Timothy P. Gauthier

Incidence and Predictors of Nephrotoxicity Associated with Intravenous Colistin in Overweight and Obese Patients

ABSTRACT Intravenous colistin is used to treat resistant Gram-negative infections and is associated with nephrotoxicity. In overweight and obese adults, a paucity of data exists regarding the incidence and predictors of such toxicity. A retrospective nested case-control study was performed over 35 months for patients receiving intravenous colistin for ≥72 h with a body mass index (BMI) of ≥25 kg/m2. The objective was to investigate the incidence and predictors of nephrotoxicity. Severity of acute kidney injury was defined by RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria. Dosing and mortality were secondarily investigated. Forty-two patients met the inclusion criteria, and 20 (48%) developed nephrotoxicity. Patients with toxicity were in the risk (15%), injury (5%), and failure (80%) categories based on RIFLE criteria. A logistic regression model identified four predictors of colistin-associated nephrotoxicity: a BMI of ≥31.5 kg/m2 (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.15 to 8.35), diabetes (OR, 2.11; 95% CI, 0.84 to 5.29), the length of hospitalization in days prior to receipt of colistin (OR, 1.04; 95% CI, 0.99 to 1.08), and age (OR, 1.08; 95% CI, 1.00 to 1.17). Among all of the patients, dosing based on the actual body weight and excessive dosing due to the use of the actual body weight were frequent at 64% and 92%, respectively. The 30-day all-cause in-hospital mortality rate was 40% in the toxicity group and 14% in the nontoxicity group (P = 0.14). Patients receiving intravenous colistin should be monitored for nephrotoxicity, especially when the BMI exceeds 31.5 kg/m2. Prospective, randomized, controlled trials are warranted to further examine nephrotoxicity incidence and predictors and appropriate dosing strategies in this population.

Cobicistat: Review of a Pharmacokinetic Enhancer for HIV Infection

PURPOSE This article reviews the clinical pharmacology, pharmacodynamic and pharmacokinetic (PK) properties, clinical efficacy and tolerability, drug interactions, and dosing and administration of cobicistat. METHODS Searches of MEDLINE and International Pharmaceutical Abstracts from 1964 to February 2015 were conducted using the search terms cobicistat and GS-9350. Relevant information was extracted from the identified clinical trials and review articles. Abstracts from the Conference on Retroviruses and Opportunistic Infections (2014-2015) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (2013-2014) were also searched. FINDINGS Cobicistat is a PK enhancer lacking antiviral activity that, via selective cytochrome P-450 (CYP) 3A inhibition, inhibits the metabolism of certain antiretroviral medications and is used for prolonging their effect. Cobicistat has been studied as a booster of elvitegravir, a second-generation integrase inhibitor, and of the protease inhibitors atazanavir and darunavir. Data on its clinical efficacy and tolerability have been presented in 2 Phase II trials and in 9 Phase III trials, which reported durable efficacy in terms of achievement of sustained suppression of HIV-1 RNA levels to <50 copies/mL for at least 48 weeks. Cobicistat was generally well-tolerated in these studies. Cobicistat may increase serum creatinine levels via the inhibition of proximal renal tubular cell transporters and thus reduce estimated glomerular filtration rate, although it does not appear to affect actual glomerular filtration rate. Given the potent CYP3A inhibition by cobicistat, its coadministration with drugs metabolized by CYP3A may result in increased plasma concentrations of such agents. Moreover, as cobicistat is metabolized predominantly by CYP3A, plasma concentrations may increase or decrease on coadministration with CYP3A inhibitors or inducers, respectively. IMPLICATIONS With potent durability through 48 weeks, a tolerability profile comparable to other first- and second-line antiretroviral therapies, and a convenient dosing schedule with low daily pill burden in fixed-dose combination tablets, cobicistat is a potential addition to the management of HIV infection as a PK enhancer. However, the effects of cobicistat on serum creatinine and its considerable drug-interaction potential may warrant additional monitoring.

Clinical infectious diseases pharmacists in the United States: a problem of both supply and demand

