Journal of Infection and Chemotherapy

The aims of this study were to develop a population pharmacokinetic model for meropenem in Japanese pediatric patients, and to use this model to assess the pharmacodynamics of meropenem regimens against common bacterial populations. Pharmacokinetic data were pooled from nine separate studies (229 plasma samples and 61 urine samples from 40 infected children), modeled using the NONMEM program, and used for a pharmacodynamic simulation to estimate the probabilities of attaining the bactericidal target (40% of the time above the MIC for the bacterium). In the final population pharmacokinetic model, body weight (BW, kg) was the most significant covariate: Clr (l/h) = 0.254 × BW, Clnr (l/h) = 3.45, V c (l) = 0.272 × BW, Q (l/h) = 1.65, and V p (l) = 0.228 × BW, where Clr and Clnr are the renal and non-renal clearances, V p and V c are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental (central–peripheral) clearance. In most typical patients (BW = 10, 20, and 30 kg), the approved regimens of 10–40 mg/kg, three times a day (0.5-h infusions), achieved a target attainment probability of >80% against Escherichia coli, Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa isolates. The results of this study provide a better understanding of the pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients.

We evaluated the resistance to 20 different antibacterial agents of 362 clinically isolated strains of Streptococcus pneumoniae accumulated from October 2000 to July 2001 (phase 1) and of 332 different strains accumulated from January to June 2004 (phase 2), from institutions throughout Japan that participated in the surveys carried out by the Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease. In phase 1, the proportions of penicillin-sensitive S. pneumoniae (PSSP), penicillin-insensitive S. pneumoniae (PISP), and penicillin-resistant S. pneumoniae (PRSP) were 35.4%, 34.8%, and 29.8%, respectively, and the proportions were almost the same in phase 2: 33.1%, 37.0%, and 29.8%, respectively. Comparison of the MIC90 values of the antibacterial agents for PRSP in phase 1 and phase 2 revealed that these values for cefditoren, cefpodoxime, cefdinir, faropenem, ceftriaxone, cefotaxime, meropenem, and vancomycin increased by twofold to fourfold during the 3 years between phase 1 and phase 2. However the MIC90 of rokitamycin increased more than fourfold. The proportion of S. pneumoniae that were PISP + PRSP remained almost constant over the 3 years between phase 1 and phase 2. The background factors of patient age, previous administration of antibacterial agents, and attendance at a day nursery were examined; we found that in phase 1, the proportion of PISP + PRSP was significantly higher than that of PSSP in patients under 4 years old who had previously received antibacterial agents, but no significant differences were found in any of these background factors in the phase 2 survey. No significant difference was found in the proportions of penicillin-resistant bacteria according to whether or not the child had attended a day nursery.

Human-origin intravenous immunoglobulin (IVIG) collected from healthy individuals was tested for its neutralizing activity against the hemolysin, toxic shock syndrome toxin-1 (TSST-1), and enterotoxins, produced by laboratory strains of methicillin-resistant Staphylococcus aureus (MRSA). The hemolytic activity of the culture supernatant against sheep red blood cells was reduced from 100% to 5.5% relative hemolysis in the presence of 0.156 mg protein/ml of IVIG. The maximum dilution endpoint of the culture supernatant for TSST-1-mediated latex aggregation was 32-fold. This level of TSST-1 activity was reduced to eightfold dilution by 0.78 mg protein/ml of IVIG, and the latex aggregation activity of undiluted TSST-1 in the culture supernatant was inhibited by 1.56 mg protein/ml of IVIG. Similarly, the enterotoxin A-mediated latex aggregation titer appeared to be a 320-fold dilution. This toxin activity was reduced to an 80-fold dilution and below a tenfold dilution by 0.049 through 0.78 and 1.56 mg protein/ml, respectively, of IVIG. These results show that IVIG has powerful neutralizing activity against hemolysin, TSST-1, and enterotoxin A. Therefore, IVIG may be useful for passive immunization therapy in patients suffering from diseases caused by MRSA exotoxins.