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The article reports on a revised consensus guideline on therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections. Topics mentioned include grading system for recommendations based on quality of evidence, key topics assigned to committee members regarding vancomycin dosing and monitoring, and the importance of generating valid estimates of the area under the curve values through Bayesian modeling techniques.

Fosfomycin was initially discovered in 1969 but has recently gained renewed interest for the treatment of multidrug‐resistant (MDR) bacterial infections, particularly in the United States. Its unique mechanism of action, bactericidal activity, broad spectrum of activity, and relatively safe and tolerable adverse effect profile make it a great addition to the dwindling antibiotic armamentarium. Fosfomycin contains a three‐membered epoxide ring with a direct carbon to phosphorous bond that bypasses the intermediate oxygen bond commonly present in other organophosphorous compounds; this structure makes the agent unique from other antibiotics. Despite nearly 50 years of parenteral fosfomycin use in Europe, fosfomycin has retained stable activity against most pathogens. Furthermore, fosfomycin demonstrated in vitro synergy in combination with other cell wall–active antibiotics (e.g., β‐lactams, daptomycin). These combinations may offer respite for severe infections due to MDR gram‐positive and gram‐negative bacteria. The intravenous (IV) formulation is currently under review in the United States, and apropos, this review collates more contemporary evidence (i.e., studies published between 2000 and early 2019) in anticipation of this development. The approval of IV fosfomycin provides another option for consideration in the management of MDR infections. Its unique structure will give rise to a promising epoxide epoch in the battle against MDR bacteria. [ABSTRACT FROM AUTHOR]

Study Objective. To evaluate the clinical response and safety of high-dose daptomycin for treatment of complicated gram-positive infections. Design. Multicenter, retrospective, observational, case series analysis. Setting. Five academic medical centers in four major United States cities. Patients. Two hundred fifty adults, not undergoing dialysis, who received high-dose daptomycin (≥ 8 mg/kg/day) for at least 72 hours for complicated gram-positive infections between January 1, 2005, and March 1, 2010. Measurements and Main Results. Clinical and microbiologic outcomes were assessed at the end of high-dose daptomycin therapy. Safety evaluations were recorded for all patients, and when available, baseline, end-of-therapy, and highest observed serum creatine phosphokinase (CPK) levels were recorded. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) were the primary organisms isolated. The median dose of daptomycin was 8.9 mg/kg/day (interquartile range [IQR] 8.0-10.0 mg/kg/day). The median duration of daptomycin during hospitalization for MRSA and VRE infection was 10 days (IQR 5-16 days) and 13 days (IQR 6-18 days), respectively. Among the 250 patients, high-dose daptomycin was primarily used as salvage therapy after vancomycin treatment (184 patients [73.6%]). Primary infections included complicated bacteremia (119 patients [47.6%1), endocarditis (59 [23.6%]), skin or wound (70 [28.0%]), and bone or joint (67 [26.8%]). Overall, clinical response and microbiologic success were assessed in 83.6% (209/250 patients) and 80.3% (175/218 patients), respectively. Isolates from 13 patients (5.2%) developed nonsusceptibility to daptomycin, with most of these patients having extended vancomycin exposure. Three patients (1.2%) developed an adverse event attributable to high-dose daptomycin therapy, with the event considered either mild or moderate in severity The median end-of-therapy CPK level was 39 U/L (IQR 26-67 U/L). No significant correlation was found between daptomycin dose and highest observed CPK level. Conclusion. Daptomycin dosages of 8 mg/kg/day or greater may be safe and effective in patients with complicated gram-positive infections. Further clinical studies are warranted. [ABSTRACT FROM AUTHOR]

