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.

ZTI-01 (fosfomycin for injection) in the treatment of hospitalized patients with complicated urinary tract infections.

Fosfomycin is a bactericidal antibiotic available since the 1970s whose intravenous formulation has been available in many countries outside the USA. Given the rise in drug-resistant bacteria, its introduction into the US market has become a necessity for addressing these organisms. This review provides an overview of the microbiology, clinical pharmacology and initial clinical experiences of the intravenous fosfomycin product (ZTI-01) that is undergoing clinical development in the USA for the treatment of complicated urinary tract infections and acute pyelonephritis.

Prolonged infusions of ß-lactam antibiotics: implication for antimicrobial stewardship.

The optimal dosage and administration of antibiotics are not only important measures to combat antimicrobial resistance, but they are also integral to antimicrobial stewardship. In light of a diminishing antibiotic pipeline and an alarming rise in resistance, the optimal dosage and administration of antimicrobial agents have been under a great deal of scrutiny. Prolonged infusions of ß-lactam antibiotics have been proposed as an alternate dosing strategy. To summarize the evidence on prolonged infusions of ß-lactam agents and provide their clinical implications for antimicrobial stewardship, we performed a MEDLINE search (1950-2011) of all relevant articles. This article provides a review of data from Monte Carlo simulations, clinical outcome analyses, and pharmacoeconomic studies. Furthermore, protocol implementation strategies are discussed to address antimicrobial stewardship.

Antibiotic drug interactions.

Drug-drug interactions in the field of infectious diseases continue to expand as new drugs are approved, metabolic enzymes and transporters are identified, and recommendations for co-administration of drugs are revised. This article provides an overview of the principles and mechanisms of drug-drug interactions and describes pharmacokinetic-pharmacodynamic interactions commonly associated with antibacterial therapy, antiviral agents (non-retroviral), and drugs for tuberculosis.

Daptomycin: a novel cyclic lipopeptide antimicrobial.

PURPOSE: The development, activity, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effects, and dosage and administration of daptomycin are reviewed. SUMMARY: Daptomycin, a novel cyclic lipopeptide antimicrobial, is bactericidal against a range of gram-positive bacteria, including many multiple-drug-resistant isolates. It has only minimal activity against anaerobic bacteria and no activity against gram-negative bacteria. Daptomycin exhibits linear pharmacokinetics, and the plasma concentration-versus-time relationship is best described by a two-compartment model with first-order elimination. The initial bactericidal activity is rapid, extensive, and concentration related. In clinical trials, daptomycin has shown efficacy in treating complicated skin and skin-structure infections (CSSSIs); the drug carries FDA-approved labeling for same. The adverse effects of daptomycin appear comparable to those of vancomycin and semisynthetic penicillins. The dosage for CSSSIs is 4 mg/kg by i.v. infusion every 24 hours. CONCLUSION: Daptomycin is bactericidal against gram-positive organisms and offers an option in the treatment of CSSSIs.

Levofloxacin plus metronidazole administered once daily versus moxifloxacin monotherapy against a mixed infection of Escherichia coli and Bacteroides fragilis in an in vitro pharmacodynamic model.

Moxifloxacin has been suggested as an option for monotherapy of intra-abdominal infections. Recent data support the use of a once-daily metronidazole regimen. The purpose of this study was to investigate the activity of levofloxacin (750 mg every 24 h [q24h]) plus metronidazole (1,500 mg q24h) compared with that of moxifloxacin (400 mg q24h) monotherapy in a mixed-infection model. By using an in vitro pharmacodynamic model in duplicate, Escherichia coli and Bacteroides fragilis were exposed to peak concentrations of 8.5 mg of levofloxacin/liter q24h, 32 mg of metronidazole/liter q24h, and 2 mg for moxifloxacin/liter q24h for 24 h. The activities of levofloxacin, metronidazole, moxifloxacin, and levofloxacin plus metronidazole were evaluated against E. coli, B. fragilis, and E. coli plus B. fragilis. The targeted half-lives of levofloxacin, metronidazole, and moxifloxacin were 8, 8, and 12 h, respectively. Time-kill curves were analyzed for time to 3-log killing, slope, and regrowth. Pre- and postexposure MICs were determined. The preexposure levofloxacin, metronidazole, and moxifloxacin MICs for E. coli and B. fragilis were 0.5 and 1, >64 and 0.5, and 1 and 0.25 mg/liter, respectively. Levofloxacin and moxifloxacin achieved a 3-log killing against E. coli and B. fragilis in all experiments, as did metronidazole against B. fragilis. Metronidazole did not decrease the starting inoculum of E. coli. The area under the concentration-time curve/MIC ratios for E. coli and B. fragilis were 171.7 and 85.9, respectively, for levofloxacin and 26 and 103.9, respectively, for moxifloxacin. Levofloxacin plus metronidazole exhibited the fastest rates of killing. The levofloxacin and moxifloxacin MICs for B. fragilis increased 8- to 16-fold after the organism was exposed to moxifloxacin. No other changes in the postexposure MICs were found. Levofloxacin plus metronidazole administered once daily exhibited activity similar to that of moxifloxacin against the mixed E. coli and B. fragilis infection. A once-daily regimen of levofloxacin plus metronidazole looks promising for the treatment of intra-abdominal infections.

A physiological pharmacokinetic model describing the disposition of lycopene in healthy men.

A physiological pharmacokinetic model was developed to describe the disposition of lycopene, delivered as a tomato beverage formulation in five graded doses (10, 30, 60, 90, or 120 mg), for a phase I study in healthy male subjects (five per dose). Blood was collected before dose administration (0 h) and at scheduled intervals until 672 h. Serum concentrations of carotenoids and vitamins were measured by high performance liquid chromatography analysis. The model was comprised of seven compartments: gastrointestinal tract, enterocytes, chylomicrons, plasma lipoproteins, fast-turnover liver, slow-turnover tissues, and a delay compartment before the enterocytes. As predicted, the percent absorption at the 10 mg dose (33.9 +/- 8.1%) was significantly greater than at the higher doses; however, the amount of lycopene absorbed (mg) was not statistically different (mean: 4.69 +/- 0.55 mg) between doses, suggesting a possible saturation of absorptive mechanisms. The slow-turnover tissue compartment served as a slow-depleting reservoir for lycopene, and the liver represented the fast-turnover pool. Independent of dose, 80% of the subjects absorbed less than 6 mg of lycopene. This may have important implications for planning clinical trials with pharmacological doses of lycopene in cancer control and prevention if absorption saturation occurs at levels that are already being consumed in the population.