromycin with amoxicillin, all recovered in both groups[4]. Indirect comparisonsdonebytheauthorsshowedthatcurerateswerebetterintheamoxyiillingroup comparedtothechloramphenicolgroup(OR4.26;95%CI2.57to7.08)andfailurerateswere lowerintheamoxicillingroup(OR0.64;95%CI0.41to1.00). The review [4] also compared treatment in hospitalised patients. Penicillin and amoxicillin performed equally well (as detailed in next para). On comparing Ampicillin with chloramphenicol plus penicillin, one trial involving 115 children between 5 months and 4 years of age (three on Jadad scale), showed cure rates (OR 0.48; 95% CI 0.15 to 1.51) and

duration of hospitalization to be similar in the two groups (weighted mean difference (WMD)0.1;95%CI1.13to0.93) Studiesincludedinthereviewaresummarisedintable1 Another Cochrane review to compare oral versus parenteral antibiotics for treatment of severecommunityacquiredpneumonia,reportontwostudies[35].Bothfoundoraltherapy tobeaseffectiveasparenteraltherapy.Oneofthosestudiesreportedin2004evaluated1702 patients comparing oral amoxicillin with intravenous penicillin for two days followed by oral amoxicillin. After 48 hours, treatment failure occurred in 161/845 (19%) in the amoxicillingroupand167/857(19%)intheparenteralpenicillingroup.Recoverywassimilar inbothgroupsat5and14days.Characteristicsofthesestudiesareintable2. To find out whether clinical failure rates due to increasing MIC of amoxicillin among S pneumoniae and H influenzae can be reduced, a randomised clinical trial was undertaken to compare standard dosage with double doses of amoxicillin. There was no significant difference in cure rates between the two regimes in children aged 2m to 59m with non severepneumonia.Thisrecentreportshowsthattreatmentwaseffectiveinbothgroups[36], withaclinicalfailurerateof5.9%onday14inthegroupreceivingstandarddosage.Another recent study reported that failure rates with amoxicillin is higher among HIV infected children with severe pneumonia compared tonon infected and the authors have called for alternateempiricaltherapyregimensinareaswithhighHIVprevalence[37] Otitismedia A Cochrane review found that all children with otitis media do not require antibiotic therapy, but antibiotics can benefit some groups [15]. Studies included in this review are summarised in table 3 Amoxicillin is effective for otitis media [38]. High dose (90mg/kg) amoxicillin is found useful for treating children with otitis media even when resistant bacteriawereisolated[32].Highdosetherapyisaseffectiveasazithromycintreatment[39] Sinusitis There is no conclusive evidence to show that routine antibiotic therapy is useful[23, 40]. However,amoxicillinisrecommendedifonedecidesonantibiotictherapy[22,23,33]. Thereisalsosomeevidencetoshowthatamoxicillinusecanfacilitatecolonisationwithnon susceptibleorganisms[41] 6. Summaryofcomparativeevidenceonsafety It is a safe drug in children[25].Hypersensitivity reactions are by far the most common adverse effects noted with the penicillins. The overall incidence of such reactions to the penicillins varies from 0.7% to 10% in different studies. Anaphylaxis occurs in less than 0.05%.Childrenwhoareallergictoonepenicillinwillbeallergictoallotherpenicillinsand mayalsobehypersensitivetocephalosporinsandother lactamantibiotics.Apatientwith manifestallergytoonepenicillinisatagreaterriskofreactionifanotherisgiven.Reactions mayappearintheabsenceofapreviousknownexposuretothedrugandwithanydosage or form of penicillin. Manifestations include maculopappular rash, urticarial rash, fever, bronchospasm, and anaphylaxis. Rashes can occur due to reasons other than hypersensitivityandsohastobecarefullyevaluatedbeforemakingadiagnosisofpenicillin hypersensitivity. Chances of rash and severity are more in those suffering from EBV infection. 9

Diarrhoeaandvomitingcanoccurandaremorecommoninchildren.Antibioticassociated diarrhoeacanalsooccur.VerylargedosescancauseCNStoxicityandconvulsions. 7. Summaryofavailabledataoncomparativecost TabcapUS$0.0147per250mgcap Powderforsuspension0.0037/mlie0.0185for5mlof125mg Ampicillininjection250mg0.1048/vial 500mg0.1057/vial 8. Comparative cost effectiveness presented as range of cost per routine out come (cost percase,costperoutcomeetc) Amoxicillin therapy with capsules is cheaper than with suspension and is only about one tenththecostofparenteraltherapy.CostforonedaywithcapsuleisaroundUS$0.1 9. Summaryofregulatorystatus FDAapproved 10. Availabilityofpharmacopoeialstandards AmpicillinislistedinUS,EuropeanandInternationalpharmacopoeias AmoxicillinislistedinUSandEuropeanpharmacopoeia 11. ProposedtextforWHOmodelformulary Amoxicillin/Ampicillinfororal/parenteraluserespectively These have action against common pathogens causing community acquired pneumonia, acuteotitismediaandsinusitis Usesinrespiratoryinfections Communityacquiredpneumonia,asfirstlinetherapy. Otitismediaasfirstlinetherapy Sinusitiswhereantibioticsarerequired Streptococcaltonsillopharyngitisasanalternativetopenicillin Dosage Amoxicillin4590mg/kgperdayas23divideddoses.Maximumdose2gm/d. AmpicillinIMorIV25mg/kgfourtimesdaily(threetimesdailyforneonates) Contraindication Hypersensitivity Precautions Checkforhypersensitivity When there is severe renal impairment (creatinine clearance < 10ml/min/1.73m2) dose or frequencyistobereduced AdversereactionsLowincidence Hypersensitivity Rash Diarrhoeaandvomiting Antibioticassociateddiarrhoea. CNStoxicityandconvulsionswithlargedoses 10

Penicillin
Trialssummarizedintables
AddoYobo2004 Camargos,1997 Campbell,1988 Cetinkaya,2004 Deivanayagam,1996 Duke,2002 Keeley,1990 Sidal,1994 Tsarouhas,1998 APPISgroup2004 Campbell,1988 Laxdal,1970 Mygind,1981 Thalin,1985 Bennike,1951 Chapple,1956 Dagnelie,1996 DeMeyere,1992 ElDaher,1991 Krober,1985 Middleton,1988 Nelson,1984 Pichichero,1987 Siegel,1961 Whitfield,1981 Zwart,2003

1. Formulationproposedforinclusion Parenteraluse BenzylPenicillin(PenicillinGsodium)1muaspowderforreconstitution Benzathinebenzylpenicillin1.2muaspowderforreconstitution Procainebenzylpenicillin1muaspowderforreconstitution Oraluse Phenoxymethylpenicillin(PenicillinV) Tabcap250mg Suspension250mg/5mlisavailable,buttabcapmaybebetter

AlldrugsonWHOessentialdrugliststrengthmaybedifferent

2. Internationalavailability(sources) Penicillin G 1mu powder IDA, UNFPA, MEDS, MISSION, IMRES, JMS, DURBIN, ORBI, ACTION Procainepenicillin1mupowderUNFPA,MISSION,IMRES,IDA Benzathinepenicillin1.2mupowderMISSION,IDA,IMRES,ORBI Phenoxymethylpenicillin250mgtabcapIDA,UNFPA,MEDS,MISSION,IMRES,JMS, DURBIN,ORBI,ACTION Phenoxymethylpenicillin250mg/5mlsuspension 3. Whether listing is requested as individual drug or as an example of a therapeutic group Individualdrug

11

4. Treatment details(dosage, regimen, duration, references to existing WHO or other guidelines,needforspecialdiagnosticortreatmentfacilitiesandskills) Penicillinisa lactamantibioticwhichactsbyinhibitingsynthesisofbacterialcellwall[24]. It is susceptible to lactamases produced by bacteria. Penicillin G is destroyed by gastric acidandisnotrecommendedfororaluse.AfterIMinjection,peakplasmaconcentrationsare obtainedin 15to30min.halflifeisonlyabout30min.Thedrugdiffuseswellintotissues and fluids, but penetration into CSF is low when there is no meningeal inflammation. It is excreted in urine. To prolong therapeutic levels in the body, repository preparations are employed. Two such compounds in use are penicillin G procaine and penicillin G benzathine. Such agents release penicillin G slowly from the injection site and produce persistentconcentrationsofantibioticintheblood.Afteraninjectionofprocainepenicillin, peak levels are achieved in 13hrs and falls to very low levels in 24 hrs. After benzathine penicillin,antibioticeffectremainsforanaverageof26days.PenicillinVisnotdestroyedby gastricacidandsocanbeadministeredorally. Penicillin has activity against most Streptococci including S. pyogenes and S. pneumoniae. However,penicillinresistantS.pneumoniaearebecomingmorecommonandarecommonin paediatricpopulationsbutprevalencevaries[3,2931].PenicillinresistanceisPBPmediated in S pneumoniae and so cannot be overcome using lactamase inhibitors. Many penicillin resistant pneumococci are also resistant to thirdgeneration cephalosporins. However, they stillmayrespondtolactamtherapy. More than 90% of Staphylococci are now resistant to penicillin. Among respiratory pathogens, Corynebacterium diphtheriae are susceptible to penicillin. With the exception of a few anaerobic Gram negative bacteria (eg Bacteroides fragilis) anaerobes are susceptible and solunginfectionswhereanaerobesareinvolvedmayrespond. Therapeuticusesofpenicillininrespiratoryinfection Severecommunityacquiredpneumonia(withgentamicininsomecases) Empiricaltherapyofsepsis/pneumoniainneonatesalongwithgentamicin StreptococcalpharyngitisthereisvirtuallynoresistancetopenicillinamongSpyogenesand itbringsabout98%cure Otitismediaasanalternativetoamoxicillin(penicillinGorV) Diphtheria Prophylacticusetopreventrheumaticfeverafterstreptococcalinfection Dosage PenicillinG 50,000units/kgevery6hours.Changetooralafterabout3days Can be administered intramuscular or slow intravenous or intravenous infusion. Intravenousrouteisrecommendedforinfantsandneonates.Useisinsevereinfections. PenicillinV 125mg,250mgor500mgorally4timesadaybasedonageandweight Thisshouldnotbeusedforsevereinfections.Itisusedforprophylaxistopreventrecurrent streptococcal infection in rheumatic fever. It can also be used for streptococcal tonsillo 12

