Performance of Four Fosfomycin Susceptibility Testing Methods against an International Collection of Clinical Pseudomonas aeruginosa Isolates.

Fosfomycin has been shown to have a wide spectrum of activity against multidrug-resistant Gram-negative bacteria; however, breakpoints have been established only for Escherichia coli or Enterobacterales per the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST), respectively. A lack of additional organism breakpoints limits clinical use of this agent and has prompted extrapolation of these interpretive categories to other organisms like Pseudomonas aeruginosa without supporting evidence. Further complicating the utility of fosfomycin is the specified method for MIC determination, namely, agar dilution, which is not widely available and is both labor and time intensive. We therefore sought to determine the susceptibility of a large international collection of P. aeruginosa isolates (n = 198) to fosfomycin and to compare testing agreement rates across four methods: agar dilution, broth microdilution, disk diffusion, and Etest. Results were interpreted according to CLSI E. coli breakpoints, with 49.0 to 85.8% considered susceptible, dependent upon the testing method used. Epidemiological cutoff values were calculated and determined to be 256 µg/ml and 512 µg/ml for agar dilution and broth microdilution, respectively. Agreement rates were analyzed using both agar dilution and broth microdilution with a resulting high essential agreement rate of 91.3% between the two susceptibility testing methods. These results indicate that broth microdilution may be a reliable method for fosfomycin susceptibility testing against P. aeruginosa and stress the need for P. aeruginosa-specific breakpoints.

Impact of an Antimicrobial Stewardship Team on Reducing Antiretroviral Medication Errors.

Background: Numerous interventions have been used to reduce medication errors related to antiretroviral (ARV) therapy for hospitalized patients with HIV. Objective: This study assessed the impact of an antimicrobial stewardship (ASP) team intervention on reducing the rate of ARV therapy errors in patients admitted to an academic medical center. Methods: This observational, retrospective study included patients who received ARV therapy from June 2016 to December 2017. The primary outcome was evaluation of ASP team performance in detecting ARV medication errors in the inpatient setting. Errors were further categorized by type (interaction, dosing, regimen). The Mann-Whitney U test and χ2 tests were utilized to analyze continuous and categorical data, respectively. Results: Medication errors occurred in 51% of patients in the preintervention group (n = 152) and 48% of patients in the postintervention group (n = 203; P = 0.43). The most frequent medication error type was drug interactions in both groups, involving integrase strand transfer inhibitors and polyvalent cations (64% vs 67%). There was a significant difference between preintervention and postintervention groups regarding number of errors detected (13 vs 106, P < 0.001), corrected (12 vs 86, P < 0.001), and persisting at discharge (106 vs 18, P < 0.001). Conclusion and Relevance: Review of ARV regimens by an ASP team significantly decreased medication errors. Drug interactions are the most common medication error found in HIV-positive patients admitted to our academic center.

Oritavancin (Orbactiv): A New-Generation Lipoglycopeptide for the Treatment Of Acute Bacterial Skin and Skin Structure Infections.

Oritavancin (Orbactiv): a new-generation lipoglycopeptide for the treatment of acute bacterial skin and skin structure infections.

