Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination ...

214 Pages·2008·1.42 MB·English

Beta lactam antibiotic monotherapy versus beta lactam-
aminoglycoside antibiotic combination therapy for sepsis
(Review)
Paul M, Grozinsky S, Soares-WeiserK, LeiboviciL
ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary
2009,Issue1
http://www.thecochranelibrary.com
Betalactamantibioticmonotherapyversusbetalactam-aminoglycosideantibioticcombinationtherapyforsepsis(Review)
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Analysis1.1.Comparison1Monotherapyversuscombinationtherapy,Outcome1Allcausefatality. . . . . . . 78
Analysis1.2.Comparison1Monotherapyversuscombinationtherapy,Outcome2Allcausefatalitybystudygroups. 82
Analysis1.3.Comparison1Monotherapyversuscombinationtherapy,Outcome3Allcausefatality(Gramnegative
infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Analysis1.4.Comparison1Monotherapyversuscombinationtherapy,Outcome4Allcausefatality(Gramnegative
bacteremia). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Analysis1.5.Comparison1Monotherapyversuscombinationtherapy,Outcome5Allcausefatality(nonurinarytract
infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Analysis2.1.Comparison2Monotherapyversuscombinationtherapy,Outcome1Clinicalfailure. . . . . . . 95
Analysis2.2.Comparison2Monotherapyversuscombinationtherapy,Outcome2Clinicalfailurebystudygroups. . 101
Analysis2.3.Comparison2Monotherapyversuscombinationtherapy,Outcome3Bacteriologicalfailure-all. . . 109
Analysis2.4.Comparison2Monotherapyversuscombinationtherapy,Outcome4UTIrelapseorre-infection. . . 113
Analysis2.5.Comparison 2Monotherapyversuscombination therapy,Outcome5Clinicalfailure(Gramnegative
infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Analysis2.6.Comparison 2Monotherapyversuscombination therapy,Outcome6Clinicalfailure(Gramnegative
bacteremia). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Analysis2.7.Comparison 2Monotherapy versuscombination therapy,Outcome7Clinical failure(Pseudomonas
aeruginosainfections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Analysis2.8.Comparison2Monotherapyversuscombinationtherapy,Outcome8Clinicalfailure(bacteremia). . . 123
Analysis2.9. Comparison 2 Monotherapy versuscombination therapy,Outcome 9Clinical failure (urinary tract
infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Analysis2.10.Comparison2Monotherapyversuscombinationtherapy,Outcome10Clinicalfailure(nonurinarytract
infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Analysis3.1.Comparison3Monotherapyversuscombinationtherapy,Outcome1Bacterialsuperinfections. . . . 133
Analysis3.2.Comparison3Monotherapyversuscombinationtherapy,Outcome2Fungalsuperinfections. . . . . 134
Analysis3.3.Comparison3Monotherapyversuscombinationtherapy,Outcome3Bacterialcolonization. . . . . 135
Analysis3.4.Comparison3Monotherapyversuscombinationtherapy,Outcome4Fungalcolonization. . . . . . 136
Analysis3.5.Comparison3Monotherapyversuscombinationtherapy,Outcome5Bacterialcolonization-surveillance
cultures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Analysis3.6.Comparison3Monotherapyversuscombinationtherapy,Outcome6Bacterialresistancedevelopment. 138
Analysis4.1.Comparison4Monotherapyversuscombinationtherapy,Outcome1Anyadverseevent. . . . . . 139
Analysis4.2.Comparison4Monotherapyversuscombinationtherapy,Outcome2Adverseeventsrequiringtreatment
discontinuation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Analysis4.3.Comparison4Monotherapyversuscombinationtherapy,Outcome3Anynephrotoxicity. . . . . . 142
Analysis5.1.Comparison5Monotherapyversuscombinationtherapy,Outcome1Drop-outsforallcausefatality. . 148
Analysis5.2.Comparison5Monotherapyversuscombinationtherapy,Outcome2Drop-outsforclinicalfailure. . . 150
Betalactamantibioticmonotherapyversusbetalactam-aminoglycosideantibioticcombinationtherapyforsepsis(Review) i
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Analysis6.1.Comparison6Monotherapyversuscombination therapy,Outcome1Allcausefatality(Grampositive
infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Analysis6.2. Comparison 6Monotherapy versuscombination therapy,Outcome2Clinical failure(Grampositive
infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Analysis6.3.Comparison6Monotherapyversuscombinationtherapy,Outcome3Bacteriologicalfailure(Grampositive
infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Analysis6.4.Comparison6Monotherapyversuscombinationtherapy,Outcome4Needforoperation(endocarditis). 155
Analysis7.1.Comparison7Monotherapyversuscombinationtherapy(sensitivityanalyses),Outcome1Allcausefatality
byallocationconcealment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Analysis7.2.Comparison7Monotherapyversuscombinationtherapy(sensitivityanalyses),Outcome2Allcausefatality
byallocationgeneration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Analysis7.3.Comparison7Monotherapyversuscombinationtherapy(sensitivityanalyses),Outcome3Allcausefatality
byITTvs.per-protocolanalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Analysis7.4.Comparison7Monotherapyversuscombinationtherapy(sensitivityanalyses),Outcome4Clinicalfailureby
allocationconcealment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Analysis7.5.Comparison7Monotherapyversuscombinationtherapy(sensitivityanalyses),Outcome5Clinicalfailureby
allocationgeneration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Analysis7.6.Comparison7Monotherapyversuscombinationtherapy(sensitivityanalyses),Outcome6Clinicalfailureby
blinding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Analysis7.7.Comparison7Monotherapyversuscombinationtherapy(sensitivityanalyses),Outcome7Clinicalfailureby
ITTversusper-protocolanalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Betalactamantibioticmonotherapyversusbetalactam-aminoglycosideantibioticcombinationtherapyforsepsis(Review) ii
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Beta lactam antibiotic monotherapy versus beta lactam-
aminoglycoside antibiotic combination therapy for sepsis
MicalPaul1,SimonaGrozinsky2,KarlaSoares-Weiser3,LeonardLeibovici4
1InfectiousDiseasesUnitandDepartmentofMedicine E,RabinMedicalCenter,Petah-Tikva, Israel.2InternalMedicineE,Rabin
Medical Center, Petah-Tikva, Israel. 3Enhance Reviews, Kfar-Saba, Israel. 4Department of Medicine E, Beilinson Campus, Rabin
MedicalCenter,Petah-Tiqva,Israel
Contact address: Mical Paul, Infectious Diseases Unit and Departmentof Medicine E, Rabin Medical Center,Beilinson Campus,
Petah-Tikva,49100,[email protected].(Editorialgroup:CochraneAnaesthesiaGroup.)
CochraneDatabaseofSystematicReviews,Issue1,2009(Statusinthisissue:Edited)
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
DOI:10.1002/14651858.CD003344.pub2
Thisversionfirstpublishedonline:25January2006inIssue1,2006.Re-publishedonlinewithedits:21January2009inIssue1,
2009.
Lastassessedasup-to-date: 10November2005.(Helpdocument-DatesandStatusesexplained)
Thisrecordshouldbecitedas: PaulM,GrozinskyS,Soares-WeiserK,LeiboviciL.Betalactamantibioticmonotherapyversusbeta
lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.:
CD003344.DOI:10.1002/14651858.CD003344.pub2.
ABSTRACT
Background
Optimalantibiotictreatmentforsepsisisimperative.Combiningabeta-lactamantibioticwithanaminoglycosideantibioticmayhave
certainadvantagesoverbeta-lactammonotherapy.
Objectives
Wecomparedclinicaloutcomesforbetalactam-aminoglycosidecombinationtherapyversusbetalactammonotherapyforsepsis.
Searchstrategy
We searchedtheCochrane CentralRegister of ControlledTrials (CENTRAL), (TheCochrane Library, Issue 3, 2004); MEDLINE
(1966toJuly2004);EMBASE(1980toMarch2003);LILACS(1982toJuly2004);andconferenceproceedingsoftheInterscience
ConferenceofAntimicrobialAgentsandChemotherapy(1995to2003).Wescannedcitationsofallidentifiedstudiesandcontacted
allcorrespondingauthors.
Selectioncriteria
Weincludedrandomizedandquasi-randomizedtrialscomparinganybeta-lactammonotherapytoanycombinationofonebeta-lactam
andoneaminoglycosideforsepsis.
Datacollectionandanalysis
Theprimaryoutcomewasall-causefatality.Secondaryoutcomesincludedtreatmentfailure,superinfections,colonization,andadverse
events.Twoauthorsindependentlycollecteddata.Wepooledrelativerisks(RR)withtheir95%confidenceintervals(CI)usingthe
fixedeffectmodel.Weextractedoutcomesbyintention-to-treatanalysiswheneverpossible.