pharyngitis, otitis media and for continuing therapy after clinical response with benzyl penicillin. Cure rate may be lower than with benzathine penicillin for tonsillo pharyngitis[10]. Prophylaxis1mto6yrs125mg;6yrsto18yrs250mgtwicedaily Procainepenicillinisaddedinsomeareastobenzathinepenicillin[10] Benzathinepenicillin1.2muIMoncefortherapyofacutestreptococcaltonsillopharyngitis. Single dose therapy ensures compliance and decreases cost. For prophylaxis, the drug is givenevery34wks.(forchildrenlessthan6yrs0.6muisused)[10] Reducedoseifsevererenalimpairment Treatment with penicillin is initiated based on clinical diagnosis for pneumonia, tonsillo pharyngitis,neonatalpneumonia/sepsisandfordiphtheria. PenicillinGisrecommendedasfirstlinetherapyforchildrenwithsevereCAPandsecond linealongwithgentamicinforverysevereCAP[34].Itisalsorecommendedforuseaspre referralsingledose[21].Itisrecommendedalongwithgentamicinforchildrenaged1wkto 2mwithseriousbacterialinfections(includingpneumonia)andinneonatalsepsis[21,34].It canbeusedinsecondarybacterialinfectionsfollowingbronchiolitis[34].Penicillinoralor parenteral (benzathine G or mixture of benzathine and procaine as single dose) is recommendedforacutestreptococcalpharyngitis[12,13].Itisalsoanalternativefortreating AOM [10]. BNF C also recommends penicillin for severe community acquired lobar pneumonia and in neonates [5]. For diphtheria procaine penicillin is recommended for 7 days[34] 5. Summary of comparative effectiveness in a variety of clinical settings: Identification of clinical evidence (search strategies, systematic reviews identified, reasons for selection,/exclusionofparticulardata) Pneumonia The Cochrane review found that penicillin is a good option for hospitalised patients with pneumonia [4] and performance is similar to amoxicillin. Failure rates were similar in children treated either with amoxicillin or procaine penicillin. For severe pneumonia also injectablepenicillinandamoxicillinperformedequallywell.Comparisonbetweenprocaine penicillin and benzathine penicillin showed that cure rates were not significantly different between the two groups (OR 0.53; 95% CI 0.27 to 1.01), but failure rates were lower in the procainepenicillingroup(OR3.31;95%CI1.45to7.55).Twostudiesinthisreviewshowed thatprocainepenicillinissignificantlybetterthancotrimoxazoleforcure(OR2.64;95%CI 1.57 to 4.45). On comparing chloramphenicol with penicillin and gentamicin for severe pneumonia,needforchangeinantibiotics,deathratesandadverseeventsweresimilarinthe twogroups.However,readmissionratesbefore30daysfavouredthepenicillingentamicin combination(OR1.6;95%CI1.02to2.55). Another Cochrane review to compare oral versus parenteral antibiotics for treatment of severe community acquired pneumonia, report on a study which evaluated 1702 patients comparing oral amoxicillin with intravenous penicillin for two days followed by oral amoxicillin. After 48 hours, treatment failure occurred in 161/845 (19%) in the amoxicillin group and 167/857 (19%) in the parenteral penicillin group. Recovery was similar in both groupsat5and14days[35]. 13

Tonsillopharyngitis A Cochrane review has concluded that antibiotic treatment of sore throat significantly reducesincidenceofacuterheumaticfeverandsuppurativecomplicationslikeotitismedia, sinusitis and quinsy, although effect on recovery from sore throat itself is minimal [11]. Characteristicsofstudiesincludedinthisreviewaresummarisedintable4.Acuterheumatic fever was reduced to about one quarter that in the placebo group (RR 0.27;95% CI 0.12 to 0.60). Few studies examined antibiotics other than penicillin. Confining the analysis to penicillin alone resulted in no difference in estimated protection (RR 0.27; 95% CI 0.14 to 0.50).Thisreviewincludedbothadultsandchildren. For neonatal sepsis penicillin is used with gentamicin. For treatment of sepsis, lactams aloneareaseffectiveascombinationwithaminoglycosides[42] 6. Summaryofcomparativeevidenceonsafety Penicillinisarelativelysafedrug.Hypersensitivityisthemajoradverseeventandcanoccur inupto10%exposedindividuals.Anaphylaxisoccursin<0.05%.Childrenwhoareallergicto one penicillin will be allergic to all other penicillins and may also be hypersensitive to cephalosporins and other lactam antibiotics. Reactions may appear in the absence of a previous known exposure to the drug and with any dosage or form of penicillin. Manifestations include maculopapular rash, urticarial rash, fever, bronchospasm, and anaphylaxis. CNS toxicity including convulsions can occur with high doses or renal impairment. Interstitial nephritis, haemolytic anaemia, leucopenia, thrombocytopenia, coagulation disordersetcarealsodescribed Antibioticassociateddiarrhoeacanfolloworalpreparations Procaine related toxicity like dizziness, tinnitus, and head ache can occur with this formulation IMinjectionscauselocalpain 7. Summaryofavailabledataoncomparativecost PenicillinG1muUS$0.0655/vial Procainepenicillin1muUS$0.0781/vial Benzathinepenicillin1.2muUS$0.1010/vial Phenoxymethylpenicillin250mgtabcapUS$0.0120 Phenoxymethylpenicillin250mg/5mlsuspensionbuyerpriceUS$0.0082/ml 8. Comparative cost effectiveness presented as range of cost per routine out come (cost percase,costperoutcomeetc) Benzathinepenicillin for a course (one injection) is US$ 0.1010. Oral penicillin for a similar courseisatleastUS$0.24 9. Summaryofregulatorystatus FDAapproved

14

10. Availabilityofpharmacopoeialstandards All formulations listed in US and European pharmaopoeias. International pharmacopoeia haspenicillinVlisted 11. ProposedtextforWHOmodelformulary

Penicillinbenzyl,procainebenzyl,benzathinebenzyl,phenoxymehtylpenicillin Hasactiononseveralpathogenscausingacuteupperandlowerrespiratoryinfections Therapeuticusesofpenicillininrespiratoryinfection Severecommunityacquiredpneumonia Empiricaltherapyofsepsis/pneumoniainneonates Streptococcalpharyngits Otitismediaasanalternativetoamoxicillin(penicillinGorV) Diphtheria Prophylacticusetopreventrheumaticfeverafterstreptococcalinfection Dosage PenicillinG150,000units/kg/dayinfourdivideddosesIMorIV Intravenousrouteisrecommendedforinfantsandneonates. PenicillinV125mg,250mgor500mgPO4timesadaybasedonageandweight Prophylaxis1mto6yrs125mg;6yrsto18yrs250mgtwicedaily Procainepenicillin25,000to50,000units/kg/dayIMor(0.6or1.2muIM/day) Benzathinepenicillin1.2muIMoncefortherapyofacutestreptococcaltonsillopharyngitis. Forprophylaxis,every34wks. Contraindications Hypersensitivity Precautions Checkforhypersensitivity Reducedoseifsevererenalimpairment AdverseeventsLowincidence Hypersensitivity CNStoxicityincludingconvulsionswithhighdosesorrenalimpairment Antibioticassociateddiarrhoeacanfolloworalpreparations Interstitial nephritis, haemolytic anaemia, leucopenia, thrombocytopenia, coagulation disordersarereported Procainerelatedtoxicitydizziness,tinnitus,andheadache IMinjectionscauselocalpain

15

Cloxacillin
1.Formulationproposedforinclusion Cloxacillin 250mgcapsulefororaluse

125mg/5mlaspowderforreconstitutionassyruporelixirfororaluse 250mgvialaspowderforreconstitutionforparenteraluse

ListedonWHOEDLasexamplefatherapeuticgroup 2. Internationalavailability(sources)

250 mg tabcap IDA, UNFPA, MEDS, MISSION, IMRES, JMS, DURBIN, ORBI, ACTION 125mg/5mlsuspensionIDA,UNFPA,MEDS,MISSION,DURBIN 250mgvialforinjectionMEDS

3. Whether listing is requested as individual drug or as an example of a therapeutic group Asexampleofatherapeuticgrouppenicillinaseresistantpenicillin 4. Treatment details(dosage, regimen, duration, references to existing WHO or other guidelines,needforspecialdiagnosticortreatmentfacilitiesandskills) Cloxacillin is a penicillinase resistant anti staphylococcal penicillin [24]. This narrow spectrumpenicillinisnotdestroyedbygastricacidandiswellabsorbedfromGITespecially onemptystomach.However,theabsorptionmaybevariableandsoparenteralrouteisused forsevereinfections.Dicloxacillinisbetterabsorbedthancloxacillin.Thisdifferencedoesnot seemtohaveanyclinicalsignificance.Thedrugisexcretedmainlythroughthekidneysbut doseadjustmentsarenotusuallyrequiredinrenalfailure. About 90% of staphylococci produce penicillinase and are penicillin resistant. Penicillinase resistant penicillins like cloxacillin is the drug of choice for treating penicillin resistant methicillinsusceptibleSaureusinfections[43]. SaureusisresponsibleforasmallproportionofsevereCAPinchildrenindifferentpartsof the world[4, 44]. This may be associated with viral infections like influenza[45] and measles[46]. S aureus can cause pneumonia/sepsis in the new borns also[47]. It is a nosocomial pathogen involved in ventilator associated pneumonias as well. Without appropriate antimicrobial therapy, these infections progress rapidly. MRSA is resistant to thisgroupofdrugs.TheprevalenceofMRSAvariesandisnowknowntocausecommunity acquiredinfectionsaswell[45]. Indicationsforuseinrespiratoryillnesses Staphylococcalpneumonia 1. EmpyemaduetoSaureus 16

Otitisexternaduetostaphylococci Staphylococcallunginfectionincysticfibrosis Dosage Oralorparenteral50mg/kgevery6hrsfor3weeks[34] Forneonatesfrequencyisreduced Staphylococcal infections are diagnosed based on culture. Lung infections due to staphylococcicanbesuspectedbasedonxrayfindings[34].Cloxacillinisrecommendedfor staphylococcal lung infection and empyema, along with gentamicin[34]. If there is no responsetopenicillinplusgentamicin,thenpenicillinisreplacedwithcloxacillininchildren with severe pneumonia[34]. Therapy in severe infection is initiated with parenteral preparation and later changed to oral[34]. Neonatal staphylococcal sepsis also cloxacillin is recommended[34]. It is recommended as second line therapy, if amoxicillin fails, in pneumonias occurring in children with measles[46]. BNF C recommends flucloxacillin for staphylococcal pneumonia[5] 5. Summary of comparative effectiveness in a variety of clinical settings: Identification ofclinicalevidence(searchstrategies,systematicreviewsidentified,reasonsforselection, /exclusionofparticulardata) Cloxacillin is has proven use in treating staphylococcal infections. It is found useful for treatingpneumoniaduetomethicillinsusceptibleSaureusaswell[48] 6. Summaryofcomparativeevidenceonsafety Incidence of adverse events is low[49]. Cholestatic jaundice and hepatitis with elevation of AST,ALT,bilirubin,andLDHcanoccurevenseveralweeksaftertherapy.Therefore,ithas to be used with caution in hepatic diseases. Avoid if previous cloxacillin related hepatic eventshaveoccurred. Other events recorded include glossitis, stomatitis, gastritis, nausea/vomiting, rash, hemolyticanemia,superinfection,pseudomembranouscolitis,seizures,interstitialnephritis, vaginiti,anorexia,hyperthermiaanditchyeyes. Riskofhypersensitivityissimilartootherlactams. 7. Summaryofavailabledataoncomparativecost 250mgtabcapUS$0.0147 125mg/5mlsuspensionUS$0.0037/ml 250mgvialUS$0.1048/vial 8. Comparative cost effectiveness presented as range of cost per routine out come (cost percase,costperoutcomeetc) This drug has only limited use in treatment of respiratory infections, but where it is specificallyrequiredthereisnoalternative.Oraltherapyischeaperthanparenteraltherapy. Costperdayfor250mgcapwillbeUS$0.06comparedto0.15forsuspension. 9. Summaryofregulatorystatus FDAapproved 17

10.

Availabilityofpharmacopoeialstandards

ListedinUS,InternationalandEuropeanpharmacopoeias. 11. ProposedtextforWHOmodelformulary

Cloxacillinfororalandparenteraluse This is a narrow spectrum antimicrobial effective against methicillin susceptible staphylococci Useinrespiratoryinfections Staphylococcallunginfections,includingthoseincysticfibrosis Otitisexternaduetostaphylococci Dosage >20kg250500mgevery6hrs; <20kg50100mgevery6hrs Forneonatesfrequencyisreduced Contraindication Hypersensitivitytopenicillingroupofdrugs Previouscloxacillinrelatedhepaticevents Precaution Checkforhypersensitivity Usewithcautioninhepaticdiseases AdverseeventsLowincidence Hypersensitivity Cholestaticjaundiceandhepatitiscanoccurevenseveralweeksaftertherapy.