Association of tenofovir disoproxil fumarate with primary allograft survival in HIV-positive kidney transplant recipients.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is an antiretroviral agent frequently used to treat human immunodeficiency virus (HIV). There are concerns regarding its potential to cause acute kidney injury, chronic kidney disease, and proximal tubulopathy. Although TDF can effectively suppress HIV after kidney transplantation, it is unknown whether use of TDF-based antiretroviral therapy (ART) after kidney transplantation adversely affects allograft survival. METHODS: We examined 104 HIV+ kidney transplant (KT) recipients at our center between 2001 and 2014. We generated a propensity score for TDF treatment using recipient and donor characteristics. We then fit Cox proportional hazards models to investigate the association between TDF treatment and 3-year, death-censored primary allograft failure, adjusting for the propensity score and delayed graft function (DGF). RESULTS: Of the 104 HIV+ KT candidates who underwent transplantation during the study period, 23 (22%) were maintained on TDF-based ART at the time of transplantation, and 81 (78%) were on non-TDF-based ART. Median age of the cohort was 48 years; 87% were male; 88% were black; and median CD4 count at transplantation was 450 cells/mm3 . Median kidney donor risk index was 1.2. At 3 years post transplantation, primary allograft failure occurred in 26% of patients on TDF-based ART and in 28% of patients on non-TDF-based ART (P=.5). TDF treatment was not associated with primary allograft failure at 3 years post transplant after adjusting for DGF and a propensity score for TDF use (hazard ratio 2.12, 95% confidence interval 0.41-10.9). CONCLUSIONS: In a large single-center experience of HIV+ kidney transplantation, TDF use following kidney transplantation was not significantly associated with primary allograft failure. These results may help inform management for HIV+ KT recipients in need of TDF therapy for adequate viral suppression.

Molecular characterization of ß-lactamase genes in clinical isolates of carbapenem-resistant Acinetobacter baumannii.

BACKGROUND: Acinetobacter baumannii is a nosocomial pathogen which is establishing as a major cause of morbidity and mortality within the healthcare community. The success of this pathogen is largely due to its ability to rapidly gain resistance to antimicrobial therapies and its capability to persist in an abiotic environment through the production of a biofilm. Our tertiary-care hospital has showed high incidence of carbapenem-resistant Acinetobacter baumannii (CRAB) isolates. METHODS: In this study we explore both genotypic and phenotypic properties of 26 CRAB isolates: 16 isolates were collected from January 2010 to March 2011, and 10 were collected between February and May 2015. RESULTS: We determined that all 26 CRAB isolates possessed multiple ß-lactamase genes, including genes from Groups A, C, and D. Specifically, 42% of the isolates possesses the potentially plasmid-borne genes of OXA-23-like or OXA-40-like ß-lactamase. The presence of mobile gene element integron cassettes and/or integrases in 88% of the isolates suggests a possible mechanism of dissemination of antibiotic resistance genes. Additionally, the location of insertion sequence (IS) ISAba1 in promotor region of of the OXA-51-like, ADC-7, and ampC genes was confirmed. Multilocus sequence typing (MLST) demonstrated that all 26 CRAB isolates were either sequence type (ST)-229 or ST-2. Interestingly, ST-2 went from being the minority CRAB strain in the 2010-2011 isolates to the predominant strain in the 2015 isolates (from 32 to 90%). We show that the ST-2 strains have an enhanced ability to produce biofilms in comparison to the ST-229 strains, and this fact has potentially led to more successful colonization of the clinical environment over time. CONCLUSIONS: This study provides a longitudinal genetic and phenotypic survey of two CRAB sequence types, and suggests how their differing phenotypes may interact with the selective pressures of a hospital setting effecting strain dominance over a 5-year period.

Sofosbuvir: A Nucleotide NS5B Inhibitor for the Treatment of Chronic Hepatitis C Infection.

