Efficacy and Pharmacokinetics of the Combination of OP0595 and Cefepime in a Mouse Model of Pneumonia Caused by Extended-Spectrum-Beta-Lactamase-Producing Klebsiella pneumoniae.

OP0595 (RG6080) is a novel diazabicyclooctane that inhibits class A and C serine beta-lactamases. Although the combination of OP0595 and cefepime (FEP) showed good in vitro activity against extended-spectrum-beta-lactamase (ESBL)-producing pathogens, the effect of the combination therapy against severe infections, such as pneumonia or bacteremia, remains unknown in vivo In this study, we investigated the efficacy and pharmacokinetics of the combination therapy of OP0595 and FEP in a mouse model of pneumonia caused by Klebsiella pneumoniae harboring SHV- and CTX-M-9-type ESBLs. The infected BALB/c mice were intraperitoneally administered saline (control), 100 mg/kg of body weight of FEP, 20 mg/kg of OP0595, or both FEP and OP0595, twice a day. The MIC of FEP against the bacteria was 8 mg/liter and markedly improved to 0.06 mg/liter with the addition of 0.5 mg/ml of OP0595. In the survival study, the combination of FEP and OP0595 significantly improved the survival rate compared with that reported with either OP0595 or FEP alone (P < 0.001). The number of bacteria in the lungs and blood significantly decreased in the combination therapy group compared to that reported for the monotherapy groups (P < 0.001). In addition, the in vivo effect depended on the dose of FEP. However, pharmacokinetic analysis revealed that the percentage of time above MIC remained constant when increasing the dose of FEP in combination with 20 mg/kg of OP0595. The results of our study demonstrated the in vivo effectiveness of the combination of OP0595 and FEP.

Efficacy and pharmacokinetics of ME1100, a novel optimized formulation of arbekacin for inhalation, compared with amikacin in a murine model of ventilator-associated pneumonia caused by Pseudomonas aeruginosa.

Background: Arbekacin is an aminoglycoside that shows strong antimicrobial activity against Gram-positive bacteria, including MRSA, as well as Pseudomonas aeruginosa . The therapeutic effectiveness of arbekacin is directly related to C max at the infection site. To maximize drug delivery to the respiratory tract and minimize the systemic toxicity, arbekacin optimized for inhalation, ME1100, is under development. In this study, we investigated the efficacy and pharmacokinetics of ME1100 in a murine model of ventilator-associated pneumonia caused by P. aeruginosa by using a customized investigational nebulizer system. Methods: The mice were treated for 5 min, once daily, with placebo, 3, 10 or 30 mg/mL ME1100 or 30 mg/mL amikacin. Results: In the survival study, the survival rate was significantly improved in the 10 and 30 mg/mL ME1100 treatment groups compared with that in the placebo group. The number of bacteria in the lungs was significantly lower in the 30 mg/mL ME1100 treatment group at 6 h after the initial treatment, compared with all other groups. In the pharmacokinetic study, the C max in the 30 mg/mL ME1100 treatment group in the epithelial lining fluid (ELF) and plasma was 31.1 and 1.2 mg/L, respectively. Furthermore, we compared the efficacy of ME1100 with that of amikacin. Although there were no significant differences in ELF and plasma concentrations between 30 mg/mL of ME1100 and 30 mg/mL of amikacin, ME1100 significantly improved the survival rate compared with amikacin. Conclusions: The results of our study demonstrated the in vivo effectiveness of ME1100 and its superiority to amikacin.

Antimicrobial susceptibility and molecular characteristics of methicillin-resistant Staphylococcus aureus in a Japanese secondary care facility.

Methicillin-resistant Staphylococcus aureus (MRSA) is prevalent in Japan, and the Staphylococcus cassette chromosome mec (SCCmec) type II is common among hospital-acquired MRSA isolates. Information pertaining to MRSA characteristics is limited, including SCCmec types, in primary or secondary care facilities. A total of 128 MRSA isolates (90 skin and soft tissue isolates and 38 blood isolates) were collected at a secondary care facility, Kawatana Medical Center, from 2005 to 2011. Antimicrobial susceptibility testing for anti-MRSA antibiotics and molecular testing for SCCmec and virulence genes (tst, sec, etb, lukS/F-PV) were performed. Strains positive for lukS/F-PV were analyzed by multilocus sequence typing and phage open-reading frame typing. SCCmec typing in skin and soft tissue isolates revealed that 65.6% had type IV, 22.2% had type II, 8.9% had type I, and 3.3% had type III. In blood isolates, 50.0% had type IV, 47.4% had type II, and 2.6% had type III. Minimum inhibitory concentrations, MIC(50)/MIC(90), against vancomycin, teicoplanin, linezolid, and arbekacin increased slightly in SCCmec II isolates from skin and soft tissue. MICs against daptomycin were similar between sites of isolation. SCCmec type II isolates possess tst and sec genes at a greater frequently than SCCmec type IV isolates. Four lukS/F-PV-positive isolates were divided into two clonal patterns and USA300 was not included. In conclusion, SCCmec type IV was dominant in blood, skin, and soft tissue isolates in a secondary care facility in Japan. Because antimicrobial susceptibility varies with the SCCmec type, SCCmec typing of clinical isolates should be monitored in primary or secondary care facilities.