Polymyxin B in Combination with Antimicrobials Lacking In Vitro Activity versus Polymyxin B in Monotherapy in Critically Ill Patients with Acinetobacter baumannii or Pseudomonas aeruginosa Infections

Abstract

There is no clinical evidence supporting the use of polymyxin B in combination with another antimicrobial for infections caused by extensively drug-resistant Acinetobacter baumannii or Pseudomonas aeruginosa isolates. We developed a cohort study of patients in two intensive care units from teaching hospitals to evaluate treatment with intravenous polymyxin B for >48 h for severe A. baumannii or P. aeruginosa infections. Covariates potentially associated with 30-day mortality were evaluated in a Cox proportional hazards model. A total of 101 patients were included; 33 (32.7%) were treated with polymyxin B in combination with an antimicrobial lacking in vitro activity and 68 (67.3%) with polymyxin B in monotherapy. The overall 30-day mortality was 59.4% (60 patients), comprising 42.4% (14 of 33) and 67.6% (46 of 68) in combination and monotherapy groups, respectively (P ‫؍‬ 0.03). The mortality rates were 18.5/1,000 patient days and 36.4/1,000 patient days in the combination and monotherapy groups, respectively (P ‫؍‬ 0.02). Combination therapy was independently associated with lower 30-day mortality (hazard ratio, 0.33; 95% confidence interval, 0.17 to 0.64; P ‫؍‬ 0.001). Creatinine clearance of >60 ml/min was also a protective factor, while a higher acute physiology and chronic health evaluation (APACHE II) score and polymicrobial infection were associated with increased mortality. The results did not change after adding a propensity score for prescribing combination therapy into the model. The protective effect remained when only combination with ␤-lactam or carbapenem was considered and in both subgroups of patients: those with A. baumannii infection and those with lower respiratory tract infections. To our knowledge, this is the first clinical study to show a benefit of combination over monotherapy with polymyxin B for severe extensively drugresistant A. baumannii or P. aeruginosa infections.T he emergence of carbapenem-resistant Gram-negative bacteria (GNB) in the last decade, mostly driven by carbapenemase-producing strains, importantly changed the epidemiology of hospital-acquired infections (1). Carbapenem-resistant GNB frequently present an extensively drug-resistant (XDR) profile (2), and these isolates have been an increasing public health concern worldwide (1, 2). Among XDR bacteria, Acinetobacter baumannii and Pseudomonas aeruginosa are pathogens of major clinical and epidemiological importance, notably in intensive care unit (ICU) patients (3, 4).Since the discovery of new anti-GNB agents has dried up, polymyxins, both B and E (colistin), have reemerged in clinical practice as agents of last resort against XDR A. baumannii and P. aeruginosa (5, 6). However, despite the in vitro activity of polymyxins, some factors, such as a possible limited clinical efficacy and the potential for the emergence of resistance during treatment, along with some support from preclinical studies, have led many physicians to prescribe combination therapy, mostly a polymyxin combined with a second agent, for patients infec...

The Mla pathway is critical for Pseudomonas aeruginosa resistance to outer membrane permeabilization and host innate immune clearance

“…The related cationic peptide antibiotics colistin and polymyxin B are increasingly being used as last-line agents for treatment of patients with highly multidrug-resistant strains of P. aeruginosa [43, 44]. Since these agents have similar charge characteristics and mechanisms of action to the host defense peptide LL-37, we examined the effect of the vacJ inactivation on sensitivity to these therapeutic agents.…”

Combination of polymyxin B and meropenem eradicates persister cells from Acinetobacter baumannii strains in exponential growth

“…Although the standard antimicrobial scheme against A. baumannii infections has not been fully established, evidence supports the fact that combination therapies including polymyxin B are more effective than polymyxin B monotherapies. Moreover, polymyxin B combined with a second antimicrobial agent was able to reduce hospital mortality rates, and has been widely recommended due to resistance emerging in some A. baumannii strains during treatments [2][3][4]. Nevertheless, antimicrobial therapy failure has been reported, especially in recalcitrance of chronic infections, which may be due to the tolerance mediated by persister cells [5,6] -a microbial subpopulation able to survive to normally lethal concentrations of bactericidal antimicrobials [7], as has been previously described in Acinetobacter spp.…”

Clinical Efficacy of Polymyxin Monotherapy versus Nonvalidated Polymyxin Combination Therapy versus Validated Polymyxin Combination Therapy in Extensively Drug-Resistant Gram-Negative Bacillus Infections

“…Like previous nonrandomized studies, we observed large variability in the baseline and treatment characteristics between the treatment groups in our study (35,36). It is noteworthy that patients in the VCT group had significantly more comorbidities, higher APACHE II scores, and higher incidences of secondary bacteremia (bacteremia complicating a primary infection site).…”