Michael L. Zeckel

Pharmacodynamics of Oritavancin (LY333328) in a Neutropenic-Mouse Thigh Model of Staphylococcus aureus Infection

ABSTRACT The pharmacokinetics and pharmacodynamics of oritavancin (LY333328), a glycopeptide antibiotic with concentration-dependent bactericidal activity against gram-positive pathogens, in a neutropenic-mouse thigh model of Staphylococcus aureus infection were studied. Plasma radioequivalent concentrations of oritavancin were determined by using [14C]oritavancin at doses ranging from 0.5 to 20 mg/kg of body weight. Peak plasma radioequivalent concentrations after an intravenous dose were 7.27, 12.56, 69.29, and 228.83 μg/ml for doses of 0.5, 1, 5, and 20 mg/kg, respectively. The maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) increased linearly in proportion to the dose. Neither infection nor neutropenia was seen to affect the pharmacokinetics of oritavancin. Intravenous administration resulted in much higher concentrations in plasma than the concentrations obtained with subcutaneous administration. Single-dose dose-ranging studies suggested a sigmoid maximum effect (Emax) dose-response relationship, with a maximal effect evident at single doses exceeding 2 mg/kg. The oritavancin dose (stasis dose) that resulted in a 24-h colony count similar to the pretreatment count was 1.53 (standard error [SE], 0.35) mg/kg. The single oritavancin dose that resulted in 50% of maximal bacterial killing (ED50) was 0.95 (SE, 0.20) mg/kg. Dose fractionation studies suggested that single doses of 0.5, 1, 2, 4, and 16 mg/kg appeared to have greater bactericidal efficacy than the same total dose subdivided and administered multiple times during the 24-h treatment period. When using an inhibitory Emax model, Cmax appears to correlate better with bactericidal activity than do the time during which the concentration in plasma exceeds the MIC (T>MIC) and AUC. These data suggest that optimal oritavancin dosing strategies will require regimens that favor high Cmax concentrations rather than long periods during which unbound concentrations in plasma exceed the MIC.

In Vitro Activities of LY333328 and Comparative Agents against Nosocomial Gram-Positive Pathogens Collected in a 1997 Global Surveillance Study

ABSTRACT The in vitro activity of LY333328 was evaluated for 1,479 nosocomial gram-positive pathogens isolated in 12 countries during 1997. LY333328 MICs at which 90% of the isolates tested were inhibited for Enterococcus faecalis (n = 351),Enterococcus faecium (n = 100),Staphylococcus aureus (n = 593), coagulase-negative Staphylococcus species (n = 325), and Streptococcus pneumoniae(n = 110) were 1, 1, 2, 2, and 0.015 μg/ml, respectively. LY333328 demonstrated potent activity against isolates of vancomycin-resistant enterococci, oxacillin-resistant staphylococci, and penicillin-resistant pneumococci.

Beyond vancomycin: new therapies to meet the challenge of glycopeptide resistance

The incidence of infections caused by resistant Gram-positive pathogens is increasing, while emergence of vancomycin resistance is reducing the number of therapeutic options. New agents are being rapidly evaluated as candidates to replace vancomycin; some of the most promising include semisynthetic glycopeptides, quinupristin-dalfopristin, oxazolidinones and everninomycins. Alternative strategies, including immunization and therapeutic vaccines, may also have a role.

Pharmacokinetic profile of loracarbef

Loracarbef, the first β-lactam antibiotic of the carbacephem class to undergo clinical evaluation, has been the subject of extensive clinical pharmacology studies. Loracarbef is well absorbed: virtually all of an orally administered dose is excreted in the urine unchanged. Following administration of a 100 mg capsule to adults twice a day for 10 days, no accumulation of drug is noted. In one study in children, following the administration of 15 mg/kg of loracarbef suspension, the mean maximum plasma concentration (Cmax) was 20.3 μg/mL. In adults, the Cmax following administration of the suspension or solution formulations is higher than that achieved following administration of the capsule formulation, and the time to reach peak concentration (Tmax) is increased when loracarbef is administered as a capsule: however, the area under the curve, plasma half-life, and percentage of oral dose excreted in the urine are comparable among all formulations. The ingestion of food decreases the Cmax and delays the Tmax compared with the fasting state. The pharmacokinetic profile of loracarbef in adults is comparable with that in children or the elderly. Because loracarbef is eliminated primarily by the kidney, dosage must be reduced in patients with moderate-to-severe renal insufficiency. Loracarbef achieves middle-ear and interstitial-fluid levels that generally exceed the minimum inhibitory concentrations for common bacterial pathogens. Loracarbef possesses a pharmacokinetic profile consistent with the efficacy and safety profile documented in controlled clinical trials.