18

Coamoxiclavulanicacid
Trialssummarizedintables
Wubbel,1999 1. Formulationproposedforinclusion Amoxicillin(astrihydrateorsodiumsalt)+Clavulanateaspotassiumsalt 125mg+31mgper5mlsuspension 250mg+125mgtablets

Othercombinationsofstrengthareavailable.Parenteralpreparationsarealsoavailable ItislistedonWHOEDLbutanotherstrength 2. Internationalavailability(sources) 125/31suspensionMEDS,ORBI 250/125tabMEDS,DURBIN,JMS

3. Whether listing is requested as individual drug or as an example of a therapeutic group Individualdrug 4. Treatment details(dosage, regimen, duration, references to existing WHO or other guidelines,needforspecialdiagnosticortreatmentfacilitiesandskills) Combining amoxicillin with clavulanic acid, a lactamase inhibitor, protects amoxicillin fromdestructionbylactamasesproducedbyamoxicillinresistantbacterialikeSaureus,H. influenzae, and some strains of E coli and K pneumoniae Clavulanic acid itself has minimal antibacterialaction[24]. Therapeuticuseinrespiratoryinfections LRI, otitis media and sinusitis due to lactamase producing organisms like H influenza. Decisiontousethisdrugisusuallytakenusingcultureandsusceptibilitydataorfollowing clinical failure with first line drugs. It is an alternative to azithromycin or erythromycin in thissituation. Forstaphylococcalinfectionscloxacillinisabetteroption. Dosage 45mg/kg/dayofamoxicillin(max2gm)

Maximumdoseofclavulanatenottoexceed6.4mg/kg/day[14]. Ifhigherdosesofamoxicillinarerequired,amoxicillinalonecanbegiventoadoseofupto 90mg/kg/dayalongwiththecombination. To be used only as second line therapy for clinical failure or for proven infections due to resistantorganisms.

19

Recommendedasalternativetoamoxicillinforsinusitis[10]andotitismedia[14]andforCAP asanalternative[5] 5. Summary of comparative effectiveness in a variety of clinical settings: Identification ofclinicalevidence(searchstrategies,systematicreviewsidentified,reasonsforselection, /exclusionofparticulardata) Cure rate was better with coamoxiclavulanic acid (OR 10.44; 95% CI 2.85 to 38.21) as compared to amoxicillin, in one openlabel study involving 100 children between 2 and 12 years of age suffering from clinically diagnosed bacterial pneumonia [4]. Co amoxyclavulanic acid was compared with azithromycin in two studies involving 283 childrenbelowfiveyearsofage.Thecurerates,failurerates(OR1.21;95%CI0.43to3.43) andimprovementrates(OR0.85;95%CI0.43to1.71)weresimilarinthetwogroups.There were fewer side effects reported in the with azithromycin group (OR 0.17; 95% CI 0.09 to 0.32). Comparison with cefpodoxime in one multicenter study on 348 children between 3 months and 11.5 years of age, showed that the response rate at the end of 10 days of treatmentwascomparableinthetwogroupsforpneumonia(OR0.69;95%CI0.18to2.6). Amoxicillinisthefirstlinedrugwhenantimicrobialsarerequiredfortreatingotitismedia. Several trials have shown that Coamoxiclav is effective and at leastequal to azithromycin [5052]forthiscndition. 6. Summaryofcomparativeevidenceonsafety Adverse events including hypersensitivity may be similar to that found with amoxicillin. Diarrhoea is more frequent with the combination as compared to amoxicillin alone[53] Cholestatic jaundice can occur and liver toxicity which is reversible is more commonwiththecombinationthanwithamoxicillinalone.Seriouscomplications,however, areveryrareinchildren There were fewer side effects reported in the azithromycin group (OR 0.17; 95% CI 0.09to0.32)comparedtoCoamoxiclavinaCochranereview[4].Adverseeventswereless in Azithromycin (1114%) treated groups compared to co amoxiclav (1767%)in another Cochranereviewalso[54].Themajorityofadverseeventswererelatedtothegastrointestinal tract (diarrhoea, vomiting, abdominal pain, nausea, anorexia) and were more common in childrenunderfiveyearsofage. Doseorfrequencymayneedtobereducedinrenalimpairment 7. Summaryofavailabledataoncomparativecost 125+31/5mlsuspensionUS$0.0336/ml 250+125tabcapUS$0.3136/tab 8. Comparative cost effectiveness presented as range of cost per routine out come (cost percase,costperoutcomeetc) Foradailydoseof1gm,thecostperdaywillbeaboutUS$1.3fortaband1.4forsuspension. Forazithromycinwhichisusedforsimilarindications,costoftherapy(250mg)foradayis approximatelyUS$0.3fortabandsuspension. 9. Summaryofregulatorystatus FDAapproved

20

10.

Availabilityofpharmacopoeialstandards

AmoxicillinandclavulanatearelistedseparatelyinUSandEuropeanpharmacopoeias 11. ProposedtextforWHOmodelformulary

Amoxicillinandclavulanicacidfororaluse Amoxicillin is the active ingredient and has action against several respiratory pathogens. Because of the presence of clavulanate the combination is active against lactamase producingorganismsaswell. Therapeuticuseinrespiratoryinfections Pneumonia, otitis media and sinusitis due to lactamase producing organisms, based on susceptibilitydataorfollowingclinicalfailurewithfirstlinedrugs. Dosage 45mg/kg/dayofamoxicillin(max2gm) Maximumdoseofclavulanatenottoexceed6.4mg/kg/day Contraindications Hypersensitivity Precautions Checkforhypersensitivity Reducedoseinsevererenalimpairment Adverseevents Hypersensitivity Diarrhoea,vomiting,nausea Antibioticassociateddiarrhoea Cholestaticjaundice

21

Erythromycin/azithromycin
Block1995 Roord,1996 Howie,1972 Harris,1998 1. Formulationproposedforinclusion Erythromycin Fororalusestearateorethylsuccinate 250mgtabcap 125mg/5mlpowderforreconstitutionforsuspension Kogan,2003 Roord,1996 Wubbel,1999

Parenteralpreparationsavailableaslactobionate

Azithromycin Capsule250mg Oralsuspension200mg/5mlpowderforreconstitution

Erythromycin is listed on WHO EDL. Azithromycin is listed for treating chlamydia infectionsonly. 2. Internationalavailability(sources) Erythromycin 250mgtabcapUNFPA,MEDS,IMRES,IDA,MISSION,ORBI,DURBIN,ACTION,JMS 125mg/5mlpowderUNFPA,MEDS,IMRES,IDA,MISSION,DURBIN,ACTION,JMS Azithromycin Capsule250mgMISSION Oralsuspension200mg/5mlMISSION 3. Whether listing is requested as individual drug or as an example of a therapeutic group Asindividualdrugs 4. Treatment details(dosage, regimen, duration, references to existing WHO or other guidelines,needforspecialdiagnosticortreatmentfacilitiesandskills) Erythromycin and azithromycin are macrolide antibiotics and act by inhibiting protein synthesisinbacteria.Theirspectrumofactivityissimilartothatofpenicillinandsoisused asanalternativetopenicillininthosehypersensitive.About15%ofSpneumoniaeisolatedin the US from community acquired pneumonia are resistant to macrolides[3]. Macrolide resistance is usually found in penicillin resistant strains. About 40% of S. pyogenes are also macrolide resistant. Macrolides are active against other bacteria that cause respiratory infections like Mycoplasma, Chlamydiae and Legionella. Most penicillin resistant staphylococci are also susceptible. Action of erythromycin on H influenzae is poor. 22

Azithromycin has better activity against H influenzae but action is slightly lesser against Grampositivebacteriaascomparedtoerythromycin. Upto40%ofLRIinchildrenarebelievedtobeduetoMycoplasmaandaremorecommonin children above 5 yrs. However problems with specific diagnosis of mycoplasma infections makeestimatesofprevalencevariableandsometimesunreliable. BotherythromycinandazithromycinareabsorbedwellfromGIT.Azithromycinhasalong tissuehalflifeandsooncedailydoseisused.Complianceisbetterwiththisdrugbecauseof dosingscheduleandfewersideeffects. Indicationsforuse 1.Alternativetopenicillin/amoxicillininthosehypersensitive 2.LRI In some guidelines, azithromycin is recommended as first line therapy for children above5yrswithnonsevereCAP[3].Forthosebelowfiveyears,thisdrugisaddedifthereis noclinicalresponsewithamoxicillinafter48hrs. 3.Otitismediathisisoneofthesecondlinedrugs,ifthereisnoresponsetoamoxicillin[14] 4.Pertussis Dosage ErythromycinNeonate2040mg/kg/din4divideddoses AzithromycinChildover2months10mg/kgonceaday(max500mg) Thedrugisusedfollowingclinicaldiagnoses. WHO recommends erythromycin for pertussis[34]. Erythromycin/ azithromycin is recommendedforotitismedia[14]andsinusitis[10]asanalternative.Itisalsorecommended for CAP in those allergic to penicillin and if there is clinical failure with amoxicillin [3]. Accordingtothisguideline,azithromycinmaybeusedasfirstchoiceinchildrenabove5yrs. BNFCalsohassimilarrecommendations[5] 5. Summary of comparative effectiveness in a variety of clinical settings: Identification ofclinicalevidence(searchstrategies,systematicreviewsidentified,reasonsforselection, /exclusionofparticulardata) In a trial involving 47 children aged between 1 m and 14 years with classical pneumonia, comparing azithromycin with amoxicillin, all recovered in both groups[4]. Co amoxyclavulanic acid was compared with azithromycin in two studies involving 283 childrenbelowfiveyearsofage.Thecurerates,failurerates(OR1.21;95%CI0.43to3.43) and improvement rates (OR 0.85; 95% CI 0.43 to 1.71) were similar in the two groups. Comparing erythromycin with azithromycin or clarithromycin also showed no significant differences[4]. ACochranereviewattemptedtoevaluatetherapyformycoplasmainfectionsinchildren[54]. Aetiological diagnosis was not stated in most included studies (only 38 children with mycoplasmainfectionidentified)butcomparedmacrolideswithlactamantibioticsforLRI in1352children.Therewerenomajordifferencesbetweentreatmentgroups.Noconclusion isdrawnoneffectivetherapyformycoplasmainfections.

