Jessica K. Ortwine

Colistin: Understanding and Applying Recent Pharmacokinetic Advances

Colistin, the most widely used polymyxin antibiotic, was originally introduced in the late 1950s before the establishment of the present‐day drug approval process. Originally shelved due to toxicity concerns, colistin, in the form of its inactive prodrug colistin methanesulfonate, has undergone a renaissance in the past 15 years. Unfortunately, this is not because of an improved adverse‐effect profile but because colistin is among the only remaining antibiotics with activity against multidrug‐resistant gram‐negative bacilli. Pharmacokinetic and pharmacodynamic data are limited to guide the appropriate use of colistin; however, important advances have occurred over the past 5 years. Since its reintroduction, published reports regarding colistin have produced discordant results in terms of both efficacy and safety. Because the efficacy and toxicity of colistin are dose dependent, the impact of discordant dosing recommendations cannot be understated. This review highlights the issues leading to differing and often conflicting dosing recommendations, reviews the recent pharmacokinetic advances, and provides recommendations for the optimal use of colistin.

Strategies for the safe use of colistin

Colistin has re-emerged as an essential antibiotic for the treatment of carbapenem-resistant Gram-negative infections. Unfortunately, its utility is limited by high rates of nephrotoxicity, even at potentially therapeutic concentrations, and an overall lack of understanding on how to optimally administer the agent. In this review, recent advancements in the understanding of the safety and efficacy of colistin are discussed and strategies and suggestions on how to balance the two are described.

Clinical considerations for optimal use of the polymyxins: A focus on agent selection and dosing

Polymyxins have remained the drug of choice for treatment due to carbapenem-resistant Gram-negative bacilli. Unfortunately, the utility of these agents has been limited by a lack of pharmacokinetic understanding, a high toxicity rate, and an extremely narrow therapeutic index. Significant advancements have been achieved in the understanding of the polymyxins over the past decade, and have led to the recognition of several differences between available intravenous formulations. The purpose of this review is to discuss the implications of these differences, assess comparative efficacy and safety of the polymyxins, and provide recommendations for polymyxin dosing and selection.

Are there any ways around the exposure-limiting nephrotoxicity of the polymyxins?

The polymyxins (colistin and polymyxin B) have emerged over the past 20 years as essential antibacterial agents that often are the only remaining active class against troublesome multidrug-resistant Gram-negative bacilli such as carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae. The utility of this class is limited by its dose-dependent nephrotoxicity, which can occur in more than one-half of patients receiving therapy with either agent. Strategies are urgently needed to optimise the use of this class of agents to ensure optimal activity while minimising the treatment-limiting nephrotoxicity. This review will focus on risk factors for polymyxin-associated nephrotoxicity, potential strategies for limiting this exposure-dependent toxicity and, finally, unknowns and future research directions pertinent to this topic.

Editorial Commentary: Optimal Usage of Colistin: Are We Any Closer?

Despite being the mainstay of treatment for carbapenem-resistant gram-negative bacilli for more than a decade, optimal strategies for dosing and administration of colistin remain unclear. Colistin dosing regimens vary considerably throughout the world. In some instances, the total daily dose delivered varies 2-fold depending on geography. Compounding the issue is the fact that the majority of dosing strategies currently utilized were developed in the absence of accurate pharmacokinetic and pharmacodynamic data. Further complicating the issue of colistin dosing is the issue of nephrotoxicity, which often limits the dose and duration of therapy. Although many risk factors for acute kidney injury (AKI) with colistin have been identified, data supporting protective factors mitigating this dose-limiting side effect are lacking. In 2011, Garonzik and colleagues published interim results from a pharmacokinetic study that described colistin exposures in critically ill patients and, for the first time, provided pharmacokinetically based dosing recommendations [1]. The authors demonstrated the need for a loading dose and developed a dosing equation for colistin. In this issue of Clinical Infectious Diseases, Dalfino and colleagues describe their experience using this dosing algorithm and its impact on the incidence of AKI [2]. After administering a loading dose, the authors utilized the maintenance dose algorithm to target a colistin steady-state concentration of 2.5 mg/L, in accordance with the recommendations from Garonzik et al [1]. As described in detail elsewhere [3, 4], this suggested target concentration is not a “magic bullet” for efficacy, but was selected by Garonzik et al by balancing efficacy and safety. Although this target concentration would only be associated with bactericidal activity for organisms at the lower end of the susceptibility range, the authors did not feel comfortable recommending higher targets given that the median colistin concentration in their study was 2.36 mg/L and the nephrotoxicity rate was 48% [1]. Additionally, given that doses in the Dalfino et al study were capped at 9 million units (270 mg of colistin base activity) for patients with creatinine clearances of 60–130 mL/minute or 12 million units in patients with clearances >130 mL/minute, patients with creatinine clearances >60 mL/minute likely did not attain the target concentration of 2.5 mg/L. When the targeted concentrations are put into context with the minimum inhibitory concentration (MIC50) and MIC90 data from pathogens presented in this article (0.5/2 mg/L for Acinetobacter baumannii, 2/2 mg/L for Pseudomonas aeruginosa, and 1/1.5 mg/L for Klebsiella pneumoniae) the free area under the curve to MIC ratio exposures that patients in this study obtained would likely only be associated at best with a 1 log10 kill, and, in some cases, a bacteriostatic effect in a significant proportion of patients [5, 6]. The 44% toxicity rate reported, even in the setting of suboptimal pharmacodynamic exposures, underscores the difficulty in safely targeting “therapeutic concentrations” with colistin. Importantly, however, despite these potential exposure limitations, the authors reported a clinical success rate of 77%. Unfortunately, interpretation of this success rate is difficult due to a lack of information on how infections were defined, the incidence and impact of polymicrobial or additional infections and their treatment, a lack of actual patient serum concentration data, and the frequent use of combination therapy. Although efficacy assessment is complex, this study provides the first analysis looking at a pharmacokinetically driven dosing regimen, with daily dose modifications based on renal function, on the incidence of AKI. Importantly, the authors Received 28 July 2015; accepted 10 August 2015; electronically published 9 September 2015. Correspondence: Jason M. Pogue, PharmD, Infectious Diseases, Sinai-Grace Hospital, Detroit Medical Center, Detroit, MI 48235 (jpogue@dmc.org). Clinical Infectious Diseases 2015;61(12):1778–80