Vancomycin is a commonly used antibiotic due to its effectiveness in treating serious gram-positive infections caused by methicillin-resistant Staphylococcus aureus. As commercial drug assays and a multitude of pharmacokinetic data from a variety of patient populations are widely available, therapeutic monitoring of serum vancomycin concentrations is frequently performed by clinicians, with the expectation that targeting the concentrations within a relatively narrow range can minimize toxicity yet still achieve therapeutic success. Much debate exists, however, over the value of routine therapeutic monitoring of vancomycin levels because of conflicting evidence regarding the ability of serum concentrations to predict effectiveness or prevent toxicity. In addition, studies have suggested that the potential for nephrotoxicity or ototoxicity with vancomycin monotherapy is minimal at conventional dosages of 1 g (15 mg/kg) every 12 hours. However, increased rates of nephrotoxicity have recently been reported with doses of 4 g/day or higher. The American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists published a consensus statement on therapeutic monitoring of serum vancomycin levels in adults. These organizations established an expert panel to review the scientific data and controversies associated with vancomycin monitoring and to make recommendations based on the available evidence. As the members of this panel, we summarize the conclusions and highlight the recommendations from the consensus statement. We determined that the area under the concentration-time curve (AUC):minimum inhibitory concentration (MIC) ratio is the most useful pharmacodynamic parameter to predict vancomycin effectiveness and suggested a target ratio of 400 or greater to eradicate S. aureus. In addition, trough serum concentration monitoring is the most accurate and practical method to monitor vancomycin serum levels. Increasing trough concentrations to 15-20 mg/L to attain the target AUC:MIC ratio may be desirable but is currently not supported by clinical trials. Alternative therapies should be considered in patients with S. aureus infections that demonstrate a vancomycin MIC of 2 mg/L or greater because the target AUC:MIC ratio (≥ 400) is unlikely to be achieved in this setting. Increasing the dosage to result in higher trough concentrations may increase the potential for toxicity; however additional clinical experience is required to determine the extent. [ABSTRACT FROM AUTHOR]

In response to the global antibiotic resistance crisis, antimicrobial stewardship programs have emerged throughout the United States. Effective programs integrate several strategic methods, including evaluation and feedback regarding the necessity and appropriateness of antimicrobial therapy, staff education, and formulary restrictions. Multidisciplinary teams as well as institutional support are needed to form effective subcommittees to monitor national and local surveillance reports and resistance patterns, and to update antibiograms. Computerized decision support programs have been effective and successful methods of antimicrobial stewardship and can be a powerful tool in stewardship programs. Successful programs have reduced not only institutional resistance rates, but also morbidity, mortality, and cost. [ABSTRACT FROM AUTHOR]

Study Objective. To differentiate the characteristics of community-associated methicillin-resistant Staphylococcus aureus (MRSA) and hospital-associated MRSA isolates on the basis of their susceptibility profiles, induction of clindamycm resistance, and staphylococcal chromosomal cassette (SCC) mec types. Design. In vitro molecular and susceptibility study of isolates obtained from December 2004-January 2006 as part of a large, ongoing clinical study. Setting. Level I trauma center in Detroit, Michigan. Bacterial Strains. Three hundred eight MRSA isolates randomly collected from patients; 130 were classified as community-associated, and 178 were classified hospital-associated by using definitions from the Centers for Disease Control and Prevention (CDC). Intervention. Minimum inhibitory concentrations were tested on the basis of current guidelines from the Clinical and Laboratory Standards Institute. Measurements and Main Results. All tested MRSA isolates were susceptible to daptomycin, linezolid, and vancomycin. In addition, community-associated MRSA isolates were significantly (all p≤0.05) more susceptible to trimethoprim-sulfamethoxazole (99%), clindamycin (96%), and a fluoroquinolone (76%) than hospital-associated MRSA isolates. Inducible resistance to clindamycin was demonstrated in 8.4% of community-associated MRSA isolates versus 50% of hospital-associated MRSA isolates (p≤0.001). Of interest, 35% of the MRSA isolates collected from hospitalized patients (> 48 hrs alter admission and according to the CDC definition) possessed SCCmec type IV. Conclusion. Overall, inducible clindamycin resistance occurred at significantly higher rates in the hospital-associated MRSA isolates, susceptibility differed significantly between community- and hospital-associated MRSA, and most of the hospital isolates contained SCCmec type IV. [ABSTRACT FROM AUTHOR]

