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Meta-Analysis
. 2014 Jan 7;2014(1):CD003344.
doi: 10.1002/14651858.CD003344.pub3.

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

Mical Paul  1 , Adi Lador, Simona Grozinsky-Glasberg, Leonard Leibovici
Affiliations
Meta-Analysis

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

Mical Paul et al. Cochrane Database Syst Rev. .

Abstract

Background: Optimal antibiotic treatment for sepsis is imperative. Combining a beta lactam antibiotic with an aminoglycoside antibiotic may provide certain advantages over beta lactam monotherapy.

Objectives: Our objectives were to compare beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy in patients with sepsis and to estimate the rate of adverse effects with each treatment regimen, including the development of bacterial resistance to antibiotics.

Search methods: In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 11); MEDLINE (1966 to 4 November 2013); EMBASE (1980 to November 2013); LILACS (1982 to November 2013); and conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (1995 to 2013). We scanned citations of all identified studies and contacted all corresponding authors. In our previous review, we searched the databases to July 2004.

Selection criteria: We included randomized and quasi-randomized trials comparing any beta lactam monotherapy versus any combination of a beta lactam with an aminoglycoside for sepsis.

Data collection and analysis: The primary outcome was all-cause mortality. Secondary outcomes included treatment failure, superinfections and adverse events. Two review authors independently collected data. We pooled risk ratios (RRs) with 95% confidence intervals (CIs) using the fixed-effect model. We extracted outcomes by intention-to-treat analysis whenever possible.

Main results: We included 69 trials that randomly assigned 7863 participants. Twenty-two trials compared the same beta lactam in both study arms, while the remaining trials compared different beta lactams using a broader-spectrum beta lactam in the monotherapy arm. In trials comparing the same beta lactam, we observed no difference between study groups with regard to all-cause mortality (RR 0.97, 95% CI 0.73 to 1.30) and clinical failure (RR 1.11, 95% CI 0.95 to 1.29). In studies comparing different beta lactams, we observed a trend for benefit with monotherapy for all-cause mortality (RR 0.85, 95% CI 0.71 to 1.01) and a significant advantage for clinical failure (RR 0.75, 95% CI 0.67 to 0.84). No significant disparities emerged from subgroup and sensitivity analyses, including assessment of participants with Gram-negative infection. The subgroup of Pseudomonas aeruginosa infections was underpowered to examine effects. Results for mortality were classified as low quality of evidence mainly as the result of imprecision. Results for failure were classified as very low quality of evidence because of indirectness of the outcome and possible detection bias in non-blinded trials. We detected no differences in the rate of development of resistance. Nephrotoxicity was significantly less frequent with monotherapy (RR 0.30, 95% CI 0.23 to 0.39). We found no heterogeneity for all these comparisons.We included a small subset of studies addressing participants with Gram-positive infection, mainly endocarditis. We identified no difference between monotherapy and combination therapy in these studies.

Authors' conclusions: The addition of an aminoglycoside to beta lactams for sepsis should be discouraged. All-cause mortality rates are unchanged. Combination treatment carries a significant risk of nephrotoxicity.

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Conflict of interest statement

Mical Paul: none known.

Adi Lador: none known.

Simona Grozinsky‐Glasberg: none known.

Leonard Leibovici: none known.

We certify that we have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of this review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony).