Pharmacokinetics and pharmacodynamics of antibacterial and antifungal agents in adult patients with thermal injury: a review of current literature.

Patients with significant thermal injury are at a high risk for developing bacterial and fungal infections due to the loss of protective integument and often require lengthy treatment courses with anti-infective agents. Dosing of these agents in the burn population is challenging as these patients experience changes in their physiology around 48 hours postinjury. These changes include increased cardiac output, increased blood flow to the kidneys and liver, and decreased albumin production. These alterations in the physiology can lead to an increased drug clearance, higher volumes of distribution, and increased or decreased total drug exposure. Currently, there are no guidelines describing the most ideal method of dosing anti-infectives in this population, and most studies that have been published include only a small number of patients. The purpose of this review is to summarize the existing literature regarding the pharmacokinetics and pharmacodynamics of antibiotics and antifungal agents in the burn population and to provide dosing suggestions whenever possible. Not all antibiotics and antifungal agents have been studied, and further research is needed in this area in order to provide optimal care for patients with thermal injury.

Nafcillin versus cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia

BACKGROUND Anti-staphylococcal penicillins have long been the first-line treatment option for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Recent retrospective data comparing nafcillin and cefazolin report similar clinical efficacy despite concerns about high inoculum MSSA infections. METHODS This was a retrospective, non-inferiority, cohort study comparing treatment failure rates between nafcillin and cefazolin in patients with MSSA bacteremia from any source, other than meningitis. Multiple logistic regression was used to adjust for confounding variables. RESULTS A total of 142 patients were included in the study. The overall treatment failure rate among patients receiving cefazolin was non-inferior to nafcillin (11.3% versus 8.5%; 90% confidence interval -5.2% to 10.8%). Rates of adverse drug events were significantly higher in the nafcillin arm (19.7% versus 7%; p=0.046). After adjustment for confounding variables, no difference between treatment groups was found in treatment failure (adjusted odds ratio (OR)=1.2; 95% CI, 0.3-4.5), but nafcillin was associated with significantly higher nephrotoxicity (adjusted odds ratio (OR)=5.4; 95% CI, 1.1-26.8). CONCLUSION Cefazolin was associated with lower nephrotoxicity and similar treatment failure rates compared to nafcillin suggesting that cefazolin is an appealing first line agent for most MSSA bloodstream infections.

Morbidity, mortality, and management of methicillin-resistant S. aureus bacteremia in the USA: update on antibacterial choices and understanding

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with significant healthcare costs, morbidity, and mortality in the United States. Complications of MRSA bacteremia include infective endocarditis, osteomyelitis, and sepsis, all of which are difficult to treat. Time to effective therapy and antibacterial choice greatly affect patient outcomes. Vancomycin and daptomycin remain first-line therapies; however, reports of vancomycin-associated treatment failure and reduced daptomycin susceptibility highlight the need to define alternative strategies for MRSA bacteremia treatment. In addition, several patient- and pathogen-specific factors influence the outcomes of MRSA bacteremia. It is, therefore, critical to explore the interaction between host- and pathogen-specific factors and its effect on MRSA bacteremia pathogenesis and mortality. This review discusses the factors that drive the development of MRSA bacteremia and examines alternative treatment strategies.