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Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis

  1. Mical Paul1,*,
  2. Adi Lador2,
  3. Simona Grozinsky-Glasberg3,
  4. Leonard Leibovici2

Editorial Group: Cochrane Anaesthesia, Critical and Emergency Care Group

Published Online: 7 JAN 2014

Assessed as up-to-date: 4 NOV 2013

DOI: 10.1002/14651858.CD003344.pub3


How to Cite

Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD003344. DOI: 10.1002/14651858.CD003344.pub3.

Author Information

  1. 1

    Rambam Health Care Campus and the Technion-Israel Institute of Technology, Division of Infectious Diseases, Haifa, Israel

  2. 2

    Beilinson Hospital, Rabin Medical Center, Department of Medicine E, Petah Tikva, Israel

  3. 3

    Dept of Medicine, Hadassah-Hebrew University Medical Center, Neuroendocrine Tumors Unit, Endocrinology & Metabolism Service, Jerusalem, Israel

*Mical Paul, Division of Infectious Diseases, Rambam Health Care Campus and the Technion-Israel Institute of Technology, 6 Ha'Aliya Street, Haifa, 31096, Israel. paulm@post.tau.ac.il. mica@zahav.net.il; MichalP2@clalit.org.il; paulm@post.tau.ac.il.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 7 JAN 2014

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Characteristics of included studies [ordered by study ID]
Abrams 1979

MethodsRCT
Empirical and semi-empirical
Gram positive infections


Participants36 IV drug users with suspected Staphylococcal endocarditis were included. Only those with Staphylococcus aureus bacteraemia and endocarditis according to inclusion criteria were evaluated Patients excluded because they did not fulfil inclusion criteria for bacteraemia were not considered as dropouts for the review


InterventionsOxacillin 12gr/d vs. oxacillin 12gr/d + gentamicin 80mgX3 (gentamicin administered for the first 2 weeks of a 4-week treatment protocol)


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Adverse events
Duration of fever


NotesUSA
Outcomes in subgroups: Bacteraemia.
Cephalothin was permitted instead of oxacillin for patients with penicillin allergy, and oxacillin was replaced by penicillin for penicillin-susceptible Staphylococcus aureus.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
High riskNumber of randomized patients is unclear

Incomplete outcome data (attrition bias)
Failure
High riskNumber of randomized patients is unclear

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Aguilar 1992

MethodsRCT
Sepsis


Participants36 patients > 16 yrs. with severe infections


InterventionsCeftizoxime 60-150 mg/kg/d vs. penicillin 20-30mU/d + gentamicin 3-5mg/kg/d


OutcomesTreatment failure (clinical and bacteriological)


NotesMexico
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll 36 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Alvarez-Lerma 2001a

MethodsRCT
Sepsis


Participants140 adult patients hospitalized in the ICU, mechanically ventilated and diagnosed with pneumonia. All infections were hospital acquired. 66% of patients were on inotropic drugs upon entry to study


InterventionsMeropenem 1grX3 for 9.3 days vs.
ceftazidime 2grX3 + amikacin 7.5mg/kgX2 for 8.3 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Bacterial superinfections
Adverse events
Duration of treatment


NotesMulticentre
Spain
Outcomes in subgroups: Gram negative and Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated in blocks of 6

Allocation concealment (selection bias)Low riskCentral randomization and by sealed opaque envelopes

Incomplete outcome data (attrition bias)
Mortality
Low riskAll 140 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk116 out of 140 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Arich 1987

MethodsRCT
Partially semi-empirical
Sepsis


ParticipantsAdult patients with enterobacteriacae bacteraemia (at least 2 positive blood cultures with same pathogen). Patients could enter the trial before or at diagnosis of bacteraemia


InterventionsCefotaxime 1grX3-4 for 17.5 days vs. cefazolin 1grX3 + tobramycin 1.5mg/kgX3 for 10 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Superinfection
Adverse events
Duration of hospitalizations, treatment and fever


NotesFrance (French)
Outcomes in subgroups:
Bacteraemia
Gram-negative infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Low riskSealed opaque numbered envelopes

Incomplete outcome data (attrition bias)
Mortality
High risk47 out of 65 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk47 out of 65 patients randomized were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Banasal 2006

MethodsRCT

Community acquired pneumonia


ParticipantsChildren aged 2-59 months with severe or very severe pneumonia with
hypoxaemia (SpO2 <90%)


Interventionssequential IV and oral amoxicillin-clavulanate Vs. IV c penicillin 50,000 IU/kg q6h +IV gentamicin 2.5 mg/kg q8h for at least 3 days


OutcomesTreatment failure (clinical)
Duration of treatment


NotesChandigarh, India

No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate randomization generation

Allocation concealment (selection bias)Low riskLabeled sealed envelopes

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll randomized (71) patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Bergeron 1988

MethodsRCT
Abdominal


Participants77 adult patients with severe biliary tract infections (cholecystitis, cholangitis and necrotizing cholecystitis)


InterventionsCefoperazone 2grX2 for 7.2 days vs. ampicillin 1grX4 + tobramycin 1.5mg/kgX3 following loading dose 2mg/kg for 6.8 days (Surgery in addition to medical treatment was performed in 28/36 monotherapy patients and in 19/29 combination patients, not counted as failure)


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Superinfections
Colonization
Treatment duration
Dropouts
Adverse events


NotesMulticentre
Canada
Outcomes in subgroups:
Bacteraemia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
High risk67 out of 77 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk67 out of 77 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Biglino 1991

MethodsRCT
Sepsis


Participants22 patients with severe infections. Patients were compromised by background diseases, including some immune-
compromise in 73%. Randomized to 4 arms monotherapy vs. combination, and high vs. low dose of imipenem


InterventionsImipenem 0.5-1grX4 vs. imipenem 0.5-1grX4 + netilmicin 5mg/kg


OutcomesTreatment failure (clinical)
Adverse events
Duration of fever and hospital stay


NotesItaly
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll randomized (22) patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Brown 1984

MethodsRCT
Sepsis


Participants48 adult patients (34 evaluated) with hospital acquired pneumonia of a documented Gram-negative origin (By sputum's Gram stain or cultures). 85% (29/34) acquired infection in the ICU


InterventionsMoxalactam 2grX3 for 10.1 days vs.
carbenicillin 66mg/kgX6 + tobramycin 1.7mg/kgX3 (following a 2-2.5mg/kg loading dose) for 10.6 days


OutcomesOverall mortality
Treatment failure (x-ray non-clearing)
Superinfections
Adverse events
Duration of treatment


NotesUSA
Outcomes in subgroups:
Gram-negative and Pseudomonas sp. infections
4 deaths among 11 excluded patients not included in outcome assessment


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
High risk34 out of 48 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk34 out of 48 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
Low riskFor failure the assessors were blinded

Carbon 1987

MethodsRCT
Probably semi-empirical
Sepsis


Participants47 patients with bacteraemia due to enterobacteriaceae, with at least 3 positive blood cultures entered the study


InterventionsCefotaxime 1grX4 for 12.9 days vs. cefotaxime 1grX4 + amikacin 7.5mg/kg loading dose followed by a renal-function adjusted maintenance dose for 13.2 days


OutcomesOverall mortality
Treatment failure (clinical)
Superinfections
Adverse events
Duration of treatment and fever


NotesMulticentre
France
Outcomes in subgroups:
Gram negative infections
Bacteraemia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (47) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (47) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Cardozo 2001

MethodsRCT
Abdominal


Participants110 children <15 years, with acute appendicitis


InterventionsAmoxycillin-sulbactam 33mg/kgX3 vs. amoxacillin
-sulbactam 33mg/kgX3 + gentamicin 5mg/kgX1


OutcomesOverall mortality
Treatment failure


NotesParaguay (Spanish)
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (110) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (110) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Cometta 1994

MethodsRCT
Sepsis


Participants313 adult patients with nosocomial pneumonia, nosocomial sepsis or severe diffuse peritonitis. 73% were in ICU and 48% on mechanical ventilation


InterventionsImipenem 500mgX4 for 10.2 days vs. imipenem 500mgX4 + netilmicin 150mgX2 for 10.5 days


OutcomesOverall mortality
Treatment failure (clinical)
Superinfections
Colonization
Adverse events
Duration of treatment


NotesMulticentre
Switzerland
Outcomes in subgroups: Gram-negative and Pseudomonas sp. infections
A secondary reference, Iten 1992, described 71 patients from this study, for whom surveillance cultures were performed, and detailed data concerning resistance development are given


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Low riskSealed, opaque numbered envelopes

Incomplete outcome data (attrition bias)
Mortality
High risk292 out of 313 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk292 out of 313 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Cone 1985

MethodsRCT
Sepsis


Participants57 hospitalized patients with pneumonia or bacteraemia. Pneumonia was community acquired or nosocomial. Only patients with positive bacteriological cultures were evaluated


InterventionsCeftazidime 2grX3 vs. ticarcillin 3grX4 + tobramycin 1mg/kgX3


OutcomesOverall mortality
Treatment failure (clinical)
Superinfections
Adverse events