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel mortality. All‐cause mortality.
5
5
Funnel failure.
1.1
1.1. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 1 All‐cause mortality.
1.2
1.2. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 2 All‐cause mortality by study groups.
1.3
1.3. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 3 Clinical failure.
1.4
1.4. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 4 Clinical failure by study groups.
1.5
1.5. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 5 UTI relapse or reinfection.
1.6
1.6. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 6 Bacteriological failure—all.
1.7
1.7. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 7 Bacterial superinfection.
1.8
1.8. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 8 Fungal superinfection.
1.9
1.9. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 9 Bacterial colonization.
1.10
1.10. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 10 Bacterial colonization—surveillance cultures.
1.11
1.11. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 11 Development of bacterial resistance.
1.12
1.12. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 12 Any adverse event.
1.13
1.13. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 13 Adverse events requiring treatment discontinuation.
1.14
1.14. Analysis
Comparison 1 Monotherapy versus combination therapy, Outcome 14 Any nephrotoxicity.
2.1
2.1. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 1 All‐cause mortality (Gram‐negative infection).
2.2
2.2. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 2 All‐cause mortality (Gram‐negative bacteraemia).
2.3
2.3. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 3 All‐cause mortality (non–urinary tract infection).
2.4
2.4. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 4 All‐cause mortality (Gram‐positive infection).
2.5
2.5. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 5 Clinical failure (Gram‐negative infection).
2.6
2.6. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 6 Clinical failure (Pseudomonas aeruginosa infection).
2.7
2.7. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 7 Clinical failure (Gram‐negative bacteraemia).
2.8
2.8. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 8 Clinical failure (bacteraemia).
2.9
2.9. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 9 Clinical failure (urinary tract infection).
2.10
2.10. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 10 Clinical failure (non–urinary tract infection).
2.11
2.11. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 11 Clinical failure (Gram‐positive infection).
2.12
2.12. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 12 Need for operation (endocarditis).
2.13
2.13. Analysis
Comparison 2 Monotherapy versus combination therapy (subgroup analyses), Outcome 13 Bacteriological failure (Gram‐positive infection).
3.1
3.1. Analysis
Comparison 3 Monotherapy versus combination therapy (sensitivity analyses), Outcome 1 All‐cause mortality by allocation concealment.
3.2
3.2. Analysis
Comparison 3 Monotherapy versus combination therapy (sensitivity analyses), Outcome 2 All‐cause mortality by allocation generation.
3.3
3.3. Analysis
Comparison 3 Monotherapy versus combination therapy (sensitivity analyses), Outcome 3 All‐cause mortality by ITT versus per‐protocol analysis.
3.4
3.4. Analysis
Comparison 3 Monotherapy versus combination therapy (sensitivity analyses), Outcome 4 Clinical failure by allocation concealment.
3.5
3.5. Analysis
Comparison 3 Monotherapy versus combination therapy (sensitivity analyses), Outcome 5 Clinical failure by allocation generation.
3.6
3.6. Analysis
Comparison 3 Monotherapy versus combination therapy (sensitivity analyses), Outcome 6 Clinical failure by blinding.
3.7
3.7. Analysis
Comparison 3 Monotherapy versus combination therapy (sensitivity analyses), Outcome 7 Clinical failure by ITT versus per‐protocol analysis.
See this image and copyright information in PMC