Mainresults
Weincluded64trials,randomizing7586patients.Twentytrialscomparedthesamebeta-lactaminbothstudyarms,whiletheremaining
compareddifferentbeta-lactamsusingabroaderspectrumbeta-lactaminthemonotherapyarm.Instudiescomparingthesamebeta-
Betalactamantibioticmonotherapyversusbetalactam-aminoglycosideantibioticcombinationtherapyforsepsis(Review) 1
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
lactam,weobservednodifferencebetweenstudygroupswithregardtoall-causefatality,RR1.01(95%CI0.75-1.35) andclinical
failure, RR 1.11 (95% CI 0.95-1.29). In studies comparing differentbeta-lactams, we observed an advantage to monotherapy: all
cause fatality RR0.85 (95% CI0.71-1.01), clinical failure RR 0.77 (95% CI 0.69-0.86). Nosignificant disparities emergedfrom
subgroupandsensitivityanalyses,includingtheassessmentofpatientswithGram-negativeandPseudomonasaeruginosainfections.We
detectednodifferencesintherateofresistancedevelopment.Adverseeventsratesdidnotdiffersignificantlybetweenthestudygroups
overall,althoughnephrotoxicitywassignificantlymorefrequentwithcombinationtherapy,RR0.30(95%CI0.23-0.39).Wefound
noheterogeneityforallcomparisons.WeincludedasmallsubsetofstudiesaddressingpatientswithGram-positiveinfections,mainly
endocarditis.Weidentifiednodifferencebetweenmonotherapyandcombinationtherapyinthesestudies.
Authors’conclusions
Theadditionofanaminoglycosidetobeta-lactamsforsepsisshouldbediscouraged.All-causefatalityratesareunchanged.Combination
treatmentcarriesasignificantriskofnephrotoxicity.
PLAIN LANGUAGE SUMMARY
Singleversuscombinationantibiotictreatment forsevereinfections:beta-lactammonotherapyversusbeta-lactam-aminogly-
cosidecombinationtherapy
Infections causedbybacteria arealeadingcause ofpreventabledeath.The mortalityassociated with severeinfections necessitating
hospitalizationisabout30%.Antibiotictreatmentimprovessurvival.
Thereareseveralclassesofantibiotics currentlyinuse.Thebeta-lactamclassisoneofthemostimportantclassinuse.Antibiotics
belongingtoit(penicillins,cephalosporins,andothers)killbacteriabydisruptingtheircellwall.Aminoglycosides(e.g.gentamicin)act
thoughadifferentmechanism,inhibitingbacterialproteinsynthesis.Studiesofbacteriaincellcultureshaveshownthatcombininga
beta-lactamwithanaminoglycosideresultsinbacterialkillingsuperiortothesimpleadditiveactivityofeachoftheseantibioticsalone,
aphenomenontermed’synergism’.
Inhumans, combination therapymay haveseveraldrawbacks, suchasanincreasedrateof adverseeffects.Wethereforedecidedto
compile clinical studies thatcompared treatmentwith abeta-lactam totreatmentwith abeta-lactam plusan aminoglycoside. Our
objectivewastoassesswhethercombinationtreatmentresultsinbetteroutcomes,mainlysurvival.
Thereviewincluded64trialsrandomizing7586patients.Patientswerehospitalizedwithurinarytract,intra-abdominal,skinandsoft
tissueinfections,pneumonia,andinfectionofunknownorigin.Antibioticswereadministeredintravenously.
Combinationantibiotictreatmentdidnotimprovetheclinicalefficacyachievedwiththebeta-lactamantibioticalone.Onesetofstudies
comparedanew,broad-spectrumbeta-lactamtoanolder,lesspotentbeta-lactamcombinedwithanaminoglycoside(44studies).In
thesestudies,mortalityandfailurewerelowerwithsinglebeta-lactamantibiotictreatment.Mortalitywasreducedby15%,butthe
differencewasnotstatisticallysignificant.Theothersetofstudiescomparedonebeta-lactamtothesamebeta-lactamcombinedwith
anaminoglycoside (20 studies). Inthesetrials,nodifferencesbetweensingle andcombination antibiotic treatmentwereseen.The
relativeriskformortalitywas1.01,denotingequivalenceofthetworegimens.
Adverseeventsratesdidnotdifferbetweenthestudygroups,overall,butrenaldamagewasmorefrequentwithcombinationtherapy.
Combinationtherapydidnotpreventthedevelopmentofsecondaryinfections.
Thereviewersconcludethatbeta-lactam-aminoglycosidecombinationtherapyoffersnoadvantagetobeta-lactamsalone.Furthermore,
combination therapyisassociatedwithanincreasedriskofrenaldamage.Paucityoftrialscomparingthesamebeta-lactaminboth
studyarmsandincompletenessofmortalityreportingmaylimittheseconclusions.Theseresultsmaynotapplytolocationsinwhich
resistanceratestonarrow-spectrumbeta-lactamsareverylow,suchasScandinaviancounties.