23

Macrolides can also be used for prophylaxis in those with cystic fibrosis. A review on this issue including both children and adults found that there is a small but significant improvementinrespiratoryfunctionfollowingtreatmentwithazithromycin[55]. ItisshowntobeeffectivefortreatingotitismediaandcomparabletoCoamoxiclav[39,50, 51] 6. Summaryofcomparativeevidenceonsafety Incidenceofadverseeventsislow.MacrolidescancauseGIdisturbanceslikenausea, vomitinganddiarrhoea. QT interval prolongation and ventricular tachycardia are serious complications. Electrolyte disturbances, anaemia, leucopoenia, renal and hepatic toxicity, allergy, reversible hearing loss, cholestatic jaundice, pancreatitis, myasthenia, Steven Johnsons syndrome, super infection with Candida etc are also recorded. Rashes and generalised exanthematous pustulareruptionscanalsooccur. Therewerefewersideeffectsreportedinthewithazithromycingroup(OR0.17;95%CI0.09 to 0.32) compared to Co amoxiclav in a Cochrane review [4]. Another Cochrane review showed adverse events in 1114% of Azithromycin treated children compared to 25 % in erythromycin; both drugs were better tolerated than co amoxi clav where 1767% had adverse events [54]. Majority of adverse events were related to the gastrointestinal tract (diarrhoea,vomiting,abdominalpain,nausea,anorexia)andweremorecommoninchildren underfiveyearsofage. 7. Summaryofavailabledataoncomparativecost Erythromycin 250mgtabcapUS$0.0236 125mg/5mlpowderUS$0.0091/ml

Azithromycin Capsule250mgUS$0.2417 Oralsuspension200mg/5mlUS$0.0500/ml

8. Comparative cost effectiveness presented as range of cost per routine out come (cost percase,costperoutcomeetc) Forazithromycin,costoforaltherapy(250mg)foradayisapproximatelyUS$0.3.Single dailydoseofthisdrugmayfacilitatecompliance. ErythromycintabcapwillcostlessthanUS$0.1perday.ForCoamoxiclav,whichisused for similar indications, a daily dose of 1gm will cost about US$ 1.3 for tab and 1.4 for suspension. 9. Summaryofregulatorystatus BotherythromycinandazithromycinareFDAapproved (Azithromycinislicensedforrespiratoryinfection,otitismediaandcysticfibrosis) 10. Availabilityofpharmacopoeialstandards

ErythromycinislistedinUS,InternationalandEuropeanpharmaopoeias 24

AzithromycinislistedinUSandEuropeanpharmaopoeias 11. ProposedtextforWHOmodelformulary

Erythromycin/azithromycin These are active against several respiratory pathogens including Mycoplasma pneumoniae, LegionellasppandChlamydiaspp. Indicationsforuse 1.Alternativetopenicillin/amoxicillininthosehypersensitive 2.CommunityacquiredLRIifthereisnoresponsetofirstlinetherapy 3.Otitismediaifthereisnoresponsetofirstlinetherapy 4.Pertussis Dosage ErythromycinNeonate2040mg/kg/din4divideddoses AzithromycinChildover2months10mg/kgonceaday(max500mg) Contraindication Precaution CoadministrationofdrugsthatcancauseQTprolongation Adverseevents GIdisturbanceslikenausea,vomitinganddiarrhoea. QTintervalprolongation Electrolyte disturbances, renal and hepatic toxicity, allergy, reversible hearing loss, cholestatic jaundice, pancreatitis, myasthenia, Steven Johnsons syndrome etc are also recorded.

25

Chloramphenicol
Trialssummarizedintables
Cetinkaya,2004 Deivanayagam,1996 Duke,2002 Mullholland,1995 Shann,1985

1. Formulationproposedforinclusion Chloramphenicol 250mgcapsulesfororaluse 1gmvialforparenteraluse

ThisislistedonWHOEDLstrengthmaybedifferent 2. Internationalavailability(sources) 250mgcapUNFPA,MEDS,IMRES,IDA,MISSION,ORBI,DURBIN,ACTION,JMS 1gmvialUNFPA,MEDS,IMRES,IDA,MISSION,DURBIN,ACTION,JMS 3. Whether listing is requested as individual drug or as an example of a therapeutic group Individualdrug 4. Treatment details(dosage, regimen, duration, references to existing WHO or other guidelines,needforspecialdiagnosticortreatmentfacilitiesandskills) Chloramphenicol is a broad spectrum antibiotic which acts by inhibiting bacterial protein synthesis. It is active against H. influenzae, S. pneumoniae and Bordetella pertussis. Most anaerobic bacteria, including grampositive cocci, Clostridium spp., and gramnegative rods includingB.fragilisaresusceptible.ChloramphenicolisactiveagainstMycoplasma,Chlamydia, andRickettsia.Itisabsorbedrapidlyfromthegastrointestinaltract,andpeakconcentrations occurwithin2to3hours.Thedrugiswidelydistributedinbodyfluids. Bonemarrowsuppressionisamajoradverseeventandsothedrugisgenerallyusedonlyfor severeinfections. Usesinrespiratoryinfections[34] FirstlinetherapyforverysevereCAPinchildren Firstlinetherapyforempyema Alternativeforneonatalsepsis Alternativeforpertussis CAPandchildisunconsciousorcannottolerateoralantimicrobials Severesecondarybacterialinfectionsfollowingbronchiolitis Dosage 25mg/kg every 8hrs Initiate with parenteral therapy and change to oral later. In neonates doseandfrequencyisreduced. 26

Totaldurationoftherapyforsevereinfectionsis10days.Forempyema,4wkstreatmentis recommended[34] Treatment with this drug can be initiated based on clinical diagnosis of severe pneumonia and sepsis [34]. WHO also recommends that one doze of chloramphenicol is given to children with CAP who are unconscious, in shock or vomiting incessantly [21] before referring. Chloramphenicol is recommended as alternative or second line therapy for pneumonia[46]andforepiglottitis[5,10] 5. Summary of comparative effectiveness in a variety of clinical settings: Identification ofclinicalevidence(searchstrategies,systematicreviewsidentified,reasonsforselection, /exclusionofparticulardata) Oncomparingchloramphenicolwithpenicillinandgentamicinforseverepneumonia,need for change in antibiotics, death rates and adverse events were similar in the two groups. However,readmissionratesbefore30daysfavouredthepenicillingentamicincombination (OR1.6;95%CI1.02to2.55)[4].Oncomparingchloramphenicolwithcotrimoxazolein111 malnourished children below five yrs in the year 1995, cure rates (OR 1.06; 95% CI 0.47 to 2.40), failure rates (OR 1.03; 95% CI0.45 to2.33), number of patients requiring a change in antibiotics (OR 1.42; 95% CI 0.46 to 4.40), relapse rates (OR 1.02; 95% CI 0.24 to 4.30) and deathrates(OR2.21;95%CI0.63to7.83)weresimilarinthetwogroups. 6. Summaryofcomparativeevidenceonsafety Bonemarrowsuppressionisthemostseriousadverseevent.Thereforebloodcount has to be monitored. Risk may be more in hepatic impairment. It is better to avoid it in severe renal impairment. Neonates, especially if premature, may develop gray baby syndrome. Other side effects include nausea, vomiting, unpleasant taste, and diarrhoea. Rarer toxic effects include blurring of vision, digital paresthesias, encephalopathy and cardiomyopathy. ChloramphenicolinhibitshepaticcytochromeP450isozymesandprolongsthehalf lives of drugs like warfarin, dicumarol, phenytoin, chlorpropamide, antiretroviral protease inhibitors, rifabutin, and tolbutamide. Concurrent administration of phenobarbital or rifampin,shortensthehalflifeoftheantibiotic. 7. Summaryofavailabledataoncomparativecost 250mgcapUS$0.0119/cap 1gmvialforparenteraluse0.2238/vial 8. Comparative cost effectiveness presented as range of cost per routine out come (cost percase,costperoutcomeetc) CostforonedayoraltherapyislessthanUS$0.1 9. Summaryofregulatorystatus FDAapproved 10. Availabilityofpharmacopoeialstandards

ChloramphenicolislistedinUS,InternationalandEuropeanpharmaopoeias

27

11.

ProposedtextforWHOmodelformulary

Chloramphenicolfororalandparenteraluse Chloramphenicol has a broad spectrum of activity and is active against several respiratory pathogens Useinrespiratoryinfection VerysevereCAP Empyema Childreninshock,unconsciousorvomitingasaprereferraldose Epiglottitis Pertussis Dosage 50100mg/kg/dayinfourdivideddoses Contraindications Severerenalandhepaticimpairment Precaution Monitorbloodcount. Considerdruginteractions Adverseevents Bonemarrowsuppressionriskmaybemoreinhepaticimpairment. Graybabysyndrome Nausea,vomiting,unpleasanttaste,anddiarrhoea Rarer toxic effects blurring of vision, digital paresthesias, encephalopathy and cardiomyopathy

28

Cotrimoxazole
Trialssummarizedintables
Catchup,2002 Campbell,1988 Keeley,1990 Mullholland,1995 1. Formulationproposedforinclusion Sulphamethoxazoletrimethoprim100+20mgtablets Oralsuspension200+40mg/5ml Otherstrengthsarealsoavailable ItislistedinWHOEDL 2. Internationalavailability(sources) 100+20tabMISSION,IDA,IMRES,DURBIN,ORBI,JMS 200+40/5mlMISSION,IDA,IMRES,ORBI,JMS,MEDS,UNFPA,DURBIN,ACTION Sidal,1994 Strauss,1998 Taylor,1977

3. Whether listing is requested as individual drug or as an example of a therapeutic group Asindividualdrug 4. Treatment details(dosage, regimen, duration, references to existing WHO or other guidelines,needforspecialdiagnosticortreatmentfacilitiesandskills) Combinationofsulphamethoxazoleandtrimethoprim(cotrimoxazole)issynergisticsince the two drugs act on sequential steps of an enzymatic reaction necessary for synthesis of tetrahydrofolic acid. The drug has activity against Staphylococci, Streptococci including S pneumoniae,H.influenzaeandavarietyofGramnegativebacilli.Agoodproportionofisolates belongingtothesespeciesarenowresistanttothisdruglimitingitsclinicalutility. Afterasingleoraldoseofthecombinedpreparation,trimethoprimisabsorbedmorerapidly thansulfamethoxazole.Peakbloodconcentrationsoftrimethoprimusuallyoccurby2hours, whereaspeakconcentrationsofsulfamethoxazoleoccurby4hoursafterasingleoraldose. The halflives of trimethoprim and sulfamethoxazole are approximately 11 and 10 hours, respectively. Useinbacterialrespiratoryinfection 1. This drug is used for LRI. However, there is mounting resistance to this drug among respiratorypathogensandsomanyauthoritiesdonotrecommendthisforempiricaltherapy of bacterial infections in the respiratory tract. It can be used if there is bacteriological evidenceforsusceptibility.However,inresourcepoorsettings,whereothersuperiordrugs are not accessible, this drug is still used. WHO recommend this drug for community management of non severe pneumonia. In this situation, children should be closely monitoredforresponse. 29

