Our results suggest that decreased bactericidal activity, or the in vitro PAE of carbapenems and fluoroquinolones, is related to the reduced in vivo protective effect against infection caused by high inoculum with S. aureus or P. aeruginosa.

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The in vitro activities of piperacillin (PIP) against ␤-lactamase-negative ampicillin (AMP)-resistant (BLNAR) Haemophilus influenzae were compared with those of cefotaxime (CTX) and ceftriaxone (CRO), and the potency of PIP as therapy for meningitis caused by BLNAR is also discussed. PIP showed good activity (MIC at which 90% of strains are inhibited, 0.25 g/ml) against 69 BLNAR strains, and its activity was comparable to that of CRO and superior to that of CTX. No significant correlation was observed between the MICs of PIP and CTX or CRO or AMP, whereas a high correlation was observed between the MICs of CTX and CRO. In the killing study, PIP showed potent bactericidal activity compared with those of CTX and CRO. By microscopic examination, PIP caused the formation of a spindle and short filamentous cells with bulges and induced cell lysis in BLNAR strains, while treatment with CTX and CRO resulted in the formation of large, spherical cells without any obvious lysis. The affinity of Bocillin FL, a fluorescent penicillin used for determination of the 50% inhibitory concentration (IC 50 s) for penicillin-binding proteins (PBPs), to PBPs 3a and 3b of BLNAR strains was drastically decreased compared with that to an AMP-susceptible strain (ATCC 33391). In the case of the BLNAR strains, the IC 50 s for PBPs 1a, 1b, and 2 were similar to those for the PBPs of ATCC 33391. Since the affinity of binding to PBPs 3a and 3b of the BLNAR strains decreased drastically, the second targets among the PBPs were PBP 2 for PIP, PBP1 (1a and 1b) for CTX and CRO. In conclusion, PIP showed excellent activities against BLNAR strains in a manner different from those of cephem antibiotics, suggesting that it could be a candidate therapeutic agent for the treatment of meningitis caused by BLNAR strains.

Objectives: Garenoxacin, a des-fluoro(6)-quinolone, exhibits potent activity against Mycoplasma pneumoniae, including macrolide-resistant strains. There has been no report on the inhibitory activity of garenoxacin against the target enzyme of M. pneumoniae.Methods: Subunits of DNA gyrase (GyrA and GyrB) proteins of M. pneumoniae FH were separately expressed as His-tagged proteins in Escherichia coli Chaperone Competent Cell BL21 by IPTG induction of plasmids containing the respective gyrA and gyrB genes. The inhibitory activities of garenoxacin, moxifloxacin, gatifloxacin and levofloxacin against DNA gyrase were evaluated by the inhibition of supercoiling activity (n ¼3).Results: Against M. pneumoniae FH, garenoxacin showed 2-to 16-fold more potent activity than the other quinolones. The mean IC 50 of garenoxacin for DNA gyrase of M. pneumoniae was 2.5 mg/L. Garenoxacin showed the most potent inhibitory activity against M. pneumoniae DNA gyrase among the quinolones tested. The IC 50 values of the quinolones for DNA gyrase roughly correlated with each MIC value. Conclusions:The antimycoplasmal activity of the quinolones was almost certainly due to inhibition of the supercoiling activity of DNA gyrase. Garenoxacin was considered a valuable quinolone in the treatment of infectious diseases caused by M. pneumoniae.