Background Daptomycin and ceftaroline (DAP-CPT) have been used for persistent methicillin-resistant Staphylococcus aureus bacteremia (MRSAB), but have rarely been compared with other therapies. This study provides an exploratory analysis of patients placed on DAP-CPT vs standard of care (SOC) for MRSAB. Methods This is a retrospective, matched cohort study MRSAB patients at 4 hospitals in the United States. Patients receiving DAP-CPT for ≥72 hours at any point in therapy were matched 2:1 when possible, 1:1 otherwise, to SOC, first by infection source, then age and renal function. SOC was empiric treatment with vancomycin or daptomycin and any subsequent combination antibiotic(s), except for DAP-CPT. Results Fifty-eight patients received DAP-CPT with 113 matched SOC. Ninety-six percent of SOC received vancomycin, and 56% (63/113) escalated therapy at least once in the treatment course. Twenty-four patients received DAP-CPT within 72 hours of index culture; 2 (8.3%) died within 30 days vs 14.2% (16/113) with SOC (P > .05). Subgroup analysis identified numerically lower mortality in DAP-CPT patients with a Charlson comorbidity index ≥3, endovascular source, and receipt of DAP-CPT within 72 hours of index culture. The median MRSAB duration was 9.3 vs 4.8 days for DAP-CPT and SOC, respectively. DAP-CPT was initiated on day 6 on average; after receipt of DAP-CPT, MRSAB duration was 3.3 days. Conclusions DAP-CPT treatment is often delayed in MRSAB. Combination therapy may be more beneficial if initiated earlier, particularly in patients at higher risk for mortality. Blinded, randomized, prospective studies are needed to eliminate selection bias inherent in retrospective analyses when examining DAP-CPT vs SOC. [ABSTRACT FROM AUTHOR]

Background We conducted this study to describe the clinical characteristics, microbiology, and outcomes of patients treated with ceftazidime-avibactam (CZA) for a range of multidrug-resistant Gram-negative (MDR-GN) infections. Methods This is a multicenter, retrospective cohort study conducted at 6 medical centers in the United States between 2015 and 2019. Adult patients who received CZA (≥72 hours) were eligible. The primary outcome was clinical failure defined as a composite of 30-day all-cause mortality, 30-day microbiological failure, and/or failure to resolve or improve signs or symptoms of infection on CZA. Results In total, data from 203 patients were evaluated. Carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas spp were isolated from 117 (57.6%) and 63 (31.0%) culture specimens, respectively. The most common infection sources were respiratory (37.4%), urinary (19.7%), and intra-abdominal (18.7%). Blood cultures were positive in 22 (10.8%) patients. Clinical failure, 30-day mortality, and 30-day recurrence occurred in 59 (29.1%), 35 (17.2%), and 12 (5.9%) patients, respectively. On therapy, CZA resistance developed in 1 of 62 patients with repeat testing. Primary bacteremia or respiratory tract infection and higher SOFA score were positively associated with clinical failure (adjusted odds ratio [aOR] = 2.270, 95% confidence interval [CI] = 1.115–4.620 and aOR = 1.234, 95% CI = 1.118–1.362, respectively). Receipt of CZA within 48 hours of infection onset was protective (aOR, 0.409; 95% CI, 0.180–0.930). Seventeen (8.4%) patients experienced a potential drug-related adverse effect (10 acute kidney injury, 3 Clostridioides difficile infection, 2 rash, and 1 each gastrointestinal intolerance and neutropenia) Conclusions Ceftazidime-avibactam is being used to treat a range of MDR-GN infections including Pseudomonas spp as well as CRE. [ABSTRACT FROM AUTHOR]