Betalactamantibioticmonotherapyversusbetalactam-aminoglycosideantibioticcombinationtherapyforsepsis(Review) 2
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
BACKGROUND
apyinpatientswithsuspectedorprovenbacterialinfections.Some
Sepsisisdefinedastheclinicalevidenceofinfection,accompanied trialshavefocusedspecificallyoninfectionscommonlycausedby
by a systemic inflammatory response such as fever.When asso- Gram-negativebacteria,suchasurinarytractinfectionsandhos-
ciatedwithorgandysfunction,decreasedbloodflowinanorgan pitalacquiredinfections,wherethebenefitofcombinationther-
(hypoperfusion),orabnormallylowbloodpressure(hypotension), apymay bemoreprominent. Nevertheless,superiority of either
sepsisisdefinedassevere(Bone1992;Mandell2004).Sepsismay monotherapy orcombination therapyhasnotbeenshowncon-
bearesponsetodirectmicrobial invasion or maybeelicitedby clusivelyinthesestudies.
microbialsignalmoleculesortoxinproduction.Infectionsmaybe
lethal,withfatalityratesrangingfromlessthan10%tomorethan
40% for those with severe sepsis (Moore 2001; Rangel-Frausto OBJECTIVES
1995;Russell2000).Appropriateempiricalantibiotictreatment,
Ourobjectiveswere:
administeredtothepatientbeforeidentificationofthepathogen
oritsantibioticsusceptibilities,hasbeenshowntohalvethefatal- 1. tocompare betalactammonotherapy versusbetalac-
ityassociatedwithsepsis(Bryant1971;Ibrahim2000;Leibovici tam-aminoglycoside combination therapy in patients
1998;Whitelaw1992). withsepsis;and
Regimensrecommendedfortheempiricaltreatmentofsepsisin-
2. toestimate therate ofadverseeffectswitheachtreat-
clude:(1)asinglebroad-spectrumagent,commonlyfromthebeta
mentregimen,includingthedevelopmentofbacterial
lactamclassof antibiotics; and (2)acombination of abetalac-
resistancetoantibiotics.
tamantibioticwithanaminoglycosideantibiotic(Mandell2004).
Combinationantibiotictherapyhasseveraltheoreticaladvantages.
First,itmayhaveabroaderantibioticspectrum.Second,thecom-
METHODS
bination may possess an enhanced potential (synergism), when
comparedtotheadditiveeffectofeachoftheantibioticsassessed
separately(Giamarellou1986;Klastersky1982).Third,combina- Criteriaforconsideringstudiesforthisreview
tiontherapyhasbeenclaimedtosuppresstheemergenceofsub-
Typesofstudies
populationsofmicroorganismsresistanttotheantibiotics(Allan
1985;Milatovic1987).Thedisadvantagesofcombination ther- Weincludedrandomizedorquasi-randomizedcontrolledtrials.
apymayincludeadditionalcosts,enhanceddrugtoxicity,thepos- Typesofparticipants
sibleinductionofresistancecausedbythebroaderantibioticspec-
Weincludedhospitalizedpatientswithsepsisacquiredeitherinthe
trum(Manian1996;Weinstein1985),andpossibleantagonism
communityorinthehospital(nosocomial).Wedefinedsepsisas
betweenspecificdrugcombinations(Moellering1986).
clinicalevidenceofinfection,plusevidenceofasystemicresponse
Aminoglycoside antibiotics are most active against Gram-nega- toinfection(Bone1992).Weexcludedneonatesandpretermba-
tivebacteria(Mandell2004).Inaddition,synergismbetweenbeta bies. We also excluded studies including more than 15% neu-
lactam antibiotics and aminoglycoside antibiotics has been re- tropenicpatients.
peatedly shown in vitro specifically for Gram-negative bacteria Typesofinterventions
(Giamarellou 1986; Klastersky 1976; Klastersky 1982). Conse-
We considered studies comparing the antibiotic regimens de-
quently, thebenefit of combination therapy,if existent, may be
scribedbelow.
moreprominentinpatientswithGram-negativeinfections.Other
1. Any intravenous beta-lactam antibiotic given as
featuresrelatedto theinfection may affectprognosis. Thesein-
monotherapy,including:
cludethesiteofinfectionandthespecificcausativepathogen.For
i) penicillins;
example,infectionscausedbyPseudomonasaeruginosahavebeen
ii) beta lactam drugs plus beta lactamase in-
showntoportendapoorprognosis(Baine2001;Geerdes1991;
hibitors(egco-amoxiclav);
Leibovici1997).Weexpecttodealwithfactorssuchasthese,ex-
iii) cephalosporins(egceftazidime,cefotaxime);
pectedtounderlieheterogeneity,using subgroup analysiswhere
iv) carbapenems(egimipenem,meropenem).