NotesUSA
Outcomes in subgroups: Bacteraemia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
High risk40 out of 57 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk40 out of 57 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Coppens 1983

MethodsRCT
Semi-empirical
Gram positive infections


Participants80 patients in whom staphylococcal infections were clinically and microbiologically suspected. Inclusion criteria mandated a positive Gram stain showing Staphylococci Patients were randomized to the designated interventions. 24-48 hours following randomization, patients with documented methicillin-
resistant Staphylococci were switched to vancomycin, only in the monotherapy group (N=14). These were excluded from analysis in the review


InterventionsCefamandole 2grX3 vs.
cefamandole 2grX3 + tobramycin 80mgX3


OutcomesTreatment failure
(clinical and bacteriological)
Bacterial superinfection and colonization


NotesBelgium
Outcomes in subgroups: Bacteraemia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate randomization generation, Consecutively numbered envelopes

Allocation concealment (selection bias)Unclear riskSealed envelopes, opaque not mentioned

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk66 out of 80 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

D'Antonio 1992

MethodsRCT
Sepsis


ParticipantsNon-neutropenic adult patients with altered immune defence, with fever > 38 lasting > 8 hours. 88% of patients with underlying haematological malignancy


InterventionsCeftriaxone 2grX1 for a median of 12 days vs. ceftriaxone 2grX1 + amikacin 5mg/kgX3 for a median of 11 days


OutcomesOverall mortality
Treatment failure
(clinical and bacteriological)
Superinfection and colonization (bacterial and fungal)
Adverse events
Treatment duration


NotesItaly
Outcomes in subgroups:
Gram-negative and Pseudomonas sp. infections Bacteraemia
Urinary tract infection


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers, stratified according to underlying malignancy

Allocation concealment (selection bias)Low riskSealed opaque envelopes

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (300) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk286 out of 300 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Damas 2006

MethodsRCT

Sepsis, ventilator associated pneumonia


Participants50 adult patients who were mechanically ventilated for more than 48 hours
and developed clinical evidence of VAP


InterventionsIV Cefepime 2 g every 8 hours, for 8-10d Vs. IV Cefepime 2 g every 8 hours+ IV AMIKACIN 20 mg/kg, once daily for 5d


OutcomesOverall mortality
Treatment failure (bacteriological)
Superinfection
Hospitalisation duration


NotesBelgium

No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (50) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Unclear riskAll (50) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Duff 1982

MethodsQuasi-randomized
Abdominal


Participants74 patients included who developed endomyo-
parametritis after caesarian section or vaginal delivery, or who developed pelvic cellulitis after hysterectomy


InterventionsCefoxitin 2grX3
vs. penicillin 5millUX4 + gentamicin 60-80mgX3


OutcomesOverall mortality
Treatment failure
Adverse events
Dropouts


NotesUSA
Outcomes in subgroups: Gram-negative infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskInadequate randomization generation - Based ob the last digit of hospitalization number, odds/evens

Allocation concealment (selection bias)High riskInadequate randomization concealment

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (74) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Unclear riskAll (74) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Dupont 2000

MethodsRCT
Abdominal


Participants241 patients evaluated with severe generalized peritonitis.


InterventionsPiperacillin- tazobactam 4grX4 for 8.2 days vs.
piperacillin- tazobactam 4grX4 + amikacin 7.5mg/kgX2 for 8.6 days. In addition all patients were operated on


OutcomesOverall mortality
Treatment failure (clinical)
Adverse events
Dropouts
Treatment duration


NotesMulticentre
France
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated in blocks of 4 patients

Allocation concealment (selection bias)Low riskCentral randomization

Incomplete outcome data (attrition bias)
Mortality
Unclear risk227 out of 241 randomized patients were evaluated for failure outcome

Incomplete outcome data (attrition bias)
Failure
Unclear risk204 out of 241 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOnly outcome assessor blinded

Felisart 1985

MethodsRCT
Sepsis


Participants73 adult patients with underlying advanced cirrhosis, presenting with severe bacterial infections. Most patients had spontaneous bacterial peritonitis


InterventionsCefotaxime 2grX6 vs.
ampicillin 2grX6 + tobramycin renal adjusted maintenance dose X3/d following 1.75mg/kg loading dose


OutcomesOverall mortality
Treatment failure (clinical)
Superinfections
Adverse events


NotesSpain
Outcomes in subgroups: Bacteraemia
Urinary tract infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskAll (73) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Unclear riskAll (73) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Figueroa-Damian 1996

MethodsRCT

Abdominal, post cesarean endometritis


Participants56 adult patients with post cesarean endometritis.


InterventionsIV pipracellin/tazobactam 500MG x 4/D for 5 days Vs. IV ampicillin 1gr X 4/d + IV Gentamicin 80mg X 3/d,  for 4 days;


OutcomesTreatment failure (clinical)
Adverse events

Duration of fever and hospitalization


NotesMexico

No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported, Randomization ratio 1:3

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
Low riskAll (56) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Finer 1992

MethodsRCT
Sepsis


Participants471 adult patients hospitalized with signs and symptoms of serious bacterial infections, thought by the physician to require parenteral antibiotic treatment


InterventionsCeftazidime 2grX2 vs. ureidopenillin + aminoglycoside used routinely in specific Center: piperacillin-
gentamicin (73p); ampicillin-
gentamicin (69p); mezlocillin-
netilmicin (44p); piperacillin-
netilmicin (20p)


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Superinfections
Colonization
Drop-outs after randomization
Adverse events


NotesMulticentre
UK
Outcomes in subgroups: Bacteraemia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated randomization

Allocation concealment (selection bias)Low riskSealed opaque envelopes

Incomplete outcome data (attrition bias)
Mortality
High riskAll (471) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk415 out of 471 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment (within 72 hours of stopping the treatment)

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

García Ramírez 1999

MethodsRCT

Sepsis, Nosocomial pneumonia


Participants60 adult patients with Nosocomial pneumonia, de vided to 2 groups.


InterventionsIV Ceftazidime Vs. IV penicillin + amikacin


OutcomesTreatment failure (clinical)
Duration of hospitalization


NotesTacuba

Outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskAccording to patient descriptives, groups very different at baseline. Randomization methods not given

Allocation concealment (selection bias)High riskAccording to patient descriptives, groups very different at baseline. Randomization methods not given

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (60) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (60) randomized patients were evaluated for mortality outcome

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Gerecht 1989

MethodsRCT
Abdominal


Participants82 patients with suspected cholangitis were randomized empirically. Only those with bacteraemia or positive bile cultures, and fulfilling clinical criteria for cholangitis were evaluated. Patients who were not evaluated because they did not meet inclusion criteria are not considered as dropouts for the review


InterventionsMezlocillin 4grX4 for 11.9 days vs. ampicillin 1grX4 + gentamicin 1.5mg/kgX3 for 10.3 days. In addition to antibiotic therapy all patients underwent surgical intervention


OutcomesTreatment failure (clinical and bacteriological)
Superinfections
Adverse events
Duration of treatment


NotesUSA
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization by computer generated table of random numbers

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskOnly infection related mortally was reported

Incomplete outcome data (attrition bias)
Failure
Low risk415 out of 82 randomized patients were evaluated for failure outcome (36 were not evaluated - 32 did not fulfil the study inclusion criteria for evaluation, 3 did not adhere to the protocol and 1 excluded because of resistant infection)

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Gomez 1990a

MethodsRCT
Sepsis


Participants197 patients with suspected Gram-negative bacteraemia randomized. Patients with proven Gram-negative bacteraemia (78) were analysed. Patients who were not evaluated because they did not meet inclusion criteria for bacteraemia were not considered as dropouts


InterventionsCeftazidime 1grX4 for 10 days vs. cefradine 1grX6 + amikacin 7.5mg/kgX2 for 10 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Superinfection (bacterial and fungal)
Adverse events
Duration of treatment


NotesSpain (Spanish)
Outcomes in subgroups:
Bacteremia
Gram-negative infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization by computer generated table of random numbers

Allocation concealment (selection bias)Low riskSealed opaque closed envelopes

Incomplete outcome data (attrition bias)
Mortality
High risk78 out of 197 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk78 out of 197 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Hasali 2005

MethodsRCT single blind

Sepsis, Community-acquired pneumonia


ParticipantsPediatric patients (aged 2m to 5 years) diagnosed with Community-acquired pneumonia


InterventionsIV ampicillin 100 mg/kg/day divided every 6 h Vs. IV ampicillin 100 mg/kg/day divided every 6 h + IV Gentamicin 5mg/kg x 1/d


OutcomesDuration of treatment, fever and hospitalization


NotesMalaysia

No outcome in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskconsecutive, fixed sample of 20 per group

Allocation concealment (selection bias)High riskconsecutive, fixed sample of 20 per group

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
Unclear riskNo failure outcome reported

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskopen (stated as single blind but no blinding described)

Blinding of outcome assessment (detection bias)
All outcomes
High riskopen (stated as single blind but no blinding described)

