Many new quinolones, namely fluoro-quinolones, have been developed since norfloxacin (NFLX) was discovered in 1978. These drugs became useful medicine for various infectious diseases including pneumonia. The researches on mode of action of quinolone and resistant mechanisms have been made great advances with the progression of these new quinolones. In this review, I would like to introduce the progress of studies on mode of action of quinolones and mechanisms of quinolone-resistance in bacteria from mid 1970s.
1. Mode of action: Target enzymes: DNA gyrase and Topoisomerase IV:
It was known that quinolones inhibit DNA replication in Escherichia coli, however, detailed mode of action was not clarified when we started the research and development of new quinolones. DNA gyrase was identified as the target enzyme of quinolone in 1977. Afterward, researches on mechanism of actions of quinolones have been made a remarkable progress using various new quinolones such as norfloxacin. Consequently, interestingfindings were reported such as formation of cleavable complex (DNA gyrase-DNA-Quinolone) by quinolone, quinolone resistance-determining region (QRDR), and structure-activity relationship for various DNA gyrase in bacteria. In 1990, new target, namely Topoisomerase IV, of quinolone other than DNA gyrase was identified. This enzyme was showed to involve with antibacterial activity of quinolones especially respiratory quinolones and quinolone-resistance mechanisms in Gram-positive bacteria.
2. Quinolone-resistance mechanisms involved in membrane:
We found that quinolone-resistant mechanisms were due to alterations in DNA gyrase and in cell permeability of outer membrane proteins in E. coli and Pseudomonas aeruginosa. In E. coil, it was suggested that quinolone might penetrate through the Onip F porin, and alterations in permeabilityto quinolones in members of the Enterobacteriaceae have been associated with the decrease of specific outer membrane proteins. We isolated three types of norfloxacin resistant mutants, nfxB, nfxC, and nalB, showed alteration in membrane permeability associated with the appearance and or increase of outer membrane proteins. Using these mutants, it was found that these mutations activated efflux pumps in P. aeruginosa, and these data suggested efflux pumps might play an important role in resistance for various antibacterial agents in P. aeruginosa.
More recently, plasmid-mediated quinolone-resistance in Gram-negative bacteria was found in US and China. These finding might be very critical for spread of quinolone-resistant genes by plasmids, therefore we will have to keep watch on this type quinolone-resistance.

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We experienced a case in which serum vancomycin (VCM) concentration was fairly lower than the expected concentration from the usual dosage in the case of a normal renal function patient with methicillin-resistant Staphylococcus aurcus (MRSA). The patient had lung cancer. Therefore, in this study, it was determined whether the presence of malignancy alters VCM pharmacokinetic parameters and dosage reuirements in Japanese cancer patients with normal renal function (serum creatinine of<0.6mg/dL).
This study evaluates the influence of malignancy on the pharmacokinetics and dosage requirements of VCM in 25 patients with cancer (age 63.4±9.7 years, mean±S. D.) compared with 27 patients without cancer (age 69.3±14.5 years) using a two-compartment Bayesian pharmacokinetic program. After dosage adjustment, patients in the malignancy group required a VCM dosage regimen of 34.86±13.09mg/kg/day to attain a mean trough serum VCM concentration of 10.96±4.07μg/mL and a mean peak serum VCM concentration of 25.51±1.92μg/mL. Patients without cancer in the control group required a mean VCM dosage regimen of 26.40±11.22mg/kg/day to attain a mean trough serum VCM concentration of 10.53±3.01μg/mL and a mean peak serum VCM concentration of 24.18±0.11μg/mL. Comparative analysis of the pharmacokinetic data revealed an increase in VCM clearance (0.077±0.029L/hr/kg) in the malignancy group as compared with that (0.056±0.018L/hr/kg) in the control group. In addition, the values of the volume of distribution (1.29±0.41L/kg) increased in the malignancy group as compared with those (1.05±0.34L/kg) in the control group.
Analysis of the predictive performance of the Bayesian program indicated that the final sets of peak and trough serum VCM concentration were predicted with minimal bias and accurate precision in both study groups. This study showed that the presence of malignancy increased VCM clearance resulting in larger dosage requirements.

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We determined the susceptibility of bacteria which were isolated from patients with various infections nationwide between 2003 and 2004, to tosufloxacin (TFLX) and other fluoroquinolones. The antimicrobial activity of TFLX against Staphylococcus except methicillin-resistant Staphylococcus aureus was potent and nearly the same as that of gatifloxacin (GFLX). TFLX showed the most potent antimicrobial activity against Streptococcus including penicillin-resistant Streptococcus pneumoniae of fluoroquinolones. These fluoroquinolones showed potent antimicrobial activity against Moraxella (Branhamella) catarrhalis and Haemophilus influenzae. Second only to GFLX, TFLX showed the potent antimicrobial activity against Mycoplasma pneumoniae, and TFLX showed the most potent antimicrobial activity against Legionelia pneumophila among fluoroquinolones tested. Second only to GFLX, TFLX showed potent antimicrobial activity against Chlamydiapneumoniae and Chiamydia trachomatis. These results indicate that TFLX shows excellent antimicrobial activity against all fresh strains isolated from patients with infections. TFLX is thus useful as a therapeutic antimicrobial for treating a variety of infections.

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Azithromycin (AZM: Zithromac^®), a 15-membered ring maclolide antibiotic, was approved in March 2000 and launched in June 2000 in Japan. A special investigation of Zithromac^®(in pediatric patients) was started in August 2001 to collect and confirm proper use information, including safety and efficacy in pediatric patients. Of 778 patients, 718 were analyzed for safety and 631 for efficacy.
Of the 718 in the safety analysis, 39 cases of adverse drug reactions (ADR) were reported in 38 patients, with an ADR incidence of 5.29%(38/718). The commonest ADRs were diarrhea (19 cases) and vomiting (7 cases). No cases of serious ADR were seen.
The incidence of gastrointestinal disorders in patients under 2 years of age, pinpointed in Precautions on the package insert, was 8.57%(12140). In all cases, seriousness was slight and the outcome of relief or resolution/recovery confirmed.
The incidence of decreased WBC count and decreased neutrophil count also pinpointed in Precautions on the package insert was 0.68%(3/442) and 0.53%(2/376).
Efficacy was 88.8%(523/589) for respiratory tract infection (laryngopharyngitis, acute bronchitis, tonsillitis and pneumonia) and 85.7%(36/42) for otolaryngology tract infections (otitis media), respectively.
The causative organism was identified only in 226, including those with multiple causative organisms, among those included in efficacy analysis in respiratory tract infection. Efficacy for commonest causative organisms was 93.1%(122/131) for Mycoplasma spp., 84.6%(11/13) for Streptococcus pneumoniae, and 77.1%(27/35) for Haemophilus influenzae.

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