Update of

References

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    1. Sculier JP, Coppens L, Klastersky J. Effectiveness of mezlocillin and endotracheally administered sisomicin with or without parenteral sisomicin in the treatment of Gram‐negative bronchopneumonia. Journal of Antimicrobial Chemotherapy 1982;9(1):63‐8. - PubMed
Sexton 1998 {published data only}
    1. Sexton DJ, Tenenbaum MJ, Wilson WR, Steckelberg JM, Tice AD, Gilbert D, et al. Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin‐susceptible streptococci. Endocarditis Treatment Consortium Group. Clinical Infectious Diseases 1998;27(6):1470‐4. - PubMed
Sieger 1997 {published data only}
    1. Sieger B, Berman SJ, Geckler RW, Farkas SA, for the Meropenem Lower Respiratory Infection Group. Empiric treatment of hospital‐acquired lower respiratory tract infections with meropenem or ceftazidime with tobramycin: a randomized study. Critical Care Medicine 1997;25(10):1663‐70. - PubMed
    1. Sieger B, Geckler RW. A comparison of meropenem and ceftazidime plus tobramycin in the treatment of hospital‐acquired lower respiratory tract infections. 33rd Interscience Conference on Antimicrobials Agents and Chemotherapy. 1993; Vol. Abstract no. 640:236.
Smith 1984 {published data only (unpublished sought but not used)}
    1. Moore RD, Smith CR, Holloway JJ, Lietman PS. Cefotaxime vs nafcillin and tobramycin for the treatment of serious infection. Comparative cost‐effectiveness. Archives of Internal Medicine 1986;146(6):1153‐7. - PubMed
    1. Moore RD, Smith CR, Lietman PS. Increased risk of renal dysfunction due to interaction of liver disease and aminoglycosides. American Journal of Medicine 1986;80(6):1093‐7. - PubMed
    1. Smith CR, Ambinder R, Lipsky JJ, Petty BG, Israel E, Levitt R, et al. Cefotaxime compared with nafcillin plus tobramycin for serious bacterial infections. A randomized, double‐blind trial. Annals of Internal Medicine 1984;101(4):469‐77. - PubMed
Speich 1998 {published and unpublished data}
    1. Speich R, Imhof E, Vogt M, Grossenbacher M, Zimmerli W. Efficacy, safety, and tolerance of piperacillin/tazobactam compared to co‐amoxiclav plus an aminoglycoside in the treatment of severe pneumonia. European Journal of Clinical Microbiology and Infectious Diseases 1998;17(5):313‐7. - PubMed
Stille 1992 {published data only}
    1. Stille W, Shah PM, Ullmann U, Hoffstedt B, Kreisl C, Bommersbach B, et al. For the German and Austrian Imipenem/Cilastatin Study Group. Randomized multicenter clinical trial with imipenem/cilastatin versus cefotaxime/gentamicin in the treatment of patients with non‐life‐threatening infections. European Journal of Clinical Microbiology and Infectious Diseases 1992;11(8):683‐92. - PubMed
Sukoh 1994 {published and unpublished data}
    1. Sukoh M, Inoue T, Morita Y, Ito K, Togano Y, Yamanaka K, et al. [Clinical evaluation of combination therapy of sulbactam/cefoperazone and aminoglycoside in respiratory tract infections]. In Japanese. Japanese Journal of Antibiotics 1994;47(2):170‐80. - PubMed
Takamoto 1994 {published data only}
    1. Takamoto M, Ishibashi T, Toyoshima H, Tanaka H, Tamaru N, Watanabe K, et al. [Imipenem/cilastatin sodium alone or combined with amikacin sulfate in respiratory infections]. In Japanese. Japanese Journal of Antibiotics 1994;47(9):1131‐44. - PubMed
Thompson 1990 {published data only}
    1. Thompson JE Jr, Pitt HA, Doty JE, Coleman J, Irving C. Broad spectrum penicillin as an adequate therapy for acute cholangitis. Surgery, Gynecology & Obstetrics 1990;171(4):275‐82. - PubMed
Thompson 1993 {published data only}
    1. Thompson JE Jr, Bennion RS, Roettger R, Lally KP, Hopkins JA, Wilson SE. Cefepime for infections of the biliary tract. Surgery, Gynecology & Obstetrics 1993;177(Suppl):30‐4. - PubMed
Trujillo 1992 {published data only}
    1. Zavala Trujillo I. Research on efficacy and safety of ceftizoxime in treating lower respiratory tract and skin and soft tissues infections [Busqueda de la eficacia y seguridad de ceftizoxima en el tratamiento de infecciones del tracto respiratorio inferior y de la piel y de los tejidos blandos]. Compend Invest Clin Latinoam 1992;12(2):31‐41.
Vergnon 1985 {published data only}
    1. Vergnon JM, Vincent M, Ros A, Brun Y, Brune J. [Comparative clinical trial of cefoperazone versus ampicillin + tobramycin in severe bronchopulmonary and pleural infectious pathology]. In French. Revue de Pneumologie Clinique 1985;41(3):205‐11. - PubMed
Verzasconi 1995 {published data only}
    1. Verzasconi R, Rodoni P, Monotti R, Marone C, Mombelli G. [Amoxicillin and clavulanic acid versus amoxicillin plus gentamicin in the empirical initial treatment of urinary tract infections in hospitalized patients] [In German]. Schweizerische Medizinische Wochenschrift 1995;125(33):1533‐9. - PubMed
Warren 1983 {published data only}
    1. Warren JW, Miller EH Jr, Fitzpatrick B, DiFranco DE, Caplan ES, Tenney JH, et al. A randomized, controlled trial of cefoperazone vs. cefamandole‐ tobramycin in the treatment of putative, severe infections with gram‐ negative bacilli. Reviews in Infectious Diseases 1983;5(Suppl 1):S173‐80. - PubMed
Wiecek 1986 {published data only}
    1. Wiecek A, Kokot F, Andrzejowska H, Grzeszczak W. [Clinical evaluation of ceftazidime and the combined administration of cefotaxime and tobramycin in the treatment of urinary tract infections. Prospective and randomized studies] In Polish. Polski Tygodnik Lekarski 1986;41(39):1242‐6. - PubMed
Wing 1998 {published and unpublished data}
    1. Wing DA, Hendershott CM, Debuque L, Millar LK. A randomized trial of three antibiotic regimens for the treatment of pyelonephritis in pregnancy. Obstetrics and Gynecology 1998;92(2):249‐53. - PubMed
Yellin 1993 {published and unpublished data}
    1. Yellin AE, Berne TV, Appleman MD, Heseltine PN, Gill MA, Okamoto MP, et al. A randomized study of cefepime versus the combination of gentamicin and mezlocillin as an adjunct to surgical treatment in patients with acute cholecystitis. Surgery, Gynecology & Obstetrics 1993;177(Suppl):23‐9. - PubMed

