Clinical management of severe infections caused by carbapenem-resistant gram-negative bacteria: a worldwide cross-sectional survey addressing the use of antibiotic combinations

Carrara, Elena; Savoldi, Alessia; Piddock, L. J. V.; Franceschi, François; Sharland, Mike; Brink, Adrian; Harris, Patrick N A; Levy-Hara, Gabriel; Rohit, Anusha; Tsioutis, Constantinos; Zayyad, Hiba; Giske, Christian G.; Chiamenti, Margherita; Bragantini, Damiano; Righi, Elda; Górska, Anna; Tacconelli, Evelina

doi:10.1016/j.cmi.2021.05.002

Cited by 12 publications

(7 citation statements)

References 26 publications

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“…Carbapenem-resistant bacteria typically display a multidrug-resistant phenotype and are associated with prolonged hospitalization and high mortality rates [ 1 , 2 , 3 ]. Combination therapy is often employed for these infections to enhance the activity of available antibiotics and improve patient outcomes [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48- and NDM-Producing Escherichia coli and Klebsiella pneumoniae

et al. 2022

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Double-carbapenem combinations have shown synergistic potential against carbapenemase-producing Enterobacterales, but data remain inconclusive. This study evaluated the activity of double-carbapenem combinations against 51 clinical KPC-2-, OXA-48-, NDM-1, and NDM-5-producing Escherichia coli and Klebsiella pneumoniae and against constructed E. coli strains harboring genes encoding KPC-2, OXA-48, or NDM-1 in an otherwise isogenic background. Two-drug combinations of ertapenem, meropenem, and doripenem were evaluated in 24 h time-lapse microscopy experiments with a subsequent spot assay and in static time-kill experiments. An enhanced effect in time-lapse microscopy experiments at 24 h and synergy in the spot assay was detected with one or more combinations against 4/14 KPC-2-, 17/17 OXA-48-, 2/17 NDM-, and 1/3 NDM-1+OXA-48-producing clinical isolates. Synergy rates were higher against meropenem- and doripenem-susceptible isolates and against OXA-48 producers. NDM production was associated with significantly lower synergy rates in E. coli. In time-kill experiments with constructed KPC-2-, OXA-48- and NDM-1-producing E. coli, 24 h synergy was not observed; however, synergy at earlier time points was found against the KPC-2- and OXA-48-producing constructs. Our findings indicate that the benefit of double-carbapenem combinations against carbapenemase-producing E. coli and K. pneumoniae is limited, especially against isolates that are resistant to the constituent antibiotics and produce NDM.

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Section: Introductionmentioning

confidence: 99%

Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48- and NDM-Producing Escherichia coli and Klebsiella pneumoniae

et al. 2022

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“…Meropenem and piperacillin-tazobactam are frequently used as empiric therapy for patients with suspected extended-spectrum beta-lactamase infection [33,34], and this explains the high rate of usage of these antibiotics in patients with infection caused by CR-GNB. In practice, clinicians prefer to use combination antibiotic therapy for treatment of CR-GNB infections [4,35]. However, there is limited evidence to support the use of combination therapy.…”

Section: Discussionmentioning

confidence: 99%

Treatments and Predictors of Mortality for Carbapenem-Resistant Gram-Negative Bacilli Infections in Malaysia: A Retrospective Cohort Study

