Pharmacokinetics and pharmacodynamics of oral cephalexin in children with osteoarticular infections.

BACKGROUND: Osteoarticular infections lead to significant morbidity in children. Cephalexin has in vitro activity against methicillin-susceptible Staphylococcus aureus, a predominant pathogen in osteoarticular infection. However, cephalexin pharmacokinetics (PK) and pharmacodynamics (PD) are poorly described in children. This study described cephalexin PK in children treated for osteoarticular infection and assessed the proportion of children achieving surrogate PK/PD target for efficacy in methicillin-susceptible S. aureus infection. METHODS: Children with osteoarticular infection, 1 to 18 years of age, were eligible for this study if they were receiving oral cephalexin per standard of care. PK plasma samples were collected at specified times after multiple doses. PK parameters were estimated using noncompartmental analysis. PK/PD target for efficacy was calculated using the child's PK parameters, minimum inhibitory concentration (MIC) of the isolate when available and previously described MIC of 2 and 4 mg/L. RESULTS: Twelve children were enrolled and PK profiles were obtained from 11 of them. Median age was 7 years, and median cephalexin dose was 40 mg/kg/dose every 8 hours. Median apparent oral clearance, apparent oral volume of distribution and elimination half-life (T1/2) were 0.29 L/h/kg, 0.44 L/kg and 1.1 h, respectively. Time above MIC (T>MIC) was greater than 40% of the dosing interval in 100%, 90% and 80% of the children when MICs were 0.25, 2 and 4 mg/L, respectively. CONCLUSIONS: Oral cephalexin achieved optimal plasma exposure and was well tolerated in children with osteoarticular infection. Correlation between osteoarticular infection clinical outcome and PK/PD parameters needs further evaluation.

Evaluation of protective efficacy of an Actinobacillus pleuropneumoniae serotype 1 lipopolysaccharide-protein conjugate in mice.

Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia. The major adhesin of A. pleuropneumoniae has previously been identified as a lipopolysaccharide (LPS), and more recently, we demonstrated that high molecular mass LPS were involved in A. pleuropneumoniae adherence to porcine respiratory tract cells. We postulated that immunization with a LPS-based vaccine may confer a protective immunity. The high molecular mass O-polysaccharides obtained after acid hydrolysis and chromatographic separation were conjugated to bovine serum albumin (BSA) as a protein carrier. Groups of mice were injected twice with the following antigen preparations: whole-cell preparation, outer membrane preparation, O-polysaccharide-BSA conjugate, hydrolyzed LPS and phenol/water extracted LPS. A combination of different adjuvants was also used during these immunization procedures to induce a stronger immunological response to the polysaccharide antigen. Two weeks after the second injection, the mice were challenged intranasally with either homologous A. pleuropneumoniae serotype 1 strain or a serotype 5 strain. The highest survival rate, up to 80%, compared to the control groups (P < 0.05), was recorded when the mice were injected twice with 15 micrograms of carbohydrates of O-polysaccharide-BSA conjugate mixed with the saponin-derived adjuvant Quil A. Survival rates of between 60 and 70%, twice those observed in the control groups immunized with PBS, were recorded in mice injected with the O-polysaccharide-BSA conjugate mixed with other adjuvant preparations such as alhydrogel, peanut oil and Freund's incomplete adjuvant. However, the protection induced by the conjugate antigen preparation was serotype specific, because mice challenged with a serotype 5 strain were killed. Taken together, these results confirm the important role of A. pleuropneumoniae LPS in pathogenesis.