Havig 1973

MethodsRCT
Abdominal


Participants68 adult patients evaluated with acute cholecystitis verified histologically or by roengten. Trial included 3 arms, of which 2 are included in the review


InterventionsIM ampicillin 0.5grX4
vs. IM chloramphenicol 1grX2 (arm not included in review) vs. IM benzyl-penicillin 400,000IEX2 + IM streptomycin 0.5grX2. In addition 10/24 patients in the ampicillin arm and 15/26 patients in the combination arm were operated on


OutcomesOverall mortality
Treatment failure (clinical)
Duration of fever


NotesNorway
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization list prepared in advanced

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
High risk50 out of 90 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk68 out of 90 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Hoepelman 1988

MethodsRCT
Sepsis


Participants105 patients with serious bacterial infections were included. Of these 18% were neutropenic and are not included for the analysis in this review


InterventionsCeftriaxone 2grX1 vs. cefuroxime 1.5grX3 + gentamicin 80mgX3 (following by an initial 1.5mg/kg dose)


OutcomesOverall mortality Treatment failure (clinical)
Superinfections
Fungal colonization
Adverse events


NotesNetherlands Outcomes for subgroups were not extracted, as they are given in the publication for the whole group including neutropenic patients
Outcomes for non-neutropenic patients were obtained from the author


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskUnclear

Allocation concealment (selection bias)Low riskAdequate randomization concealment by sealed opaque envelopes

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (86) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (86) randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Holloway 1985

MethodsRCT
Sepsis
Semi-empirical


Participants43 adult patients with suspected Gram-negative septicaemia, or pneumonia, randomized when blood cultures were positive for a Gram-negative pathogen


InterventionsTicarcillin-clavulanic acid 3.1grX4-6 vs. piperacillin 50mg/kgX4-6 + tobramycin 1-1.5mg/kgX3-4


OutcomesTreatment failure (clinical and bacteriological)
Adverse events


NotesUSA
Outcomes in subgroups:
Bacteremia
Gram-negative infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
High risk33 out of 43 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Iakovlev 1998

MethodsRCT
Sepsis


Participants95 adult patients with severe nosocomial infections


InterventionsMeropenem 1grX3 for 9 days vs. ceftazidime 1grX3 + amikacin 500mgX2 for 9 days


OutcomesTreatment failure (clinical and bacteriological)
Duration of treatment
Adverse events


NotesMulticentre
Russia (Russian)
Outcomes in subgroups: Urinary tract and Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskBy sealed envelopes, opaque not mentioned

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
Low riskAll (95) randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Jaspers 1998

MethodsRCT
Sepsis


Participants79 elderly patients ( > 65yrs.) with sepsis syndrome and suspected bacteraemia, pneumonia, intra-abdominal sepsis, or complicated urinary tract infection


InterventionsMeropenem 1grX3 for 7.5 days vs. cefuroxime 1.5grX3 + gentamicin 4mg/kgX1 for 7.4 days (metronidazole 500mgX4 added to patients receiving combination in case of abdominal sepsis (15 patients overall)


OutcomesOverall mortality
Treatment failure (clinical and microbiological)
Bacterial superinfections
Adverse events
Duration of treatment


NotesMulticentre
Netherlands
Outcomes in subgroups:
Urinary tract infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers in consecutive envelopes

Allocation concealment (selection bias)Low riskRandomization by consecutive sealed, opaque envelopes

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (79) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (79) randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment (end of treatment)

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Klastersky 1973

MethodsRCT
Sepsis


Participants75 adult patients with disseminated cancer and life threatening infections, presumed Gram-negative. Randomized to 3 arms, of which 2 are relevant for the review. 18% of patients leukopenic (leukopenia not defined) - no information for neutropenia


InterventionsCarbenicillin 10grX3 for 8.3 days vs. carbenicillin 10grX3 + gentamicin 160mgX3 (IM or IV) for 9 days vs. gentamicin 160mgX3 (3rd arm, not included in review)


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Colonization and Superinfection
Duration of treatment
Dropouts


NotesBelgium
Outcomes in subgroups:
Gram-negative and Pseudomonas sp. infections
Bacteremia
Urinary tract infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
High risk45 out of 50 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk46 out of 50 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Kljucar 1990

MethodsRCT
Sepsis


Participants150 patients > 14yrs. hospitalized in the intensive care unit and ventilated, with nosocomially acquired pneumonia. Randomized to 3 arms (2 combination and 1 monotherapy)


InterventionsCeftazidime 2grX3 vs.
ceftazidime 2grX3 + tobramycin 80mgX3 vs. azlocillin 5mgX3 + tobramycin 80mgX3, overall for 6.6 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)


NotesGermany
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated randomization

Allocation concealment (selection bias)Low riskAdequate randomization concealment by sealed consecutive envelopes

Incomplete outcome data (attrition bias)
Mortality
Low risk99 out of 100 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low risk99 out of 100 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Koehler 1990

MethodsRCT
Sepsis


Participants144 patients > 18 yrs. with nosocomially acquired pneumonia


InterventionsCeftazidime 1grX3 vs. piperacillin 4grX3 + tobramycin 80mgX3


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Bacterial and fungal colonization
Dropouts


NotesMulticentre
Germany
Outcomes in subgroups:
Gram negative and Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (144) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk127 out of 144 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Korzeniowski 1982

MethodsRCT
Partially semi-empirical
Gram positive infections


Participants156 patients with clinically suspected infective endocarditis were randomized (prior antibiotic treatment of < 48 hours permitted) 78 patients with Staphylococcus aureus bacteraemia and endocarditis were analysed: 48 drug addicts and 30 non-addicts (14 patients randomized semi-empirically)


InterventionsNafcillin 1.5-6grX6 vs. nafcillin 1.5-6grX6 + gentamicin 1mg/kgX3 administered for the first 2 weeks of a 4-week treatment protocol


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Dropouts
Need for surgery
Adverse events
Duration of bacteraemia and fever are other outcomes shown in the study, but these are shown by groups of empirical treatment regimen which was not always randomly allocated


NotesMulticentre
USA
Outcomes in subgroups:
Bacteremia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomization by table of random number

Allocation concealment (selection bias)Low riskAdequate randomization concealment, central randomization

Incomplete outcome data (attrition bias)
Mortality
High risk74 out of 156 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk74 out of 156 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Landau 1990

MethodsQuasi-randomized
Urinary tract infections


Participants40 adult patients hospitalized with complicated urinary tract infection


InterventionsCeftriaxone 2grX1
vs. cefazolin 1grX3 + gentamicin 80mgX3


OutcomesOverall mortality
Treatment failure (bacteriological only)
Adverse events
Drop-outs after randomization
Duration of fever


NotesIsrael (Hebrew) Outcomes in subgroups:
Urinary tract and
Gram-negative infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskRandomization according to last digit of identification number - odds vs. evens

Allocation concealment (selection bias)High riskInadequate randomization concealment

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (40) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (40) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Limson 1988

MethodsRCT
Sepsis


Participants54 adult patients randomized, of which 40 patients with severe Gram-negative infections were evaluated


InterventionsCeftazidime 2grX2 vs.
ticarcillin 3grX3-4 + amikacin 500mgX2 (or 15mg/kgX1)


OutcomesTreatment failure (clinical and microbiological)
Fungal superinfections
Adverse events


NotesThe Philippines Outcomes in subgroups:
Bacteremia
Gram negative, and Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
High risk40 out of 54 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Mandell 1987

MethodsRCT
Sepsis


Participants110 patients > 16yrs. evaluated with community acquired or nosocomial pneumonia (2/3 nosocomial)


InterventionsCeftazidime 2grX3 vs.
cefazolin 1.5grX3 or ticarcillin 3grX4 + tobramycin 1.7mg/kgX3


OutcomesTreatment failure (clinical and bacteriological)
Superinfections
Colonization (including resistant development)
Adverse events


NotesMulticentre
Canada
Outcomes in subgroups:
Bacteraemia
Gram-negative infections.
Cefazolin replaced by ticarcillin for combination group patients with documented Pseudomonas infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskGenerated by coin tosses

Allocation concealment (selection bias)Unclear riskSealed envelopes opened in numerical order, opaque not mentioned

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
High risk110 out of 129 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Martin 1991

MethodsRCT
Urinary tract infections


Participants116 patients hospitalized with suspected pyelonephritis


InterventionsCeftriaxone 2grX1 vs. ampicillin 1grX4 + gentamicin 1mg/kgX3


OutcomesTreatment failure (clinical)
Superinfection (relapse and re-infections)
Dropouts
Adverse events


NotesBrussels (French)
Outcomes in subgroups:
Urinary tract infections
Bacteremia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAllocation by randomization table

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
Unclear risk94 out of 116 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

McCormick 1997

MethodsRCT
Sepsis


Participants128 adult patients with chronic liver disease (cirrhosis) and suspected or proven sepsis


InterventionsCeftazidime 2grX2 for 5 days vs. mezlocillin 5grX3 + netilmicin 3mg/kgX2 for 4 days


OutcomesOverall mortality
Treatment failure
(clinical)
Adverse events
Duration of treatment and hospital stay