References to studies excluded from this review

Alvarez‐Lerma 2001b {published data only}
    1. Alvarez‐Lerma F, Insausti‐Ordenana J, Jorda‐Marcos R, Maravi‐Poma E, Torres‐Marti A, Nava J, et al. Efficacy and tolerability of piperacillin/tazobactam versus ceftazidime in association with amikacin for treating nosocomial pneumonia in intensive care patients: a prospective randomized multicenter trial. Intensive Care Medicine 2001;27(3):493‐502. - PubMed
Badaro 2002 {published data only}
    1. Badaro R, Molinar F, Seas C, Stamboulian D, Mendonca J, Massud J, et al. A multicenter comparative study of cefepime versus broad‐spectrum antibacterial therapy in moderate and severe bacterial infections. Brazilian Journal of Infectious Diseases 2002;6(5):206‐18. - PubMed
Benlloch 1995 {published data only}
    1. Benlloch C, Costa E, Segarra V, Velazquez JA, Ruiz CS. Systemic antibiotherapy in acute appendicitis. Comparison of three antibiotic regimes [Antibioterapia sistemica en apendicitis aguda. Comparacion entre tres pautas antibioticas]. Acta Pediatrica Espanola 1995;53(6):367‐9.
Blumer 2003 {published data only}
    1. Blumer JL, Minkwitz M, Saiman L, San Gabriel P, Iaconis J, Melnick D. Meropenem (MEM) compared with ceftazidime (CAZ) in combination with tobramycin (TOB) for treatment of actue pulmonary exacerbations (APE) in patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa (PA) or Burkholderia cepacia (BC). Pediatric Pulmonology. 2003; Vol. Suppl 25:294.
Bodey 1976 {published data only}
    1. Bodey GP, Feld R, Burgess MA. Beta‐lactam antibiotics alone or in combination with gentamicin for therapy of gram‐negative bacillary infections in neutropenic patients. The American Journal of the Medical Sciences 1976;271(2):179‐86. - PubMed
Cetto 1983 {published data only}
    1. Cetto GL, Todeschini G, Caramaschi G, Vinante F, Benini F, Perona G. Empiric therapy of infections in hematologic malignancies: a prospective, randomized trial. Tumori 1983;69(2):155‐60. - PubMed
Chaudhary 2008 {published data only}
    1. Chaudhary M, Shrivastava SM, Varughese L, Sehgal R. Efficacy and safety evaluation of fixed dose combination of cefepime and amikacin in comparison with cefepime alone in treatment of nosocomial pneumonia patients. Current Clinical Pharmacology 2008;3(2):118‐22. [ISRCTN65171867] - PubMed
Chaudhary 2009 {published data only}
    1. Chaudhary M, Shrivastava SM, Sehgal R. Evaluation of efficacy and safety of fixed dose combination of ceftazidime‐tobramycin in comparison with ceftazidime in lower respiratory tract infections. Current Clinical Pharmacology 2009;4(1):62‐6. [ISTCRN69844323] - PubMed
Ciftci 1997 {published data only}
    1. Ciftci AO, Tanyel FC, Buyukpamukcu N, Hicsonmez A. Comparative trial of four antibiotic combinations for perforated appendicitis in children. European Journal of Surgery 1997;163(8):591‐6. - PubMed
Crenshaw 1983 {published data only}
    1. Crenshaw C, Glanges E, Webber C, McReynolds DB. A prospective random study of a single agent versus combination antibiotics as therapy in penetrating injuries of the abdomen. Surgery Gynecology & Obstetrics 1983;156(3):289‐94. - PubMed
Croce 1993 {published data only}
    1. Croce M, Fabian TC, Stewart RM, Pritchard FE, Minard G, Trenthem L, et al. Empiric monotherapy versus combination therapy of nosocomial pneumonia in trauma patients. The Journal of Trauma 1993;35(2):303‐9. - PubMed
De Louvois 1992 {published data only}
    1. Louvois J, Dagan R, Tessin I. A comparison of ceftazidime and aminoglycoside based regimens as empirical treatment in 1316 cases of suspected sepsis in the newborn. European Society for Paediatric Infectious Diseases‐‐Neonatal Sepsis Study Group. European Journal of Pediatrics 1992;151(12):876‐84. - PubMed
Extermann 1995 {published data only}
    1. Extermann M, Regamey C, Humair L, Murisier F, Rhyner K, Vonwiller HM. Initial treatment of sepsis in non‐neutropenic patients ‐ ceftazidime alone versus best guess combined antibiotic therapy. Chemotherapy 1995;41:306‐15. - PubMed
Fainstein 1983 {published data only}
    1. Fainstein V, Bodey GP, Elting L, Bolivar R, Keating MJ, McCredie KB, et al. A randomized study of ceftazidime compared to ceftazidime and tobramycin for the treatment of infections in cancer patients. Journal of Antimicrobial Chemotherapy 1983;12 Suppl A:101‐10. - PubMed