Background Vancomycin (VAN) has been the standard empiric antibiotic for the treatment of hospitalized patients with acute bacterial skin and skin structure infections (ABSSSI) for decades but its use can be complicated by acute kidney injury (AKI). The substantial morbidity and mortality associated with AKI underscores the need to identify ABSSSI patients at increased risk for this complication. The objective of this study was to derive a clinical prediction model for VAN-associated AKI (VAN-AKI) in hospitalized patients with ABSSSI and at least one baseline traditional risk factor for AKI. Methods This was a multicenter, retrospective, case–control study between 2015 and 2018 conducted at seven academic medical centers in the USA. The population of interest was hospitalized adults with ABSSSI treated with VAN ≥72 h and initiated ≤24 h of admission. Cases consisted of patients who developed AKI according to the RIFLE criteria during VAN or ≤72 h of discontinuation. Patients who did not develop AKI served as controls. Independent predictors of VAN-AKI were identified through multivariable logistic regression. A risk score was derived using a weighted coefficient-based scoring system. Results A total of 284 patients (28 cases and 256 controls) were included. Independent predictors of VAN-AKI included in the score were: metastatic cancer, ICU admission at VAN initiation, alcohol abuse, ≥2 nephrotoxins, mental health disease, lower extremity ABSSSI and prior ABSSSI within 1 year. Patients with mental health disease had a variety of advanced chronic comorbidities and substance use. The median risk score in cases and controls was 9 (7, 11) and 4 (3.7) (P < 0.001), respectively. The risk score area under the receiver operator curve was 0.803 (95% CI 0.712, 0.894). The sensitivity, specificity, positive predictive value and negative predictive value of the risk score using a threshold of 5 points was 89.29% (95% CI 70.63%, 97.19%), 51.56% (42.27%, 57.81%), 16.78% (11.35%, 23.97%) and 97.78% (93.14%, 99.42%), respectively. Conclusion The risk score developed in this study provides a standardized, evidenced-based approach to identify hospitalized patients with ABSSSI at higher risk for VAN-AKI. External validation is required before widespread use. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Purpose The coronavirus disease 2019 (COVID-19) pandemic has impacted the activities of healthcare workers, including postgraduate pharmacy trainees. Quality training experiences must be maintained to produce competent pharmacy practitioners and maintain program standards. Methods A cross-sectional survey of postgraduate pharmacy trainees in the United States was conducted to evaluate training experience changes and assess perceived impacts on residents and fellows following the COVID-19 pandemic's onset. Results From June 4 through June 22, 2020, 511 pharmacy trainees in 46 states completed the survey. Participants' median age was 26 (interquartile range [IQR], 25-28) years, with included responses from postgraduate year 1 residents (54% of sample), postgraduate year 2 residents (40%), and postgraduate fellows (6%). Compared to experiences prior to the onset of the COVID-19 pandemic, fewer trainees conducted direct patient care (38.5% vs 91.4%, P < 0.001), more worked from home (31.7% vs 1.6%, P < 0.001), and less time was spent with preceptors per day (2 [IQR, 2-6] hours vs 4 [IQR, 1-4] hours, P < 0.001). Sixty-five percent of respondents reported experiencing changes in their training program, 39% reported being asked to work in areas outside of their routine training experience, and 89% stated their training shifted to focus on COVID-19 to some degree. Most respondents perceived either major (9.6%) or minor (52.0%) worsening in quality of experience, with major and minor improvement in quality of experience reported by 5.5% and 8.4% of respondents, respectively. Conclusion Pharmacy resident/fellow experiences were perceived to have been extensively impacted by the COVID-19 pandemic in varying ways. Our findings describe shifts in postgraduate training and may aid in the development of best practices for optimizing trainee experiences in future crises. [ABSTRACT FROM AUTHOR]

Purpose: Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin. Methods: All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed. Findings: Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus, 2 methicillinsusceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis). Bacteremia persisted for a median of 10 days (range, 3-23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1-6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model. Implications: Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen. [ABSTRACT FROM AUTHOR]

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a difficult-to-treat nosocomial pathogen responsible for significant morbidity and mortality. Sulbactam-durlobactam (SUL-DUR), formerly ETX2514SUL, is a novel β-lactam-β-lactamase inhibitor designed specifically for the treatment of CRAB infections. The United States Food and Drug Administration (FDA) fast-track approval of SUL-DUR for the treatment of CRAB infections is currently pending after completion of the phase III ATTACK trial, which compared SUL-DUR to colistin, both in combination with imipenem-cilastatin (IMI) for patients with CRAB-associated hospital-acquired bacterial pneumonia, ventilator-associated pneumonia, and bacteremia. The results of this trial demonstrated that SUL-DUR was non-inferior to colistin for CRAB while also possessing a much more favorable safety profile. SUL-DUR was well-tolerated with the most common side effects being headache, nausea, and injection-site phlebitis. With the current landscape of limited effective treatment options for CRAB infections, SUL-DUR represents a promising therapeutic option for the treatment of these severe infections. This review will discuss the pharmacology, spectrum of activity, pharmacokinetics/pharmacodynamics, in vitro and clinical studies, safety, dosing, administration, as well as the potential role in therapy for SUL-DUR., (© 2023 Pharmacotherapy Publications, Inc.)

Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400-600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Recent vancomycin PK/PD and toxicodynamic studies enable a reassessment of the current dosing and monitoring guideline in an attempt to further optimize the efficacy and safety of vancomycin therapy. The area-under-the-curve to minimum inhibitory concentration (AUC/MIC) has been identified as the most appropriate pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin. The 2009 vancomycin consenus guidelines recommended specific trough concentrations as a surrogate marker for AUC/MIC. However, more recent toxicodynamic studies have reported an increase in nephrotoxicity associated with trough monitoring., Methods and Results: This is the executive summary of the new vancomycin consensus guidelines for dosing and monitoring vancomycin therapy and was developed by the American Society of Health-Systems Pharmacists, Infectious Diseases Society of America, Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee., Conclusions: The recommendations provided in this document are intended to assist the clinician in optimizing vancomycin for the treatment of invasive MRSA infections in adult and pediatric patients. An AUC/MIC by broth microdilution (BMD) ratio of 400 to 600 (assuming MICBMD of 1 mg/L) should be advocated as the target to achieve clinical efficacy while improving patient safety for patients with serious MRSA infections. In such cases, AUC-guided dosing and monitoring is the most accurate and optimal way to manage vancomycin therapy., (© 2020 Pharmacotherapy Publications, Inc.)

Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and P. aeruginosa was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population ( n  = 226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio [aOR], 2.472 and 95% confidence interval [CI], 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ≥1 adverse effect (9 acute kidney injury, 13 Clostridioides difficile infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections., (Copyright © 2020 American Society for Microbiology.)

We sought to define trends in and predictors of carbapenem consumption across community, teaching, and university-affiliated hospitals in the United States and Canada. We conducted a retrospective multicenter survey of carbapenem and broad-spectrum noncarbapenem beta-lactam consumption between January 2011 and December 2013. Consumption was tabulated as defined daily doses (DDD) or as days of therapy (DOT) per 1,000 patient days (PD). Multivariate mixed-effects models were explored, and final model goodness of fit was assessed by regressions of observed versus predicted values and residual distributions. A total of 20 acute-care hospitals responded. The centers treated adult patients ( n  = 19/20) and pediatric/neonatal patients ( n  = 17/20). The majority of the centers were nonprofit ( n  = 17/20) and not affiliated with medical/teaching institutions ( n  = 11/20). The median (interquartile range [IQR]) carbapenem consumption rates were 38.8 (17.4 to 95.7) DDD/1,000 PD and 29.7 (19.2 to 40.1) DOT/1,000 PD overall. Carbapenem consumption was well described by a multivariate linear mixed-effects model (fixed effects, R 2 = 0.792; fixed plus random effects, R 2 = 0.974). Carbapenem consumption increased by 1.91-fold/quarter from 48.6 DDD/1,000 PD ( P  = 0.004) and by 0.056-fold/quarter from 45.7 DOT/1,000 PD ( P  = 0.93) over the study period. Noncarbapenem consumption was independently related to increasing carbapenem consumption (beta = 0.31 for increasing noncarbapenem beta-lactam consumption; P < 0.001). Regular antibiogram publication and promotion of conversion from intravenous (i.v.) to oral (p.o.) administration independently affected carbapenem consumption rates. In the final model, 58.5% of the observed variance in consumption was attributable to between-hospital differences. Rates of carbapenem consumption across 20 North American hospitals differed greatly, and the observed differences were correlated with hospital-specific demographics. Additional studies focusing on the drivers of hospital-specific carbapenem consumption are needed to determine whether these rates are justifiable., (Copyright © 2019 American Society for Microbiology.)

Study Objectives: To describe the implementation of vancomycin dosing and monitoring practices recommended by the consensus guidelines in a diverse sample of hospitals, and to identify needs for quality improvement and research., Design: Cross-sectional study using an online survey instrument., Setting: Making a Difference in Infectious Diseases Pharmacotherapy (MAD-ID) Research Network., Participants: A total of 163 respondents from MAD-ID who work in antimicrobial stewardship and represent unique hospitals., Measurements and Main Results: The survey population represented a wide range of patient populations (96% adult, 49% pediatric, and 23% long-term care) and settings (52% not-for-profit nonuniversity, 31% university based, and 11% for profit). Automatic consultation of pharmacy services for all vancomycin dosing was reported in 51% of the institutions. Among the dosing and monitoring practices endorsed by the consensus guidelines, participant institutions commonly followed these recommendations: use of trough concentrations without peak concentrations, maintenance of trough concentration higher than 10 mg/L, and target trough concentrations of 15-20 mg/L for complicated infections. In contrast, there was less consistent application of appropriate timing of trough concentrations, use of loading doses, and use of actual body weight. The remaining challenges and controversies surrounding vancomycin dosing are discussed., Conclusion: Despite the availability of consensus guideline recommendations, practices for dosing and monitoring of vancomycin are not universally applied. The findings of this survey highlight many opportunities for future research and quality improvement strategies., (© 2013 Pharmacotherapy Publications, Inc.)

