Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli

Scudeller, Luigia; Righi, Elda; Chiamenti, Margherita; Bragantini, Damiano; Menchinelli, Giulia; Cattaneo, Paolo; Giske, Christian G.; Lodise, Thomas P.; Sanguinetti, Maurizio; Piddock, Laura J. V.; Franceschi, François; Ellis, Sally; Carrara, Elena; Savoldi, Alessia; Tacconelli, Evelina

doi:10.1016/j.ijantimicag.2021.106344

Cited by 63 publications

(39 citation statements)

References 138 publications

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“…In this study, the combination of colistin plus fosfomycin did not result in synergy (20 % additive, 80 % indifference). This contrasts with a recent meta-analysis that suggested a 'moderate' rate of synergy based on eight pharmacokinetic/pharmacodynamic studies and two using time-kill methods in carbapenem resistant K. pneumoniae isolates [24]. This may reflect the different methodologies, and that our sample was mostly E. coli, but it is also unclear as to whether synergy is a phenomenon that is more likely to be identified in highly resistant isolates.…”

Section: Discussioncontrasting

confidence: 80%

Evaluation of in vitro activity of fosfomycin, and synergy in combination, in Gram-negative bloodstream infection isolates in a UK teaching hospital

Suich

Mawer

Woude

et al. 2022

Journal of Medical Microbiology

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Introduction. Fosfomycin has retained activity against many multi-drug resistant (MDR) Gram-negatives, and may be useful against extended spectrum beta-lactamase (ESBL) producing and carbapenem-resistant Enterobacterales to improve clinical outcomes. Hypothesis/Gap Statement. There are few data from the UK on the susceptibility of invasive Gram-negative isolates to fosfomycin, especially in the era of increasing use of oral fosfomycin for urinary tract infections (UTIs). Aim. We evaluated fosfomycin susceptibility against 100 consecutive Gram-negative bloodstream isolates, both individually, and in combination with other mechanistically similar and differing antibiotics. The aim was to investigate the synergy between antibiotic combinations against several E. coli, K. pneumoniae and P. aeruginosa isolates with variable levels of resistance. Methodology. Disc diffusion and MIC test strip methods applying revised EUCAST guidelines for Fosfomycin were used, followed by the MTS™ ‘cross synergy’ method for ‘resistant’ isolates as defined below: (a) Fosfomycin resistant by MIC test strip; (b) MDR isolates defined as being resistant to ≥3 classes of antibiotics (based on routine sensitivity testing; beta lactams were considered as a single class), and/or (c) AMP C or ESBL or carbapenemase producers (or carbapenem resistant). FIC Index (Fractional Inhibitory Concentration Index) calculations were used to interpret findings, whereby: FIC = (MICA combination A+B/ MIC agent A) + (MICB combination A+B/ MIC agent B). A result of ≤0.5 was taken to indicate ‘synergy’, >0.5 and ≤1.0 to indicate ‘additive’ effect, >1.0 and ≤4.0 to indicate ‘indifference’, and >4.0 to indicate ‘antagonism’. Results. We found that 95/100 isolates were susceptible to fosfomycin by MIC test strip, with 88/100 isolates susceptible to fosfomycin by disc, based on EUCAST guideline breakpoints. A total of 30/100 isolates (the more ‘resistant’ of the 100) were eligible for synergy testing according to our definitions (see Methodology), with the remaining 70 isolates not tested further. Seventeen out of 30 were MDR, 2/30 were AMP C producers and 9/30 were ESBL producers. Overall, 34/300 (11 %) of all combination tests showed synergy and 161/300 (54 %) were additive. Synergy was most commonly detected between fosfomycin and beta-lactam antibiotics, including piperacillin/tazobactam (10/30; 33 %), ceftazidime/avibactam (10/30; 30 %), and temocillin (8/30; 27 %). An additive effect was most commonly detected with aztreonam (25/30; 83 %) and meropenem (25/30; 83 %), but 100 % indifference was found with tigecycline (30/30). No antagonism was identified with any antibiotic combination. Conclusion. Fosfomycin non-susceptibility by MIC test strip was unusual. Synergy was variable when combining fosfomycin with other antibiotics against the more ‘resistant’ isolates. Synergistic/additive effects were detected for beta-lactam/fosfomycin combinations in >80 % of all such combinations, suggesting beta-lactams may be the preferred partner for fosfomycin. Agents with a discordant site of action were more likely to result in indifference. Antagonism was not detected.