TO THE EDITOR—The importance of antimicrobial stewardship (AS) to the future of healthcare is emphasized by recent statements of the US government calling for widespread implementation of robust AS programs, which applies to >5700 US hospitals [1]. The Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance AS identify a clinical pharmacist with infectious diseases (ID) training as 1 of 2 core AS team members [2]. The Society of Infectious Diseases Pharmacists (SIDP) and Infectious Diseases Practice Research Network of the American College of Clinical Pharmacy (ACCP) recommend that future pharmacists seeking a clinical ID position complete a postgraduate year 1 (PGY-1) pharmacy practice residency and postgraduate year 2 (PGY-2) ID specialty residency [3]. Today, concern exists over the shortages of adequately trained ID pharmacists [4, 5], and as such, the future supply of clinical ID pharmacists is dependent on the availability of postgraduate ID training opportunities. The purpose of this correspondence is to objectively describe the current state of (1) postgraduate training opportunities for pharmacists looking to specialize in ID and (2) demand for clinical ID pharmacists. To quantify and characterize postgraduate training opportunities, we accessed pharmacy residency and fellowship directories of SIDP, American Society of Health-System Pharmacists (ASHP), and ACCP. Site information was crossreferenced to account for duplication, and available data points were collected for analysis. To assess the demand for clinical ID pharmacists, we utilized Web-based searches (eg, www.monster. com, www.usajobs.gov) and accessed employment postings provided by relevant pharmacy organizations (eg, ASHP, SIDP). These were compiled using Microsoft Excel software and evaluated individually to prevent duplication. We performed this snapshot assessment in October 2014, identifying 89 postgraduate ID training programs and 32 clinical ID pharmacist employment listings. Collected data are presented in Table 1. For training programs, none focused specifically on AS, although by nature AS concepts are incorporated into training and accreditation standards for PGY-2 ID residencies mentions AS briefly [7]. For employment, 23 (72%) mentioned AS within the job description and 29 (91%) were inpatient positions. In addition to the 32 clinical ID pharmacist positions, 5 academic and 10 industrybased (eg, medical science liaison) ID pharmacist jobs were found. If AS programs are destined to become part of the healthcare landscape and clinical ID pharmacists are essential for such a transition, the data presented here represent cause for substantial concern. Quantitatively and geographically, current opportunities for training and employment are considerably inadequate to fulfill the anticipated future needs for thousands of US institutions. Indeed, alternative educational programs such as certificate programs [8, 9] may assist in filling some existing gaps, but are limited in their scope. As healthcare continues to evolve and the role of AS grows, early recognition of existing barriers by stakeholders is essential to future success. The impact of the current clinical ID pharmacist supply and demand deficiencies within the United States noted here requires consideration during this AS program implementation and expansion period.

Management of Bacteriuria in Veterans Affairs Hospitals

Background Bacteriuria contributes to antibiotic overuse through treatment of asymptomatic bacteriuria (ASB) and long durations of therapy for symptomatic urinary tract infections (UTIs), yet large-scale evaluations of bacteriuria management among inpatients are lacking. Methods Inpatients with bacteriuria were classified as asymptomatic or symptomatic based on established criteria applied to data collected by manual chart review. We examined frequency of treatment of ASB, factors associated with treatment of ASB, durations of therapy, and frequency of complications including Clostridium difficile infection, readmission, and all-cause mortality within 28 days of discharge. Results Among 2225 episodes of bacteriuria, 64% were classified as ASB. After excluding patients with non-UTI indications for antibiotics, 72% of patients with ASB received antibiotics. When evaluating only patients not meeting SIRS criteria, 68% of patients with ASB received antibiotics. The mean (±SD) days of antibiotic therapy for ASB, cystitis, CA-UTI and pyelonephritis were 10.0 (4.5), 11.4 (4.7), 12.0 (6.1), and 13.6 (5.3), respectively. In sum, 14% of patients with ASB were treated for greater than 14 days, and fluoroquinolones were the most commonly used empiric antibiotic for ASB [245/691 (35%)]. Complications were rare but more common among patients with ASB treated with antibiotics. Conclusions The majority of bacteriuria among inpatient veterans is due to ASB with high rates of treatment of ASB and prolonged durations of therapy for ASB and symptomatic UTIs.

A call to action for outpatient antibiotic stewardship

OBJECTIVES To address the public health threat of antibiotic resistance, there has been an enhanced call for antibiotic stewardship programs throughout the health care continuum. SUMMARY While antibiotic stewardship programs have been well described in the inpatient setting, data on effectiveness and guidance on implementing outpatient programs is scarce. Establishing stewardship practices in the outpatient setting is necessary because more than 60% of human antibiotic use occurs in this setting. CONCLUSION In this article, we highlight the importance and need for stewardship in the outpatient setting, discuss strategies for the development of stewardship teams, and discuss potential metrics that can be used to assess effectiveness of antibiotic stewardship interventions.

Outpatient antibiotic stewardship: Interventions and opportunities

Improving the use of antibiotics across the continuum of care is a national priority. Data outlining the misuse of antibiotics in the outpatient setting justify the expansion of antibiotic stewardship programs (ASPs) into this health care setting; however, best practices for outpatient antibiotic stewardship (AS) are not yet defined. In a companion article, we focused on recommendations to overcome challenges related to the implementation of an outpatient ASP (e.g., building the AS team and defining program metrics). In this document, we outline AS interventions that have demonstrated success and highlight opportunities to enhance AS in the outpatient arena. This article summarizes examples of point-of-care testing, policies and interventions, and education strategies to improve antibiotic use that can be used in the outpatient setting.

