Association Between Colistin Dose and Microbiologic Outcomes in Patients With Multidrug-Resistant Gram-Negative Bacteremia

Vicari, Giulia; Bauer, Seth; Neuner, Elizabeth; Lam, Simon W.

doi:10.1093/cid/cis909

Cited by 98 publications

(85 citation statements)

References 19 publications

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“…Subsequently, a study by Dalfino and colleagues (10) treated patients with a dosing schedule involving a loading dose of 9 million units (300 mg CBA) and a maintenance dose of 4.5 million units (150 mg CBA) every 12 h. This dosing regimen led to a clinical cure rate of 82%, which is the highest reported clinical cure rate reported for the use of systemic colistin for the treatment of multidrug-resistant Gramnegative infections (10). One of our previous studies similarly concluded that an increased dose of colistin independently predicts day 7 microbiologic success (2.9 versus 1.5 mg/kg/day; P ϭ 0.11) and is correlated with day 7 mortality (2.7 versus 1.5 mg/kg/ day; P ϭ 0.007) (12). The global cure rate of 40% in the current study is lower than that observed in previous studies, which may be attributable to our more stringent definition of global cure.…”

Section: Discussionmentioning

confidence: 79%

“…By using CART analysis, the current study was able to determine a cutoff of 4.4 mg/kg/day by IBW (about 300 mg CBA per day for a patient with an IBW of 70 kg) to be most predictive of improvements in global cure rates. Another unique aspect of the current study is the incorporation of dose adjustments and adjudication of doses based on renal function, which were not discussed in the previous studies (11,12). Recent advances in the understanding of colistin elimination provide further insights into the need for renal adjustments (21).…”

Section: Discussionmentioning

confidence: 99%

“…Several recent investigations demonstrated improvements in clinical cure, microbiologic success, and mortality associated with the use of a higher colistin dose (10)(11)(12). Despite a link between colistin dose and clinical and microbiologic outcomes, the specific dose at which improved outcomes are observed is unknown, thus warranting further investigation.…”

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confidence: 99%

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Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli

Gibson

Bauer

Neuner

et al. 2016

Antimicrob Agents Chemother

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The increasing prevalence of multidrug-resistant (MDR) nosocomial infections accounts for increased morbidity and mortality of such infections. Infections with MDR Gram-negative isolates are frequently treated with colistin. Based on recent pharmacokinetic studies, current colistin dosing regimens may result in a prolonged time to therapeutic concentrations, leading to suboptimal and delayed effective treatment. In addition, studies have demonstrated an association between an increased colistin dose and improved clinical outcomes. However, the specific dose at which these outcomes are observed is unknown and warrants further investigation. This retrospective study utilized classification and regression tree (CART) analysis to determine the dose of colistin most predictive of global cure at day 7 of therapy. Patients were assigned to high-and low-dose cohorts based on the CART-established breakpoint. The secondary outcomes included microbiologic outcomes, clinical cure, global cure, lengths of intensive care unit (ICU) and hospital stays, and 7-and 28-day mortalities. Additionally, safety outcomes focused on the incidence of nephrotoxicity associated with high-dose colistin therapy. The CART-established breakpoint for high-dose colistin was determined to be >4.4 mg/kg of body weight/day, based on ideal body weight. This study evaluated 127 patients; 45 (35%) received high-dose colistin, and 82 (65%) received low-dose colistin. High-dose colistin was associated with day 7 global cure (40% versus 19.5%; P ‫؍‬ 0.013) in bivariate and multivariate analyses (odds ratio [OR] ‫؍‬ 3.40; 95% confidence interval [CI], 1.37 to 8.45; P ‫؍‬ 0.008). High-dose colistin therapy was also associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury. We concluded that high-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 global cure.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli

Gibson

Bauer

Neuner

et al. 2016

Antimicrob Agents Chemother

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“…Compared to those suggested by the manufacturers, the regimens in recent studies support the administration of a loading dose and of higher doses of CMS in order to achieve adequate colistin concentrations leading to a better therapeutic effect (21,41,47). The dosing regimen currently recommended by the recent literature (for patients with good renal function) is a loading dose of 4.5 MU of CMS followed by maintenance doses of 4.5 MU twice daily (48)(49)(50).…”

Section: Use Of Colistin In Human and Veterinary Medicine Use In Humamentioning

confidence: 99%

Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

2017

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SUMMARY Polymyxins are well-established antibiotics that have recently regained significant interest as a consequence of the increasing incidence of infections due to multidrug-resistant Gram-negative bacteria. Colistin and polymyxin B are being seriously reconsidered as last-resort antibiotics in many areas where multidrug resistance is observed in clinical medicine. In parallel, the heavy use of polymyxins in veterinary medicine is currently being reconsidered due to increased reports of polymyxin-resistant bacteria. Susceptibility testing is challenging with polymyxins, and currently available techniques are presented here. Genotypic and phenotypic methods that provide relevant information for diagnostic laboratories are presented. This review also presents recent works in relation to recently identified mechanisms of polymyxin resistance, including chromosomally encoded resistance traits as well as the recently identified plasmid-encoded polymyxin resistance determinant MCR-1. Epidemiological features summarizing the current knowledge in that field are presented.