In published studies, cohorts of patients with bacteremia due to vancomycin-resistant Enterococcus (VRE) have predominantly been infected with Enterococcus faecium. Little is known about the epidemiology and outcomes associated with bacteremia due to VR Enterococcus faecalis. A retrospective study of isolates obtained from January 2008 to October 2010 was conducted at Detroit Medical Center (DMC). Unique patients with blood cultures positive for VRE were reviewed. Outcomes were analyzed using logistic regression. During the study period, 105 cases of bacteremia due to VR E. faecalis and 197 cases of bacteremia due to VR E. faecium were identified. The mean age in the study cohort was 61.5 ± 15 years; 162 subjects (53.6%) were male. After controlling for a propensity score, bacteremia due to VR E. faecalis was associated with >2-fold-lower in-hospital mortality than bacteremia due to VR E. faecium. Interestingly, bacteremia due to VR E. faecalis was associated with longer hospital stay after VRE isolation, although total length of stay was similar for groups with VR E. faecalis and VR E. faecium. Bacteremia due to VR E. faecalis was associated with a >2-fold-lower risk for mortality than bacteremia due to VR E. faecium, possibly due to the availability of β-lactam therapeutics for treatment of VR E. faecalis.

Background: The bactericidal activities of vancomycin and daptomycin were evaluated in a large collection of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia strains from nine major USA medical centres., Objectives: To evaluate the occurrence of heterogeneous vancomycin-intermediate S. aureus (hVISA) among MRSA strains tolerant to vancomycin and/or with increased vancomycin or daptomycin MIC values. The accuracy of the macro Etest method (MET) compared with population analysis profiling (PAP) for the detection of hVISA was also assessed., Methods: A total of 1800 MRSA strains were collected from bloodstream infections at the nine sites (40 strains per year, per medical centre during the 2002-06 study period). Vancomycin and daptomycin MIC testing was performed by reference broth microdilution (all strains) and MBC tests on 50% of strains (randomly selected). A subset of isolates (n = 268) having an increased vancomycin MBC (> or =16 mg/L), an increased vancomycin MIC (> or =1 mg/L) and/or an increased daptomycin MIC (>0.5 mg/L) were tested for susceptibility to vancomycin and teicoplanin by MET., Results: Overall, 181 of 900 (20.1%) MRSA tested exhibited vancomycin tolerance, varying from 10% to 43% among the medical centres evaluated, and from 11.7% in 2004 to 27.8% in 2005. No resistance trend was observed in any medical centre or in the overall study data. Daptomycin showed bactericidal activity against all strains tested. The accuracy of MET for identifying hVISA strains varied significantly with the criteria applied for positivity., Conclusions: The most frequently used criteria to define hVISA, i.e. MET reading values > or =8 mg/L for both vancomycin and teicoplanin or > or =12 mg/L for teicoplanin only, detected 20 of 36 PAP-positive strains (55.6% sensitivity), indicating that the prevalence of hVISA could be higher than currently appreciated. Daptomycin was bactericidal against hVISA strains.