2. Other uses include therapy of acute otitis media and secondary bacterial LRI following bronchiolitis 3. It is currently recommended as drug of choice for prophylaxis and treatment of pneumocystisjirovecipneumonia,treatmentoftoxoplasmosisandnocardiosis. 4.UsingthisdrugforprophylaxisinchildrenwithHIVinfectionreducedmortality,mainly fromrespiratoryinfections,inonestudyinadevelopingcountry[56,57].Suchprophylaxis maybeofuseinneonatesborntoHIVinfectedmothersalso. Dosageforbacterialinfections 20+4mg/kgtwicedailyfor5days Forrespiratoryinfections,antibiotictherapyisinitiatedbasedonclinicalevidence. Co trimoxazole is recommended as first line therapy for non severe CAP and acute ear infections[20,21].Itisalsorecommendedasanalternativeforsinusitis[10].Itcanbeusedfor secondarybacterialinfectionsfollowingbronchiolitis[34] 5. Summary of comparative effectiveness in a variety of clinical settings: Identification ofclinicalevidence(searchstrategies,systematicreviewsidentified,reasonsforselection, /exclusionofparticulardata) A recent Cochrane review has found amoxicillin [4] to be better than co trimoxazole for community acquired pneumonia. Two multicenter double blinded studies in children between 2 m and 59m of age showed that failure rate was significantly higher in the co trimoxazolegroupcomparedtotheamoxicillingroup(OR1.33;95%CI1.05to1.671).Two studies in this review also showed that procaine penicillin is significantly better than co trimoxazole for cure (OR 2.64; 95% CI 1.57 to 4.45). In 111 malnourished children, co trimoxazoleandchloramphenicolshowedsimilarresults. In a more recent study, failure rate was 11.6% with Cotrimoxazole [58]. But the authors conclude that this is an acceptable drug for management of non severe pneumonia at first level health facility. Cotrimoxazole along with monitoring for treatment failures using testedcriteria[59]maybeanoptionforcommunitylevelmanagementofpneumonia. ACochranereviewidentifiedonestudyon534children,whichmetthecriteriaforinclusion, on effect of prophylaxis in HIV infected children. Prophylaxis with Co trimoxazole significantly reduced mortality[56]. The excess mortality in the placebo group was mainly duetorespiratoryinfections[57].BacterialresistancetoCotrimoxazoleishighinthestudy area. Antimicrobial use for serious infections was also significantly higher in the placebo group. 6. Summaryofcomparativeevidenceonsafety Thereisverylittletoxicityandismostlyskinrelated.Exfoliativedermatitis,StevensJohnson syndromeandtoxicepidermalnecrolysisarereported,mostlyinolderindividuals. GI events like nausea and vomiting can occur. Glossitis, stomatitis, mild and transient jaundice, headache, depression, and hallucinations are reported. It is better to avoid this druginthosewithhepaticimpairment. Hematological effects include anemias, coagulation disorders and granulocytopenia. Renal dysfunctioncanalsooccur.Dosemaybereducedifthereisrenaldysfunction

30

Itshouldbeavoidedinchildrenbelow1mofage[21]becauseofriskofkernicterus.Usein HIVprophylaxisisanexception. 7. Summaryofavailabledataoncomparativecost 100+20tab0.0027/tab 200+40suspension0.0037/ml 8. Comparative cost effectiveness presented as range of cost per routine out come (cost percase,costperoutcomeetc) For one day the cost of treatment is approximately US$ 0.04 compared to US$ 0.1 for amoxicillin 9. Summaryofregulatorystatus FDAapproved (AccordingtoBNFCitisnotlicensedforuseinchildrenunder6wks) 10. Availabilityofpharmacopoeialstandards

SulfamethoxazoleandtrimethoprimarelistedseparatelyinUS,InternationalandEuropean pharmaopoeias 11. ProposedtextforWHOmodelformulary

Cotrimoxazolefororaluse Cotrimoxazolehasactiononbacteriacausingrespiratoryinfections.However,resistanceis increasing. Indicationsforuse(bacterialrespiratoryinfections) Communitymanagementofnonseverepneumonia Acuteotitismedia ProphylaxisforchildrenwithHIVinfection Dosageforbacterialinfections 20+4mg/kgtwicedaily Precautions Childrenwithpneumoniashouldbemonitoredforresponse. Usewithcautioninhepaticimpairment Dosemaybereducedifthereisrenaldysfunction Avoidinchildrenbelow6wksofage(exceptforpneumocystisprophylaxis)becauseofrisk ofkernicterus Contraindications Adverseevents Lowincidenceskinrelatedmostlyrash,exfoliativedermatitis,StevensJohnsonsyndrome andtoxicepidermalnecrolysis Nausea, vomiting, glossitis, stomatitis, mild and transient jaundice, headache, depression, hallucinations,anaemia,coagulationdisorders,granulocytopenia

31

Gentamicin
Trialssummarizedintables
Duke,2002 1. Formulationproposedforinclusion 40mg/mlforparenteraluse 10mg/mlforparenteraluse

ListedinWHOEDL 2. Internationalavailability(sources) 10mg/mlMEDS,UNFPA,MISSION,IDA 40mg/mlUNFPA,IDA,IMRES,MEDS,MISSION,JMS,DURBIN,ORBI,ACTION

3. Whether listing is requested as individual drug or as an example of a therapeutic group Individualdrug 4. Treatment details(dosage, regimen, duration, references to existing WHO or other guidelines,needforspecialdiagnosticortreatmentfacilitiesandskills) Gentamicin is an aminoglycoside and acts by inhibiting protein synthesis. This drug is not absorbed from the gut and is to be given parenterally. Excretion is predominantly via the kidneysandcanaccumulateifthereisrenaldysfunction.Clearanceisrapidinchildrenwith cysticfibrosisandsohigherdosesarerequired. GentamicinisactiveagainstseveralGramnegativebacilliincludingpseudomonas.Although gentamicin is active against some Gram positive cocci, its activity against S pyogenes and S pneumoniaeispoorandisinactiveagainstanaerobes.Thereforegentamicinaloneshouldnot beusedfortreatingpneumonia. Useinrespiratoryinfections ForempiricaltherapyofseriousLRIofunknownaetiologyincludingnosocomialpneumonia andpneumonia/sepsisinthenewborns,thisdrugisusedalongwithalactamantibiotic, usually penicillin. If staphylococcal infection is suspected, cloxacillin is used instead of penicillin. Because of the high probability of dose related toxicity, drug level monitoring is recommended.Prolongedusealsoshouldbeprevented. Dosage Although gentamicin can be given as 23 divided doses, once daily dosage is more convenient and ensures adequate serum concentration. Authors of a recent Cochrane review[60]havestatedthatthereisinsufficientevidencetoconcludewhetheronceadayor multiple doses a day regimen is superior in treating bacteriologically confirmed neonatal sepsis. However, the pharmacokinetic properties of once a day regimen are superior to multipledosesadaysinceitachieveshigherpeaklevelswhileavoidingtoxictroughlevels. 32

There was no change in nephrotoxicity or auditory toxicity. Once a day regimen may be therefore superior in treating neonatal sepsis. For infants less than 32 week gestation with their decreased glomerular filtration rates, a further extended regimen of once in 36 to 48 hoursmaybeappropriate. Loading and maintenance doses are calculated based on body weight and renal function. Doses are then adjusted based on serum concentrations. Usual starting dosage is 7mg/kg/day.Higherdosemayberequiredinthosewithcysticfibrosis. Treatmentwithgentamicincanbeinitiatedbasedonclinicaldiagnosis.Monitoringofdrug levelsrequirelaboratoryfacility. ItisrecommendedincombinationwithalactamantibioticforverysevereCAP,neonatal sepsis and staphylococcal infections[34]. This combination is also recommended as pre referral single dose [21]. BNF C also recommended it for severe bacterial infections (includingpneumonia)inneonatesandinfants[5]. 5. Summary of comparative effectiveness in a variety of clinical settings: Identification ofclinicalevidence(searchstrategies,systematicreviewsidentified,reasonsforselection, /exclusionofparticulardata) TherearenotmanytrialscomparingPenicillin+gentamicincombinationswithotherdrugs forseverepneumonia.TheCochranereviewontherapyforpneumoniainchildren,foundon comparingchloramphenicolwithpenicillinandgentamicinforseverepneumonia,needfor change in antibiotics, death rates and adverse events were similar in the two groups. However,readmissionratesbefore30daysfavouredthepenicillingentamicincombination (OR1.6;95%CI1.02to2.55)[4]. ArecentCochranereviewonmanagementofsepsisdidnotfindanyadditionaladvantage when lactam aminoglycoside combinations were used compared to lactam monotherapy[42]. Nephrotoxicity is significantly more with combination therapy RR 0.30 (95%CI0.230.39). 6. Summaryofcomparativeevidenceonsafety Major adverse events like ototoxicity (vestibular and auditory) and nephrotoxicity canoccurinupto25%ofthosereceivingtherapy.Theseadverseeventsaredoserelatedand somonitoringisrecommended.Doseorfrequencyisreducedbasedondruglevels.Renal, auditoryandvestibularfunctionsalsoneedtobemonitored.Prolongeduseandconcomitant useofotherdrugsthatcanincreasetoxicityshouldbeavoided.Toxicityismoreinchildren withrenalimpairment. The drug can impair neuromuscular transmission and so is to be avoided in children with myasthenia. OnestudyinaCochranereviewreported2of13and1of11neonatesreceivingonceadayor multiple doses a day respectively developed ototoxicity. Three other studies which looked forototoxicitydidnotfindany[60]. 7. Summaryofavailabledataoncomparativecost 10mg/ml0.0347/vial 40mg/ml0.0331/vial

33

8. Comparative cost effectiveness presented as range of cost per routine out come (cost percase,costperoutcomeetc) ForonedaytherapycostislessthanUS$0.1 9. Summaryofregulatorystatus FDAapproved 10. Availabilityofpharmacopoeialstandards

ListedinUS,Europeanandinternationalpharmacopeia 11. ProposedtextforWHOmodelformulary

Gentamicinforparenteraluse GentamicinhasactionagainstGramnegativebacilli. Indicationsinrespiratoryinfection For empirical therapy of serious pneumonia of unknown aetiology including nosocomial pneumonia and pneumonia/sepsis in the new borns to be used along with a lactam antibiotic,usuallypenicillin Dosage 7mg/kg/dayassingledailydoseoras23divideddoses Loading and maintenance doses are calculated based on body weight and renal function. Dosesarethenadjustedbasedonserumconcentrations. Precautions Shouldnotbeusedasmonotherapyforrespiratoryinfections Druglevelmonitoringisrecommended.Prolongeduseandconcomitantuseofotherdrugs thatcanincreasetoxicityshouldbeprevented. Renal,auditoryandvestibularfunctionsneedtobemonitored. Contraindications Canimpairneuromusculartransmissionandsoavoidinchildrenwithmyasthenia Adverseevents Ototoxicity(vestibularandauditory) Nephrotoxicity Toxicityismoreinchildrenwithrenalimpairment. Impairmentofneuromusculartransmission

34

Ceftriaxone/cefotaxime
Trialssummarizedintables
Cetinkaya,2004 1. Formulationproposedforinclusion Ceftriaxone250mgvialforparenteraluse 500mgvialforparenteraluse

ItislistedonWHOEDLasanexampleofatherapeuticgroup 2. Internationalavailability(sources) MISSION,IDA,DURBIN,MEDS

3. Whether listing is requested as individual drug or as an example of a therapeutic group Exampleofthirdgenerationcephalosporins 4. Treatment details(dosage, regimen, duration, references to existing WHO or other guidelines,needforspecialdiagnosticortreatmentfacilitiesandskills) Cefotaxime and Ceftriaxone[24], are third generation cephalosporins with good activity against Enterobacteriaceae and H influenzae including those producing penicillinase. Their actiononGrampositivecoccilikeS.aureus,Spneumoniae,andS.pyogenesiscomparableto that of firstgeneration agents. Achievable serum concentrations exceed MICs for most penicillinresistant isolates of S pneumoniae, H. influenzae and S. aureus. The antimicrobial spectrumofcefotaxime andceftriaxoneisthereforesuitedforthetreatmentofpneumonia, when cause is not identified. It is also useful for other severe infections caused by H influenzae,likeepiglottitis. Ceftriaxonehasahalflifeofabout8hoursandsooncedailyadministrationiseffectivefor treating most infections. About half the drug can be recovered from the urine and the remainingfrombile. Useinrespiratoryinfections Severecommunityacquiredpneumonia[61] Maybeofuseinhospitalacquiredpneumonia[62] Epiglottitis Dosage 5075mg/kg/dIVorIM(max2gm/day) BNF C recommends this drug for epiglottitis [5]. It is recommended for severe CAP and otitismedia[3,14].Itmaybeofuseintreatinghospitalacquiredpneumonias[62].

