Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function.

This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL(CR)s) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL(CR)s of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL(CR)s of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC(τ)) was computed as dose/CL. The probability of achieving an AUC(τ)/MIC ratio of ≥ 219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC(τ)/MIC ratio of ≥ 219 for MIC values as high as 2 mg/liter. For patients with CL(CR)s of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC0₋24 (AUC from 0 to 24 h) and AUC24₋48 intervals for MICs of ≤ 1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC0₋24 and AUC24₋48 intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate.

Therapeutic decisions: assessing clinical fit.

Quality health care has been defined as the maximization of desired outcomes while minimizing undesirable consequences. Therefore, the optimal antimicrobial agent for a given clinical condition will be one that is the most rapidly effective, produces the least patient discomfort, results in minimal disruption of the patient's or hospital flora, and causes minimal dissatisfaction with the treatment program and its attendant costs. The clinical utility of antimicrobials is generally judged on the basis of in vitro activity, kinetic disposition, resistance trends, safety, and cost. Fluoroquinolones possess characteristics in each of these areas; for example, broad, potent gram-negative spectrum coupled with excellent oral absorption and tissue penetration, and relative safety and reduced cost compared with parenteral therapy. Drawbacks include the emergence of resistance among certain bacteria, particularly staphylococci and Pseudomonas aeruginosa, drug interactions that may compromise efficacy, and greater cost than other potentially useful oral antimicrobial agents. Indications for the agents' use can be categorized as appropriate (gram-negative osteomyelitis, complicated urinary tract infection, prostatitis, certain sexually transmitted diseases, bacterial gastroenteritis), potential (gastrointestinal tract decontamination in granulocytopenic patients, exacerbations of chronic obstructive pulmonary disease, nosocomial pneumonia and bacteremia, eradication of certain bacterial carrier states), or inappropriate (community-acquired pulmonary infections, especially aspiration pneumonitis, serious gram-positive infections, uncomplicated urinary tract infection, surgical prophylaxis except prostatic surgery). Gram-negative osteomyelitis serves as a model to demonstrate the fluoroquinolones as agents for quality health care. Current and future investigations should focus on the cost effectiveness and cost utility of the agents.

Efficacy of ofloxacin in experimental Staphylococcus aureus endocarditis.

The efficacy of ofloxacin was compared with that of vancomycin in the therapy of experimental Staphylococcus aureus endocarditis. Rabbits infected with either a methicillin-susceptible (MSSA-1199) or a methicillin-resistant (MRSA-494) test strain were treated with ofloxacin (20 mg/kg of body weight every 8 h) or vancomycin (17.5 mg/kg of body weight every 6 h) for 4 days. The antimicrobial agents were found to be equally effective in clearing bacteremia and in reducing bacterial counts in vegetations and in renal and splenic tissue of animals infected with either test strain. The drugs were of equal efficacy in curing MRSA-494 endocarditis. No resistance to ofloxacin emerged in either test strain during therapy. We conclude that in this model ofloxacin is as efficacious as vancomycin and that, unlike for other fluoroquinolones we have evaluated, resistance to the drug does not develop during therapy of this serious S. aureus infection.

Ciprofloxacin and rifampin, alone and in combination, for therapy of experimental Staphylococcus aureus endocarditis.

The therapeutic activities of ciprofloxacin (25 mg/kg every 8 h), rifampin (10 mg/kg every 24 h), ciprofloxacin plus rifampin, and vancomycin (17.5 mg/kg every 6 h) were compared by using the rabbit model of Staphylococcus aureus endocarditis. Animals infected with one of two test strains (SA1199 or SA487) were randomized into treatment groups and received 6 days of therapy. For SA1199, ciprofloxacin plus rifampin was most effective at reducing vegetation bacterial counts. For SA487, ciprofloxacin plus rifampin was as effective as vancomycin but less effective than ciprofloxacin alone. Resistance to ciprofloxacin at 5- and 10-fold the MIC emerged in the test strain in 82 and 55%, respectively, of rabbits infected with SA1199 and receiving ciprofloxacin monotherapy. The combination of ciprofloxacin and rifampin decreased these frequencies to 60% (P = 0.27) and 10% (P = 0.04). No resistance to ciprofloxacin was found in rabbits infected with SA487. We conclude that ciprofloxacin and ciprofloxacin plus rifampin are as efficacious as vancomycin in this model and that combining rifampin with ciprofloxacin may decrease the frequency at which high-level resistance to ciprofloxacin emerges. However, with respect to improved efficacy, the combination of ciprofloxacin and rifampin is unpredictable and may be detrimental.

The emergence of resistance to ciprofloxacin during treatment of experimental Staphylococcus aureus endocarditis.

The efficacy of ciprofloxacin was compared with that of vancomycin in the rabbit model of methicillin-susceptible Staphylococcus aureus endocarditis. Animals were treated with ciprofloxacin, 25 mg/kg iv every 8 h or vancomycin, 17.5 mg/kg iv every 6 h, for 3, 6, or 9 days. Both drugs were found to be equally effective in the therapy of this infection, but the degree of reduction in bacterial counts was less than expected on the basis of previous studies. Additionally, resistance to ciprofloxacin in the test strain of S. aureus was seen to emerge in 12.5% of animals that received the drug. This raises concern about the use of ciprofloxacin as a single agent in the therapy of humans with serious systemic S. aureus infections.

Ciprofloxacin versus vancomycin in the therapy of experimental methicillin-resistant Staphylococcus aureus endocarditis.

We compared the efficacy of ciprofloxacin with that of vancomycin by using the rabbit model of methicillin-resistant Staphylococcus aureus endocarditis. Endocarditis was treated with ciprofloxacin (25 mg/kg [body weight] intravenously every 8 h) or vancomycin (17.5 mg/kg intravenously every 6 h) for 3 days. Vancomycin and ciprofloxacin were equally efficacious in clearing bacteremia. Both reduced vegetation bacterial counts by 5 log10 CFU/g and renal and splenic bacterial counts by more than 3 log10 CFU/g as compared with untreated control rabbits after 26 h of infection (P less than 0.001). Both antimicrobial agents were able to eradicate the infectious process in an equivalent proportion of animals. No methicillin-resistant S. aureus that was recovered from ciprofloxacin-treated rabbits developed resistance to ciprofloxacin during therapy. Peak concentrations of ciprofloxacin in the sera of rabbits with endocarditis were significantly higher than those predicted by single-dose studies in uninfected rabbits. This finding was likely due to changes in the pharmacokinetics of the drug with multiple dosing and in infected versus uninfected rabbits. This study demonstrated that intravenously administered ciprofloxacin is as efficacious as vancomycin is in an in vivo model of a serious systemic methicillin-resistant S. aureus infection.

Clinical use of the new beta-lactam antimicrobial drugs. Practical considerations for physicians, microbiology laboratories, pharmacists, and formulary committees.

New beta-lactam antimicrobial agents with extended antibacterial activity for gram-negative bacilli are being developed and marketed. These drugs provide major advances, especially for treatment of serious infections caused by multiresistant organisms. Several of the drugs have been marketed and many more will be available. Some of these drugs are considerably more costly than the older beta-lactams. The large number of new antimicrobial drugs coupled with their high costs pose complex problems for physicians, microbiology laboratories, and pharmacists. Community hospitals, large general hospitals, and tertiary care hospitals have different needs for patient care and will need different formats for unbiased education, susceptibility testing, pharmacy stocking, and controlling or monitoring for inappropriate use.