Polymyxin Monotherapy vs. Combination Therapy for the Treatment of Multidrug-resistant Infections: A Systematic Review and Meta-analysis

Abstract

A bstract Objectives The objective of this review was to compare the effectiveness of Colistin monotherapy and combination therapy for the treatment of multidrug-resistant gram-negative bacterial infections. Data sources PubMed, Cochrane Library. Study eligibility, interventions, and exclusions In this systematic review, we included all retrospective and prospective studies and randomized controlled trials (RCTs) that compared intravenous polymyxin monotherapy and combination therapy with any other antibiotic for treating multidrug-resistant infections. Studies using inhaled polymyxins with 5 or less than 5 patients were excluded. The primary outcome was 30-day all-cause mortality and if not reported at day 30 we extracted and documented the closest time point. Both crude outcome rates and adjusted effect estimates were extracted for mortality. Study appraisal, data extraction and synthesis Search string used was “(Colistin OR polymyxin) AND ( Enterobacteriaceae OR Klebsiella OR Acinetobacter OR Escherichia coli OR Pseudomonas ) AND (random OR prospective OR retrospective OR cohort OR observational OR blind).” Thirty-nine studies were included in our analysis; out of which 6 RCTs were included and 9 studies used carbapenem as the adjunctive antibiotic. Each study was screened and reviewed for eligibility independently by two authors and data extrapolated on an Excel sheet. Results The meta-analysis of polymyxin monotherapy vs. combination therapy in multidrug-resistant infections yielded an odds ratio (OR) of 0.81 (95% confidence interval [CI]: 0.65–1.01) with minimal heterogeneity ( I 2 = 40%), whereas pooled analysis of this comparison in studies that included carbapenem as combination therapy yielded an OR of 0.64 (CI: 0.40–1.03; I 2 = 62%). Likewise, the pooled analysis of the RCTs yielded an OR of 0.82 (95% CI: 0.58–1.16, I 2 = 22%). All these showed no statistical significance. However, it was seen that polymyxin combination therapy was more effective in multidrug-resistant infections compared to polymyxin monotherapy. The effectiveness was more glaring when carbapenems were used as the combination drug instead of any other antibiotic and more so in many in vitro studies that used polymyxin combination therapy. Conclusion Although statistically insignificant, it would be prudent to use polymyxin combination therapy to treat multidrug-resistant gram-negative bacilli (GNB) infection over monotherapy with preference to use carbapenem as the adjunct alongside polymyxins. How to cite this article Samal S, Mishra SB, Pat...

Efficacy and safety of ceftazidime–avibactam versus polymyxins in the treatment of carbapenem-resistant Enterobacteriaceae infection: a systematic review and meta-analysis

“…Given the heterogeneously resistant nature of polymyxins, the combination administration is recommended as the first-line treatment. However, a recent meta-analysis did not observe an advantage of polymyxins combination therapy on multidrug-resistant gram-negative bacterial infections 30. In addition, another meta-analysis suggested that CAZ-AVI in monotherapy or combination therapy for CRE infections demonstrated similar effect on mortality and microbiological cure rates 31.…”

“…However, a recent meta-analysis did not observe an advantage of polymyxins combination therapy on multidrug-resistant gram-negative bacterial infections. 30 In addition, another meta-analysis suggested that CAZ-AVI in monotherapy or combination therapy for CRE infections demonstrated similar effect on mortality and microbiological cure rates. 31 Therefore, both combined and single-drug regimens were included in our meta-analysis.…”

Antimicrobial Drug–Drug Interactions in the Treatment of Infectious Keratitis

“…Combination antimicrobial therapy can afford multiple advantages in the clinical care of patients including providing broad coverage in cases of diagnostic uncertainty, as well as potentially improved efficacy against drug-resistant organisms due to bacterial killing from multiple mechanisms of action. 11,[27][28][29] This therapeutic strategy extends well-beyond ophthalmology and has been widely used to treat a variety of diseases including gastrointestinal infections, HIV, and TB. [30][31][32] Moreover, antibiotic combination therapy is part of management guidelines for several severe infectious diseases such as hospital-acquired, ventilator-associated, and health care-associated pneumonia 33 as well as sepsis and septic shock.…”

Efficacy of Combination Therapies for the Treatment of Multi-Drug Resistant Gram-Negative Bacterial Infections Based on Meta-Analyses

“…Samal et al [22] performed a meta-analysis with similar eligibility criteria as the previously mentioned study [21]. This study included seventeen prospective studies (6 RCTs) and twenty-two retrospective studies.…”

“…Therefore, we comprehensively summarize published meta-analyses and illustrate the significance and feature of combination therapy as a therapeutic option against MDR pathogens. Table 1 shows a list of studies that reported meta-analyses of antibiotic combinations [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24].…”