35

5. Summary of comparative effectiveness in a variety of clinical settings: Identification of clinical evidence (search strategies, systematic reviews identified, reasons for selection,/exclusionofparticulardata) IntheCochranereviewontherapyofCAP[4]onedoubleblindstudyinvolving97children between 2 to 24 months of age diagnosed with severe CAP was identified comparing ceftriaxonewithpenicillinandchloramphenicolcombination.Cureratesinthetwogroups weresimilar(OR1.36;95%CI0.47to3.93). 6. Summaryofcomparativeevidenceonsafety Adverse events are rare[63, 64]. Hypersensitivity can occur. A proportion of individuals hypersensitivetopenicillinwillbehypersensitivetocephalosporinsalso Thesedrugscanalsocausenephrotoxicity,diarrhoea,vomitingandskinrash[63,64] SuperinfectionwithCandidasppcanoccur 7. Summaryofavailabledataoncomparativecost 250mgvialUS$1.0141/vial 500mgvialUS$1.4460/vial 8. Comparative cost effectiveness presented as range of cost per routine out come (cost percase,costperoutcomeetc) It is an expensive drug, to be used only for selected indications where there are few other options 9. Summaryofregulatorystatus FDAapproved 10. Availabilityofpharmacopoeialstandards

ListedinUSandEuropeanpharmacopoeia 11. ProposedtextforWHOmodelformulary

Ceftriaxoneforparenteraluse Itsspectrumoactivityissuitablefortreatingseverepneumonias Useinrespiratoryinfections Severecommunityacquiredpneumonia Epiglottitis Dosage 5075mg/kg/dIVorIM(max2gm/day) Contraindications Hypersensitivity Precautions Thosehypersensitivetopenicillinmaybehypersensitivetocephalosporins

36

Adversereactions Diarrhoea,vomiting,skinrash Superinfectionwithcandidaspp Hypersensitivity Nephrotoxicity

37

References
1. 2. WHOandUNICEF,Pneumoniatheforgottenkillerofchildren.2006. Sazawal,SandBlack,RE,Effectofpneumoniacasemanagementonmortalityinneonates, infants,andpreschoolchildren:ametaanalysisofcommunitybasedtrials.LancetInfectDis, 2003.3(9):p.54756. Evidencebasedcareguidelineforchildrenwithcommunityacuiredpneumonia.HealthPolicy andClinicalEffectivenessProgramme,CincinnatiChildrensHospitalMedicalCentre,2005. Kabra,SK,Lodha,RandPandey,RM,Antibioticsforcommunityacquiredpneumoniain children..CochraneDatabaseofSystematicReviews,Issue3.CD004874.,2006. BritishNationalFormularyforChildren.2006. Diagnosisandmanagementofbronchiolitis.AmericanAcademyofPediatrics.,2006. NGC:005271. ClinicalPracticeGuidelines;UseofAntibioticsinPaediatricCare.2002,MinistryofHealth: Singapore. Spurling,GKP,Fonseka,K,Doust,JandC.,DM,Antibioticsforbronchiolitisinchildren. CochraneDatabaseofSystematicReviews;1.CD005189,2007. WHO,Consultativemeetingtoreviewevidenceandresearchprioritiesinthemanagementof acuterespiratoryinfections.2003,DepartmentofChildandAdolescentHealthand Development:Geneva. Rodriguez,R,Acuterespiratorytractinfectionsoftheupperrespiratorytract,inRespiratory infectionsinchildren,IMCIseriesHCT/AIEP1.1,Y.Benguigui,etal.,Editors.1999,PAHO, WHO. DelMar,CB,Glasziou,PPandSpinks,AB,Antibioticsforsorethroat.CochraneDatabaseof SystematicReviews,Issue4.CD000023,2006. Bisno,AL,Gerber,MA,Gwaltney,JM,Jr.,Kaplan,ELandSchwartz,RH,Practiceguidelines forthediagnosisandmanagementofgroupAstreptococcalpharyngitis.InfectiousDiseases SocietyofAmerica.ClinInfectDis,2002.35(2):p.11325. Sorethroatandtonsillitis.FinnishMedicalSocietyDuodecim.In:EBMGuidelines.EvidenceBased Medicine[CDROM].Helsinki,Finland:DuodecimMedicalPublications,2005. Evidencebasedclinicalpracticeguidelineformedicalmanagementofacuteotitismediain children2monthsto13yearsofage.HealthPolicyandClinicalEffectivenessProgramme, CincinnatiChildrensHospitalMedicalCentre,2004. Glasziou,PP,DelMar,CB,Sanders,SLandHayem,M,Antibioticsforacuteotitismediain children.CochraneDatabaseofSystematicReviews,Issue1.CD000219.,2004. WHO,Primaryearandhearingcare,Trainingresource,trainersmanual.2003. PreventionofHearingimpairementfromchronicotitismedia.ReportofaWHO,CIBA FoundationWorkshop,1996. WHO,Chronicsuppurativeotitismediaburdenofillnessandtreatmentoptions.Childand AdolescentHealthandDevelopment,2004. Leach,AJandMorris,PS,Antibioticsforthepreventionofacuteandchronicsuppurative otitismediainchildren.CochraneDatabaseofSystematicReviews,Issue4.CD004401.,2006.

3. 4. 5. 6. 7. 8. 9.

10.

11. 12.

13. 14.

15. 16. 17. 18. 19.

38

20. 21. 22. 23. 24. 25. 26.

WHOandUNICEF,Modelchapterfortextbook,IntegratedManagementofChildhood illnesses.DepartmentofChildandAdolescentHealthandDevelopment,2001. WHO,IntegratedManagementofChildhoodillnesses.2005. Taylor,A,Sinusitis.PediatrRev,2006.27(10):p.3957;discussion397. ContopoulosIoannidis,DG,Ioannidis,JPandLau,J,Acutesinusitisinchildren:current treatmentstrategies.PaediatrDrugs,2003.5(2):p.7180. Goodman&GilmansThePharmacologicalBasisofTherapeutics,11thEdition,ed.L.L. Brunton,etal.2006. Malik,ZAandLitman,N,Ampicillinandamoxicillin.PediatrRev,2006.27(11):p.4346. Qin,L,Watanabe,H,Asoh,N,Watanabe,K,Oishi,K,Mizota,TandNagatake,T, AntimicrobialsusceptibilityandgeneticcharacteristicsofHaemophilusinfluenzaeisolated frompatientswithrespiratorytractinfectionsbetween1987and2000,includingbeta lactamasenegativeampicillinresistantstrains.EpidemiolInfect,2006:p.14. Jansen,WT,Verel,A,Beitsma,M,Verhoef,JandMilatovic,D,LongitudinalEuropean surveillancestudyofantibioticresistanceofHaemophilusinfluenzae.JAntimicrobChemother, 2006.58(4):p.8737. Hasegawa,K,Kobayashi,R,Takada,E,Ono,A,Chiba,N,Morozumi,M,Iwata,S,Sunakawa, KandUbukata,K,Highprevalenceoftypebbetalactamasenonproducingampicillin resistantHaemophilusinfluenzaeinmeningitis:thesituationinJapanwhereHibvaccinehas notbeenintroduced.JAntimicrobChemother,2006.57(6):p.107782. Camargos,P,Fischer,GB,Mocelin,H,Dias,CandRuvinsky,R,Penicillinresistanceand serotypingofStreptococcuspneumoniaeinLatinAmerica.PaediatrRespirRev,2006.7(3):p. 20914. Kohanteb,JandSadeghi,E,PenicillinresistantStreptococcuspneumoniaeinIran.MedPrinc Pract,2007.16(1):p.2933. Lauderdale,TL,Lee,WY,Cheng,MF,Huang,IF,Lin,YC,Hseih,KS,Huang,IWandChiou, CC,HighcarriagerateofhighlevelpenicillinresistantStreptococcuspneumoniaeina Taiwankindergartenassociatedwithacaseofpneumococcalmeningitis.BMCInfectDis,2005. 5:p.96. Piglansky,L,Leibovitz,E,Raiz,S,Greenberg,D,Press,J,Leiberman,AandDagan,R, Bacteriologicandclinicalefficacyofhighdoseamoxicillinfortherapyofacuteotitismediain children.PediatrInfectDisJ,2003.22(5):p.40513. Leung,AKandKellner,JD,Acutesinusitisinchildren:diagnosisandmanagement.JPediatr HealthCare,2004.18(2):p.726. WHO,ManagementofChildwithaSeriousInfectionorSevereMalnutritionGuidelinesfor careatfirstreferrallevelindevelopingcountries.2000. Rojas,MXandGranados,C,Oralantibioticsversusparenteralantibioticsforsevere pneumoniainchildren.CochraneDatabaseofSystematicReviews,Issue2.CD004979.,2006. Hazir,T,Qazi,SA,Nisar,YB,Maqbool,S,Asghar,R,Iqbal,I,Khalid,S,Randhawa,S,Aslam, S,Riaz,S,andAbbasi,S,Comparisonofstandardversusdoubledoseofamoxicillininthe treatmentofnonseverepneumoniainchildrenaged259months:Amulticentre,double blind,randomizedcontrolledtrialinPakistan.ArchDisChild,2006. Jeena,P,Thea,DM,MacLeod,WB,Chisaka,N,Fox,MP,Coovadia,HMandQazi,S,Failure ofstandardantimicrobialtherapyinchildrenaged359monthswithmildorasymptomatic HIVinfectionandseverepneumonia.BullWorldHealthOrgan,2006.84(4):p.26975.

27.

28.

29.

30. 31.

32.

33. 34. 35. 36.

37.

39

38.