NotesIreland
Outcomes in subgroups:
Bacteremia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAllocation by randomization table

Allocation concealment (selection bias)Low riskSealed opaque envelopes

Incomplete outcome data (attrition bias)
Mortality
High risk128 out of 147 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk128 out of 147 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Mergoni 1987

MethodsRCT
Sepsis


Participants42 adult patients in ICU with severe infections


InterventionsAzlocillin 13+-2.2gr for 6.5 days vs. azloclillin 14.1+-1gr + amikacin 1.16+-0.027gr for 7.2 days (all in for daily doses)


OutcomesTreatment failure (clinical and bacteriological)
Adverse events
Duration of treatment


NotesItaly
Outcomes in subgroups:
Gram negative and Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Low riskSealed opaque envelopes that were provided by the study c enter

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
Low riskAll (42) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Moreno 1997

MethodsRCT
Sepsis


ParticipantsRenal or (kidney-
pancreas) transplant patients with fever and suspected bacterial infection


InterventionsImipenem-cilastatin 500mgX4 vs. piperacillin 4grX3 + tobramycin 80mgX2


OutcomesTreatment failure (clinical and bacteriological)


NotesSpain
Outcomes in subgroups:
Gram negative and Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
High risk58 out of 70 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Mouton 1990

MethodsRCT
Sepsis


Participants211 adult patients hospitalized in intensive care unit with respiratory tract infections


InterventionsImipenem 500mgX4 for 11.1 days vs. cefotaxime 1grX4 + amikacin 5mg/kgX3 for 10.4 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Superinfections
Colonization
Hospitalization duration
Duration of treatment


NotesMulticentre
France (French) Outcomes in subgroups:
Bacteremia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (211) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (211) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Mouton 1995

MethodsRCT
Sepsis


Participants237 adult patients with community or hospital acquired serious infections, excluding intra-abdominal sepsis (urinary tract infection included)


InterventionsMeropenem 1grX3 for 8.8 days vs. ceftazidime 2grX3 + amikacin 5-7.5mg/kgX2-3 for 8.3 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Superinfections
Adverse events
Dropouts
Duration of treatment


NotesMulticentre
Europe
Outcomes in subgroups:
Bacteremia
Gram negative and Pseudomonas sp. and urinary tract infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNo reported

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (237) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk229 out of 237 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment (end of treatment)

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Muller 1987

MethodsRCT
Abdominal


ParticipantsTrial includes 3 arms (2 monotherapies, 1 combination treatment)
106 patients evaluated with acute cholecystitis or cholangitis


InterventionsPiperacillin 3grX6 for 7.4 days vs. cefoperazone 2grX3 for 8.1 days vs.
ampicillin 2grX4 + tobramycin 1-1.5mg/kgX3 following 1.5mg/kg loading dose for 11.1 days


OutcomesTreatment failure (clinical)
Adverse events
Duration of treatment


NotesBi-centre
USA
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe randomization was computer generated for each c enter

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
High risk106 out of 131 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Naime Libien 1992

MethodsRCT
Sepsis


Participants30 children aged 1m - 11yr with severe lower respiratory tract infections


InterventionsCeftizoxime 20-50mg/kgX2-3 vs. penicillin 0.7-1.7 megaunit/kgX3 + gentamicin 1-1.5mg/kgX2


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Adverse events
Duration of fever


NotesMexico (Spanish)
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (30) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (30) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Piccart 1984

MethodsRCT
Sepsis


Participants105 adult, non-neutropenic, cancer patients with suspected Gram-negative infections. Study included both neutropenic and non-neutropenic patients, but analysis was completely separated Patients with Gram-positive bacteraemia were excluded


InterventionsCefoperazone 6grX2 vs.
cefoperazone 2grX2 + amikacin 500mgX2


OutcomesTreatment failure (clinical and bacteriological)
Superinfections (bacterial and fungal)
Drop-outs after randomization


NotesBelgium
Outcomes in subgroups:
Gram-negative and Pseudomonas sp. infections
Bacteremia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
High risk87 out of 105 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Rapp 1984

MethodsRCT
Sepsis


Participants35 adult patients hospitalized in a neurosurgical intensive care unit. All with nosocomial pneumonia


InterventionsCeftazidime 2grX3 vs.
ticarcillin 3grX4 + tobramycin pharmacokinetically adjusted doses after 1.75mg/kd loading dose


OutcomesTreatment failure (clinical and bacteriological)
Adverse events


NotesUSA
Outcomes in subgroups:
Gram negative bacteraemia
Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
Low riskAll (35) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Rasmussen 1986

MethodsRCT
Urinary tract infections


Participants62 adult patients hospitalized in a urosurgical department with urinary tract infections, mostly post-operative


InterventionsCefotaxime 3grX3 for 5.4 days vs. ampicillin 1grX4 + netilmicin 150mgX3 for 7 days


OutcomesTreatment failure (clinical)
Relapse
Duration of fever and treatment
Adverse events


NotesDenmark
Outcomes in subgroups:
Urinary tract infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUsing a table of random numbers

Allocation concealment (selection bias)Unclear riskSealed envelopes, opaque not mentioned

Incomplete outcome data (attrition bias)
Mortality
High risk59 out of 62 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk59 out of 62 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Ribera 1996

MethodsRCT
Semi-empirical
Gram-positive infections


ParticipantsSpain
90 intravenous drug users randomized, of which 74 had Staphylococcus aureus right-sided endocarditis. 90.5% of patients were HIV positive. Diagnostic criteria for possible (13% of study patients), probable (34%) and definitive endocarditis (53%) are defined in study


InterventionsCloxacillin 2grX6 vs. cloxacillin 2grX6 + gentamicin 1mg/kgX3


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Relapse, re-infection and need for surgery
Duration of treatment
Adverse events


NotesSpain
Journal publication.
Outcomes in subgroups:
Bacteremia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate randomization generation

Allocation concealment (selection bias)Low riskOpaque sealed envelops

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (90) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (90) randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Rubinstein 1995

MethodsRCT
Sepsis


Participants580 adult patients with serious hospital acquired infections and a diagnosis of sepsis, pneumonia or upper urinary tract infection


InterventionsCeftazidime 2grX2 for 9 days vs. ceftriaxone 2grX1 + tobramycin 3-5mg/kgX1 following 2mg/kg loading dose for 9 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Superinfections
Duration of treatment
Adverse events


NotesMulticentre
Europe, Middle East, Asia, South America
Outcomes in subgroups:
Gram-negative and Pseudomonas sp. infections
Bacteremia
Urinary tract infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated randomization

Allocation concealment (selection bias)Low riskOpaque sealed envelopes

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (580) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk491 out of 580 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment - 14 days after treatment cessation

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessor was blinded

Sage 1987

MethodsRCT
Sepsis


Participants93 patients > 14yrs. randomized to 3 arms, of which 2 are usable in the review. The 3rd arm is aminoglycoside monotherapy. Patients were suspected of a life threatening sepsis, thought to be caused by Enterobacteriaceae or Staphylococci


InterventionsCefotaxime 1-2grX4 for 7.4 days vs. cefotaxime 1-2grX4 + netilmicin 2-3mg/kgX3 (3rd arm, not used - netilmicin 2-3mg/kgX3) for 8.7 days


OutcomesTreatment failure (clinical and bacteriological)
Bacterial and fungal superinfections
Dropouts
Adverse events
Duration of treatment


NotesUK
Outcomes in subgroups:
Bacteremia
Gram negative and urinary tract infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNo reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
High risk48 out of 61 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Sandberg 1997

MethodsRCT
Urinary tract infections


Participants73 adult female patients with suspected pyelonephritis


InterventionsCefotaxime 1grX2 for 2 days followed by oral cefadroxil 1grX2 vs.
cefotaxime 1grX2 + tobramycin 160mgX1 for 2 days, followed by oral cefadroxil 1 grX2


OutcomesTreatment failure (clinical and bacteriological)
Superinfection and colonization (relapse, re-infections and asymptomatic bacteriuria recurrence)
Adverse events
Drop-outs after randomization
Duration of fever


NotesMulticentre
Sweden
Outcomes in subgroups: Urinary tract infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated lists in blocks of four were used at each c enter

Allocation concealment (selection bias)Low riskSealed opaque envelope allocation

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (73) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk61 out of 73 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Sanfilippo 1989

MethodsRCT
Abdominal


Participants26 female patients aged 16-19 years with acute pelvic inflammatory disease


InterventionsMezlocillin 62.5mg/kgX4 vs. penicillin 480,000U/kgX4 + tobramycin 1mg/kgX3


OutcomesTreatment failure (clinical)


NotesUSA
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated code

Allocation concealment (selection bias)Low riskAdequate central randomization

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
Low riskAll (26) randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment - 4 weeks after discharge

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessment were blinded

Sculier 1982

MethodsRCT
Sepsis


Participants20 adult, intubated, patients with Gram-negative pneumonia in the neurosurgical intensive-care unit Patients were randomized when presenting with radiographic broncho-
pneumonia, purulent sputum and Gram-negative rods on sputum direct smear


InterventionsMezlocillin 10grX3 vs. mezlocillin 10grX3 + sisomicin 75mgX3.
In addition to allocated systemic treatment, all patients received intra-tracheal sisomycin 25mgX3/d


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Bacterial colonization
Resistance development
Adverse events


NotesBelgium
Outcomes in subgroups:
Gram negative and Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (20) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (20) randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment -1 week after treatment cessation

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Sexton 1998

MethodsRCT
Semi-empirical
Gram-positive infections


Participants67 adult patients randomized, of which 51 with native valve endocarditis (defined by Duke criteria) caused by penicillin-
susceptible Streptococci.