Fernandez 1991 {published data only}
    1. Fernandez GM, Gudiol F, Rodriguez TA, Arnau C, Valdes L, Vallve C. Nosocomial pneumonia: comparative multicentre trial between monotherapy with cefotaxime and treatment with antibiotic combinations. Infection 1991;19(Suppl 6):S320‐5. - PubMed
Foord 1985 {published data only}
    1. Foord RD. Aspects of clinical trials with ceftazidime worldwide. American Journal of Medicine 1985;79(2A):110‐3. - PubMed
Gentry 1980 {published data only}
    1. Gentry LO, Wood BA, Martin MD, Smythe J. Cefamandole alone and combined with gentamicin or tobramycin in the treatment of acute pyelonephritis. Scandinavian Journal of Infectious Diseases 1980;suppl(25):96‐100. - PubMed
Gentry 1984 {published data only}
    1. Gentry LO, Feliciano DV, Lea AS, Short HD, Mattox KL, Jordan GL Jr. Perioperative antibiotic therapy for penetrating injuries of the abdomen. Annals of Surgery 1984;200(5):561‐6. - PMC - PubMed
Gentry 1985 {published data only}
    1. Gentry LO. Treatment of skin, skin structure, bone, and joint infections with ceftazidime. American Journal of Medicine 1985;79(2A):67‐74. - PubMed
Gerber 1989 {published data only}
    1. Gerber B, Retzke F, Wilken H. [Effectiveness of perioperative preventive use of antibiotics with ampicillin/gentamycin or cefotiam in abdominal cesarean section]. Zentralblatt für Gynäkologie 1989;111(10):658‐63. - PubMed
Gilbert 1998 {published data only}
    1. Gilbert DN, Lee BL, Dworkin RJ, Leggett JL, Chambers HF, Modin G, et al. A randomized comparison of the safety and efficacy of once‐daily gentamicin or thrice‐daily gentamicin in combination with ticarcillin‐clavulanate. American Journal of Medicine 1998;105(3):182‐91. - PubMed
Giraud 1989 {published data only}
    1. Giraud JR, Chartier M, Ciraru Vigneron N, Becue J, Landes P, Leng JJ, et al. [A comparison of the efficacy of and tolerance to Augmentin used alone and as one of three drugs used to treat acute upper genital tract infections. Results of a multicentre trial 152 cases] [Comparaison de l'efficacite et de la tolerance de l'Augmentine en monotherapie versus triple association dans le traitment des infections genitales hautes aigues. Resultats d'une etude multicentrique portant sur 152 cas]. Contraception, Fertilité, Sexualité 1989;17(10):941‐8.
Gold 1985 {published data only}
    1. Gold R, Overmeyer A, Knie B, Fleming PC, Levison H. Controlled trial of ceftazidime vs. ticarcillin and tobramycin in the treatment of acute respiratory exacerbations in patients with cystic fibrosis. Pediatric Infectious Disease 1985;4(2):172‐7. - PubMed
Gomez 1990b {published data only}
    1. Gomez J, Moldenhauer F, Ruiz Gomez J, Ros CM, Martinez Hernandez J, Canteras M, et al. Monotherapy versus antibiotic combinations in bacteremias in an internal medicine department. A prospective study in 1987 [Monoterapia frente a combinaciones antibioticas en las bacteriemias de un departamento de medicina interna. estudio prospectivo durante 1987]. Revista Espanola de Microbiologia Clinica 1990;5(2):89‐93.
Greco 1989 {published data only}
    1. Greco T. Treatment of nosocomial pneumonia: monotherapy versus combination therapy. Geriatrics 1989;44 Suppl A:28‐31. - PubMed
Gribble 1983 {published data only}
    1. Gribble MJ, Chow AW, Naiman SC, Smith JA, Bowie WR, Sacks SL, et al. Prospective randomized trial of piperacillin monotherapy versus carboxypenicillin‐aminoglycoside combination regimens in the empirical treatment of serious bacterial infections. 21st Interscience Conference on Antimicrobial Agents and Chemotherapy. 1981. - PMC - PubMed
    1. Gribble MJ, Chow AW, Naiman SC, Smith JA, Bowie WR, Sacks SL, et al. Prospective randomized trial of piperacillin monotherapy versus carboxypenicillin‐aminoglycoside combination regimens in the empirical treatment of serious bacterial infections. Antimicrobial Agents and Chemotherapy 1983;24(3):388‐93. - PMC - PubMed
Haffejee 1984 {published data only}
    1. Haffejee IE. A therapeutic trial of cefotaxime versus penicillin‐gentamicin for severe infections in children. Journal of Antimicrobial Chemotherapy 1984;14 Suppl B:147‐52. - PubMed
Hall 1988 {published data only}
    1. Hall MA, Ducker DA, Lowes JA, McMichael J, Clarke P, Rowe D, et al. A randomised prospective comparison of cefotaxime versus netilmicin/penicillin for treatment of suspected neonatal sepsis. Drugs 1988;35(Suppl 2):169‐77. - PubMed