et al. 2022

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This study evaluated the treatments, mortality rate and patient-related factors associated with mortality. This is a retrospective study involving hospitalised patients with infections caused by carbapenem-resistant Gram-negative bacilli (CR-GNB) in a tertiary hospital in Malaysia from January 2018 to June 2020. A clinical pharmacist reviewed patients’ electronic records and collected the data according to a pre-designed form. Data were analysed using both descriptive and inferential tests. The study included 145 patients with CR-GNB infections including 77, 40 and 28 Acinetobacter baumannii, enterobacteriaceae and Pseudomonas aeruginosa, respectively. The mean age was 57.9 ± 15.8 years. Pneumonia (40.7%) and bacteremia (25.5%) were the most common infections. Meropenem (24.7%) and piperacillin-tazobactam (20.4%) were the most commonly used empiric antibiotics while colistin (63.3%) and amikacin (8.3%) were the most common definitive antibiotics. The mean duration before active antibiotics was 4.6 ± 3.3 days. Overall, the in-hospital mortality rate was 41.4%. Multivariate logistic regression analysis showed that intensive care unit (ICU) admission (adjusted odds ratio (AOR): 5.201; 95% confidence interval (CI): 1.603–16.872; p = 0.006), sepsis/septic shock (AOR: 3.430; 95% CI: 1.021–11.522; p = 0.049) and elevated serum creatinine (AOR: 2.752; 95% CI: 1.005–7.536; p = 0.049) were independently associated with mortality. The mortality rate among patients with CR-GNB infection is high. A high rate of inappropriate antibiotic use was observed, including combination antibiotic therapy and delays in starting active antibiotics. Mortality was significantly associated with ICU admission, sepsis/septic shock and elevated serum creatinine.

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“… 2 , 3 Combination therapy is frequently prescribed to enhance the activity of the available antibiotics and improve patient outcomes. 4 Polymyxin B and E (colistin) have been widely used and recommended as part of combination therapy including a second in vitro active antibiotic. 3 , 5 In practice, polymyxin-based combinations remain last-resort treatments in cases where newer antibiotics (e.g.…”

Section: Introductionmentioning

confidence: 99%

Synergy of polymyxin B and minocycline against KPC-3- and OXA-48-producing Klebsiella pneumoniae in dynamic time–kill experiments: agreement with in silico predictions

Olsson,

Malmberg,

Zhao

et al. 2023

Journal of Antimicrobial Chemotherapy

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Objectives Combination therapy is often used for carbapenem-resistant Gram-negative bacteria. We previously demonstrated synergy of polymyxin B and minocycline against carbapenem-resistant Klebsiella pneumoniae in static time–kill experiments and developed an in silico pharmacokinetic/pharmacodynamic (PK/PD) model. The present study assessed the synergistic potential of this antibiotic combination in dynamic experiments. Methods Two clinical K. pneumoniae isolates producing KPC-3 and OXA-48 (polymyxin B MICs 0.5 and 8 mg/L, and minocycline MICs 1 and 8 mg/L, respectively) were included. Activities of the single drugs and the combination were assessed in 72 h dynamic time–kill experiments mimicking patient pharmacokinetics. Population analysis was performed every 12 h using plates containing antibiotics at 4× and 8× MIC. WGS was applied to reveal resistance genes and mutations. Results The combination showed synergistic and bactericidal effects against the KPC-3-producing strain from 12 h onwards. Subpopulations with decreased susceptibility to polymyxin B were frequently detected after single-drug exposures but not with the combination. Against the OXA-48-producing strain, synergy was observed between 4 and 8 h and was followed by regrowth. Subpopulations with decreased susceptibility to polymyxin B and minocycline were detected throughout experiments. For both strains, the observed antibacterial activities showed overall agreement with the in silico predictions. Conclusions Polymyxin B and minocycline in combination showed synergistic effects, mainly against the KPC-3-producing K. pneumoniae. The agreement between the experimental results and in silico predictions supports the use of PK/PD models based on static time–kill data to predict the activity of antibiotic combinations at dynamic drug concentrations.

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Clinical management of severe infections caused by carbapenem-resistant gram-negative bacteria: a worldwide cross-sectional survey addressing the use of antibiotic combinations

Cited by 12 publications

References 26 publications

Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48- and NDM-Producing Escherichia coli and Klebsiella pneumoniae

Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48- and NDM-Producing Escherichia coli and Klebsiella pneumoniae

Treatments and Predictors of Mortality for Carbapenem-Resistant Gram-Negative Bacilli Infections in Malaysia: A Retrospective Cohort Study

Synergy of polymyxin B and minocycline against KPC-3- and OXA-48-producing Klebsiella pneumoniae in dynamic time–kill experiments: agreement with in silico predictions

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