Empiric therapy for gram-negative pathogens in nosocomial and health care-associated pneumonia: starting with the end in mind.

Nosocomial pneumonia is a major cause of morbidity and mortality for hospitalized patients. Antimicrobial resistance is increasing, creating a strain between ensuring the provision of adequate empiric therapy and slowing the development of antimicrobial resistance. Excessive antimicrobial therapy places patients are at greater risk of drug interactions, adverse events, and superinfections. Ways to maximize adequate empiric therapy include (1) categorizing each patient's risk of being infected with a multidrug-resistant pathogen and knowledge of local susceptibility patterns, (2) de-escalating antimicrobial therapy to decrease the rates of superinfections such as Clostridium difficile, and (3) limiting the duration of therapy to decrease the likelihood of adverse events, drug interactions, and antimicrobial resistance. Pharmacodynamically enhanced dosing regimens also have the potential to improve clinical outcomes and slow the development of antimicrobial resistance. Drugs whose killing is optimized by the percentage time above the minimum inhibitory concentration (MIC), such as beta-lactams, can be given by continuous or extended infusion to provide superior pharmacodynamic (PD) target attainment rates compared with traditional regimens. Drugs whose killing is optimized with a high-peak plasma concentration to MIC ratio (eg, aminoglycosides) should be administered once daily to maximize the likelihood of achieve optimal target attainment rates. Drugs whose killing is optimized by the ratio of the area under the curve (AUC) to MIC ratio (eg, fluoroquinolones) depend on the total daily dose as opposed to the dosing schedule or infusion time. Determining the optimal drug dosing schedules for obese patients remains critical because these patients have may have significantly increased volumes of distribution and clearance rates compared to normal weight patients. Optimizing the use of current antimicrobials is paramount to ensure quality treatment options are available, given the lack of gram-negative antimicrobials in the pipeline.

Vancomycin-associated nephrotoxicity: grave concern or death by character assassination?

Vancomycin-associated nephrotoxicity was reported in 0% to 5% of patients in the 1980s. This has been confirmed by numerous clinical trials comparing novel anti-methicillin-resistant Staphylococcus aureus agents with vancomycin at the Food and Drug Administration-approved dosage of 1 g every 12 hours. Treatment failures of vancomycin in patients with methicillin-resistant S. aureus infections have been reported despite in vitro susceptibility. These failures have led to the use of vancomycin doses higher than those approved by the Food and Drug Administration. Higher doses are being administered to achieve goal vancomycin trough concentrations of 10 to 20 microg/mL recommended by several clinical practice guidelines endorsed by the Infectious Diseases Society of America. Recent studies suggest that increased rates of nephrotoxicity are associated with aggressive vancomycin dosing. These increased rates are confounded by concomitant nephrotoxins, renal insufficiency, or changing hemodynamics. These studies also have demonstrated that vancomycin's nephrotoxicity risk is minimal in patients without risk factors for nephrotoxicity. Clinicians unwilling to dose vancomycin in accordance with clinical practice guidelines should use an alternative agent because inadequate dosing increases the likelihood of selecting heteroresistant methicillin-resistant S. aureus isolates.