Combination antibiotic therapy for multidrug-resistant Gram-negative bacteria

Abstract

Combination antibiotic therapy for Gram-negative sepsis is controversial. The present review provides a brief summary of the existing knowledge on combination therapy for severe infections with multidrug-resistant Pseudomonas spp., Acinetobacter spp., and Enterobacteriaceae. Empirical combination antibiotic therapy is recommended for severe sepsis and septic shock to reduce mortality related to inappropriate antibiotic treatment. Because definitive combination therapy has not been proven superior to monotherapy in meta-analyses, it is generally advised to de-escalate antibiotic therapy when the antibiotic susceptibility profile is known, although it cannot be excluded that some subgroups of patients might still benefit from continued combination therapy. Definitive combination therapy is recommended for carbapenemase-producing Enterobacteriaceae and should also be considered for severe infections with Pseudomonas and Acinetobacter spp. when beta-lactams cannot be used. Because resistance to broad-spectrum beta-lactams is increasing in Gram-negative bacteria and because no new antibiotics are expected to become available in the near future, the antibacterial potential of combination therapy should be further explored. In vitro data suggest that combinations can be effective even if the bacteria are resistant to the individual antibiotics, although existing evidence is insufficient to support the choice of combinations and explain the synergistic effects observed. In vitro models can be used to screen for effective combinations that can later be validated in animal or clinical studies. Further, in the absence of clinical evidence, in vitro data might be useful in supporting therapeutic decisions for severe infections with multidrug-resistant Gram-negative bacteria.

Acinetobacter baumannii: biology and drug resistance — role of carbapenemases

“…In the recent study, a combination of meropenem with minocycline was synergistic to tested XDR (extensively drug-resistant) A. baumannii isolates, but neither showed bactericidal activity alone. Furthermore, the authors observed that also colistin and meropenem presented synergistic effect and showed bactericidal activity against all tested strains [54,55].…”

Colistin-Resistant Klebsiella pneumoniae: Prevalence of Integrons and Synergistic Out Turn for Colistin-Meropenem

“…Antibiotic combinations of colistin plus rifampin (23), ertapenem plus doripenem (27), tigecycline plus colistin, fosfomycin plus meropenem, and colistin plus carbapenem (imipenem, meropenem) were extensively studied against colistin resistant Klebsiella pneumoniae. Combinations of colistin-carbapenem or an aminoglycoside, tigecycline, fosfomycin, and rifampin have been advocated for carbapenemase-producing Klebsiella species (28)(29)(30)(31)(32). In addition, 3 drug combinations were also assessed to have benefited imipenem plus tigecycline in combination with amikacin showed bactericidal activity (23,33).…”

“…Our data showed that the synergistic effect of colistin-meropenem by checkerboard method was 86% (21/24) and by the timekill studies were 76% (16/21). In modified time-kill analysis, our aim was to expose the isolates initially with colistin and the later addition of meropenem at different time intervals, which allows colistin to disrupt the outer cell membrane making easy permeability of carbapenem (30,31). Depending on the mechanisms of action, both colistin and meropenem in combination can act as a bactericidal (33,34).…”

In vitro assessment of cefoperazone-sulbactam based combination therapy for multidrug-resistant Acinetobacter baumannii isolates in China

“…However, emergence of resistance to these antimicrobial agents has also been reported (8). Notwithstanding, combination therapy has been considered superior to single-drug therapy against MDRAB, with regards to both efficacy and lower risk of adverse reactions and drug toxicity (9)(10)(11). Tigecycline based therapy with various combinations such as cefoperazone-sulbactam, carbapenem, quinolone, or aminoglycoside antibiotics, has been adopted for treatment of MDRAB infections (12,13).…”