Hammerberg 1989 {published data only}
    1. Hammerberg O, Kurnitzki C, Watts J, Rosenbloom D. Randomized trial using piperacillin versus ampicillin and amikacin for treatment of premature neonates with risk factors for sepsis. European Journal of Clinical Microbiology and Infectious Diseases 1989;8(3):241‐4. - PubMed
Hanson 1982 {published data only}
    1. Hanson B, Coppens L, Klastersky J. Comparative studies of ticarcillin and mezlocillin plus sisomicin in Gram‐negative bacillary bacteraemia and bronchopneumonia. Journal of Antimicrobial Chemotherapy 1982;10(4):335‐41. - PubMed
Hoogkamp 1983 {published data only}
    1. Hoogkamp‐Korstanje JA, Laag J. Piperacillin and tobramycin in the treatment of Pseudomonas lung infections in cystic fibrosis. Journal of Antimicrobial Chemotherapy 1983;12(2):175‐83. - PubMed
Iakovlev 1997 {published data only}
    1. Iakovlev SV, Shakhova TV, Dvoretskii LI, Romanovskii I, Eremina LV, Koroleva TA, et al. [Use of piperacillin/tazobactam as empirical monotherapy in the treatment of bacterial infections in a resuscitation department]. Antibiotiki i Khimioterapia 1997;42(2):33‐7. - PubMed
Iakovlev 2000 {published data only}
    1. Iakovlev SV, Dvoretskii LI, Shakhova TV. [The clinical efficacy of ticarcillin/clavulanate in severe pneumonia]. Antibiotiki i Khimioterapia 2000;45(3):30‐4. - PubMed
Iakovlev 2006 {published data only}
    1. Iakovlev SV, Beloborodov VB, Sidorenko SV, Iakovlev VP, Grigor'ev KB, Eliseeva EV, et al. Multicentre study of comparative efficacy of meropenem and combined regimens for empirical antibacterial therapy of severe nosocomial infections: results of clinical and pharmacoeconomic analysis. Antibiotiki i khimioterapii︠a︡ 2006;51(7):15‐27. - PubMed
Ker 1989 {published data only}
    1. Ker CG, Hou MF, Chen JS, Lee KT, Sheen PC, Akbary MA. A comparative study of cefotaxime sodium versus a combination of cefapirin and gentamicin in the prophylactic treatment of patients undergoing cholecystectomy. Methods and Findings in Experimental and Clinical Pharmacology 1989;11(11):711‐5. - PubMed
Krumpe 1999 {published data only}
    1. Krumpe PE, Cohn S, Garreltes J, Ramirez J, Coulter H, Haverstock D, et al. Intravenous and oral mono‐ or combination‐therapy in the treatment of severe infections: ciprofloxacin versus standard antibiotic therapy. Ciprofloxacin Study Group. Journal of Antimicrobial Chemotherapy 1999;43(Suppl A):117‐28. - PubMed
Ludwig 1980 {published data only}
    1. Ludwig G, Knebel L. Cefotaxime in urinary tract infections‐‐comparative clinical studies with gentamicin and with cefoxitin. Journal of Antimicrobial Chemotherapy 1980;6 Suppl A:207‐11. - PubMed
Maller 1991 {published data only}
    1. Maller R, Ahrne H, Eilard T, Eriksson I, Lausen I. Efficacy and safety of amikacin in systemic infections when given as a single daily dose or in two divided doses. Scandinavian Amikacin Once Daily Study Group. Journal of Antimicrobial Chemotherapy 1991;27(Suppl C):121‐8. - PubMed
Mangi 1988 {published data only}
    1. Mangi RJ, Greco T, Ryan J, Thornton G, Andriole VT. Cefoperazone versus combination antibiotic therapy of hospital‐acquired pneumonia. American Journal of Medicine 1988;84(1):68‐74. - PubMed
McArdle 1987 {published data only}
    1. McArdle C, Morran C, Greig J, Mason B, Haddock G, Sleigh J, et al. Comparison of cefotetan and gentamicin/ampicillin in high‐risk biliary tract surgery. Chemioterapia 1987;6(2 Suppl):593‐4. - PubMed
McCarty 1988 {published data only}
    1. McCarty JM, Tilden SJ, Black P, Craft JC, Blumer J, Waring W, et al. Comparison of piperacillin alone versus piperacillin plus tobramycin for treatment of respiratory infections in children with cystic fibrosis. Pediatric Pulmonology 1988;4(4):201‐4. - PubMed
McLaughlin 1983 {published data only}
    1. McLaughlin FJ, Matthews WJ Jr, Strieder DJ, Sullivan B, Taneja A, Murphy P, et al. Clinical and bacteriological responses to three antibiotic regimens for acute exacerbations of cystic fibrosis: ticarcillin‐tobramycin, azlocillin‐tobramycin, and azlocillin‐placebo. Journal of Infectious Diseases 1983;147(3):559‐67. - PubMed
    1. McLaughlin FJ, Matthews WJ, Jr, Strieder DJ, Sullivan B, Goldmann DA. Randomized, double‐blind evaluation of azlocillin for the treatment of pulmonary exacerbations of cystic fibrosis. Journal of Antimicrobial Chemotherapy 1983;11(Suppl B):195‐203. - PubMed
