Dataset Information

Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms.

ABSTRACT:

Background

Pneumonia and bloodstream infections (BSI) due to extensively drug-resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections.

Methods

The OVERCOME (Colistin Monotherapy versus Combination Therapy) trial was an international, randomized, double-blind, placebo-controlled trial. We randomly assigned participants to receive colistin (5 mg/kg once followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI caused by XDR A. baumannii, XDR P. aeruginosa, or CRE. The primary outcome was 28-day mortality, and secondary outcomes included clinical failure and microbiologic cure.

Results

Between 2012 and 2020, a total of 464 participants were randomly assigned to treatment, and 423 eligible patients comprised the modified intention-to-treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43 vs. 37%; P=0.17), clinical failure (65 vs. 58%; difference, 6.8 percentage points; 95% confidence interval [CI], -3.1 to 16.6), microbiologic cure (65 vs. 60%; difference, 4.8 percentage points; 95% CI, -5.6 to 15.2), or adverse events (acute kidney injury, 52 vs. 49% [P=0.55]; hypersensitivity reaction, 1 vs. 3% [P=0.22]; and neurotoxicity, 5 vs. 2% [P=0.29]) between patients receiving monotherapy and combination therapy, respectively.

Conclusions

Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI caused by these pathogens. (Funded by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases protocol 10-0065; ClinicalTrials.gov number, NCT01597973.).

SUBMITTER: Kaye KS

PROVIDER: S-EPMC10398788 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms.

Kaye Keith S KS Marchaim Dror D Thamlikitkul Visanu V Carmeli Yehuda Y Chiu Cheng-Hsun CH Daikos George G Dhar Sorabh S Durante-Mangoni Emanuele E Gikas Achilles A Kotanidou Anastasia A Paul Mical M Roilides Emmanuelle E Rybak Michael M Samarkos Michael M Sims Matthew M Tancheva Dora D Tsiodras Sotirios S Kett Daniel D Patel Gopi G Calfee David D Leibovici Leonard L Power Laura L Munoz-Price Sylvia S Stevenson Kurt K Susick Laura L Latack Katie K Daniel Jolene J Chiou Christine C Divine George W GW Ghazyaran Varduhi V Pogue Jason M JM

NEJM evidence 20221206 1

<h4>Background</h4>Pneumonia and bloodstream infections (BSI) due to extensively drug-resistant (XDR) <i>Acinetobacter baumannii</i>, XDR <i>Pseudomonas aeruginosa</i>, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections.<h4>Methods</h4>The OVERCOME (Colistin Monotherapy ...[more]

PMID: 37538951

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Project description:This research focused on evaluating the clinical results of patients suffering from pneumonia caused by carbapenem-resistant Klebsiella pneumoniae (CRKP), who received treatment with either ceftazidime-avibactam (CZA) alone or in combination with other antibiotics. From January 2020 to December 2023, we retrospectively analyzed CRKP-related pneumonia patients treated in two Chinese tertiary hospitals. Mortality was measured at 14 and 30 days as the primary outcome. Secondary outcomes included the 14-day microbiological cure rate and the 14-day clinical cure rate. Factors contributing to clinical failure were evaluated via both univariate analysis and multivariate logistic regression. To account for confounding factors, propensity score matching (PSM) was utilized. Among the 195 patients with CRKP infections, 103 (52.8 %) received CZA combination therapy, and 92 (47.2 %) patients received CZA monotherapy. The combination therapy group exhibited superior clinical and microbiological cure rates compared to the monotherapy group, with a 14-day clinical cure rate of 60.1 % vs. 45.7 % (P = 0.042) and a 14-day microbiological cure rate of 72.8 % vs. 58.6 % (P = 0.038), respectively. Combination therapy reduced mortality rates at 14 days (7.8 % vs. 17.4 %, P = 0.041), but not at 30 days (14.6 % vs. 25.0 %, P = 0.066). Even after using PSM, the group treated with the CZA combination continued to had a lower mortality rate at 14 days (5.9 % vs. 17.6 %, P = 0.039). The 14-day clinical cure rate for the combination therapy group was 63.2 %, and the 14-day microbial cure rate was 77.9 %. Both of these statistics were notably greater than those observed in the monotherapy group. Furthermore, the multivariate logistic regression model indicated a significant link between combination therapy and a decrease in clinical failure. Carbapenems were noted to be the most effective class of concomitant agents. Our findings indicate that patients with pneumonia due to CRKP benefit from combination treatment of CZA rather than monotherapy; administering carbapenem in combination with CZA in the early stages could provide considerable survival benefits.