InterventionsCeftriaxone 2grX1 for 4 weeks vs. ceftriaxone 2grX1 + gentamicin 3mg/kgX1 for 2 weeks


OutcomesTreatment failure (clinical and bacteriological)
Relapse and re-infection Adverse events
Dropouts
Duration of hospital stay
Need for surgery


NotesMulticentre
USA
Outcomes in subgroups:
Bacteremia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
High risk51 out of 67 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment (3 month)

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Sieger 1997

MethodsRCT
Sepsis


Participants211 adults >18yrs. with hospital-
acquired lower respiratory tract infections. 70% intubated and 27% with severe pneumonia


InterventionsMeropenem 1grX3 for 7.8 days vs. ceftazidime 2grX3 + tobramycin 1mg/kgX3 (following 1.5-2mg/kg loading dose) for 7.4 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological) Superinfections
Adverse events
Duration of treatment


NotesMulticentre
USA
Outcomes in subgroups:
Gram-negative and Pseudomonas sp. infections.
Study performs both efficacy and ITT analysis, with a drop-out rate of 43% for the efficacy analysis. Outcomes were extracted by ITT. Superinfections and subgroup analyses are given only by efficacy analysis in study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (211) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (211) randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment (30 days)

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Smith 1984

MethodsRCT
Sepsis


Participants200 adult patients randomized with suspected or proven serious infections. 195 who actually received study drugs were evaluated for efficacy


InterventionsCefotaxime 2grX6
+ placebo X3 for 5 days vs.
nafcillin 1.5grX6 + tobramycin 2mg/kgX3 for 5.3 days
(Addition of clindamycin 600mgX3 to both groups permitted for suspected anaerobic infections)


OutcomesOverall mortality
Treatment failure
(clinical and microbiological)
Bacterial superinfections
Colonization
Adverse events
Duration of treatment


NotesUSA
Outcomes in subgroups:
Urinary tract and Gram negative infections.
Two additional references refer to the same trial: Moore 1986a (cost-effectiveness analysis), and Moore 1986b (nephrotoxicity analysis). Overall mortality, and treatment duration are taken from Moore 1986a that analysed all patients given study drugs. Cost outcome not included in the review


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization by table of random numbers

Allocation concealment (selection bias)Low riskCentral randomization. Identically labelled mini bottles containing antibiotic or placebo, with colour added to mask the yellow colour of cefotaxime.

Incomplete outcome data (attrition bias)
Mortality
High risk187 out of 200 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk195 out of 200 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinded

Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinded

Speich 1998

MethodsRCT
Sepsis


Participants89 adults >16yrs. with severe pneumonia. Community acquired in 89%


InterventionsPiperacillin-tazobactam 4.5grX3 for 10.2 days vs.
amoxicllin-clavulonic acid 2.2grX3 + gentamicin or netilmicin 3-6mg/kgX1 for 10.1 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Dropouts
Adverse events
Duration of treatment


NotesMulticentre
Switzerland
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization by computer derived program

Allocation concealment (selection bias)Low riskSealed opaque envelopes

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (89) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk84 out of 89 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Stille 1992

MethodsRCT
Sepsis


Participants337 adult patients randomized with non-life-
threatening infections, of abdominal, gynaecological or respiratory tract origin (UTI, skin, bone, and CNS infections excluded)


InterventionsImipenem 500mgX3 for 8.4 days vs. cefotaxime 2grX3 + gentamicin 0.66-1mg/kgX3 for 8.2 days (metronidazile allowed in combination treatment group for suspected anaerobic infection)


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Colonization and resistance development
Adverse events
Duration of treatment


NotesMulticentre
Germany and Austria
Outcomes in subgroups:
Gram negative and Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy a computer generated list of blocks of 16 patients

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskAll (337) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Unclear riskAll (337) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Sukoh 1994

MethodsRCT
Sepsis


Participants63 patients with respiratory tract infections and underlying respiratory disease


InterventionsCefoperazone/ sulbactam 1-4gr/d for 11.7 days vs. Cefoperazone/ sulbactam 2-6gr/d + one of several aminoglycosides in low doses (amikacin 100-400 mg/d 16 patients, tobramycin 40-180 mg/d 15 patients, isepamicin 400 mg/d 1 patient, netilmicin 200 mg/d 1 patient) for 11.1 days


OutcomesTreatment failure (clinical and bacteriological)


NotesJapan (Japanese)
Outcomes in subgroups:
Gram-negative and Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskRandomized by envelope method

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
Low riskAll (63) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Takamoto 1994

MethodsRCT
Sepsis


Participants171 adult patients with respiratory tract infections


InterventionsImipenem/cilastatin sodium vs.
imipenem/cilastatin sodium + amikacin sulfate


OutcomesTreatment failure (clinical and bacteriological)
Drop-outs after randomization
Adverse events


NotesMulticentre Japan (Japanese) Outcomes in subgroups:
Gram-negative and Pseudomonas sp. infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy a computer generated code

Allocation concealment (selection bias)Unclear riskSealed envelopes

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
High risk154 out of 171 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Thompson 1990

MethodsRCT
Abdominal


Participants96 patients evaluated with acute cholangitis (cholecystitis not included)


InterventionsPiperacillin 3grX6 for 8.4 days vs. ampicillin 2grX4 + tobramycin 1-1.5mg/kgX3 for 9.1 days (following 1.5mg/kg loading dose). In addition 35/96 patients were operated on


OutcomesOverall mortality
Treatment failure (clinical)
Adverse events
Treatment duration


NotesMulticentre
USA
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy computer generated for each c enter

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
High risk96 out of 106 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk96 out of 106 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Thompson 1993

MethodsRCT
Abdominal


Participants120 patients evaluated with acute biliary tract infections (cholecystitis and cholangitis)


InterventionsCefepime 2grX2 for 7.5 days vs. mezlocillin 3grX6 + gentamicin 1.5mg/kgX3 for 7 days. In addition, 118/120 patients were operated on


OutcomesOverall mortality
Treatment failure (clinical)
Adverse events
Treatment and hospitalization duration


NotesMulticenter
USA
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy computer generated for each c enter

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
High risk120 out of 147 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk120 out of 147 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Trujillo 1992

MethodsRCT
Sepsis


Participants30 adult patients with severe skin and soft tissue or respiratory tract infections


InterventionsCeftizoxime 1-2grX3 vs. ampicillin 1-3grX4 + gentamicin 3-5mg/kg/d, overall for 10 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Adverse events
Fever duration


NotesMexico (Spanish)
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskAll (30) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Unclear riskAll (30) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Vergnon 1985

MethodsRCT
Sepsis


Participants30 adult patients with severe broncho-
pulmonary infections


InterventionsCefoperazone 2grX2 for 16.8 days vs. ampicillin 1.5grX4 + tobramycin 1mg/kgX3 for 11.8 days


OutcomesTreatment failure (clinical)
Resistant colonization
Adverse events
Duration of treatment


NotesFrance (French)
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate randomization generation

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
Low riskAll (30) randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Verzasconi 1995

MethodsRCT
Urinary tract infections


Participants93 adult patients with acute pyelonephritis or complicated urinary tract infections


InterventionsAmoxicillin-clavulonate 2.2grX3 for 4.1 days vs. amoxicillin 2grX3 + gentamicin 1.5mg/kg loading followed by maintenance for 4.2 days


OutcomesTreatment failure (bacteriological)
Superinfection
Dropouts
Treatment and fever duration
Adverse events


NotesBi-centre
Switzerland (German)
Outcomes in subgroups:
Urinary tract infection


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Unclear riskNo mortality outcome reported

Incomplete outcome data (attrition bias)
Failure
High risk87 out of 93 randomized patients were evaluated for mortality outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinded

Warren 1983

MethodsRCT
Sepsis


Participants120 adult patients with suspected or known life-threatening infections caused by Gram-negative bacilli


InterventionsCefoperazone 1.5grX4 for a median of 9 days vs.
cefamandole 2grX6 + tobramycin 1.7mg/kg loading dose, followed by drug- level-adjusted maintenance dose for a median of 8 days


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Superinfection
Duration of treatment
Adverse events
Drop-outs after randomization


NotesUSA
Outcomes in subgroups:
Bacteremia
Gram-negative infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate randomization generation by random numbers

Allocation concealment (selection bias)Unclear riskBy sealed envelopes

Incomplete outcome data (attrition bias)
Mortality
High risk120 out of 123 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk120 out of 123 randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment (14 days after treatment cessation)

