The objective of this study was to determine the effect of delayed therapy on morbidity and mortality associated with nosocomial Staphylococcus aureus bacteremia. The study included all episodes of S. aureus bacteremia that developed >2 days after hospital admission during 1999 to 2001. Classification and regression tree analysis (CART) was used to select the mortality breakpoint between early and delayed treatment. During the 25-month study period, 167 patients met the inclusion criteria. The breakpoint between delayed and early treatment derived using CART was 44.75 hours. On multivariate analysis, delayed treatment was found to be an independent predictor of infection-related mortality (odds ratio, 3.8; 95% confidence interval, 1.3-11.0; P=.01) and was associated with a longer hospital stay than was early treatment (20.2 days versus 14.3 days; P=.05). These findings support the notion that delay of therapy has deleterious effects on clinical outcomes, and efforts should be made to ensure that appropriate therapy is initiated promptly.

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Pharmacokinetic/pharmacodynamic surrogate relationships have been used to describe the antibacterial activity of various classes of antimicrobial agents. Studies that have evaluated these relationships were reviewed to determine which of these surrogate markers were further dependent on antimicrobial class. The fluoroquinolone and aminoglycoside agents exhibit concentration-dependent killing. Studies have demonstrated that peak serum concentration: minimum inhibitory concentration (MIC) and area under the serum concentration-time curve (AUC): MIC ratios are important predictors of outcome for these antimicrobial agents. Area under the inhibitory concentration-time curve (AUIC24) [i.e. AUC24/MIC] is a useful parameter for describing efficacy for these agents, while an adequate peak concentration: MIC ratio seems necessary to prevent selection of resistant organisms. For beta-lactam antibiotics, the duration of time that the serum concentration exceeds the MIC (T > MIC) was the significant pharmacokinetic/pharmacodynamic surrogate in cases where the bacterial inoculum was low, or where very sensitive organisms were tested. However, in studies using more resistant organisms or larger inoculum sizes there is some concentration-dependence to the observed effect. Studies using reasonable dosage intervals have demonstrated covariance between T > MIC and AUC/MIC ratio for beta-lactam antibiotics. Since glycopeptide antibiotics display relatively slow but concentration-independent killing, and are cell wall active agents similar to beta-lactams, it has been presumed that T > MIC is the important pharmacokinetic surrogate related to efficacy for these agents. Some studies have shown that a concentration multiple of the MIC may be necessary for successful outcome with vancomycin. AUIC24 may prove to be an important pharmacokinetic surrogate if both time and concentration are indeed important parameters. To select an appropriate antimicrobial agent, the clinician must consider many patient-specific as well as organism-specific factors. Utilisation of known pharmacokinetic/pharmacodynamic surrogate relationships should help to optimise treatment outcome.

We conducted a prospective, open-label study to delineate a relationship between exposure and outcomes in 36 patients treated with cefepime. Twenty patients had documented Gram-negative infections. Timed blood and urine samples were obtained at steady state to determine pharmacokinetic and pharmacodynamic parameters. Microbiological success was significantly correlated with the proportion of the dosing interval that cefepime concentrations exceeded 4.3 x MIC. Our results support in vitro data that suggest bactericidal activity of beta-lactams is optimized at concentrations approximately 4 x MIC. These results should be validated by large prospective clinical trials.

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This study evaluated the pharmacokinetics of cefepime in 36 patients with different levels of renal function. Pharmacokinetic and pharmacodynamic parameters were calculated using samples obtained at steady state. Patients with creatinine clearance (CL CR ) of >100 ml/min had more rapid clearance (CL) and a lower minimum concentration in serum (C min ). C min in this group was found to be 3.3 ؎ 3.6 mg/liter (mean and standard deviation), compared to 19.5 ؎ 21.5 mg/liter in patients with a CL CR of between 60 and 100 ml/min (P ‫؍‬ 0.025) and 14.0 ؎ 11.5 mg/liter in patients with a CL CR of <60 ml/min (P ‫؍‬ 0.009). Patient data were also analyzed by the nonparametric expectation maximization method and Bayesian forecasting. The median volume of distribution in the central compartment was 27.08 liters. CL and CL CR were highly correlated (P ‫؍‬ 0.00033) according to the equation CL‫؍‬ 0.324 liters/h ؉ (0.0551 ؋ CL CR ). The median rate constants from the central compartment to the peripheral compartment and from the peripheral compartment to the central compartment were 12.58 and 41.09 h ؊1 , respectively. The time-concentration profiles for 1,000 patients (CL CR s, 120, 60, and 30 ml/min) each receiving various dosing regimens were simulated by using Monte Carlo simulations. Standard dosing resulted in a C min that was greater than or equal to the MIC in more than 80% of the simulated profiles with MICs <2 mg/liter. Current dosing recommendations may be suboptimal for monotherapy of infections due to less susceptible pathogens (e.g., those for which MICs are >4 mg/liter), particularly when CL CR exceeds 120 ml/min.Cefepime is a parenteral fourth-generation cephalosporin antibiotic with an extended spectrum of antimicrobial activity. It is active against many gram-positive and gram-negative bacteria, including most members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus (12,13). It is excreted primarily unchanged in the urine. The terminal half-life (t 1/2 ) in plasma is approximately 2 h in normal renal function and increases proportionately to 13.5 h as renal function declines toward anuria. A good correlation has been demonstrated between cefepime clearance (CL) and creatinine clearance (CL CR ) in healthy volunteers with various degrees of renal function (1-4). Dosage adjustment for renal insufficiency has been recommended in order to prevent drug accumulation, which may result in a higher incidence of adverse drug events and/or an unnecessary increase in drug costs (9).The dosage adjustment recommended is primarily based on the proportional decrease in the rate of elimination and healthy volunteer data. However, modification of the dosing regimen based on renal impairment should also take into consideration pharmacodynamic parameters predicting clinical outcome (17). In vitro data have suggested that the bactericidal activity of ␤-lactams is generally concentration independent and that there is a lack of a postantibiotic effect against gramnegative bacteria (8,19). Time abov...

To assess the degree of morbidity and mortality attributable to vancomycin resistance in enterococcal bacteremia (EB), a matched case-control study was conducted. Patients with bacteremia due to vancomycin-resistant enterococcus (VRE) were matched to control patients with bacteremia due to vancomycin-susceptible enterococcus. During 1996--2000, 65 patients with cases of clinically significant VRE bacteremia were identified, and 53 of these patients were successfully matched. In this group of patients, VRE bacteremia was found to be an independent predictor of crude mortality (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.2--13.3) and the infection-related mortality rate (OR, 5.2; 95% CI, 1.4--20.0). It was also an independent predictor of the rate of clinical failure at day 7 after the onset of EB (OR, 4.6; 95% CI, 1.2--17.3) and overall clinical failure (OR, 4.3; 95% CI, 1.3--14.5) and was associated with a longer mean length of hospitalization after the onset of EB, compared with that for control patients (22.7plus minus1.88 vs. 15.9 +/- 1.7, P=.006). These observations indicate that vancomycin resistance in EB independently affects outcomes.