appropriate.Specificguidelineshavebeeninstitutedfortheem-
2. Combination therapy of a beta lactam antibiotic (as
pirical treatmentof cancer patientwith neutropenia, basing the
specified)withoneofthefollowingaminoglycosidean-
suspicion of sepsis on fever alone (Hughes 2002). The authors
tibiotics:
have therefore considered studies addressing these patients in a
i) gentamicin;
separatereview(Paul2001).
ii) tobramycin;
Numerous studies have been conducted comparing beta lactam iii) amikacin;
monotherapy to beta lactam-aminoglycoside combination ther- iv) netilmicin;
Betalactamantibioticmonotherapyversusbetalactam-aminoglycosideantibioticcombinationtherapyforsepsis(Review) 3
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
v) streptomycin; We searched the Cochrane Controlled Trials Register, (CEN-
vi) isepamicin; TRAL), (The Cochrane Library, Issue 3, 2004) using the same
vii) sisomicin. searchterms.
We searched the following electronic databases in combination
Typesofoutcomemeasures
withthesearchstrategydevelopedbyTheCochraneCollabora-
Primaryoutcomes tionanddetailedintheCochraneHandbookforSystematicRe-
viewsofInterventionstolimitthesearchforrandomizedorquasi-
All-causefatalitybytheendofthestudyfollow-up.
randomizedtrials(Higgins2005):
Secondaryoutcomes 1. MEDLINE (1966 to July 2004) using the search:
(aminoglycoside*ORnetilmicin*ORgentamicin*OR
1. Treatmentfailuredefinedasdeathand/oroneormore
amikacin* OR tobramycin* OR streptomycin* OR
seriousmorbidevents(persistence,recurrence,orwors-
isepamicin* OR sisomicin*) AND (combination OR
eningofclinicalsignsorsymptomsofpresentinginfec-
combi*). In a second search, the terms (combination
tion;anymodificationoftheassignedempiricalantibi-
ORcombi*)werereplacedbyendocarditis, Staphylo-
otictreatment;oranytherapeuticinvasiveintervention
coccus, Streptococcus or pneumonia to enhance the
requirednotdefinedintheprotocol).
sensitivity andspecificityof oursearchtotheseinfec-
2. Lengthofhospitalstay.
tions.
3. Dropouts:numberofpatientsexcludedfromtheout-
2. EMBASE(1980toMarch2003)usingthesamesearch
comeassessmentafterrandomization.
terms.
4. Superinfection:recurrentinfectionsdefinedasnew,per-
3. LILACS (1982 to July 2004) using the same search
sistent,orworsening symptomsand/orsignsofinfec-
terms.
tion associated with the isolation of a new pathogen
(different pathogen, or same pathogen with different Searchingotherresources
susceptibilities)orthedevelopmentofanewsiteofin- WesearchedtheInterscienceConferenceofAntimicrobialAgents
fection. and Chemotherapy conference proceedings (1995 to 2003) for
5. Colonizationbyresistantbacteria:theisolationofbac- relevantabstracts.
teriaresistant to thebetalactamantibiotic, during or Wecontactedthefirstorcorrespondingauthorofeachincluded
followingantibiotictherapy,withnosignsorsymptoms study,andtheresearchersactiveinthefield,forinformationre-
ofinfection. gardingunpublishedtrialsorcomplementaryinformationontheir
6. Adverseeffects: owntrials.
i) life-threateningorassociatedwithpermanent We also checked the citations of major reviews and of all trials
disability(severenephrotoxicity;ototoxicity; identifiedbytheabovemethodsforadditionalstudies.
anaphylaxis;severeskinreactions); Wedidnothavealanguagerestriction.
ii) serious:requiringdiscontinuationoftherapy
(othernephrotoxicity;seizures;pseudomem-
Datacollectionandanalysis
branouscolitis;otherallergicreactions);
iii) anyother(othergastrointestinal;otheraller- Studyselection
gicreactions).
Oneauthor(MP)inspectedtheabstractofeachreferenceidenti-
fiedinthesearchandappliedtheinclusioncriteria.Whererelevant
Searchmethodsforidentificationofstudies articleswereidentified,thefullarticlewasobtainedandinspected
independentlybytwoauthors(MP,ISorLL).