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Wiecek 1986

MethodsRCT
Urinary tract infections


Participants20 adult patient with acute pyelonephritis


InterventionsCeftazidime 1grX3 vs.
cefotaxime 1grX2 + tobramycin 1mg/kgX3


OutcomesTreatment failure (bacteriological)
Re-infection
Adverse events


NotesPoland
Outcomes in subgroups:
Gram negative and Pseudomonas sp. infections
Urinary tract infections
Bacteremia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (20) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (20) randomized patients were evaluated for bacteriologic failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Wing 1998

MethodsRCT
Urinary tract infections


Participants179 pregnant women <24 weeks gestation with pyelonephritis randomized to 2 monotherapy arms and 1 combination therapy arm


InterventionsCefazolin 1grX3 vs. ceftriaxone 1grX1 vs. ampicillin 2grX4 + gentamicin 1.75mg/kgX3 (after 2mg/kg loading)


OutcomesOverall mortality
Treatment failure (clinical and bacteriological)
Re-infection
Fever and hospitalization duration


NotesBi-centre
USA
Outcomes in subgroups:
Urinary tract infections


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated random number table n

Allocation concealment (selection bias)Low riskSealed opaque envelopes

Incomplete outcome data (attrition bias)
Mortality
Low riskAll (179) randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
Low riskAll (179) randomized patients were evaluated for failure outcome

Other biasUnclear riskFixed time for outcome assessment (2 weeks following treatment cessation)

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen

Yellin 1993

MethodsRCT
Abdominal


Participants179 patients with clinically suspected cholecystitisOnly those operated on while on allocated treatment were evaluated (infection proven at surgery) Patients who were not evaluated because surgery was not performed or incorrect diagnosis are not considered as drop-outs for the review


InterventionsCefepime 2grX2 for 7.3 days vs. mezlocillin 4grX4 + gentamicin 1.5mg/kgX3 for 7.2 days. In addition to antibiotic treatment all patients operated


OutcomesOverall mortality
Treatment failure (clinical)
Fever, treatment and hospitalization duration


NotesUSA
No outcomes in subgroups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy table of random numbers

Allocation concealment (selection bias)Low riskCentral randomization at the research pharmacy

Incomplete outcome data (attrition bias)
Mortality
High risk90 out of 149 randomized patients were evaluated for mortality outcome

Incomplete outcome data (attrition bias)
Failure
High risk90 out of 149 randomized patients were evaluated for failure outcome

Other biasUnclear riskNo fixed time for outcome assessment

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe clinician was kept blinded throughout the study

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Alvarez-Lerma 2001bBeta-lactam-aminoglycoside combination treatment versus beta-lactam-aminoglycoside combination treatment.

Badaro 2002Allocation to additional aminoglycoside treatment not randomized. Patients were randomized to treatment with beta-lactam monotherapy versus 'standard' antibiotic treatment, which was a beta-lactam with or without an aminoglycoside.

Benlloch 1995Antibiotic regimens incompatible with protocol. Randomization to 3 arms: 1) beta-lactam-aminoglycoside-nitroimmidazole combination 2) beta-lactam-aminoglycoside combination 3) double beta-lactam combination.

Blumer 2003No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the definition of exacerbation does answer the criteria for sepsis as defined in review.

Bodey 1976Study includes 100% patients with neutropenia.

Cetto 1983Study includes 71% patients with neutropenia.

Chaudhary 2008Sepsis was not mandated for inclusion to the study. Patients with bronchitis were included.

Chaudhary 2009Sepsis was not mandated for inclusion to the study. Patients with bronchitis were included.

Ciftci 1997Antibiotic regimens incompatible with protocol. Randomization to 4 arms: 1) beta-lactam-aminlglycoside-lincosamide combination 2) beta-lactam-aminoglycoside-imidazole combination 3) beta-lactam monotherapy 4) beta-lactam-imidazole combination.

Crenshaw 1983Prophylaxis study. Randomization to beta-lactam monotherapy versus beta-lactam aminoglycoside combination therapy as preventive therapy for patients with penetrating abdominal wounds requiring surgical intervention.

Croce 1993Not a randomized trial. Monotherapy and combination therapy groups were studied consecutively.

De Louvois 1992Included patients were newborns with suspected sepsis.

Extermann 1995Randomization to beta-lactam monotherapy versus best-guess antibiotic treatment as chosen by physician. The best guess treatment group includes monotherapy and various combinations.

Fainstein 1983Study includes 62.5% neutropenic patients. The study randomized 321 episodes, of which 275 were evaluable - 172 in neutropenic patients and 103 episodes in non-neutropenic patients. Although analysis was intended to be separated, the number of evaluated patients in each group, is not separated to neutropenic and non-neutropenic patients. Although outcomes (death and failures) are given for non-neutropenic patients, the number of patients in the group is unknown. Information was unavailable from authors.

Fernandez 1991Randomization to beta-lactam monotherapy versus
combination therapy commonly used in specific centre (multicentre trial). Combinations consisted of different beta-lactams with aminoglycoside antibiotics in 211/273 patients evaluated in the combination group, and other antibiotic combinations in 62/273 patients. Outcomes are given per specific combination (failure), but the study is excluded since the decision as to which combination the patient received was left to the care-taker.

Foord 1985Not a randomized trial. Article describes all patients on Glaxo data files who have been administered Ceftazidime monotherapy in comparative and non-comparative trials. No references in the article.

Gentry 1980Not a randomized trial. Study describes centre's experience with monotherapy versus combination therapy. One study group was previously reported. All prospective, comparative, but no mention of randomization.

Gentry 1984Prophylaxis study. Randomization to 3 arms (2 beta-lactam monotherapy arms and 1 beta-lactam-aminoglycoside combination therapy arm), as perioperative prophylaxis for patients with penetrating injuries of the abdomen.

Gentry 1985Pooled analysis of patients with skin, soft-tissue and bone infections, comparing ceftazidime monotherapy to control regimens, including ticalcillin and tobramycin combination therapy. However, randomized patients cannot be separate from those who entered open comparative trials.

Gerber 1989Prophylaxis study. Antibiotic treatment was administered as prophylaxis and patients did not fulfil the criteria for sepsis when randomized.

Gilbert 1998Study includes 18% neutropenic patients (32/175 evaluable patients). In addition neutropenic patients were not randomized - all were allocated only to the combination regimen. Outcome data was unavailable separating randomized from non randomized (neutropenic) patients.

Giraud 1989Antibiotic regimens incompatible with protocol. Randomization to 2 arms: 1) beta-lactam monotherapy versus 2) beta-lactam-aminoglycoside-nitroimidazole triple combination therapy.

Gold 1985No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the definition of exacerbation does answer the criteria for sepsis as defined in review.

Gomez 1990bObservational study according to author correspondence.

Greco 1989Non-randomized prospective comparative trial.

Gribble 1983Study includes 60% neutropenic patients (30/50 evaluable episodes).

Haffejee 1984Included patients were neonates and children.

Hall 1988Included patients were neonates.

Hammerberg 1989Included patients were premature neonates with risk factors for sepsis (31/72 patients between ages 0-1 months).

Hanson 1982Antibiotic regimens incompatible with protocol. Combination therapy versus combination therapy.

Hoogkamp 1983Not a randomized trial. Study groups were studied sequentially. In addition study population consists of cystic fibrosis patients with an exacerbation - sepsis not part of inclusion criteria.

Iakovlev 1997Aminoglycoside was added only to patients that did not respond to the initial beta-lactam monotherapy that was administered empirically.

Iakovlev 2000Not a randomized trial.

Iakovlev 2006Study compares meropenem to "standard regimen" for sepsis at the study hospital (betalactams and fluoroquinolones in combination with aminoglycosides and/ or metronidazole).

Ker 1989Prophylaxis study. Randomization to prophylactic antibiotic treatment, patients did not fulfil criteria for sepsis when randomized.

Krumpe 1999Patients first stratified by disease severity to monotherapy (severe disease) or combination therapy. Following stratification, the patients were randomized to 4 arms: 1) quinolone monotherapy 2) 'standard monotherapy'' from a defined choice of various beta-lactams, at investigator's discretion 3) quinolone-beta-lactam combination therapy 4) 'standard combination therapy' which consisted of various possible combinations of beta-lactams and aminoglycosides at investigators discretion.

Ludwig 1980Description of two separate randomized trials: 1) beta-lactam versus aminoglycoside 2) beta-lactam versus beta-lactam. All administered as monotherapies.

Maller 1991Randomization to once daily aminoglycoside treatment versus twice daily aminoglycoside treatment. In addition to the aminoglycoside, a beta-lactam was administered if considered necessary. Administration of the beta-lactam not randomized (interim analysis of a multicentre study).

Mangi 1988Randomization to beta-lactam monotherapy versus combination. The combination group consisted of clindamycin-aminoglycoside or beta-lactam-aminoglycoside combinations. The decision as to which combination treatment was administered was made on a case-by-case basis, according to the sputum's Gram stain. Patients with Gram-negative bacilli in the sputum were administered the beta-lactam based combination while all others received the clindamycin-based regimen. Outcomes for the two different combination treatments are given together.