Risk of Hepatic Events in Patients Treated with Vancomycin in Clinical Studies

AbstractBackground: Routine surveillance of spontaneous reporting data and subsequent disproportionality analyses have indicated that the use of vancomycin might be associated with an increased risk of hepatic events. Objective: To conduct a meta-analysis of published randomized controlled clinical trials (RCTs) to better understand if the use of vancomycin is potentially associated with an increased risk of hepatic events. Data Sources: A comprehensive search and review of published clinical studies indexed in MEDLINE, PubMed, International Pharmaceutical Abstracts and the Cochrane Library from 1950 to June 2010 was conducted. Study Selection: The inclusion criteria consisted of (i) published RCTs comparing vancomycin with/without other additional treatments to other comparators; and (ii) studies that reported hepatic events. Data Extraction: The data related to any hepatic events reported in RCTs were extracted and examined. The quality of selected studies was assessed based on the Jadad scale. The effect size was presented as a risk ratio (RR) with a 95% CI and number needed to harm. The pooled RRs were calculated by using both fixed-effects and random-effects models. The impact of publication bias was assessed by funnel plot and the Egger’s test. Data Synthesis: A total of 20 RCTs, including 7419 patients, met the study inclusion criteria and were selected. An increased incidence of hepatic events, specifically elevated serum aminotransferase levels, was observed in patients receiving vancomycin, when compared with other comparators (pooled RR= 1.95; 95% CI 1.62, 2.36; ps< 0.001), but the majority of the events were mild to moderate in nature. No evidence is currently available suggesting that the use of vancomcycin confers a risk of progressive or severe drug-induced liver injury. Conclusions: Continuous monitoring of hepatic events on a routine basis among patients with the use of vancomycin is suggested.

Penetration of Loracarbef into the maxillary sinus : a pharmacokinetic assessment

Loracarbef, a beta-lactam antibiotic of the carbacephem class, is active in vitro against pathogens associated with acute maxillary sinusitis. To study the extent and duration of maxillary sinus fluid penetration after administration of loracarbef, 20 patients (10 men, 10 women; average age, 41 +/- 13 years) with acute sinusitis were treated with loracarbef 400 mg every 12 hours for 10 days. A lavage catheter was inserted into the maxillary sinus, and 150-microL sinus fluid samples were obtained at 0 (baseline), 0.5, 1, 1.5, 2, and 2.5 hours after the first dose and at 24 and 48 hours (12 hours after the second and fourth doses, respectively). Venous blood samples were obtained at the same times. Maxillary fluid and serum samples were frozen immediately at -20 degrees C to -70 degrees C until later bioassay using a direct agar diffusion method. Excluding missing data or inappropriately timed samples, the mean (+/- SD) sinus fluid concentrations were 0.16 +/- 0.12 microgram/mL at baseline, 0.23 +/- 0.17 microgram/mL at 0.5 hour, 1.11 +/- 1.44 micrograms/mL at 1 hour, 1.63 +/- 2.07 micrograms/mL at 1.5 hours, 1.75 +/- 2.01 micrograms/mL at 2 hours, and 1.60 +/- 1.96 micrograms/mL at 2.5 hours after dose. The mean sinus fluid concentration before the third dose (approximately 12 hours after the second dose) was 1.01 +/- 0.89 microgram/mL and before the fifth dose (approximately 12 hours after the fourth dose) was 0.88 +/- 0.90 microgram/mL. Taking the highest sinus fluid concentration measured in each patient, the mean peak sinus fluid concentration was 2.12 +/- 1.98 micrograms/mL (range, 0 to 6.7 micrograms/mL). The pretherapy peripheral leukocyte count appeared to have a statistically significant association (P < 0.01) with loracarbef sinus fluid penetration as estimated by the sinus fluid area under the concentration-time curve at 0 to 2.5 hours. Loracarbef 400 mg twice daily achieved sinus fluid concentrations that appeared to exceed the minimum concentration required to inhibit 90% of relevant acute sinusitis pathogens throughout the 12-hour interdose interval in most patients with acute maxillary sinusitis.