Electronicsearches Qualityassessment
Weformulatedacomprehensivesearchstrategyinanattemptto Weassessedthequalityofthetrialstobeincludedforallocation
identifyallrelevantstudiesregardlessoflanguageorpublication sequence,allocationconcealment,blinding, fatalityoutcomere-
status(published,unpublished,inpress,andinprogress).Thekey porting, intention-to-treat analysis, and number of patients ex-
wordsusedforthesearchstrategyareshowninAppendix1. cludedfromoutcomeassessment.Twoauthors(MP,ISorKSW)
WesearchedtheCochraneInfectiousDiseasesGroupspecialized independentlyperformedqualityassessment.Webasedmethod-
trialsregister forrelevanttrialsuptoDecember2002 using the ologicalqualityclassificationontheevidenceofastrongassocia-
searchterms:((aminoglycoside*ORnetilmicin*ORgentamicin* tionbetweenpoorallocationconcealmentandoverestimationof
ORamikacin*ORtobramycin*ORstreptomycin*ORisepam- effect.Wedefineditas:A(lowriskof bias; adequate allocation
icin* ORsisomicin*) AND(pneumonia* ORinfection ORin- concealment);B(moderateriskofbias;somedoubtaboutalloca-
fect*ORsepsisORbacter*ORbacteremiaORsepticemia). tionconcealment);andC(highriskofbias;inadequateallocation
Betalactamantibioticmonotherapyversusbetalactam-aminoglycosideantibioticcombinationtherapyforsepsis(Review) 4
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
concealment) (Schulz 1995). We performed sensitivity analyses 1. antibiotictypeanddose;
toassesstheeffectofstudyqualitymeasuresoneffectestimates. 2. durationoftherapy(mean).
Weintendtoassesstheeffectofnumberofexclusionsoneffect Characteristicsofoutcomemeasures:
estimates(aboveorbelow20%)infutureupdatesofthereview. 1. numberofdeathsattheendofthefollow-upperiod;
Datacollection 2. numberofpatientsfailingtreatment(asdefined);
3. adversereactions(asdefined)ineachgroup;
Two authors(MP,ISorSG)independentlyextracteddatafrom
4. lossoffollow-up(dropouts)beforetheendofthestudy
includedtrials.Incaseofdisagreementbetweenthetwoauthors,a
ineachgroup;
thirdauthor(KSW,LL)independentlyextractedthedata.Athird
5. numberofpatientsdevelopingsuper-infection;
author(KSWorLL)alsoextractedthedatain10%ofthestudies,
6. numberofpatientsdevelopingcolonization(asdefined)
selected at random. We discussed data extraction, documented
withresistantbacteria;
decisions, and contacted authors of all studies for clarification.
7. durationoffeverandhospitalstay.
We resolveddifferencesin the data extractedby discussion. We
We collected outcome measures on an intention-to-treat basis
alsodocumentedthejustificationforexcludingstudiesfromthe
wheneverpossible.Wheresuchdatawerenotpresented,wesought
review.
information from the authors, and if unavailable, per-protocol
Weidentifiedthetrialsbythenameofthefirstauthorandtheyear
resultswereused.For failureoutcome,weperformedsensitivity
inwhichthetrialwasfirstpublished,andlistedinchronological
analyses comparing these results with a ’presumed all intention
order.Weextracted,checkedandrecordedthefollowingdata.
totreat’,whichweachievedbycountingalldropoutsasfailures.
Characteristicsoftrials:
Wecouldnotmakesuchanassumption instudiesthatdidnot
1. date,location,andsettingoftrial;
specifythenumberofdropoutsperstudyarm,andweanalysed
2. publicationstatus;
thesestudiesseparately.
3. countryoforigin;
4. design(intention-to-treat,methodofrandomization); Datasynthesis
5. durationofstudyfollow-up; We calculated relative risks for dichotomous data. Continuous
6. performance of surveillance cultures (routine cultures outcomeswereunavailableforthisreview.Wewilluseweighted
forthedetectionofcolonization); mean differences for continuous outcomes in future updates of
7. sponsoroftrial. thereview.Weinitiallyassessedheterogeneityintheresultsofthe
Characteristicsofpatients: trialsusingachi-squaredtestofheterogeneity(p<0.1).Weused
1. numberofparticipantsineachgroup; afixedeffectmodelthroughoutthereview,astheI2 measureof
2. age (mean and standard deviation, or median and inconsistency waslowforallcomparisons. Wecomparedresults
range); obtainedbythefixedeffectmodeltothoseobtainedbyarandom
3. numberofpatientswithrenalfailurebeforetreatment; effectmodelforthemajoroutcomes.Weexploredthefollowing
4. numberofpatientswithshock. factorstoexplainheterogeneityinrelationtothemajoroutcomes:
Characteristicsofinfection: 1. infectionscausedbyPseudomonas sp.versusallother
1. number ofpatientswithinfectionscausedbybacteria infections;
resistanttotheadministeredbetalactamantibiotic; 2. Gram-negativeversusallotherinfections;and
2. numberofpatientswithnosocomialinfections; 3. urinarytractinfectionsversusothersitesofinfection.