LeSaux,N,Gaboury,I,Baird,M,Klassen,TP,MacCormick,J,Blanchard,C,Pitters,C, Sampson,MandMoher,D,Arandomized,doubleblind,placebocontrollednoninferiority trialofamoxicillinforclinicallydiagnosedacuteotitismediainchildren6monthsto5years ofage.Cmaj,2005.172(3):p.33541. Arguedas,A,Emparanza,P,Schwartz,RH,Soley,C,Guevara,S,deCaprariis,PJand Espinoza,G,Arandomized,multicenter,doubleblind,doubledummytrialofsingledose azithromycinversushighdoseamoxicillinfortreatmentofuncomplicatedacuteotitismedia. PediatrInfectDisJ,2005.24(2):p.15361. Garbutt,JM,Goldstein,M,Gellman,E,Shannon,WandLittenberg,B,Arandomized, placebocontrolledtrialofantimicrobialtreatmentforchildrenwithclinicallydiagnosedacute sinusitis.Pediatrics,2001.107(4):p.61925. Toltzis,P,Dul,M,ORiordan,MA,Toltzis,HandBlumer,JL,Impactofamoxicillinon pneumococcalcolonizationcomparedwithothertherapiesforacuteotitismedia.PediatrInfect DisJ,2005.24(1):p.248. Paul,M,Silbiger,I,Grozinsky,S,SoaresWeiser,KandLeibovici,L,Betalactamantibiotic monotherapyversusbetalactamaminoglycosideantibioticcombinationtherapyforsepsis. CochraneDatabaseofSystematicReviews,Issue1.Art.No.:CD003344.,2006. Turnidge,JandGrayson,ML,Optimumtreatmentofstaphylococcalinfections.Drugs,1993. 45(3):p.35366. Tagbo,O,Uchenna,OandAnthony,H,ChildhoodparapneumonicpleuraleffusioninEnugu. NigerPostgradMedJ,2005.12(1):p.2832. Hageman,JC,Uyeki,TM,Francis,JS,Jernigan,DB,Wheeler,JG,Bridges,CB,Barenkamp,SJ, Sievert,DM,Srinivasan,A,Doherty,MC,McDougal,LK,Killgore,GE,Lopatin,UA,Coffman, R,MacDonald,JK,McAllister,SK,Fosheim,GE,Patel,JB,andMcDonald,LC,Severe communityacquiredpneumoniaduetoStaphylococcusaureus,200304influenzaseason. EmergInfectDis,2006.12(6):p.8949. WHO,Casemanagementofepidemicpronediseases,inCommunicablediseasetoolkit Burundi,Angola,Iraqcrisisetc.2006(latestmodified). Jeong,IS,Jeong,JSandChoi,EO,Nosocomialinfectioninanewbornintensivecareunit (NICU),SouthKorea.BMCInfectDis,2006.6:p.103. Gonzalez,C,Rubio,M,RomeroVivas,J,Gonzalez,MandPicazo,JJ,Bacteremicpneumonia duetoStaphylococcusaureus:Acomparisonofdiseasecausedbymethicillinresistantand methicillinsusceptibleorganisms.ClinInfectDis,1999.29(5):p.11717. RodriguezSolares,A,PerezGutierrez,F,Prosperi,J,Milgram,EandMartin,A,A comparativestudyoftheefficacy,safetyandtoleranceofazithromycin,dicloxacillinand flucloxacillininthetreatmentofchildrenwithacuteskinandskinstructureinfections.J AntimicrobChemother,1993.31SupplE:p.1039. Guven,M,Bulut,Y,Sezer,T,Aladag,I,Eyibilen,AandEtikan,I,Bacterialetiologyofacute otitismediaandclinicalefficacyofamoxicillinclavulanateversusazithromycin.IntJPediatr Otorhinolaryngol,2006.70(5):p.91523. Hoberman,A,Dagan,R,Leibovitz,E,Rosenblut,A,Johnson,CE,Huff,A,Bandekar,Rand Wynne,B,Largedosageamoxicillin/clavulanate,comparedwithazithromycin,forthe treatmentofbacterialacuteotitismediainchildren.PediatrInfectDisJ,2005.24(6):p.52532. Block,SL,Schmier,JK,Notario,GF,Akinlade,BK,Busman,TA,Mackinnon,GE,3rd, Halpern,MTandNilius,AM,Efficacy,tolerability,andparentreportedoutcomesforcefdinir

39.

40.

41.

42.

43. 44. 45.

46. 47. 48.

49.

50.

51.

52.

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vs.highdoseamoxicillin/clavulanateoralsuspensionforacuteotitismediainyoungchildren. CurrMedResOpin,2006.22(9):p.183947. 53. 54. Acuteotitismediainchildren:amoxicillinremainsthestandardantibiotic,butjustifiedin certainsituationsonly.PrescrireInt,2003.12(67):p.1849. Gavranich,JBandChang,AB,Antibioticsforcommunityacquiredlowerrespiratorytract infections(LRTI)secondarytoMycoplasmapneumoniaeinchildren.CochraneDatabaseof SystematicReviews,Issue3.CD004875.,2005. Southern,KW,Barker,PMandSolis,A,Macrolideantibioticsforcysticfibrosis.Cochrane DatabaseofSystematicReviews,Issue2.CD002203,2004. Grimwade,KandSwingler,GH,Cotrimoxazoleprophylaxisforopportunisticinfectionsin childrenwithHIVinfection.CochraneDatabaseSystRev,2006(1):p.CD003508. Mulenga,V,Ford,D,Walker,AS,Mwenya,D,Mwansa,J,Sinyinza,F,Lishimpi,K,Nunn,A, Gillespie,S,Zumla,A,Chintu,C,andGibb,DM,Effectofcotrimoxazoleoncausesofdeath, hospitaladmissionsandantibioticuseinHIVinfectedchildren.Aids,2007.21(1):p.7784. Noorani,QA,Qazi,SA,Rasmussen,ZA,Rehman,GN,Khan,SS,Muhammadullah,I, Mohammad,YK,Sher,GAandMunir,NH,Responsetocotrimoxazoleinthemanagementof childhoodpneumoniainfirstlevelhealthcarefacilities.IntJTubercLungDis,2006.10(8):p. 9328. Hazir,T,Qazi,SA,Nisar,YB,Maqbool,S,Asghar,R,Iqbal,I,Khalid,S,Randhawa,S,Aslam, S,Riaz,S,andAbbasi,S,CanWHOtherapyfailurecriteriafornonseverepneumoniabe improvedinchildrenaged259months?IntJTubercLungDis,2006.10(8):p.92431. Rao,S,Ahmed,MandHagan,R,Onedoseperdaycomparedtomultipledosesperdayof gentamicinfortreatmentofsuspectedorprovensepsisinneonates.CochraneDatabaseof SystematicReviews,Issue1.Art.No.:CD005091.,2006. Evidencebasedcareguidelineforcommunityacquiredpneumoniainchildren60days through17yearsofage.CincinnatiChildrensHospitalMedicalCenter.Cincinnati,2006. Guidelinesforthemanagementofadultswithhospitalacquired,ventilatorassociated,and healthcareassociatedpneumonia.AmJRespirCritCareMed,2005.171(4):p.388416. Mazzeo,F,Capuano,A,Avolio,A,Filippelli,AandRossi,F,Hospitalbasedintensive monitoringofantibioticinducedadverseeventsinauniversityhospital.PharmacolRes,2005. 51(3):p.26974. Jacobs,RF,Darville,T,Parks,JAandEnderlin,G,Safetyprofileandefficacyofcefotaximefor thetreatmentofhospitalizedchildren.ClinInfectDis,1992.14(1):p.5665.

55. 56. 57.

58.

59.

60.

61. 62. 63.

64.

41

Table1StudiesincludedintheCochranereviewontherapyofcommunityacquiredpneumoniain children[4]

Author,year,centre
AddoYobo2004 ConcealmentDnotused Block1995 Bunclear

Design
RCT

Subjects
3to59monthswithsevere pneumonia 3to16yearswith radiographicallydiagnosed pneumonia

Interventions
1.DailyIMpenicillin200,000IU/kg 2.POamoxicillin45mg/kg/day 1.POclarithromycin(15mg/kg/day)for 10days 2.POerythromycin40mg/kg/dayfor10 days 1.POamoxicillin25mg/kg/dayfor5 days 2.Cotrimoxazole20/4mg/kg/dayfor5 days 1.Singledoseofbenzathinepenicillin (600,000Uforpatientsbelow20kg weightand1,200,000Uforthoseabove 20kg), 2.Procainepenicillin300,000IU/kg/day IMfor7days

Outcome
Failurerateat48hours,5days and14daysanddeathrate Curerates,resolutionofsigns andsymptoms,improvement, failureorworsening

RCT

Catchup,2002 AAdequate

RCT

2to59monthswithnon severepneumonia

Curerate,failurerate,change ofantibiotics Curerate,failurerate,lostto followup

Camargos,1997 D

RCT

2yearsto12yearswithnon severepneumonia

Campbell,1988 D

RCT

1monthto4yearsofage withnonseverepneumonia

1.DailycotrimoxazolePOfor5days 2.Singledoseprocainepenicillinwith dailyPOampicillin

Curerate,hospitalisationrate, deathrate

42

Author,year,centre
Cetinkaya,2004 A

Design
RCT

Subjects
6monthsto16yearswith clinicalorradiological evidenceofpneumonia

Interventions

Outcome

1.IVchloramphenicol15mg/kgevery6 Clinicalrecovery hourspluspenicillin25,000IU/kgevery 4hoursfor10days 2.ceftriaxone50mg/kgevery12hours

Deivanayagam,1996 D

RCT

5monthsto4yearswith pneumoniaadmittedto hospital

1.IM/IVampicillin(100mg/kg/day)for Curerate,failurerate 48hoursthenPO, 2.IVpenicillin(100000IU/kg/day)plus chloramphenicol (100mg/kg/day)

Duke,2002 D

RCT

1to59monthsage,with severepneumonia

1.IMchloramphenicol(25mg/kg6 hourlyforatleast5days) 2.penicillin(50mg/kg6hourly)and gentamicin(7.5mg/kg/dsingledose) foratleast5days

death,changeinantibiotics, absconded,readmissionwithin 30days),rateof hospitalization,durationof hospitalstay Curerate(15,19d) improvementrate,failurerate

Harris,1998 D

RCT

6monthsto16yearswith clinicalorradiological evidenceofpneumonia

1.POazithromycin(10mg/kg/day1 followedby5mg/kg/dayfor4days) 2.amoxicillinclavulanicacid(40 mg/kg/day)for10days 3.erythromycin(40mg/kg/day)for10 days

Jibril,1989 D

RCT

2yearsto12yearsage,with nonseverepneumonia

1.Amoxicillinandclavulanicacid(250+ Curerate,poorornoresponse 62.5mgor500+125mgtds)for19days 2.amoxicillin(250mgor500mgtds)for 10days

43

Author,year,centre
Keeley,1990 D Klein,1995 B

Design
RCT

Subjects
3monthsto12yearswith nonseverepneumonia 3monthsto11.5years

Interventions

Outcome

1.Cotrimoxazoleperoralfor5d. Curerate,treatmentfailure, 2.ProcainepenicillinIMdailyfor5days hospitalization,wellatfinal followupanddeathrate 1.Cefpodoxime5to12mg/kg/dayPO for10days 2.coamoxyclavulanicacid6to13 mg/kg/dayfor10days Responserate

RCT

Kogan,2003 D

RCT

1monthto14yearswithnon 1.Azithromycin(10mg/kg/day)POfor severepneumonia 3daysr 2.amoxicillinPO75mg/kg/dayfor7 days

Clinicalandradiologicalcure rates,feveronday3andday7, chestxrayonday14

Mullholland,1995 A

RCT

below5yearsofagewith malnutritionandclinicalor radiologicalevidenceof pneumonia 2monthsto16yearswith nonseverepneumonia (acuteLRTI)

1.Cotrimoxazolefor1week 2.Chloramphenicolfor1week

Curerate,failurerate,relapse rate,deathrate

Roord,1996 D

RCT

1.Azithromycin10mg/kg/dayfor3 days 2.erythromycin40mg/kg/dayfor10 days 1.IMchloramphenicoldailyuntil switchedovertooral 2.IMchloramphenicolwithbenzyl penicillinuntilswitchedovertooral

Curerate,failurerateatday10 to14,improvementatday10, andbetweendays25to30 Goodimprovement,discharge fromhospital

Shann,1985 D

RCT

children

44

Author,year,centre
Sidal,1994 D

Design
RCT

Subjects
3monthsto14yearswith nonseverepneumonia (includingmoderate pneumonia) 2monthsto59monthswith nonseverepneumonia

Interventions
1.POcotrimoxazole(40mg/kg/day)for 10days 2.IMprocainepenicillin(50,000 IU/kg/day)for10days 1.POcotrimoxazole20mg/kg/dayfor5 days 2.amoxicillin45mg/kg/dayfor5days