Variability Within Investigations of Intravenous Colistin: The Scope of the Problem

An accurate understanding of this lastline antibacterial drug is essential as clinicians worldwide care for patients infected by drug-resistant organisms. Unfortunately, although concerns exist, the full magnitude and range of discrepancies within this area of research have not been well described. The purpose of this letter is to provide objective data detailing the extensive variability in current colistin literature as it relates to study populations, endpoint selection, and other reporting practices. We searched Scopus (www.scopus. com/home/url) and PubMed (www. ncbi.nlm.nih.gov/pubmed) using the Medical Subject Heading terms “colistin” and “colistimethate” along with the operator “OR” to identify human research published in English between January 1990 and July 2013 with an abstract available. Publications reporting original research or outcomes data for a cohort of adult (age>18years)patientswhoreceived intravenous colistin were included. Of the 1695 identified studies, 51 (3%) articles met inclusion criteria and were evaluated for this descriptive report. Included studies ranged from 1999 to 2013, with two-thirds published after 2008. Prospective studies composed 35% of the sample. Studies originated from 21 unique countries, with the United States and Greece being most frequent at 22% and 20% of publications, respectively. Of the articles reporting doses in milligrams of CBA, two-thirds were from North America, whereas none of the articles reporting in international units of CMS originated from this region.

An Elective Course on Antimicrobial Stewardship

Objective. To implement an antimicrobial stewardship (AS) elective course for second-year and third-year pharmacy students and to assess its impact on students’ perceptions regarding the application of AS principles. Design. A 2-credit elective course focusing on principles of AS incorporated prelecture didactic recordings with primary literature and guideline-based reading assignments, in-class active-learning group work and student-led presentations, and student-generated examination items. Assessment. Perceptions were assessed by precourse and postcourse survey items. Graded course assessments included completion of preclass assignments (readings, prerecorded lecture and writing assessment items), in-class active participation and group presentations, a midpoint examination, and a final examination. Conclusion. An AS-themed elective course in a doctor of pharmacy curriculum incorporating preclass, self-directed learning and in-class group-based active-learning strategies positively impacted students’ perceived understanding of AS strategies.

Editorial Commentary: Rifampicin Plus Colistin in the Era of Extensively Drug-Resistant Acinetobacter baumannii Infections

employthistherapyremainsunknownand resistance may develop on therapy [4, 5]. Approaching the dilemma from an alternate angle, experimental models of infection reveal that rifampicin monotherapy has activity versus XDR Acb, although high-level resistance develops early during monotherapy, presumably through overexpression of efflux pumps or rpoB gene mutation. The combination of colistin plus rifampicin has been shown to prevent the development of resistant mutants and to be synergistic versus a number of Acb isolates, with available in vitro and in vivo datasuggestingsafetyand efficacy.Whether enhanced bacterial killing translates into improved outcomes for critically ill patients infected with XDR Acb nonsusceptible to carbapenems is the focus of the trial by Durante-Mangoni et al in this issue of Clinical Infectious Diseases [6].

Pharmacist engagement within a hepatitis C ambulatory care clinic in the era of a treatment revolution

OBJECTIVES To describe an innovative hepatitis C virus (HCV) care program and treatment outcomes resulting from pharmacist services. SETTING Adult ambulatory care HCV clinic within the Miami Veteran Affairs Healthcare System. PRACTICE DESCRIPTION Pharmacists with limited prescriptive authority are integrated into a medical hepatology care team. PRACTICE INNOVATION Pharmacists screen patients with HCV infection for treatment eligibility, counsel patients upon treatment initiation, assess ongoing treatment success and toxicity through patient appointments, telephone calls, and the ordering of pertinent laboratory data, and provide oversight of all patients on HCV therapies. Treatment outcomes are reported to the institutional Antimicrobial Stewardship Program. EVALUATION Data produced from a continuous quality assurance initiative were utilized. Descriptive statistics were used to present data. RESULTS From January 2014 through September 2015 there were 1619 pharmacist encounters for 532 unique patients and 597 screenings (including 578 approvals) were completed by a pharmacist. During this time 555 patients were initiated on at least 1 HCV treatment course, with 565 total treatment courses initiated. As new agents became available for use, fluctuation in regimen selection was seen. The most commonly prescribed medications were sofosbuvir (46%), ledipasvir/sofosbuvir (37%), and simeprevir (33%). Of the 565 HCV treatment courses initiated, 360 were completed, 29 were stopped early during treatment, and 176 were ongoing. Of the 360 completed courses, 249 had sustained virologic response at week 12 results available, of which 225 (90%) achieved treatment success and 24 (10%) relapsed. Of the 29 courses stopped early, 11 were due to poor medication adherence and 8 were due to adverse drug reaction. CONCLUSION Through a structured process employing a scope of practice, pharmacists can extend the capacity of medical hepatology providers and provide pharmacotherapy services to enhance care. Information provided here may serve beneficial to others looking to initiate or expand existing HCV pharmacist services.