OBJECTIVE: To review the use of sofosbuvir for the treatment of chronic hepatitis C virus (HCV). DATA SOURCES: Review and nonreview articles were identified through MEDLINE (1996-April 2014), citations of articles, and meeting abstracts using keywords, including NS5B polymerase inhibitor, GS-7977, sofosbuvir, direct-acting antiviral (DAA), and others. STUDY SELECTION AND DATA EXTRACTION: Phase 1, 2, and 3 studies describing dose-ranging potential, pharmacokinetics, efficacy, safety, and tolerability of sofosbuvir were identified. DATA SYNTHESIS: Sofosbuvir is an NS5B polymerase inhibitor that was approved for use by the Food and Drug Administration in December 2013 for the treatment of chronic HCV in combination with pegylated interferon (peg-IFN) and ribavirin (RBV) for genotype 1. Additionally, it has been evaluated with other oral DAAs, such as simeprevir and others in the pipeline. It is not recommended as monotherapy because of lower sustained virological response (SVR) rates in clinical studies. Most of the treatment regimens are 12 weeks in duration; however, certain populations require a longer duration. Sofosbuvir has activity against all 6 genotypes, although most clinical trials evaluated genotypes 1 to 3. Sofosbuvir has a favorable safety and tolerability profile, making it a recommended first-line agent for chronic HCV infection. CONCLUSION: In clinical trials, 12 weeks of sofosbuvir with concomitant peg-IFN and RBV therapy in treatment-naïve and experienced HCV genotype 1 patients resulted in SVR rates of >90%. An all-oral regimen of sofosbuvir and RBV is highly effective for genotype 2 and 3 patients. Sofosbuvir was found to be tolerable with minimal adverse effects (AEs), and no treatment discontinuations occurred secondary to drug related AEs..

Incidence of Antiretroviral Drug Interactions During Hospital Course: The Role of a Pharmacist-Led Antiretroviral Stewardship Program.

Background: Human immunodeficiency virus (HIV) providers are treating more comorbid conditions with additional pharmacologic agents, resulting in patients with HIV being disproportionately at risk for clinically significant drug-drug interactions (CSDDIs). There is a potential to overlook these interactions and ultimately place patients at risk for drug toxicity, resistance, and virologic failure. Objective: To assess the burden of CSDDIs among patients receiving antiretroviral therapy (ART) within 24 hours of admission and to evaluate the effect of a clinical pharmacist operating through an antiretroviral stewardship (ARVSP) program in identifying and correcting potential drug interactions. Methods: Adult HIV-positive patients receiving ART who were admitted to The Brooklyn Hospital Center from November 2010 through January 2012 were included in the analysis. Drug interactions were categorized according to time frame (ie, within 24 hours of admission vs after 24 hours of admission) and type (ie, contraindicated combinations, dosage modifications, and frequency alterations). The Liverpool HIV drug reference, Micromedex drug database, and the Department of Health and Human Services Guidelines were used as comprehensive tools for identification of antiretroviral drug errors. Results: Eighty-four CSDDIs were identified from 252 admissions among 158 patients receiving ART during the study period. Of the identified CSDDIs, 61 (73%) occurred within 24 hours of admission and 23 (27%) later in the hospital course. Forty-eight drug interactions (57%) represented contraindicated drug combinations. Protease inhibitor-based regimens were associated with the highest percentage of CSDDIs (98%). Of all CSDDIs, the most common interacting drug class was acid-suppressive therapy (63%). Clinical pharmacists identified and intervened in 80% of the CSDDIs that occurred on patient admission with all interventions accepted. Conclusions: CSDDIs are common among patients receiving ART at the time of admission and throughout the hospital course. Interventions including medication review by clinical pharmacists are critical in the prevention of CSDDIs on admission.

Duration of Perioperative Antimicrobial Prophylaxis in Orthotopic Liver Transplantation Patients.

INTRODUCTION: According to clinical guidelines, there are no differences in early infection rates when utilizing antimicrobial prophylaxis regimens beyond 24 hours. We shortened the prophylaxis regimen from 72 to 24 hours in liver transplant recipients due to rising rates of resistance. The objective of this study is to evaluate the difference in posttransplant outcomes, following the protocol change. DESIGN: We reviewed adult patients undergoing orthotopic liver transplantation between June 2013 and December 2015. Patients were stratified into 2 cohorts: 24 and 72 hours. Patients were excluded if donor cultures were positive. The primary objective of this study is to evaluate the incidence and time to posttransplant infections. The secondary objectives included analysis of total and intensive care unit length of stay and rates of Clostridioides difficile infection. RESULTS: Forty-four patients were included, 20 in the 72-hour and 24 in the 24-hour cohorts. The incidence of post-OLT infection (30% vs 8%, P = .115, 95% CI: -1% to 45%) was higher in the 72-hour cohort. Total (21 vs 14, P = .332, 95% CI: -4% to 28%) and intensive care unit LOS (11 vs 6, P = .201, 95% CI, -5% to 31%) were longer in the 72-hour group. No difference was observed in the incidence of CDI (15% vs 13%, P = 1.000). DISCUSSION: There was no increase in posttransplant infections in the 24-hour cohort. Shorter antibiotic exposure may be associated with a reduction in length of stay and be favorable in this patient population.

