Effect of Aminoglycoside and β‐Lactam Combination Therapy versus β‐Lactam Monotherapy on the Emergence of Antimicrobial Resistance: A Meta‐analysis of Randomized, Controlled Trials

Bliziotis, Ioannis A.; Samonis, George; Vardakas, Konstantinos Z.; Chrysanthopoulou, Stavroula A.; Falagas, Matthew E.

doi:10.1086/430912

Cited by 198 publications

(105 citation statements)

References 69 publications

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“…Evidence derived from clinical and in vitro studies reveals that a combination of antibiotics might prevent the emergence of resistant strains during therapy (39,40). However, clinical data do not clearly support the idea that antibiotic combinations reduce the emergence of resistance (41). Synergy is another potential benefit arising from the use of antibiotic combinations (42)(43)(44), but in vitro synergy of specific antibiotics may not always translate into clinical effectiveness.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, there is clinical evidence suggesting that the tigecycline-colistin combination may be superior to colistin monotherapy in terms of emergence of colistin resistance during therapy for infection due to carbapenem-resistant K. pneumoniae (39). In contrast, a meta-analysis focusing on beta-lactams showed that a beta-lactam combined with an aminoglycoside was not superior to beta-lactam monotherapy with regard to emergence of resistance (41). Administration of colistin in combination with an aminoglycoside has also been reported (11,14,16,25); however, attention should be paid during therapy since both agents can cause nephrotoxicity.…”

Section: Discussionmentioning

confidence: 99%

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Antibiotic Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae: Systematic Evaluation of the Available Evidence

Falagas

Lourida

Poulikakos

et al. 2014

Antimicrob Agents Chemother

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321

216

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We sought to evaluate the effectiveness of the antibiotic treatment administered for infections caused by carbapenemase-producing Enterobacteriaceae. The PubMed and Scopus databases were systematically searched. Articles reporting the clinical outcomes of patients infected with carbapenemase-producing Enterobacteriaceae according to the antibiotic treatment administered were eligible. Twenty nonrandomized studies comprising 692 patients who received definitive treatment were included. Almost all studies reported on Klebsiella spp. In 8 studies, the majority of infections were bacteremia, while pneumonia and urinary tract infections were the most common infections in 12 studies. In 10 studies, the majority of patients were critically ill. There are methodological issues, including clinical heterogeneity, that preclude the synthesis of the available evidence using statistical analyses, including meta-analysis. From the descriptive point of view, among patients who received combination treatment, mortality was up to 50% for the tigecycline-gentamicin combination, up to 64% for tigecycline-colistin, and up to 67% for carbapenem-colistin. Among the monotherapy-treated patients, mortality was up to 57% for colistin and up to 80% for tigecycline. Certain regimens were administered to a small number of patients in certain studies. Three studies reporting on 194 critically ill patients with bacteremia showed individually significantly lower mortality in the combination arm than in the monotherapy arm. In the other studies, no significant difference in mortality was recorded between the compared groups. Combination antibiotic treatment may be considered the optimal option for severely ill patients with severe infections. However, well-designed randomized studies of specific patient populations are needed to further clarify this issue.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antibiotic Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae: Systematic Evaluation of the Available Evidence

Falagas

Lourida

Poulikakos

et al. 2014

Antimicrob Agents Chemother

Self Cite

321

216

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“…A meta-analysis of 8 randomized, controlled trials comparing ␤-lactam monotherapy with ␤-lactam and aminoglycoside combination therapy was conducted, with the primary outcome of emergence of resistance and a secondary outcome of the development of a superinfection (23). Antimicrobial-resistant organisms were defined as bacterial isolates that became resistant to the administered drug during therapy with a change from "susceptible" to "intermediate" or "resistant" or from "intermediate" to "resistant."…”

Section: Prevention Of Resistancementioning

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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“…Such interactions between drugs are classified as additive, synergistic, or antagonistic depending on whether their combined effect on bacterial growth is equal to, greater than, or less than expected based on the inhibitory abilities of the individual drugs (8,9). Two main goals of drug treatment are stopping bacterial growth and preventing the evolution of drug resistance (5,(10)(11)(12). Although synergistically interacting drugs are often favored because of their greater combined ability to inhibit growth (13), little direct evidence for their ability to suppress the evolution of resistance exists, and some studies even suggest the contrary (14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

Accelerated evolution of resistance in multidrug environments

Hegreness

Shoresh

Damian

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

276

329

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The emergence of resistance during multidrug chemotherapy impedes the treatment of many human diseases, including malaria, TB, HIV, and cancer. Although certain combination therapies have long been known to be more effective in curing patients than single drugs, the impact of such treatments on the evolution of drug resistance is unclear. In particular, very little is known about how the evolution of resistance is affected by the nature of the interactions-synergy or antagonism-between drugs. Here we directly measure the effect of various inhibitory and subinhibitory drug combinations on the rate of adaptation. We develop an automated assay for monitoring the parallel evolution of hundreds of Escherchia coli populations in a two-dimensional grid of drug gradients over many generations. We find a correlation between synergy and the rate of adaptation, whereby evolution in more synergistic drug combinations, typically preferred in clinical settings, is faster than evolution in antagonistic combinations. We also find that resistance to some synergistic combinations evolves faster than resistance to individual drugs. The accelerated evolution may be due to a larger selective advantage for resistance mutations in synergistic treatments. We describe a simple geometric model in which mutations conferring resistance to one drug of a synergistic pair prevent not only the inhibitory effect of that drug but also its enhancing effect on the other drug. Future study of the profound impact that synergy and other drug-pair properties can have on the rate of adaptation may suggest new treatment strategies for combating the spread of antibiotic resistance.adaptation ͉ antagonism ͉ synergy ͉ antibiotics ͉ antibiotic resistance

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Effect of Aminoglycoside and β‐Lactam Combination Therapy versus β‐Lactam Monotherapy on the Emergence of Antimicrobial Resistance: A Meta‐analysis of Randomized, Controlled Trials

Abstract: Compared with beta-lactam monotherapy, the aminoglycoside/ beta-lactam combination was not associated with a beneficial effect on the development of antimicrobial resistance among initially antimicrobial-susceptible isolates.

Cited by 198 publications

References 69 publications

Antibiotic Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae: Systematic Evaluation of the Available Evidence

Antibiotic Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae: Systematic Evaluation of the Available Evidence

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

Accelerated evolution of resistance in multidrug environments

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