McArdle 1987Prophylaxis study. Randomization to beta-lactam monotherapy versus beta-lactam aminoglycoside combination therapy for prophylaxis prior to high-risk biliary tract surgery.

McCarty 1988No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the definition of exacerbation does answer the criteria for sepsis as defined in review.

McLaughlin 1983No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the definition of exacerbation does answer the criteria for sepsis as defined in review.

Mondorf 1987Infection or sepsis not mentioned as part of inclusion criteria. Patients were randomized to receive beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy, and the only outcome given is urinary enzyme excretion.

Mondorf 1989No outcomes relevant for this review. The study randomized patients with severe infections to beta-lactam monotherapy versus beta-lactam aminoglycoside combination therapy. The only outcomes given are renal functions, mainly urinary enzyme levels, and mean serum creatinine per group. Author contacted to ask number of patients per group developing nephrotoxicity and other outcomes - but did not respond.

Moreno-Martinez 1998Comparison of oral cefixime versus oral amoxicillin and intramuscular netilmicin. By protocol only intravenously administered beta-lactams are included.

Mouton 1985Study published as conference proceeding, comparative without mention on randomization. No further details regarding the study were available.

Oblinger 1982Randomization to beta-lactam monotherapy versus combination of antibiotics as deemed appropriate by the attending physicians.

Odio 1987Included patients were neonates with proven invasive bacterial infections.

Padoan 1987Inclusion criteria did not mandate sepsis for all included patients. Study included patients with acute exacerbation of cystic fibrosis, but the definition of exacerbation does answer the criteria for sepsis as defined in review.

Paoletti 1989Comparison between aminoglycoside monotherapy (netimicin) to beta-lactam-aminoglycoside combination therapy (ampicillin + netilmicin).

Pereira 2009Study include patients with neutropenia and fever.

Rodloff 1998Study randomized patients to imipenem monotherapy versus various combination regimens: beta-lactam-aminoglycoside, two beta-lactams, beta-lactam-beta-lactamsa inhibitor, beta-lactam-anaerobic agent and quinolone-anaerobic agent. Patients allocated to the combination group were analysed as one group.

Romanelli 2002Study randomized patients to beta-lactam monotherapy versus macrolide-aminogycoside or macrolide-beta-lactam combination therapy.

Schoengut 1983Non-randomized, prospective comparative trial.

Schuler 1995Randomization to meropenem versus cefotaxime monotherapy. Aminoglycoside added to the cefotaxime arm for urinary tract infections and metronidazole added to the cefotaxime arm when anaerobic infection was suspected. These additions were performed non-randomly, by protocol.

Scott 1987Randomization to 3 arms comparing beta-lactam monotherapy versus beta-lactam-metronidazole-aminoglycoside triple combination therapy versus beta-lactam-metronidazole combination therapy.

Sexton 1984ICAAC abstract. Twenty-two patients were enrolled in a prospective randomized trial, and 8 patients received monotherapy in an open study. Results are shown for all 30 patients combined. Author contacted and replied that original data are no longer available, and therefore randomized patients cannot be separated from the non-randomized. However, results of these trials were pooled with other trials and are described in Gentry 1985.

Sheftel 1986No relevant outcomes for this review. The study randomized patients with osteomyelitis and provides outcomes only for evaluated patients at a follow up range of 2-38 months (appropriate for the type of infection). The number of randomized patients is unknown and outcomes at 30-days were unavailable.

Smith 1999No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the definition of exacerbation does answer the criteria for sepsis as defined in review.

Solberg 1995Article describes results from 4 separate trials. Randomization to meropenem versus ceftazidime monotherapy. An aminoglycoside was added to patients allocated to ceftazidime when resistance to ceftazidime and severe infections were suspected.

Solomkin 1986Inadequate methodology. A publication stating that 'case report forms from an open multicentre study were reviewed': 69 patients assigned to ceftazidime and 66 patients assigned to ticarcillin and tobramycin with soft tissue infections are reported. Information obtained through author contact: these were the only arms of the trial, all patients included in the trial are reported in the publication, and this is the only report of the trial. However, according to the author, the study was not well designed and considered more as a collection of case reports, as stated in the publication.

Stack 1985No sepsis in inclusion criteria. Study included patients with acute exacerbation of cystic fibrosis, but the definition of exacerbation does answer the criteria for sepsis as defined in review.

Tally 1986Randomization to beta-lactam monotherapy (moxalactam) versus another beta-lactam (cefoxitime). An aminoglycoside could be added to the cefoxitime arm by the attending physician's decision, in consultation with an infectious diseases consultant.

Thompson 1980Oral versus intravenous antibiotic administration. Study randomized women with PID to monotherapy of oral amoxicillin versus combination therapy consisting of IV penicillin + IV gentamicin. Inclusion criteria for the review specify IV administration of the beta-lactam in both arms.

Vazquez 1994Prophylaxis study. Antibiotic treatment administered for prophylaxis, without sepsis. In addition trial is probably not randomized.

Vetter 1987No sepsis in inclusion criteria. Study randomized patients with acute exacerbations of chronic bronchitis. Only 19/102 included patients were febrile.

Vetter 1992Comparison of monotherapy (meropenem) versus monotherapy (ceftazidime)

Watanakunakorn 1997Non-randomized comparison of penicillin versus penicillin + gentamicin for Staphylococcus aureus endocarditis.

Yildirim 2008Study included children with neutropenic fever.

 
Characteristics of ongoing studies [ordered by study ID]
Aziz 2012

Trial name or titleComparison of Ampicillin/Sulbactam versus Ampicillin/Gentamicin for Treatment of Intrapartum Chorioamnionitis: A Randomized Controlled Trial

MethodsRandomized controlled trial, double-blind

ParticipantsPregnant women in labor or undergoing induction of labor diagnosed with chorioamnionitis

InterventionsUnasyn 3 grams intravenously every six hours, plus intravenous normal saline placebo dose every eight hours until 24 hours post delivery

versus

Gentamicin 1.5 mg/kg intravenously every eight hours plus ampicillin 2 grams intravenously every six hours until 24 hours post delivery

Outcomes
  • Proportion of participants in each arm experiencing treatment failure as indicated by resolution of maternal infection
  • Maternal adverse events
  • Neonatal adverse outcomes
  • Cost

Starting dateMay 2009

Contact informationPrincipal Investigator: Natali Aziz, MD, Stanford University

NotesEstimated completion date: May 2014

 
Comparison 1. Monotherapy versus combination therapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All-cause mortality44Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Same BL
131431Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.73, 1.30]

    1.2 Different BL
314146Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.71, 1.01]

 2 All-cause mortality by study groups41Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Same sepsis
7839Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.75, 1.55]

    2.2 Same abdominal
2331Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.54, 1.55]

    2.3 Same UTI
173Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.4 Different sepsis
213298Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.69, 0.99]

    2.5 Different abdominal
6550Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.56, 2.15]

    2.6 Different UTI
4298Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.34, 5.21]

 3 Clinical failure66Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Same BL
201870Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.95, 1.29]

    3.2 Different BL
464933Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.67, 0.84]

 4 Clinical failure by study groups61Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Same sepsis
121196Risk Ratio (M-H, Fixed, 95% CI)1.25 [1.01, 1.55]

    4.2 Same abdominal
2308Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.80, 1.32]

    4.3 Same UTI
161Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.46, 2.09]

    4.4 Different sepsis
313743Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.64, 0.81]

    4.5 Different abdominal
10731Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.62, 1.18]

    4.6 Different UTI
5459Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.65, 1.91]

 5 UTI relapse or reinfection6458Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.61, 1.67]

 6 Bacteriological failure—all44Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Same BL
15801Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.87, 1.48]

    6.2 Different BL
292760Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.69, 0.94]

 7 Bacterial superinfection283135Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.57, 0.99]

 8 Fungal superinfection111119Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.42, 1.48]

 9 Bacterial colonization141635Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.65, 1.10]

 10 Bacterial colonization—surveillance cultures6751Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.60, 1.01]

 11 Development of bacterial resistance91370Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.54, 1.45]

 12 Any adverse event405001Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.83, 1.01]

 13 Adverse events requiring treatment discontinuation203098Risk Ratio (M-H, Random, 95% CI)0.89 [0.52, 1.52]

 14 Any nephrotoxicity465269Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.23, 0.39]

    14.1 Once-daily aminoglycoside
5865Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.06, 0.53]

    14.2 Twice-daily aminoglycoside
71127Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.24, 0.77]

    14.3 Thrice-daily aminoglycoside
242138Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.20, 0.39]

    14.4 Non-specified aminoglycoside regimen
101139Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.19, 0.58]

 
Comparison 2. Monotherapy versus combination therapy (subgroup analyses)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All-cause mortality (Gram-negative infection)8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Same BL
3117Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.08, 4.07]

    1.2 Different BL
5313Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.80, 1.95]

 2 All-cause mortality (Gram-negative bacteraemia)5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Same BL
385Risk Ratio (M-H, Fixed, 95% CI)1.62 [0.30, 8.75]