Safety and Efficacy of Universal Postoperative Decolonization for Kidney Transplant Recipients.

OBJECTIVES: Infection is a common cause of morbidity and mortality after kidney transplant. Based on the well-documented successes of reducing infections with decolonization of patients in intensive care units, we began a universal immediate posttransplant decolonization program for all kidney transplant recipients. Herein, we report safety and efficacy of this decolonization program. MATERIALS AND METHODS: We compared a consecutive cohort of kidney transplant recipients who underwent universal decolonization (intervention group) with a cohort of transplant patients from an era immediately prior to this practice (control group). Universal decolonization included daily chlorhexidine body wash and nasal mupirocin ointment. RESULTS: Seventy-eight patients who underwent universal decolonization were compared with 43 patients in the control group. Ten microbiologically proven infections (8.3%) occurred in the 30 days after discharge: 7 (9%) in the intervention group and 3 (7%) in the control group. Forty-five transplant recipients (37.2%) were readmitted in the 30 days after discharge: 31 (39.7%) in the intervention group and 14 (32.6%) in the control group. No patients in the intervention group had adverse drug events from mupirocin and chlorhexidine use. CONCLUSIONS: A universal decolonization protocol was successfully implemented and was well tolerated by all patients. Despite successful implementation, we did not observe any significant differences in infection rates between treated patients and historical controls.

Ceftolozane-tazobactam and ceftazidime-avibactam activity against ß-lactam-resistant Pseudomonas aeruginosa and extended-spectrum ß-lactamase-producing Enterobacterales clinical isolates from U.S. medical centres.

BACKGROUND: Despite availability of ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) for several years, the individual spectrum of activity of each agent may not be widely known. We compared the activity of C/T and CZA against convenience samples of 119 extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales and 60 ß-lactam-resistant Pseudomonas aeruginosa clinical isolates collected from three U.S. institutions. METHODS: Minimal inhibitory concentrations (MICs) for C/T and CZA were determined by broth microdilution. Molecular identification of nine ß-lactamase gene targets was conducted for Enterobacterales and P. aeruginosa isolates with increased MICs to C/T or CZA. RESULTS: More than 90% of Enterobacterales isolates demonstrated susceptibility to both C/T and CZA, in contrast to the other traditional ß-lactam agents tested, which were much less active. The MIC50/90 values were nearly equivalent between agents. The most common ß-lactamase genes identified in Enterobacterales isolates with MIC values ≥2 mg/L were the CTX-M-1 group (85%) and CMY-2-like (23%) ß-lactamases. Both agents were active against >80% of ß-lactam-resistant P. aeruginosa isolates tested, most of which had oprD mutations identified. One P. aeruginosa isolate was positive for a Klebsiella pneumoniae carbapenemase-type gene but remained meropenem-susceptible. The MIC50 values were four-fold lower in favour of C/T (1 mg/L vs. 4 mg/L) against P. aeruginosa. CONCLUSIONS: Our data suggest that either agent may be a reasonable choice for centres with a high proportion of ESBL producers; however, C/T may have improved activity against P. aeruginosa and may be preferred in institutions with a higher frequency of resistant pseudomonal isolates.

Impact of an antimicrobial stewardship initiative on time to administration of empirical antibiotic therapy in hospitalized patients with bacteremia.

