Prevention of death in bacterium-infected mice by a synthetic antimicrobial peptide, L5, through activation of host immunity.

In our previous study, we found that the antibacterial peptide KLKLLLLLKLK-NH(2) (L5) and its d-enantiomer (DL5) activate neutrophils to produce superoxide anions (O(2)(-)) and prevent death due to infection by methicillin-resistant Staphylococcus aureus, suggesting that these peptides may elicit in vivo antimicrobial activities through host inflammatory responses mediated by neutrophils. In this study, we investigated the mechanisms behind in vivo antimicrobial prophylaxis by the use of L5 for the treatment of bacterial infection introduced via intra-abdominal implantation. We found that the intraperitoneal treatment with L5 before bacterial infection markedly reduced rates of death due to infection. Treatments with L5 were highly effective in preventing death due to intraperitoneal inoculation of not only S. aureus Smith but also Enterococcus faecalis SR1004 and Escherichia coli EC14. The intra-abdominal administration of L5 induced accumulation of neutrophils, increased levels of reactive oxygen species, and augmented antibacterial activity in the abdominal cavity. In addition, administration of L5 upregulated the expression of the Mig/CXCL9 chemokine gene in thioglycolate-elicited peritoneal macrophages. Our results suggested that the prevention of death by treatment of infected mice with L5 might occur primarily through the activation of a host immune response.

Susceptibility of Pseudomonas aeruginosa clinical isolates in Japan to doripenem and other antipseudomonal agents.

We investigated the susceptibility of 694 Pseudomonas aeruginosa clinical isolates to nine antipseudomonal agents including doripenem. Test strains were collected from 23 Japanese medical facilities from 1992 to 2004. Doripenem showed a minimum inhibitory concentration for 90% of the organisms (MIC(90)) of 8 microg/mL, which was the lowest among the tested antipseudomonal agents. The MIC(90) of doripenem was 2-fold lower than that of meropenem, imipenem and amikacin and was > or =4-fold lower than that of piperacillin/tazobactam, ceftazidime, cefepime, ciprofloxacin and tobramycin. Amikacin showed the lowest rate of resistance against all clinical isolates (5.8%) followed by doripenem (7.1%). No remarkable changes were observed from 1992 to 2004 in the frequency of P. aeruginosa strains resistant to the tested agents, except for imipenem. Of 116 ceftazidime-resistant strains, from 44.0% to 50.8% were susceptible to the three carbapenems, but only 2.6% to cefepime. Of 138 imipenem-resistant strains, from 44.2% to 51.4% were susceptible to doripenem and both cephems, but 25.4% to meropenem. Doripenem was more active against imipenem- or ceftazidime-resistant strains than meropenem, although the activity of doripenem correlated well with that of meropenem. In conclusion, doripenem had the most potent in vitro activity against P. aeruginosa clinical isolates among the tested antibiotics. Considering the trend of antimicrobial resistance of the clinical isolates in well-focused surveillance, pseudomonal infections should be treated with appropriate chemotherapy using antimicrobial agents with potent antipseudomonal activity and low resistance rates, such as doripenem, in order to prevent the outbreak of resistant strains.

Pharmacodynamic assessment based on mutant prevention concentrations of fluoroquinolones to prevent the emergence of resistant mutants of Streptococcus pneumoniae.

The objective of this study was to investigate the relationship between pharmacokinetic and pharmacodynamic parameters, on the basis of the mutant prevention concentration (MPC) concept, and the emergence of resistant mutants of Streptococcus pneumoniae to fluoroquinolone antibacterials. Some clinical isolates with various MIC and MPC values of moxifloxacin and levofloxacin were exposed under conditions simulating the time-concentration curves observed when moxifloxacin (400 or 80 mg, once a day) or levofloxacin (200 mg, twice a day) was orally administered by using an in vitro pharmacodynamic model. The decrease in susceptibility was evaluated by altering the population analysis profiles after moxifloxacin or levofloxacin treatment for 72 h. When the area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MPC and peak concentration (C(max))/MPC were above 13.41 and 1.20, respectively, complete eradication occurred and no decrease in susceptibility was observed. On the other hand, when AUC(0-24)/MPC and C(max)/MPC were below 0.84 and 0.08, respectively, the susceptibility decreased. However, the time inside the mutant selective window and the time above the MPC did not show any correlation with the decrease in susceptibility. These results suggest that AUC(0-24)/MPC and C(max)/MPC are important parameters for predicting the emergence of resistant mutants and that higher values indicate greater effectiveness.