Outcome
Curerateandimprovementat days5and10,failurerate

Strauss,1998 A Tsarouhas,1998 D

RCT

Clinicalandradiological failurerate

RCT

6monthsto18yearswith pneumonia

1.POamoxicillin(50mg/kg/day) 2.procainepenicillinIM(50,000IU/ kg/day) 1.POazithromycin(10mg/kgonday onefollowedby5mg/kg/dayfornext4 days) 2.POcoamoxiclavulanicacid40 mg/kg/dayfor10daysinchildren under5yearsofage;anderythromycin 40mg/kg/dayfor10daysinchildren over5years

Hospitalizationrate,failure rate,temperaturemorethan 38.5,illappearance,increased respiratoryrate Curerates,failurerates, improvementclinically diagnosed

Wubbel,1999 D

RCT

6monthsa16yearswith pneumonia

45

Table2StudiesincludedintheCochranereviewonoralversusparenteraltherapyforCAPinchildren[35]
Author,year APPISgroup2004 A Design Multicentre, randomized,open label,equivalency study Intentiontotreat analysisforthe mainoutcome Multicentre, controlled Intentiontotreat analyses Subjects Children,admittedtotertiary carecentresineight developingcountriesinAsia, AfricaandSouthAmerica aged3to59months WHOdefinedsevere pneumonia Agemean=22months Childrenfromsevenrural villagesofTheGambia WHOdefinedsevere pneumonia Interventions 1.Oral:amoxicillinsyrup45 mg/kgperdayinthreedoses (857) 2.Parenteral:intravenous penicillinGcrystalline200.000 IU/kgperdayinfourdoses (845) Oral:cotrimoxazole,fivedays courseofWHOrecommended doses(66) Parenteral+Oral:procaine penicillin(4megaunits)+ benzylpenicillin(1megaunit) onedose,followedbyfiveday courseoforalampicillinWHO recommendeddoses(68) Outcome Treatmentfailureupto 48hours,serious adversedrugreaction, necessityofother antibioticordeath

Campbell,1988 Cinadequate 7thdayfollowupwas blindedand 14thdayoutcome evaluationwasunblinded

Treatmentfailureat sevendaysand14days Incompleterecovery. Requirementfor furthertreatment

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Table3StudiesincludedintheCochranereviewonotitismediainchildren[15]
Author,year Appleman,1991 Netherlands A Design Randomised Doubleblind Subjects 121childreninageneral practiceaged6monthsto12 yearswithAOManda previousepisodeofotitis mediawithin1to12m Agedbetween3and10years Acuteearacheandatleastone abnormaleardrum 240childrenbetween6mand 2yrsattendinggeneral practice.Diagnosisaccording toDutchguidelines Clinicaldiagnosisofacute otitismedia,excludedif ruptureorrecentantibiotics Age2.5yearsorless clinicaldiagnosisofacute otitismedia Interventions 1.Amoxycillin/clavulanate (weighttailoreddose) 2.Placebo. Duration:7days Outcome 3dfeverandotalgia;14d otorrhoea;1motoscopy andtympanometry. failure=eitherotalgiaor feverorbothat3d. Symptomsat24hrs,5 7days

Burke,1991 UK A Damoiseaux,2000 Netherlands A Halsted,1968 USA B Howie,1972 USA A

Randomised Doubleblind

1.Amoxycillin250mgtds 2.Placebotds Duration:7days. 1.Amoxicillinsuspension 40mg/kg/din3divideddoses 2.Placebosuspension Duration:10days

Randomised

Symptomsat4days (earache,fever,crying irritably)

Randomised Blinded

1.Ampicillin100mg/kg/day Cultureresults,clinical 2.phenethicillin30mg/kg/day improvement +sulfisoxazole150mg/kg/d 3.placebo 1. Erythromycin,ampicillin, ortriplesulphonamideplus erythromycin 2. placebo culture

Randomised

47

Author,year Kaleida,1991 USA A Laxdal,1970 Canada C Mygind,1981 Denmark A Thalin,1985 Sweden A VanBuchem,1981(a) Netherlands A Withoutmyringotomy VanBuchem,1981(b) Netherlands A Withmyringotomy

Design Randomised Doubleblind

Subjects Agebetween7mand12yrs Acuteotitismedia:otoscopic middleeareffusionplus generalsymptomsorsigns Clinicaldiagnosisofacute otitismediaforatleastone ear;excludedifrupturehad occurred Ageonetotenyears, Acuteotitismedia,whohad hadearacheforI24hours. Age2to15years Acuteotitismedia=clinical diagnosis Age212years acuteotitismediaclinical diagnosis

Interventions 1.Amoxycillin40mg/kg/day in3doses 2.Placeboin3divideddoses Duration:14days

Outcome Treatmentfailure

Notclear

1.Penicillin250mg/sq.m./day Treatmentfailuremiddle qidorampicillin earinflammation7thday 250mg/sq.m./dayqid 2.symptomatictherapyonly 1.PenV55mg/kg/din3doses 2.Placebo Duration:7days 1.Penicillin50mg/kg/din3 doses 2.Placebo Duration:7days 1.Amoxicillin250mgtds 2.placebo;sham myringotomy Duration:7days Symptoms Tympanometry Otoscopy

Randomised, doubleblind

Randomised, doubleblind

clinicalexamination0,3 4,810,30d Audiogramonday30 Parentreportofpain Clinicalassessment:day2, 7,14,28,56. Audiogramat>2weeks

Randomised, doubleblind

Randomised

Childrenaged212years acuteotitis

1. Amoxicillin250mgtdsand Parentreportofpain Clinicalassessment:day2, myringotomy 7,14,28,56. 2. Placeb,myringotomy Audiogramat>2weeks Duration:7days

48

Table4StudiesincludedinCochranereviewonsorethroat[11]
(Studieswhereonlyadultswereincludedarenotlistedbelow) Author,year Bennike,1951 C Design Open,non randomised Subjects 669patientsagedfromlessthanone yeartogreaterthan50years Interventions 1.Penicillin 2.Notreatment Outcome Incidenceofrheumatic fever,otitismedia,quinsy, sinusitisandsymptomsof sorethroatandheadache Incidenceofrheumatic fever,otitismedia,and symptomofsorethroat

Chapple,1956 A

Randomised, doubleblind

308subjectsagedgreaterthantwoyears 1.Oralpenicillin old.Datafrom283subjectsincludedin 2.sulphadimidine analyses 3.bariumsulphate (placebo)forfivedays 239patientsaged4to60,presentingto 1. PenicillinV generalpracticeswhowereclinically 2. Placebo suspectedofGABHSsorethraot 173patientsaged5to50yrs Belgium 1.Oralpenicillin 2.Oralplacebo

Dagnelie,1996 A Netherlands DeMeyere,1992 A ElDaher,1991 A Krober,1985 A

Randomised doubleblind

Resolutionofsorethroat, fever,andreturntodaily activities(assessedfor7d) Symptomsofsorethroat

Doubleblind

Randomised, doubleblind

229childrenwithpositiveculturefor GABHS

1. Oralpenicillinfor10d Symptomsofsorethroat andheadacheonday3 2. Placebofor2d,then oralpenicillinfor8d 1.Oralpenicillin 2.Oralplacebo 3timesadayfor3days Symptomoffever

Randomised doubleblind

44childrenpresentingtoapaediatric clinic.26yieldedgroupABHSfrom throatswabs

49

Author,year Leelarasamee,2000 A

Design Randomised doubleblind

Subjects

Interventions

Outcome Durationofsorethroat andfever.incidenceof complicationsandadverse reactions Durationofsymptoms, satisfaction,compliance withandperceived efficacyofantibiotics,time offschoolorwork. Temperature Symptomsofsorethroat andfever

1.Amoxicillin 1217patientsagedover5years presentingtocommunitybased 2.placebo medicalcentreswithcomplaintsof feverorsorethroatoflessthantendays forsevendays duration 716patientsaged4yearsandover, presentingtotheirGPwithasore throat,withanabnormalphysical findinglocalisedtothethroat(e.g. inflamedtonsilsorpharynx,etc) 1.Antibioticfor10days; 2.Noprescription 3.Offerofantibiotic prescriptionifsymptoms werenotstartingtosettle after3days 1.Eightindividualdoses ofpenicillin 2.Unmedicatedplacebo

Little,1997 C

Randomised,Not blinded

Middleton,1988

Multicentre, randomised, doubleblind

178patientsaged4to29yrswith streptococcalpharyngitis;symptom duration<4days. Resultsreportedfor57withsevere illnessonly

Nelson,1984 C

51childrenaged5to11years.16were excludedbecausethroatswabswere negativeforGroupABHS.(i.e.n=35) Childrenwithhistoryofpenicillin hypersensitivitywerealsoexcluded

1.IMpenicillin 2.Oralsyrupplacebo

Symptomsofsorethroat andfever

Pichichero,1987 A

Randomised, doubleblind

114GroupABetaHaemolytic Streptococcuspositivechildrenaged4 to18years.Childrenwereexcludedif, allergictopenicillin;hadreceived penicillininpast7days;hadanother acuteillnesswithin7days,hadaGroup 50

1.Oralpenicillinforforty eighthours 2.Oralplaceboused

Incidenceofotitismedia, quinsy,sinusitis

Author,year

Design

Subjects ABHSpositiveswabinpastmonth,or hadanotherconcurrentinfectionthat requiredantibiotics

Interventions

Outcome

Siegel,1961 C

Randomised,open

1.IMpenicillin 1213patientsaged316years. Suppurativecomplicationsoccurringin 2.Notreatment thecontrolgroupweretreatedwith sulphonamides.Subjectswereexcluded iftherewasacomplication. 122childrenaged210years. 1.Oralamoxicillin

Incidenceofrheumatic fever

Taylor,1977 A

Doubleblind, randomised

2.Oralcotrimoxazole ChildrenwithpositiveStreptococcus throatswabswereexcluded 3.Oralplacebo Ninechildrenwereexcludedbecauseof preexistingsuppurativecomplications 3timesadayfor5days 745,Age>10yrs,presentingtogeneral practitionerwithsorethroat. Only528returnedquestionnaires. Subjectswereexcludedifpoor compliancewassuspected;previous reactiontopenicillin;aprevious episodeofrheumaticfeveroracute nephritis

Incidenceofotitismedia andsinusitisand symptomsofsorethroat andfever

Whitfield,1981 A

Doubleblind, randomised

1.Oralpenicillin4timesa fever dayfor5days 2.Orallactoseplacebo4 timesadayfor5days

Zwart,2003 A

Randomised, doubleblind

165childrenaged4to15years presentingwithsorethroatoflessthan 7daysduration

1.PenicillinVfor7days 2.PenicillinVfor3days andplacebofor4days 3.Placebofor7days

Durationofsymptomsof sorethroat,occurrenceof streptococcalsequelae

51

 1. 2. 3. 4. Kabra, SK, Lodha, R and Pandey, RM, Antibiotics for community acquired pneumonia in children. . Cochrane Database of Systematic Reviews,Issue3.CD004874.,2006. Rojas, MX and Granados, C, Oral antibiotics versus parenteral antibiotics for severe pneumonia in children. Cochrane Database of SystematicReviews,Issue2.CD004979.,2006. Glasziou, PP, Del Mar, CB, Sanders, SL and Hayem, M, Antibiotics for acute otitis media in children. Cochrane Database of Systematic Reviews,Issue1.CD000219.,2004. DelMar,CB,Glasziou,PPandSpinks,AB,Antibioticsforsorethroat.CochraneDatabaseofSystematicReviews,Issue4.CD000023,2006.

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