PURPOSE: The impact of an antimicrobial stewardship initiative on time to first antibiotic dose and clinical outcomes in bacteremic patients was evaluated. METHODS: A single-center, retrospective study was conducted for adult inpatients who received antibiotics before and after implementation of a rapid administration of antimicrobials by an infectious diseases specialist (RAIDS) protocol. Patients admitted to an inpatient service from June to October 2011 (pre-RAIDS protocol) and from December 2011 to February 2012 (post-RAIDS protocol) were eligible for inclusion if (1) they were age 18 years or older, (2) their infection occurred two or more days after hospital admission, and (3) they had a blood culture growing an organism other than common skin contaminants (i.e., coagulase-negative staphylococci, Bacillus species). The primary outcome was the time to the first antibiotic dose (TFAD), defined as the time that elapsed from a positive blood culture result to administration of the first empirical antimicrobial dose. RESULTS: A total of 111 bacteremic patients were included in the analysis. Implementation of the RAIDS protocol led to significantly faster antibiotic order entry, verification, and administration of empirical antibiotics in patients with bacteremia. The median TFAD was approximately 8 hours faster in the post-RAIDS group than in the pre-RAIDS group (9:09 hr:min versus 1:23 hr:min, p < 0.001). Patients in the post-RAIDS group had a significant reduction in infection-related mortality (p = 0.047), though all-cause 30-day mortality was similar. CONCLUSION: Early notification of an infectious diseases pharmacist about positive blood cultures using the RAIDS protocol led to increased appropriateness of empirical drug selection and a dramatic reduction in the administration of antibiotics and was associated with decreased infection-related mortality.

Activity of minocycline against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae clinical isolates, with comparison to doxycycline and tigecycline.

We examined the in vitro activity of minocycline against 103 Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae isolates and found approximately half had susceptible (26%) or intermediate (26%) MICs. For a subset of 35 isolates, susceptibility was highest to tigecycline (71% FDA vs. 20% EUCAST) followed by minocycline (14%) and then doxycycline (6%).

Critical evaluation of ceftolozane-tazobactam for complicated urinary tract and intra-abdominal infections.

The rise in resistant Gram-negative pathogens continues to challenge clinicians treating infections. These resistant infections have inspired the development of new antimicrobial agents, including ceftolozane-tazobactam, a novel ß-lactam/ß-lactamase inhibitor combination approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) in combination with metronidazole. Ceftolozane exhibits bactericidal activity by inhibiting penicillin-binding proteins (PBPs), with high affinity for PBP1b, PBP1c, and PBP3. The addition of tazobactam protects ceftolozane from hydrolysis by irreversibly binding to some ß-lactamase enzymes. Ceftolozane-tazobactam is active against a wide range of Gram-negative pathogens, including extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa, several streptococcal species, and Bacteroides fragilis. When anaerobic coverage is needed, it should be used in combination with metronidazole. Ceftolozane demonstrates linear pharmacokinetics, low protein binding, and minimal accumulation with repeated dosing. The major pharmacokinetic/pharmacodynamic index for ceftolozane is the percentage of the dosing interval in which the plasma free drug concentration remains higher than the minimum inhibitory concentration (%T.MIC). Phase III clinical trials for the treatment of cUTIs and cIAIs have been completed, showing that it is an effective and safe alternative for the treatment of these infections. The approved dose for cUTIs and cIAIs is 1.5 g (1 g ceftolozane and 500 mg tazobactam) infused over 1 hour every 8 hours. A higher 3 g dose is currently in Phase III trials for the treatment of ventilated nosocomial pneumonia. Dosage adjustments are necessary for patients with moderate-to-severe renal impairment. Current data suggest that ceftolozane-tazobactam is a promising carbapenem-sparing alternative agent for the treatment of cUTIs and cIAIs, including those caused by ESBL-producing Enterobacteriaceae and MDR P. aeruginosa.