Clinical implications of β-lactam–aminoglycoside synergism: systematic review of randomised trials

Marcus, Ronit; Paul, Mical; Elphick, Heather; Leibovici, Leonard

doi:10.1016/j.ijantimicag.2010.11.029

Cited by 68 publications

(36 citation statements)

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“…Indeed, with beta-lactam-aminoglycoside combination therapy, despite strong in vitro data showing synergy and prevention of resistance development with combination therapy against Gram-negative bacteria, clinical studies could not show a benefit for combination therapy. Systematic reviews of randomized, controlled trials of neutropenic and nonneutropenic patients with sepsis showed no advantage of combination therapy with regard to survival or resistance development as assessed by superinfections (24)(25)(26)(27). Of note, since EUCAST and CLSI criteria differ, synergy rates described for the carbapenem-resistant, colistinsusceptible group may not be applicable in instances where CLSI breakpoints are used.…”

Section: Discussionmentioning

confidence: 99%

Systematic Review and Meta-Analysis of In Vitro Synergy of Polymyxins and Carbapenems

Zusman

Avni

Leibovici

et al. 2013

Antimicrob Agents Chemother

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170

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e Our objective was to examine the evidence of in vitro synergy of polymyxin-carbapenem combination therapy against Gramnegative bacteria (GNB). A systematic review and meta-analysis were performed. All studies examining in vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB were used. A broad search was conducted with no language, date, or publication status restrictions. Synergy rates, defined as a fractional inhibitory concentration index of <0.5 or a >2-log reduction in CFU, were pooled separately for time-kill, checkerboard, and Etest methods in a mixed-effect meta-analysis of rates. We examined whether the synergy rate depended on the testing method, type of antibiotic, bacteria, and resistance to carbapenems. Pooled rates with 95% confidence intervals (CI) are shown. Thirty-nine published studies and 15 conference proceeding were included, reporting on 246 different tests on 1,054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI, 64 to 87%) for Acinetobacter baumannii, 44% (95% CI, 30 to 59%) for Klebsiella pneumoniae, and 50% (95% CI, 30 to 69%) for Pseudomonas aeruginosa, with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii, meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill studies. The use of combination therapy led to less resistance development in vitro. The combination of a carbapenem with a polymyxin against GNB, especially A. baumannii, is supported in vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies.

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Section: Discussionmentioning

confidence: 99%

Systematic Review and Meta-Analysis of In Vitro Synergy of Polymyxins and Carbapenems

Zusman

Avni

Leibovici

et al. 2013

Antimicrob Agents Chemother

Self Cite

218

170

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“…As there have been a number of studies conducted to assess the appropriateness of combination therapy for infections caused by Gram-negative organisms, several meta-analyses have been compiled to summarize these data (Table 1) (23,67,68,80,161,194,(196)(197)(198)(199)212). In general, meta-analyses of observational studies have shown a benefit of combination therapy, while those including RCTs have not demonstrated such a benefit (161).…”

Section: Meta-analysesmentioning

confidence: 99%

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

2012

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SUMMARY Combination antibiotic therapy for invasive infections with Gram-negative bacteria is employed in many health care facilities, especially for certain subgroups of patients, including those with neutropenia, those with infections caused by Pseudomonas aeruginosa , those with ventilator-associated pneumonia, and the severely ill. An argument can be made for empiric combination therapy, as we are witnessing a rise in infections caused by multidrug-resistant Gram-negative organisms. The wisdom of continued combination therapy after an organism is isolated and antimicrobial susceptibility data are known, however, is more controversial. The available evidence suggests that the greatest benefit of combination antibiotic therapy stems from the increased likelihood of choosing an effective agent during empiric therapy, rather than exploitation of in vitro synergy or the prevention of resistance during definitive treatment. In this review, we summarize the available data comparing monotherapy versus combination antimicrobial therapy for the treatment of infections with Gram-negative bacteria.

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“…Empirical antibiotic treatments including AGs could be more appropriate in up to 15 to 20% of cases than a ␤-lactam alone (5,6). In the ICU setting, modifications of the empirical antibiotic treatment or the addition of a new antibiotic occurs less frequently after bitherapy including an AG than after monotherapy (7).…”

mentioning

confidence: 99%

Propensity-Based Study of Aminoglycoside Nephrotoxicity in Patients with Severe Sepsis or Septic Shock

Picard

Bazin

Clouzeau

et al. 2014

Antimicrob Agents Chemother

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cTo assess the risk of acute kidney injury (AKI) attributable to aminoglycosides (AGs) in patients with severe sepsis or septic shock, we performed a retrospective cohort study in one medical intensive care unit (ICU) in France. Patients admitted for severe sepsis/septic shock between November 2008 and January 2010 were eligible. A propensity score for AG administration was built using day 1 demographic and clinical characteristics. Patients still on the ICU on day 3 were included. Patients with renal failure before day 3 or endocarditis were excluded. The time window for assessment of renal risk was day 3 to day 15, defined according to the RIFLE (risk, injury, failure, loss, and end-stage renal disease) classification. The AKI risk was assessed by means of a propensity-adjusted Cox proportional hazards regression analysis. Of 317 consecutive patients, 198 received AGs. The SAPS II (simplified acute physiology score II) score and nosocomial origin of infection favored the use of AGs, whereas a preexisting renal insufficiency and the neurological site of infection decreased the propensity for AG treatment. One hundred three patients with renal failure before day 3 were excluded. AGs were given once daily over 2.6 ؎ 1.1 days. AKI occurred in 16.3% of patients in a median time of 6 (interquartile range, 5 to 10) days. After adjustment to the clinical course and exposure to other nephrotoxic agents between day 1 and day 3, a propensity-adjusted Cox proportional hazards regression analysis showed no increased risk of AKI in patients receiving AGs (adjusted relative risk ‫؍‬ 0.75 [0.32 to 1.76]). In conclusion, in critically septic patients presenting without early renal failure, aminoglycoside therapy for less than 3 days was not associated with an increased risk of AKI.A minoglycosides (AGs) have bactericidal activity, which has been proven to be synergic with that of ␤-lactams. Although adding an AG to a standard antibiotic treatment did not translate into a reduction of mortality in Gram-negative-bacterial sepsis in subgroups of patients with globally moderate degrees of severity (1), a decrease in mortality was recently reported in a meta-analysis comparing a bitherapy to therapy with a ␤-lactam alone for patients with septic shock (2). In addition, AGs widen the spectrum of the antibiotic treatment, which should be advantageous in populations with an increased risk of resistant bacteria, such as intensive care unit (ICU) patients (3, 4). Empirical antibiotic treatments including AGs could be more appropriate in up to 15 to 20% of cases than a ␤-lactam alone (5, 6). In the ICU setting, modifications of the empirical antibiotic treatment or the addition of a new antibiotic occurs less frequently after bitherapy including an AG than after monotherapy (7).Unfortunately, nephrotoxicity is an important potential limitation of AGs. There is a consensus that AG-related nephrotoxicity has decreased over the years due to better consideration of both reduced duration of treatment and once-daily administration (8). However...

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Clinical implications of β-lactam–aminoglycoside synergism: systematic review of randomised trials

Cited by 68 publications

References 100 publications

Systematic Review and Meta-Analysis of In Vitro Synergy of Polymyxins and Carbapenems

Systematic Review and Meta-Analysis of In Vitro Synergy of Polymyxins and Carbapenems

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

Propensity-Based Study of Aminoglycoside Nephrotoxicity in Patients with Severe Sepsis or Septic Shock

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