Mondorf 1987 {published data only}
    1. Mondorf A, Mondorf W, Banzer S. A multiple‐center comparative study of the kidney tolerance of ceftazidime versus cefotaxime and tobramycin. Chemioterapia 1987;6(2 Suppl):331‐2. - PubMed
Mondorf 1989 {published data only}
    1. Mondorf AW, Bonsiepe C, Mondorf W. Randomized multi center study comparing nephrotoxicity of ceftazidime versus the combination of piperacillin and netilmicin with and without furosemide. Advances in Experimental Medicine and Biology 1989;252:307‐12. - PubMed
Moreno‐Martinez 1998 {published data only}
    1. Moreno Martinez A, Mensa J, Martinez JA, Marco F, Vila J, Almela M, et al. Cefixime versus amoxicillin plus netilmicin in the treatment of community‐acquired non‐complicated acute pyelonephritis. Medicina Clinica 1998;111(14):521‐4. - PubMed
Mouton 1985 {published data only}
    1. Mouton Y, Deboscker Y, Beuscart C, Beaucaire G, Fourrier A. Third generation cephalosporins in combination with aminoglycosides or in monotherapy for life‐threatening infections in an intensive care unit. 25th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1985:Abstract no. 958.
Oblinger 1982 {published data only}
    1. Oblinger MJ, Bowers JT, Sande MA, Mandell GL. Moxalactam therapy vs. standard antimicrobial therapy for selected serious infections. Reviews of Infectious Diseases 1982;4(Suppl):S639‐49. - PubMed
Odio 1987 {published data only}
    1. Odio CM, Umana MA, Saenz A, Salas JL, McCracken GH. Comparative efficacy of ceftazidime vs. carbenicillin and amikacin for treatment of neonatal septicemia. Pediatric Infectious Diseases Journal 1987;6(4):371‐7. - PubMed
Padoan 1987 {published data only}
    1. Padoan R, Cambisano W, Costantini D, Crossignani RM, Danza ML, Trezzi G, et al. Ceftazidime monotherapy vs. combined therapy in Pseudomonas pulmonary infections in cystic fibrosis. Pediatric Infectious Diseases Journal 1987;6(7):648‐53. - PubMed
Paoletti 1989 {published data only}
    1. Paoletti V, Mammarella A, Mariani A, Filippello CP, Franchino L, Barlattani M. Netilmicin in the treatment of infections of the lower urinary tract [La netilimicina nel trattamento delle infeziono delle basse vie urinarie]. Clinical Therapeutics 1989;128(6):405‐9. - PubMed
Pereira 2009 {published data only}
    1. Pereira CA, Petrilli AS, Carlesse FA, Luisi FA, Silva KV, Martino Lee ML. Cefepime monotherapy is as effective as ceftriaxone plus amikacin in pediatric patients with cancer and high‐risk febrile neutropenia in a randomized comparison. Journal of Microbiology, Immunology, and Infection 2009;42(2):141‐7. - PubMed
Rodloff 1998 {published data only}
    1. Rodloff AC, Kujath P, Lunstedt B, Gaus W. Comparative study of the cost‐effectiveness of initial therapy with imipenem/cilastatin in secondary peritonitis. Chirurgia 1998;69(10):1093‐100. - PubMed
Romanelli 2002 {published data only}
    1. Romanelli G, Cravarezza P, Pozzi A, Franchino L, Ravizzola G, Zulli R, et al. Carbapenems in the treatment of severe community‐acquired pneumonia in hospitalized elderly patients: a comparative study against standard therapy. Journal of Chemotherapy 2002;14(6):609‐17. - PubMed
Schoengut 1983 {published data only}
    1. Schoengut H, Jelinek R. Comparative study of the effects of ceftazidime compared with tobramycin plus cefamandole in the treatment of gall bladder empyema. Journal of Antimicrobial Chemotherapy 1983;12 Suppl A:219‐22. - PubMed
Schuler 1995 {published data only}
    1. Schuler D, and the Meropenem Paediatric Study Group. Safety and efficacy of meropenem in hospitalised children: randomised comparison with cefotaxime, alone and combined with metronidazole or amikacin. Journal of Antimicrobial Chemotherapy 1995;36(Suppl A):99‐108. - PubMed
Scott 1987 {published data only}
    1. Scott SD, Saddler B, Lowes JA, Karran SJ. Comparison of cefotetan versus combination therapy in peritonitis and serious intra‐abdominal sepsis. Chemioterapia 1987;6(2 Suppl):475‐6. - PubMed
Sexton 1984 {published data only}
    1. Sexton DJ, Wlodaver CG, Tobey LE, Finn LA, Chubb JM. Ceftazidime therapy for Gram‐negative bone and joint infections. 24th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1984; Vol. Abstract no. 1213:305.
Sheftel 1986 {published data only}