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Section: Discussioncontrasting

confidence: 80%

Evaluation of in vitro activity of fosfomycin, and synergy in combination, in Gram-negative bloodstream infection isolates in a UK teaching hospital

Suich

Mawer

Woude

et al. 2022

Journal of Medical Microbiology

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“…This result corroborates other in vitro studies where synergistic/bactericidal activity has been demonstrated with polymyxin B-containing combinations. Synergy rates between 30 and 59% for K. pneumoniae have been reported, and polymyxins in combination with carbapenems have demonstrated bactericidal activity in several in vitro studies ( Zusman et al, 2013 ; Lenhard et al, 2016 ; Scudeller et al, 2021 ). The utility of polymyxin combinations has mechanistic plausibility.…”

Section: Discussionmentioning

confidence: 99%

In vitro Bactericidal Activities of Combination Antibiotic Therapies Against Carbapenem-Resistant Klebsiella pneumoniae With Different Carbapenemases and Sequence Types

Teo

Tan

et al. 2021

Front. Microbiol.

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Carbapenem-resistant Klebsiella pneumoniae (CRKP) is becoming increasingly problematic due to the limited effectiveness of new antimicrobials or other factors such as treatment cost. Thus, combination therapy remains a suitable treatment option. We aimed to evaluate the in vitro bactericidal activity of various antibiotic combinations against CRKP with different carbapenemase genotypes and sequence types (STs). Thirty-seven CRKP with various STs and carbapenemases were exposed to 11 antibiotic combinations (polymyxin B or tigecycline in combination with β-lactams including aztreonam, cefepime, piperacillin/tazobactam, doripenem, meropenem, and polymyxin B with tigecycline) in static time-kill studies (TKS) using clinically achievable concentrations. Out of the 407 isolate-combination pairs, only 146 (35.8%) were bactericidal (≥3 log10CFU/mL decrease from initial inoculum). Polymyxin B in combination with doripenem, meropenem, or cefepime was the most active, each demonstrating bactericidal activity in 27, 24, and 24 out of 37 isolates, respectively. Tigecycline in combination with β-lactams was rarely bactericidal. Aside from the lower frequency of bactericidal activity in the dual-carbapenemase producers, there was no apparent difference in combination activity among the strains with other carbapenemase types. In addition, bactericidal combinations were varied even in strains with similar STs, carbapenemases, and other genomic characteristics. Our findings demonstrate that the bactericidal activity of antibiotic combinations is highly strain-specific likely owing to the complex interplay of carbapenem-resistance mechanisms, i.e., carbapenemase genotype alone cannot predict in vitro bactericidal activity. The availability of WGS information can help rationalize the activity of certain combinations. Further studies should explore the use of genomic markers with phenotypic information to predict combination activity.

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“…One approach that has been taken to improve treatment outcomes with daptomycin or polymyxin antibiotics is to use them in combination with other antibiotics. This is supported by in vitro assays showing that both classes of antibiotic synergize with several other antibiotics [207, 208].…”

Section: Polymyxins and Daptomycin Synergize With Several Other Antib...mentioning

confidence: 92%

Polymyxin and lipopeptide antibiotics: membrane-targeting drugs of last resort

Ledger

Sabnis

2022

Microbiology

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The polymyxin and lipopeptide classes of antibiotics are membrane-targeting drugs of last resort used to treat infections caused by multi-drug-resistant pathogens. Despite similar structures, these two antibiotic classes have distinct modes of action and clinical uses. The polymyxins target lipopolysaccharide in the membranes of most Gram-negative species and are often used to treat infections caused by carbapenem-resistant species such as Escherichia coli , Acinetobacter baumannii and Pseudomonas aeruginosa . By contrast, the lipopeptide daptomycin requires membrane phosphatidylglycerol for activity and is only used to treat infections caused by drug-resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. However, despite having distinct targets, both antibiotic classes cause membrane disruption, are potently bactericidal in vitro and share similarities in resistance mechanisms. Furthermore, there are concerns about the efficacy of these antibiotics, and there is increasing interest in using both polymyxins and daptomycin in combination therapies to improve patient outcomes. In this review article, we will explore what is known about these distinct but structurally similar classes of antibiotics, discuss recent advances in the field and highlight remaining gaps in our knowledge.

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Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli

Cited by 63 publications

References 138 publications

Evaluation of in vitro activity of fosfomycin, and synergy in combination, in Gram-negative bloodstream infection isolates in a UK teaching hospital

Evaluation of in vitro activity of fosfomycin, and synergy in combination, in Gram-negative bloodstream infection isolates in a UK teaching hospital

In vitro Bactericidal Activities of Combination Antibiotic Therapies Against Carbapenem-Resistant Klebsiella pneumoniae With Different Carbapenemases and Sequence Types

Polymyxin and lipopeptide antibiotics: membrane-targeting drugs of last resort

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