3. numberofpatientswithbacteremia; Weperformedsubgroupanalysisbythesefactorswheredatawere
4. numberofpatientswithbacteriologicallydocumented available.Forsubgroupanalysesweextractedall-causefatalityand
infection; treatment failures outcomes. We adjusted the descriptive mean
5. number of patients with infections caused by Gram- mortalityrateinincludedstudiestotheinverseofthemortality
negativebacteria; variancebetweenthetrials.
6. numberofpatientswithGram-negativebacteremia; WeexaminedafunnelplotofSE(log(relativerisk))versusrelative
7. numberofpatientswithdocumentedPseudomonasin- risk of each study in order to estimate potential selection bias
fections (Pseudomonas isolatedintheblood orspeci- (publicationandlanguage).
men(s)obtainedfromsuspectedsite(s)ofinfection);
8. numberofpatientswith:
i) urinarytractinfection;
ii) pneumonia;
iii) intra-abdominalinfection; RESULTS
iv) skinandsofttissueinfection;and
v) infectionofunknownorigin. Descriptionofstudies
Characteristicsofinterventions:
Betalactamantibioticmonotherapyversusbetalactam-aminoglycosideantibioticcombinationtherapyforsepsis(Review) 5
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
See:Characteristicsofincludedstudies;Characteristicsofexcluded
studies.
Thesearchstrategyresultedin5568references.Wefiltereddouble
references,andscreened2805differentabstractsforinclusion.We
didnotevaluatestudiesinwhichthecomparatorantibioticreg-
imenswereclearlyincompatiblewithinclusioncriteriaindepth.
Wesimilarlyexcludednon-randomizedandnon-humanstudies.
Weretrieved145studiesforfull-textinspection,ofwhichweex-
cluded67publications,representing63studies(seetableof’Char-
acteristicsofexcludedstudies’), andcategorizedtwoasawaiting
assessment(seeAdditionalTable1,and’Tableofstudiesawaiting
assessment’).Severalstudiescomparedmonotherapyversuscom-
bination therapyamongpatientswithcysticfibrosis. Patientsin
thesestudies typically donot have feveror other signs of sepsis
whenenteringthetrial,andthusdidnotfulfilinclusioncriteria
forthisreview.Thesestudiesareincludedinaseparatereview(
Elphick 2001). Seventy-eight studies fulfilled inclusion criteria.
Fourteen were double publications, and thus we have included
64trialsinthisreview.Werequestedcomplementaryinformation
fromnearlyalltheauthors,andincludedcomplementarydatain
22studies(seereferencestostudies).
Table1. Tableofstudiesawaitingassessment
StudyID Explanation Contactdetails
Alberto1999 According to abstract (LILACS) patients with
community acquired pneumonia were divided (’al
azar’) randomly to ceftazidime versus penicillin +
amikacin.Awaitingfulltextavailabilityforinclusion
anddataextraction.
FigueroaDamian1996 According to abstract (LILACS) patients were in-
cluded sequentially (Aleatoriamente), and given
piperacillin-tazobactam or ampicillin+gentamicin
for postcaesarean endometiris. Awaiting full text
availabilitytoinspectwhetherstudyindeedrandom-
ized.
Thestudiesdifferedbythetypeofpopulationandinfectiontar-
geted(seetableof’Characteristicsofincludedstudies’).Mosttri-
Wehavedetailedstudycharacteristicsinthetableof’Character- als(designated ’sepsis’)includedpatients with severesepsis, sus-
isticsofincludedstudies’.Theincludedstudieswereperformed pectedGram-negativeinfections(25trials),orpneumonia(16tri-
betweentheyears1968to2001.Twenty-twoweremulti-centred. als). The adjusted mean fatality rate in thesestudies was 8.6%.