Project description:BackgroundFor resistant Gram-positive bacteria, evidence suggests that combination therapy is more effective. However, for resistant Gram-negative bacteria, no consensus has been reached. This study aims to comprehensively summarize the evidence and evaluate the impact of combination versus monotherapy on infections caused by carbapenem-resistant Gram-negative bacteria (CRGNB).MethodsA systematic search was conducted in PubMed, Cochrane library, Web of Science, and Embase up to June 15, 2024, to identify relevant studies. This study included comparisons of monotherapy and combination therapy for treating infections caused by CRGNB. Topical antibiotics (i.e., inhalational or intratracheal administration) and monotherapy with sulbactam/relebactam was excluded. The primary outcome was mortality, and the secondary outcomes were clinical success and microbiological eradication. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated in order to systematically assess effect of treatment on mortality, clinical success and microbiological eradication. Subgroup analyses, publication bias tests, and sensitivity analyses were also performed.ResultsA total of 62 studies, including 8342 participants, were analyzed, comprising 7 randomized controlled trials and 55 non-randomized studies. Monotherapy was associated with higher mortality (OR = 1.29, 95%CI: 1.11-1.51), lower clinical success (OR = 0.74, 95%CI: 0.56-0.98), and lower microbiological eradication (OR = 0.71, 95%CI: 0.55-0.91) compared to combination therapy for CRGNB infections. Specifically, patients with carbapenem-resistant Enterobacteriaceae (CRE) infections receiving monotherapy had higher mortality (OR = 1.50, 95%CI: 1.15-1.95), comparable clinical success (OR = 0.57,95%CI: 0.28-1.16), and lower microbiological eradication (OR = 0.48,95%CI:0.25-0.91) than those receiving combination therapy. For carbapenem-resistant Acinetobacter baumannii (CRAB) infections, no significant differences were observed in mortality (OR = 1.15.95%CI: 0.90-1.47), clinical success (OR = 0.95,95%CI: 0.74-1.24) and microbiological eradication (OR = 0.78,95%CI: 0.54-1.12).ConclusionsMonotherapy or combination therapy is controversial. The systematic review and meta-analysis suggested that monotherapy is associated with higher mortality, lower clinical success, and lower microbiological eradication for treating infection caused by CRGNB. The available evidence suggests that treatment should be selected based on the specific bacteria and antibiotic used. Monotherapy for CRE infections may lead to adverse outcomes. For CRAB infections, no significant differences were found between combination therapy and monotherapy.Systematic review registrationPROSPERO CRD42022331861.

Project description:Carbapenem-resistant Acinetobacter baumannii (CRAB) is a Priority 1 (Critical) pathogen urgently requiring new antibiotics. Polymyxins are a last-line option against CRAB-associated infections. This transcriptomic study utilized a CRAB strain to investigate mechanisms of bacterial killing with polymyxin B, colistin, colistin B and colistin/sulbactam combination therapy. After 4 h of 2 mg/L polymyxin monotherapy, all polymyxins exhibited common modes of action which primarily involved disruption to amino acid and fatty acid metabolism. Of the three monotherapies, polymyxin B induced the greatest number of differentially expressed genes (DEGs), including for genes involved with fatty acid metabolism. Gene disturbances with colistin and colistin B were highly similar (89% common genes for colistin B), though effects on gene expression were generally lower (0-1.5-fold in most cases) with colistin B. Colistin alone (2 mg/L) or combined with sulbactam (64 mg/L) resulted in rapid membrane disruption as early as 1 h. Transcriptomic analysis of this combination revealed the effects were driven by colistin and included disturbances in fatty acid synthesis and catabolism and inhibition of nutrient uptake. Combination therapy produced substantially higher fold changes in 72% of DEGs shared with monotherapy, resulting in substantially greater reductions in fatty acid biosynthesis and increases in biofilm, cell wall and phospholipid synthesis. This indicates synergistic bacterial killing with the colistin/sulbactam combination results from a systematic increase in perturbation of many genes associated with bacterial metabolism. These mechanistic insights enhance our understanding of bacterial responses to polymyxin mono- and combination therapy and will assist to optimize polymyxin use in patients. Carbapenem-resistant Acinetobacter baumannii (CRAB) is a Priority 1 (Critical) pathogen urgently requiring new antibiotics. Polymyxins are a last-line option against CRAB-associated infections. This transcriptomic study utilized a CRAB strain to investigate mechanisms of bacterial killing with polymyxin B, colistin, colistin B and colistin/sulbactam combination therapy. After 4 h of 2 mg/L polymyxin monotherapy, all polymyxins exhibited common modes of action which primarily involved disruption to amino acid and fatty acid metabolism. Of the three monotherapies, polymyxin B induced the greatest number of differentially expressed genes (DEGs), including for genes involved with fatty acid metabolism. Gene disturbances with colistin and colistin B were highly similar (89% common genes for colistin B), though effects on gene expression were generally lower (0-1.5-fold in most cases) with colistin B. Colistin alone (2 mg/L) or combined with sulbactam (64 mg/L) resulted in rapid membrane disruption as early as 1 h. Transcriptomic analysis of this combination revealed the effects were driven by colistin and included disturbances in fatty acid synthesis and catabolism and inhibition of nutrient uptake. Combination therapy produced substantially higher fold changes in 72% of DEGs shared with monotherapy, resulting in substantially greater reductions in fatty acid biosynthesis and increases in biofilm, cell wall and phospholipid synthesis. This indicates synergistic bacterial killing with the colistin/sulbactam combination results from a systematic increase in perturbation of many genes associated with bacterial metabolism. These mechanistic insights enhance our understanding of bacterial responses to polymyxin mono- and combination therapy and will assist to optimize polymyxin use in patients.

Dataset Information

Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms.

Background

Methods

Results

Conclusions

Publications

Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms.

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