    1. Sheftel TG, Mader JT. Randomized evaluation of ceftazidime or ticarcillin and tobramycin for the treatment of osteomyelitis caused by gram‐negative bacilli. Antimicrobial Agents and Chemotherapy 1986;29(1):112‐5. - PMC - PubMed
Smith 1999 {published data only}
    1. Smith AL, Doershuk C, Goldmann D, Gore E, Hilman B, Marks M, et al. Comparison of a beta‐lactam alone versus beta‐lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis. Journal of Pediatrica 1999;134(4):413‐21. - PubMed
Solberg 1995 {published data only}
    1. Solberg CO, Sjursen H. Safety and efficacy of meropenem in patients with septicaemia: a randomised comparison with ceftazidime, alone or combined with amikacin. Journal of Antimicrobial Chemotherapy 1995;36(Suppl A):157‐66. - PubMed
Solomkin 1986 {published data only}
    1. Solomkin JS, Cocchetto DM. Ceftazidime versus tobramycin plus ticarcillin in the treatment of soft‐tissue infections. Clinical Therapeutics 1986;9(1):123‐34. - PubMed
Stack 1985 {published data only}
    1. Stack BHR, Geddes DM, Williams KJ, Dinwiddie R, Selkon JB, Godfrey RC, for the British Thoracic Society Research Committee. Ceftazidime compared with gentamicin and carbenicillin in patients with cystic fibrosis, pulmonary pseudomonas infection, and an exacerbation of respiratory symptoms. Thorax 1985;40(5):358‐63. - PMC - PubMed
Tally 1986 {published data only}
    1. Tally FP, Kellum JM, Ho JL, O'Donnell TF, Barza M, Gorbach SL. Randomized prospective study comparing moxalactam and cefoxitin with or without tobramycin for the treatment of serious surgical infections. Antimicrobial Agents and Chemotherapy 1986;29(2):244‐9. - PMC - PubMed
Thompson 1980 {published data only}
    1. Thompson SE, Hager WD, Wong KH, Lopez B, Ramsey C, Allen SD, et al. The microbiology and therapy of acute pelvic inflammatory disease in hospitalized patients. American Journal of Obstetrics & Gynecology 1980;136(2):179‐86. - PubMed
Vazquez 1994 {published data only}
    1. Vazquez Vela Sanchez G, Leon Zavala J, Ochoa Cozares M. Comparative study of two preventive antibiotic programs for treatment of open fractures [Estudio comparativo de dos esquemas de antibioticos para la prevencion de la infeccion en las fracturas expuestas]. Revista Mexicana de Trastornos Alimentarios 1994;8(5):263‐4.
Vetter 1987 {published data only}
    1. Vetter N, Feist H, Armbruster C, Drlicek M. Comparison of the effectiveness of ceftazidime and cefazolin/tobramycin in patients with inflammatory diseases of the lower respiratory tract. In German [Efficacy of ceftazidime and cefazolin/tobramycin in lower respiratory tract infections]. Infection 1987;15(Suppl 4):S192‐4. - PubMed
    1. Vetter N, Feist H, Muhar F, Williams KJ. A comparative study of the efficacy of ceftazidime versus cefazolin and tobramycin in patients with acute exacerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 1983;12(Suppl A):35‐9. - PubMed
Vetter 1992 {published data only}
    1. Vetter N. Efficacy of meropenem in the treatment of respiratory tract infection: a comparative evaluation. Journal of Chemotherapy. 1993; Vol. 5 Suppl 1.
    1. Vetter N. Efficacy of meropenem in the treatment of respiratory tract infection:a comparative evaluation. Proceedings of the Eighth Mediterranean Congress of Chemotherapy. 1992:175.
Watanakunakorn 1997 {published data only}
    1. Watanakunakorn C, Baird IM. Prognostic factors in Staphylococcus aureus endocarditis and results of therapy with a penicillin and gentamicin. The American Journal of Medical Sciences 1977;273(2):133‐9. - PubMed
Yildirim 2008 {published data only}
    1. Yildirim I, Aytac S, Ceyhan M, Cetin M, Tuncer M, Cengiz AB, et al. Piperacillin/tazobactam plus amikacin versus carbapenem monotherapy as empirical treatment of febrile neutropenia in childhood hematological malignancies. International Journal of Pediatric Hematology/Oncology 2008;25(4):291‐9. - PubMed

References to ongoing studies

Aziz 2012 {unpublished data only}
    1. Comparison of Ampicillin/Sulbactam vs. Ampicillin/Gentamicin for Treatment of Intrapartum Chorioamnionitis: a randomized controlled trial. NCT00879190 on ClinicalTrials.gov.

Additional references

Allan 1985
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References to other published versions of this review

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