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“…Despite these recent advancements in our understanding of the PK and PD of polymyxins, few studies have reported clinical outcomes in patients receiving these agents, and most evaluated colistin (12)(13)(14). Due to differences in PK and PD parameters, these results may not apply to polymyxin B (15).…”

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confidence: 99%

Clinical Outcomes Associated with Polymyxin B Dose in Patients with Bloodstream Infections Due to Carbapenem-Resistant Gram-Negative Rods

Nelson

Eiras

Gomez‐Simmonds

et al. 2015

Antimicrob Agents Chemother

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There is significant variation in the use of polymyxin B (PMB), and optimal dosing has not been defined. The purpose of this retrospective study was to evaluate the relationship between PMB dose and clinical outcomes. We included patients with bloodstream infections (BSIs) due to carbapenem-resistant Gram-negative rods who received >48 h of intravenous PMB. The objective was to evaluate the association between PMB dose and 30-day mortality, clinical cure at day 7, and development of acute kidney injury (AKI). A total of 151 BSIs were included. The overall 30-day mortality was 37.8% (54 of 151), and the median PMB dosage was 1.3 mg/kg (of total body weight)/day. Receipt of PMB dosages of <1.3 mg/kg/day was significantly associated with 30-day mortality (46.5% versus 26.3%; P ‫؍‬ 0.02), and this association persisted in multivariable analysis (odds ratio [OR] ‫؍‬ 1.58; 95% confidence interval [CI] ‫؍‬ 1.05 to 1.81; P ‫؍‬ 0.04). Eighty-two percent of patients who received PMB dosages of <1.3 mg/kg/day had baseline renal impairment. Clinical cure at day 7 was not significantly different between dosing groups. AKI was more common in patients receiving PMB dosages of >250 mg/day (66.7% versus 32.0%; P ‫؍‬ 0.03), and this association persisted in multivariable analysis (OR ‫؍‬ 4.32; 95% CI ‫؍‬ 1.15 to 16.25; P ‫؍‬ 0.03). PMB dosages of <1.3 mg/kg/day were administered primarily to patients with renal impairment, and this dosing was independently associated with 30-day mortality. However, dosages of >250 mg/day were independently associated with AKI. These data support the use of PMB without dose reduction in the setting of renal impairment. O ver the last decade, carbapenem-resistant Gram-negative rods (CRGNRs) have emerged as important health care-associated pathogens that are associated with significant morbidity and mortality (1, 2). Due to broad antimicrobial resistance among CRGNRs, clinicians have been increasingly forced to rely upon polymyxins for the treatment of infections caused by these organisms (3-5). The polymyxins, colistin and polymyxin B, came into use in the 1960s, but due to high rates of nephrotoxicity and neurotoxicity, they were replaced with less toxic alternatives (6, 7). Unfortunately due to the early development of polymyxins and a subsequent lack of use in a clinical setting, there is a paucity of information describing optimal dosing (6).Several recent studies have provided a better description of polymyxin B pharmacokinetics (PK) and pharmacodynamics (PD). As with colistin, the bactericidal activity of polymyxin B is concentration dependent and appears to be best correlated with the area under the concentration-time curve over 24 h in steady state divided by the MIC (AUC/MIC) (8). However, unlike with colistin, polymyxin B elimination is minimally affected by creatinine clearance, and dose reduction in the setting of renal impairment may result in subtherapeutic serum drug concentrations and decreased efficacy (9-11). In clinical practice, polymyxin B doses have traditionally been reduced ...

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Association Between Colistin Dose and Microbiologic Outcomes in Patients With Multidrug-Resistant Gram-Negative Bacteremia

Abstract: Higher colistin dose independently predicted microbiological success, which may partially explain the similar association with 7-day mortality. However, higher colistin doses may also precipitate worsening renal function.

Cited by 98 publications

References 19 publications

Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli

Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli

Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

Clinical Outcomes Associated with Polymyxin B Dose in Patients with Bloodstream Infections Due to Carbapenem-Resistant Gram-Negative Rods

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