Vancomycin MIC creep has been reported by some institutions but not confirmed in large surveillance studies. We evaluated the possible occurrence of MIC creep when testing vancomycin and daptomycin against methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA) by using precise incremental reference MIC methods. Nine hospitals (one in each U.S. census region) randomly selected bloodstream MRSA strains (target, 40/year) from 2002 to 2006. MICs were determined by the reference broth microdilution method using incremental dilutions (eight for each log(2) dilution step). Isolates for which vancomycin MICs were >1 microg/ml were typed by pulsed-field gel electrophoresis (PFGE). The vancomycin MIC mode was either 0.625 microg/ml (for eight hospitals) or 0.813 microg/ml (for one hospital), and vancomycin MIC results for 72.9% of strains were between 0.563 and 0.688 microg/ml. No yearly variation in the central tendency of vancomycin MICs for the wild-type population in any medical center was observed; however, when data were analyzed by the geometric mean statistic, vancomycin MIC increases (at three sites) and declines (at three sites) were observed. The daptomycin MIC mode varied from 0.156 microg/ml (2003 to 2005) to 0.219 microg/ml (2002 and 2006), and MIC results for 83.5% (80.3 to 89.2% in each of the centers) of isolates fell between these values. Among PFGE-typed strains, 43 of 55 (78%; from seven hospitals) showed a pattern consistent with that of the USA100 clone, which was represented by all strains from two hospitals and 64 to 88% of strains from five other medical centers; only one strain (2%) was USA300. In conclusion, the perception of MIC creep may vary according to the methods used to analyze the data. Geometric mean MIC data revealed a possible, very-low-level MIC creep at three of nine sites over the 5-year period, which was not evident using modal MICs or the data from all nine hospitals (+0.02 mug/ml). The occurrence of isolates for which the vancomycin MIC was >1 microg/ml was very unusual, with no increased trend, but these organisms were usually clonal (USA100).

Community-acquired respiratory tract infections (CARTIs), including community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis, remain substantial sources of morbidity and mortality in the US. The increasing prevalence of antimicrobial-resistant strains among the common respiratory pathogens, particularly Streptococcus pneumoniae, has complicated the choice of antimicrobials and threatens the efficacy of treatment for CARTIs. This highlights the need both for ongoing surveillance efforts to track current resistance patterns and for the development of new antimicrobial agents effective against resistant organisms. To provide current and ongoing antimicrobial resistance surveillance data, including comparisons of telithromycin (the first ketolide to undergo clinical development and be approved by the Food and Drug Administration) with other agents, a longitudinal global surveillance study--Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT)--was launched in 1999. A US component of this study was initiated in 2000, and results from the first respiratory infection tracking season (2000-2001) are discussed in this article. Providing resistance data on the national, regional, and local levels, PROTEKT US has thus far confirmed the increasing prevalence of resistant S. pneumoniae isolates to beta-lactams and macrolides, as well as the emergence of fluoroquinolone resistance in the US. Importantly, telithromycin was highly active against S. pneumoniae, including resistant isolates.

Background: The PROTEKT US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the United States) surveillance programme was started in 2000, to chart the emergence and spread of antimicrobial resistance among isolates of Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae from across the USA., Methods: In 2001-2002 (Year 2 of PROTEKT US) 242 centres from 46 states and the territory of Puerto Rico submitted a total of 10 012 S. pneumoniae, 4508 S. pyogenes and 3296 H. influenzae isolates from community-acquired respiratory tract infections (CARTIs). Susceptibility testing was performed and interpreted using NCCLS methodology and criteria., Results: Overall, 35.4% of S. pneumoniae were non-susceptible to penicillin (14.2% intermediate, MIC 0.12-1 mg/L; 21.2% resistant, MIC > or =2 mg/L) and 27.9% were resistant to erythromycin (MIC > or =1 mg/L) (0.2% intermediate, MIC 0.5 mg/L). A total of 105 (1.0%) isolates were resistant to levofloxacin (MIC > or =8 mg/L). More than 99.2% of isolates were susceptible to telithromycin (MIC < or =1 mg/L) irrespective of penicillin and/or erythromycin resistance. All S. pyogenes isolates were susceptible to penicillin (MIC < or =0.12 mg/L) and 5.7% were resistant to erythromycin (MIC > or =1 mg/L) (0.3% intermediate, MIC 0.5 mg/L). The MIC90 of telithromycin for S. pyogenes was 0.03 mg/L. A total of 27.5% of H. influenzae isolates were beta-lactamase producers. Overall, 27.8% were resistant (MIC > or =4 mg/L) and 1.1% were intermediate to ampicillin (MIC 2 mg/L). A total of 96.3% of H. influenzae isolates were susceptible to telithromycin (MIC < or =4 mg/L)., Conclusions: Antimicrobial resistance continues to be a problem in the USA. The ketolide telithromycin continues to show high activity against common CARTI pathogens, including those resistant to beta-lactams and macrolides.