    2.2 Different BL
2125Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.63, 2.70]

 3 All-cause mortality (non–urinary tract infection)17Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Same BL
4401Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.50, 1.31]

    3.2 Different BL
131458Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.52, 0.95]

 4 All-cause mortality (Gram-positive infection)3188Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.12, 1.58]

 5 Clinical failure (Gram-negative infection)28Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Same BL
10432Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.90, 1.68]

    5.2 Different BL
181403Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.66, 1.09]

 6 Clinical failure (Pseudomonas aeruginosa infection)18Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Same BL
6124Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.68, 1.51]

    6.2 Different BL
12302Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.80, 1.82]

 7 Clinical failure (Gram-negative bacteraemia)11Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Same BL
4101Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.45, 2.56]

    7.2 Different BL
7198Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.38, 1.48]

 8 Clinical failure (bacteraemia)22Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Same BL
5141Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.77, 2.66]

    8.2 Different BL
17624Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.46, 0.89]

 9 Clinical failure (urinary tract infection)17Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 Same BL
484Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.59, 2.13]

    9.2 Different BL
13708Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.80, 1.87]

 10 Clinical failure (non–urinary tract infection)44Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Same BL
101248Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.99, 1.42]

    10.2 Different BL
343132Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.59, 0.78]

 11 Clinical failure (Gram-positive infection)5305Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.40, 1.19]

 12 Need for operation (endocarditis)4243Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.41, 1.39]

 13 Bacteriological failure (Gram-positive infection)5300Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.47, 1.69]

 
Comparison 3. Monotherapy versus combination therapy (sensitivity analyses)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All-cause mortality by allocation concealment44Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 A same BL
61068Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.71, 1.31]

    1.2 B same BL
7363Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.47, 2.30]

    1.3 A different BL
122154Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.75, 1.19]

    1.4 B different BL
171878Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.53, 0.93]

    1.5 C different BL
2114Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.34, 5.21]

 2 All-cause mortality by allocation generation44Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 A same BL
61068Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.71, 1.31]

    2.2 B same BL
7363Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.47, 2.30]

    2.3 A different BL
192957Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.72, 1.09]

    2.4 B different BL
101075Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.50, 1.04]

    2.5 C different BL
2114Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.34, 5.21]

 3 All-cause mortality by ITT versus per-protocol analysis44Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 ITT—same BL (type one studies)
5519Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.28, 1.19]

    3.2 Per-protocol—same BL (type two and three studies)
6761Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.80, 1.51]

    3.3 Unknown—same BL (type four studies)
2151Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.06, 13.25]

    3.4 ITT—different BL (type one studies)
152989Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.71, 1.07]

    3.5 Per-protocol—different BL (type two and three studies)
121037Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.54, 1.07]

    3.6 Unknown—different BL (type four studies)
4120Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.34, 5.21]

 4 Clinical failure by allocation concealment66Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 A same BL
81138Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.93, 1.32]

    4.2 B same BL
12732Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.79, 1.50]

    4.3 A different BL
142099Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.60, 0.86]

    4.4 B different BL
292660Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.69, 0.93]

    4.5 C different BL
3174Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.39, 0.92]

 5 Clinical failure by allocation generation66Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 A same BL
91319Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.91, 1.29]

    5.2 B same BL
11551Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.83, 1.69]

    5.3 A different BL
263288Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.66, 0.88]

    5.4 B different BL
171471Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.63, 0.94]

    5.5 C different BL
3174Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.39, 0.92]

 6 Clinical failure by blinding66Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Non-blinded—same BL
191666Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.93, 1.35]

    6.2 Any blinding—same BL
1204Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.82, 1.37]

    6.3 Non-blinded—different BL
403996Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.70, 0.91]

    6.4 Any blinding—different BL
6937Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.50, 0.77]

 7 Clinical failure by ITT versus per-protocol analysis66Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 ITT—same BL (type one)
2110Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.43, 1.40]

    7.2 ITT assuming failure for dropouts—same BL (type two)
9902Risk Ratio (M-H, Fixed, 95% CI)1.32 [1.09, 1.60]

    7.3 Per-protocol—same BL (type three studies)
4580Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.91, 1.33]

    7.4 Type four studies—same BL
5278Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.56, 1.61]

    7.5 ITT—different BL (type one)
131589Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.60, 0.85]

    7.6 ITT assuming failure for dropouts—different BL (type two)
142065Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.73, 0.94]

    7.7 Per-protocol—different BL (type three studies)
121031Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.62, 0.95]

    7.8 Type four studies—different BL
7248Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.52, 1.69]

 
Summary of findings for the main comparison. Monotherapy versus combination therapy compared for sepsis

Monotherapy versus combination therapy compared for sepsis

Patient or population: participants with sepsis
Settings:
Intervention: monotherapy versus combination therapy
Comparison:

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Monotherapy versus combination therapy

All-cause mortalitysame beta lactam
Survival
Follow-up: mean 30 days1
Study populationRR 0.97
(0.73 to 1.3)
1431
(13 studies)
⊕⊕⊝⊝
low2,3

112 per 1000109 per 1000
(82 to 145)

High

300 per 1000291 per 1000
(219 to 390)

All-cause mortalitydifferent beta lactam
Follow-up: mean 30 days1
Study populationRR 0.85
(0.71 to 1.01)
4146
(31 studies)
⊕⊕⊝⊝
low3,4

113 per 100096 per 1000
(80 to 114)

High

300 per 1000255 per 1000
(213 to 303)

Clinical failuresame beta lactam
Antibiotic modifications
Follow-up: two to 30 days5
232 per 1000258 per 1000
(221 to 300)
RR 1.11
(0.95 to 1.29)
1870
(20 studies)
⊕⊝⊝⊝
very low6,7

Clinical failuredifferent beta lactam
Antibiotic modifications
Follow-up: two to 30 days5
227 per 1000170 per 1000
(152 to 190)
RR 0.75
(0.67 to 0.84)
4933
(46 studies)
⊕⊝⊝⊝
very low6,7

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

Same and different beta lactams refer to comparisons involving the same beta lactam with versus without aminoglycoside and comparisons between one beta lactam versus a different beta lactam combined with an aminoglycoside, respectively.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Extracted preferentially at 30 days and if unavailable in-hospital or at end of follow-up.
295% confidence intervals range from 27% improved survival to 30% higher risk of death with monotherapy.
3Funnel plot asymmetrical pointing out missing studies (unpublished or published but not reporting on mortality) favouring combination therapy.
4Advantage of monotherapy accentuated in studies with unclear allocation concealment and per-protocol analysis.
5Days after treatment cessation.
6Assessment of treatment failure in open trials prone to bias.
7Although this was the primary outcome in all studies, its clinical significance is unclear, and correlation with mortality is unclear (see discussion).
 
Table 1. Beta lactam monotherapies

MonotherapyNo. studiesNo. of participants treatedDoses (no. studies: dose)

ceftazidime12939Four: 2 g × 2/d; five: 2 g × 3/d; one:1 g × 4/d; one: 1 g × 3/d; one: NS

cefotaximeSeven281One:1 g × 4/d; one: 2 g × 6/d; one: 3 g × 3/d; 1 to 2 g × 4/d; one: 1 g × 2/d; one: 2 g × 6/d; one: 1 g × 3 to 4/d

imipenemSix580Three: 500 mg × 4/d; one: 500 to 1000 mg × 4/d; one: 500 mg × 3/d; one: NS

cefoperazoneSix238Two: 2 g × 2/d; one: 2 g × 3/d; one: 6 g × 2/d; one: 1 to 4 g/d; one: 1.5 gr × 4/d

meropenemFive376Five: 1 g × 3/d

ceftriaxoneThree237Three: 2 g × 1/d; one: 2 g × 2/d

piperacillin-tazobactamThree269One: 4 g × 4/d; one: 0.5 g × 4/d; two: 4.5 g × 3/d

cefepimeThree160One: 2 g × 3/d; two: 2 g × 2/d

ceftizoximeThree50One: 60 to 150 mg/kg/d; one: 1 to 2 g × 3/d; one: 20 to 50 mg/kg × 2 to 3/d

mezlocillinThree47One: 4 g × 4/d; one: 62.5 mg/kg × 4/d; one: 10 g × 3/d

piperacillinTwo83Two: 3 g × 6/d

amoxicillin-clavulanateTwo81One: 2.2 gr × 3/d; one: NS

ampicillinTwo44One: 25 mg/kg × 4/d, one: 500 mg × 4/d

cefazoline One58One: 1 g × 3/d

amoxicillin-sulbactamOne56One: 33 mg/kg × 3/d

cefoxitinOne31One: 2 g × 3/d

carbenicillinOne25One: 10 g × 3/d

ticarcillin-clavulanic acidOne21One: 3.1 g × 4 to 6/d

azlocillinOne20One: 13 + -2.2 gr/d

moxalactamOne18One: 2 g × 3/d

Gram-positive infection

oxacillinOne12One: 12 g/d 

cloxacillinOne45One: 2 g × 6/d

cefamandoleOne36One: 2 g × 3/d

nafcillinOne33One: 1.5 to 6 g × 6/d

ceftriaxoneOne67One: 2 g × 1/d