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.

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 ß-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 drug-resistant A. baumannii or P. aeruginosa infections.

KPC-producing Klebsiella pneumoniae bloodstream isolates from Brazilian hospitals: What (still) remains active?

OBJECTIVES: This study assessed susceptibility to polymyxin B (PMB) and alternative antimicrobials, with focus on aminoglycosides and tigecycline, according to different breakpoints in KPC-producing Klebsiella pneumoniae (KPC-Kp) bloodstream isolates from Brazilian hospitals. METHODS: Bloodstream K. pneumoniae isolates non-susceptible to any of the three carbapenems (meropenem, imipenem or ertapenem) from four Brazilian tertiary-care hospitals were selected. Antimicrobial susceptibility was determined and interpreted according to distinct breakpoints. Twenty-nine PMB-resistant KPC-Kp isolates were selected for molecular typing. RESULTS: A total of 158 KPC-Kp were analysed. MIC50/90 values for PMB were 0.25/16mg/L; 40 isolates (25.3%) were resistant to PMB. MIC50/90 values for meropenem were 32/≥256mg/L; no isolates were susceptible to meropenem according to CLSI, but 10 isolates were intermediate using EUCAST breakpoints (1, MIC=4mg/L; 9, MIC=8mg/L). MIC50/90 values for tigecycline were 2/8mg/L; 53 (33.5%) and 94 (59.5%) isolates were susceptible according to EUCAST and FDA breakpoints, respectively. MIC50/90 values were 32/≥64mg/L for amikacin and ≥16/≥16mg/L for gentamicin; 48 (30.4%), 28 (17.7%) and 16 (10.1%) were susceptible to amikacin according to CLSI, EUCAST and USCAST, respectively, but susceptibility rates to gentamicin were <7.0%. Eighteen distinct clonal profiles were identified among 29 PMB-resistant isolates by DNA macrorestriction. Most clones belonged to CC11. CONCLUSION: Elevated rates of PMB-resistant KPC-Kp bloodstream infections were found in four Brazilian hospitals, mostly of polyclonal origin. Alternative antimicrobials with the highest in vitro activity were tigecycline and amikacin, although susceptibility rates significantly decreased using criteria with stricter breakpoints (e.g. EUCAST, USCAST).

Emergence of polymyxin B resistance in a polymyxin B-susceptible KPC-producing Klebsiella pneumoniae causing bloodstream infection in a neutropenic patient during polymyxin B therapy.

The emergence of resistance to polymyxins in KPC-producing Klebsiella pneumoniae isolates has been a major clinical problem. This study evaluated the molecular mechanisms associated with polymyxin B (PMB) resistance that emerged in a previously PMB-susceptible KPC-2-producing K. pneumoniae during PMB therapy for a bloodstream infection in a neutropenic patient. The first isolate (PMB-susceptible) was obtained while the patient was receiving meropenem and other isolates were recovered from 2 sets of blood cultures in different dates while the patient was receiving PMB therapy (4 of 6 blood cultures bottles yielded isolates with full PMB resistance). The population analysis profile of the first isolate revealed the growth of resistant subpopulations with PFGE profile distinct from the parental isolate but undistinguishable from those obtained in subsequent days under PMB exposure. Resistant subpopulations were obtained from all parental PMB-susceptible and in one PMB-resistant isolate recovered from the patient. The molecular mechanism observed in the hetero-resistant subpopulations (IS1-like in mgrB-promoter region, increased rstB transcription with no mutation and non-identified mechanism) differed from those found in the PMB-resistant isolates, in which no mutation or transcriptional alterations were detected. This study showed that the mechanism of resistance to PMB that emerged during PMB therapy was not related to those observed in subpopulations selected in vitro from PMB-susceptible isolates recovered from the patient. The absence of mutations in the former isolates may be due to adaptive resistance occurred because of sub-optimal PMB levels as well as amikacin and meropenem used in combination.