Therapeutic Monitoring of Vancomycin for Serious Methicillin-resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review 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.

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.

Executive Summary: Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review of 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.

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.

Discrepancy in Vancomycin AUC/MIC Ratio Targeted Attainment Based upon the Susceptibility Testing in Staphylococcus aureus.

This study demonstrated a statistically significant difference in vancomycin minimum inhibitory concentration (MIC) for Staphylococcus aureus between a common automated system (Vitek 2) and the E-test method in patients with S. aureus bloodstream infections. At an area under the serum concentration time curve (AUC) threshold of 400 mg∙h/L, we would have reached the current Infectious Diseases Society of America (IDSA)/American Society of Health System Pharmacists (ASHP)/Society of Infectious Diseases Pharmacists (SIDP) guideline suggested AUC/MIC target in almost 100% of patients while using the Vitek 2 MIC data; however, we could only generate 40% target attainment while using E-test MIC data (p < 0.0001). An AUC of 450 mg∙h/L or greater was required to achieve 100% target attainment using either Vitek 2 or E-test MIC results.

Microbiological Assessment of Polymyxin B Components Tested Alone and in Combination.

We investigated the antimicrobial activity of four polymyxin B components, B1, B2, B3, and isoleucine (Ile)-B1, individually and in combination. B3 was the most active agent against all organisms tested except Acinetobacter baumannii, for which Ile-B1 was most active. One combination met the criteria for synergy, B3 plus Ile-B1. No combinations exhibited antagonism. The dominant components of polymyxin B products (B1 and B2) were associated with the lowest probability of improved antibacterial activity when combined.

Polymyxins: wisdom does not always come with age.

We currently face a lack of new antimicrobial therapies in an era of increasingly common multidrug-resistant (MDR) bacteria. The polymyxins have become last-line treatments for patients with MDR bacterial infections. An increasing body of published literature has attempted to answer questions about dosing, pharmacology, and susceptibility testing of these drugs, yet each takes for granted purity and potency of the 2 available polymyxin products. In the case of polymyxin B, true potency may vary by as much as 40% from the content reported in prescribing information. This poor accuracy is related to quality assurance assays established in the 1940s and currently in use, which have been shown to be significantly flawed in recent investigations. This review discusses the limitations of pharmacological knowledge about polymyxin antimicrobials, the clinical impact of these limitations, and suggestions for further study of these drugs in order to optimize their use clinically.

The Economic Impact of Starting, Stopping, and Restarting an Antibiotic Stewardship Program: A 14-Year Experience.

Regions Hospital started a multidisciplinary antibiotic stewardship program (ASP) in 1998. The program effectively shut down from 2002-2004 as key personnel departed and was then restarted but without the dedicated pharmacist and infectious diseases physician. Purchasing data (in dollars or dollars/patient/day) unadjusted for inflation served as a surrogate marker of antibiotic consumption. These data were reviewed monthly, quarterly, and yearly along with antibiotic susceptibility patterns on a semi-annual basis. Segmented regression analysis was use to compare restricted antibiotic purchases for performance periods of 1998-2001 (construction), 2002-2004 (de-construction), and 2005-2011 (reconstruction). After 4 years (1998-2001) of operation, a number of key participants of the ASP departed. For the following three years (2002-2004) the intensity and focus of the program floundered. This trend was averted when the program was revitalized in early 2005. The construction, deconstruction, and reconstruction of our ASP provided a unique opportunity to statistically examine the financial impact of our ASP or lack thereof in the same institution. We demonstrate a significant economic impact during ASP deconstruction and reconstruction.

Streptococcus pneumoniae serotypes: nine-year experience at a level-one trauma center.

Streptococcus pneumoniae isolates from adults hospitalized with invasive pneumococcal disease (IPD) were collected at Regions Hospital in St. Paul from 2002 through 2010. Of 200 sequential, nonduplicative isolates collected and serotyped, serotypes 3, 7F and 19A were found to be the most common. Since 2008, all IPD cases have been caused by non-PCV7 serotypes. This article describes the study and its findings. It also provides an overview of the three vaccines used to protect against IPD.

Optimal use of fluoroquinolones in the intensive care unit setting.

Fluoroquinolones have become a staple antimicrobial in a variety of settings for a wide spectrum of infectious diseases. Although fluoroquinolones have been associated with a broad spectrum of adverse events, the side effect profile is generally acceptable. Their use in the intensive care unit as empiric therapy is becoming compromised due to the development of multiple drug resistant gram negative pathogens and collateral damage with C difficile & MRSA. Fluoroquinolones should be used along with another antibiotic of different chemical structure, mechanism of action, and pharmacodynamic profile to ensure adequate initial antimicrobial coverage and maximize the likelihood of a favorable clinical and microbiologic response.

Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.

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.

Comparative pharmacodynamics of intermittent and prolonged infusions of piperacillin/tazobactam using Monte Carlo simulation and steady-state pharmacokinetic data from hospitalized patients.

With increasing antibiotic resistance in gram-negative pathogens, dosing strategies that optimize pharmacodynamic parameters of currently available antibiotics play an important role in treatment. The likelihood of success with piperacillin/tazobactam, a widely used broad-spectrum antibiotic, can be manipulated by increasing the amount of time that unbound drug concentrations remain above the pathogen's minimum inhibitory concentration (MIC). However, this success depends greatly on knowing the MIC value as well as accurately estimating the individual's pharmacokinetic parameters. Clinicians should carefully factor these variables into their decision-making process when considering prolonged infusion strategies with piperacillin/tazobactam.

Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists.

Practice guidelines for therapeutic monitoring of vancomycin treatment for Staphylococcus aureus infection in adult patients were reviewed by an expert panel of the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. A literature review of existing evidence regarding vancomycin dosing and monitoring of serum concentrations, in addition to patient outcomes combined with expert opinion regarding the drug's pharmacokinetic, pharmacodynamic, and safety record, resulted in new recommendations for targeting and adjustment of vancomycin therapy.

In vitro pharmacodynamics of moxifloxacin versus levofloxacin against 4 strains of Streptococcus pneumoniae: 1 wild type, 2 first-step parC mutants, and 1 pump mutant.

Levofloxacin binds topoisomerase IV, whereas moxifloxacin preferentially binds DNA gyrase. Most 1st-step pneumococcal mutants have alterations in the parC gene of topoisomerase IV. Because of differential binding affinity, moxifloxacin may have superior activity against 1st-step mutants compared with levofloxacin. The purpose of this work was to compare rates and extent of bacterial killing of genetically characterized Streptococcus pneumoniae with moxifloxacin and levofloxacin. Four strains of S. pneumoniae were used: a wild type, 2 first-step parC mutants, and a pump mutant. Using an in vitro pharmacodynamic model run in duplicate, we exposed bacteria to unbound moxifloxacin and levofloxacin peaks of 2 and 4.5 mg/L, respectively, which emulated clinical dosing. Additional experiments were done in which the area under the curve (AUC)/MIC ratio of 1 agent was matched to the competing drug's clinical dose AUC/MIC ratio. Time kill curves were analyzed for rate and extent of bacterial kill and regrowth. Pre- and postexposure MIC and polymerase chain reaction (PCR) testing were done. Moxifloxacin and levofloxacin displayed similar rates and extent of bacterial kill for the wild type, efflux pump type, and parC mutant 27-1361B. Moxifloxacin initially achieved a faster rate of kill, regardless of the AUC/MIC ratio, against parC mutant 7362 (P < 0.05) but not an advantage in time to 3 log kill. Postexposure MIC values were elevated for strain 7362 in 2 moxifloxacin experiments and 1 levofloxacin experiment. Post-PCR analysis revealed new gyrA mutations for all 3 isolates. Both moxifloxacin and levofloxacin are effective against multiple strains of S. pneumoniae.

Frequency of 1st- and 2nd-step topoisomerase mutations in Streptococcus pneumoniae following levofloxacin and moxifloxacin exposure.

Seven Streptococcus pneumoniae isolates were exposed to inhibitory concentrations of levofloxacin and moxifloxacin in antibiotic-containing agar dilution plates. Colony counts were used to calculate the frequency of mutation. DNA was sequenced to detect mutations in the quinolone resistance-determining regions of the gyrA, gyrB, parC, and parE genes. The wild-type S. pneumoniae isolate developed a parC mutation after exposure to levofloxacin more frequently than it developed a gyrA mutation after exposure to moxifloxacin. The 1st-step gyrA mutant developed a 2nd-step gyrA-parC mutation more frequently after exposure to levofloxacin. Conversely, the transformation from a 1st-step parC mutant to a 2nd-step parC-gyrA mutant occurred more frequently following exposure to moxifloxacin. Our data suggest that the occurrence of a 2nd mutation will be contingent on the location of the 1st mutation and the preferential binding site of the fluoroquinolone that drives the transformation from 1st- to 2nd-step mutant.

In vitro evaluation of the activities of telavancin, cefazolin, and vancomycin against methicillin-susceptible and methicillin-resistant Staphylococcus aureus in peritoneal dialysate.

This study compared the ability of telavancin to the ability of cefazolin and vancomycin to eliminate staphylococci from peritoneal dialysis fluid by using a static in vitro model to simulate the conditions of peritoneal dialysis. The results showed that telavancin exhibited statistically significantly better kill (P < 0.05) against both methicillin-susceptible and methicillin-resistant Staphylococcus aureus.