Twenty-onewereperformedintheUSAorCanada,34inEurope, Eleven trials included patients with intra-abdominal infections,
and10inothercountries. relatedmainlytothebiliarytract(designated’abdominal’).The
meanfatalityinthesetrialswas1.7%.Seventrialswererestricted
Thestudiesincluded7586 patients.Themediannumberofin-
topatientswithurinarytractinfections(UTIs),allhospitalized,
cludedpatientspertrialwas87.5(range20to580).Twotrials(
mainlywomen(UTI).Fiveofthesestudiesreportedfatality,and
Cardozo2001;NaimeLibien1992)includedchildren,whileall
nodeathsoccurredinfour.Finally,fiveofthestudiesincludedin
othertrialswererestrictedtoorincludedmostlyadults.
Betalactamantibioticmonotherapyversusbetalactam-aminoglycosideantibioticcombinationtherapyforsepsis(Review) 6
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
thereviewtargetedpatientswithGram-positiveinfections,mainly separated.
endocarditis.Wewillpresentresultsfortheseinfectionsseparately,
Thespecificantibioticregimensusedaredetailedinthetableof’
inadditiontotheirinclusionintheoverallanalysis.
Charcteristicsofincludedstudies’.Forty-fourstudiescompareda
singlebeta-lactamdrugtoadifferent,narrowerspectrum,beta-lac-
Moststudiescomparedtheinitial,empiricalantibiotictreatment tamcombinedwithanaminoglycoside(designated’differentBL’).
administeredtothepatients.Four studiesassessedtheempirical Sixteen’differentBL’studiesreportedbaselinesusceptibilityrates
treatmentofaspecificinfectionbyrandomizingpatientsempiri- of thepathogens isolated onadmission to thebeta-lactam. The
callyandevaluatingonlythosesubsequentlyfulfillingcriteriafor beta-lactamusedinthecombinationarmcoveredlesspathogens
thespecificinfection.Twosuchstudiesrandomizedpatientswith than the monotherapy beta-lactam in 13 studies, while the op-
suspected endocarditis and evaluated only those with Staphylo- positeoccurredintwostudiesonly.Twentystudiescomparedthe
coccusaureusbacteremiaandprovenendocarditis(Abrams1979; same beta-lactam(designated ’sameBL’). Results obtained from
Korzeniowski 1982). The other two randomized patients with studiescomparingsameanddifferentbeta-lactamswerekeptsep-
suspectedbiliarytractinfectionsandevaluatedonlypatientswith aratedthroughoutallefficacyanalyses.Theaminoglycoside was
asurgicallyprovendiagnosis(Gerecht1989;Yellin1993).Non- administeredoncedailyinsixtrials(Cardozo2001;Jaspers1998;
evaluatedpatientsinthesestudieswerenotcountedasdropouts, Rubinstein 1995; Sandberg 1997; Sexton 1998; Speich 1998).
since the study design defined evaluation only for patients ful- Othertrialsadministeredtheaminoglycosidesmultipledaily(47
fillingdefinitivecriteria.Eightstudies,focusingonpatientswith trials),ordidnotspecifytheadministrationschedule(11trials).
specificinfectionsorpathogens(e.g.,cholecystitis,Staphylococcal Meanantibiotictreatmentdurationrangedbetween4to17.5days
infections,etc.),testedtheeffectofmonotherapyversuscombina- inthesepsisstudies,6.8to11.9intheabdominalstudies,4.1to
tiontherapysemi-empirically.Inthesestudies(designated’semi- 7daysintheUTIstudies,and2to4weeksintheendocarditis
empirical’,seetableof’Characteristicsofincludedstudies’)ran- studies.
domizationoccurredafterthespecificinfectionwasdocumented,
Riskofbiasinincludedstudies
andpatientscouldhavereceivedpriorantibiotictreatmentforthis
infection.Analysisofempiricalandsemi-empiricalstudieswasnot (SeeAdditionalTable2:Studyqualityassessmenttable.)
Table2. Studyqualityassessment
StudyID Alloc.generation Alloc.concealment Blinding Intentiontotreat Losttofollowup
Abrams1979 Noinformation Noinformation None No 12of36randomized
patients, but none
outofpatientsfulfill-
ing pre-specified in-
clusion cri-
teria(staphylococcus
aureusbacteremia)
Aguilar1992 Noinformation Noinformation None Unknown Noreferencetodrop-
outsinstudy
Alvarez-Lerma Computer gen- Central and sealed Formortalityonly 24 of 140 random-
2001 eratedinblocksof6 opaqueenvelopes izedpatientsforfail-
patients ure
Arich1987 Table of random Sealed opaque en- None No 18of65randomized
numbers velopes patients
Betalactamantibioticmonotherapyversusbetalactam-aminoglycosideantibioticcombinationtherapyforsepsis(Review) 7
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.