Fluoroquinolone-resistant mutant strains were sequentially isolated from the wild-type Streptococcus pneumoniae IID 553 by selection with various fluoroquinolones. The first-step mutant strains, which were obtained by selection with trovafloxacin (TVFX), levofloxacin (LVFX), norfloxacin (NFLX) and ciprofloxacin (CPFX), possessed single point mutations in the parC gene. These parC mutant strains had decreased in susceptibilities to the selecting agents. Other first-step mutant strains, which were obtained by selection with gatifloxacin (GFLX) and sparfloxacin (SPFX), possessed single point mutations in the gyrA gene. These gyrA mutant strains had decreased in susceptibility to GFLX and SPFX but not to the other fluoroquinolones. The second-step mutant strains obtained from the first-step parC and gyrA mutant strains possessed additional gyrA and parC mutations, respectively. As a result, all of the secondstep mutant strains possessed both gyrA and parC mutations. The susceptibilities of the second-step mutant strains to all of the fluoroquinolones were lower than those of the first-step mutant strains. These results suggest that in wild-type S. pneumoniae the primary target of TVFX, LVFX, NFLX and CPFX is topoisomerase IV, whereas the primary target of GFLX and SPFX is DNA gyrase, and in the parC and gyrA mutant strains the primary target of all the quinolones are DNA gyrase and topoisomerase IV, respectively. The frequencies of appearance of the first-and the second-step mutant strains were different among the fluoroquinolones used for selection. Moreover, the fluoroquinolones which selected mutant strains with a low frequency showed slight decreased activity against the mutant strains obtained. These results suggest that the fluoroquinolones which select the mutant strains with a low frequency inhibit both DNA gyrase and topoisomerase IV at nearly the same levels in S. pneumoniae. Among 99 recent clinical isolates of S. pneumoniae, only six fluoroquinolone-resistant (MIC of CPFX≤6.25μg/mL) strains were observed. This indicates that fluoroquinolone-resistance is not prevalent in recent clinical isolates of S. pneumoniae in Japan. Therefore, in the clinical use of fluoroquinolones for the treatment of S. pneumoniae infections, it is important to consider the ability of the agents to select mutant strains in addition to the profiles of antipneumococcal activity, pharmacokinetics, and safety.

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In conducting studies titled “Studies on Evaluation of Drug-Resistant Bacteria Causing Hospital Infections and Measures to Counter Them” supported by a Grant-in Aid for Scientific Research from the Ministry of Health and Welfare for 1999 (Comprehensive Research Project for Drug Safety), we thought it necessary to clarify from what point of view to understand, and how to evaluate, the “Domestic and Foreign Situation Regarding Changes in Drug-Resistant Bacteria and The Infections They cause”. Firstly, therefore, we went back to the days when antimicrobial chemotherapy originated and confirmed the basics of what meaning to seek in antimicrobial chemotherapy. Then, we stated the role that antimicrobial chemotherapy has played in the control of communicable infections in the context of infection control measures, such as vaccine therapy and the preparation of a good living environment. Second, we discussed the background of infections caused by sulfa-resistant Shigella, multidrug-resistant Shigella, multidrugresistant staphylococci, multidrug-resistant gram-negative bacilli, Pseudomonas spp., MRSA, penicillinresistant pneumococci, β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae, vancomycin-resistant enterococci, and multidrug-resistant Mycobacterium tuberculosis all of which have emerged successively with the development of antimicrobial agents. Third, we addressed microbial resistance mechanisms faced by β-lactam antibiotics, aminoglycosides, macrolides, new quinolones, vancomycin, rifampicin, and antifungal drugs. Lastly, in view of the above-mentioned three problems, we referred to the ideal antimicrobial therapy as a medical treatment at present and in the future.

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Using the agar dilution method, susceptibilities to various antimicrobial agents were examined for methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, Escherichia coli and Pseudomonas aeruginosa that had been isolated from patients with complicated urinary tract infections (UTIs) in the Department of Urology, Kagoshima University, from January 1997 through December 1998, at an inoculum size of 10⁶CFU/mL. Vancomycin showed the most potent antibacterial activity against MRSA and E. faecalis, with MIC₉₀ of 0.78 and 3.13μg/mL, respectively. Carbapenems showed potent antibacterial activity against E. faecalis, with an MIC₉₀ of less than 12.5μg/mL. Carbapenems and most of the cephems showed potent antibacterial activity against E. coli, that of meropenem (MEPM) being especially high with an MIC₉₀ of less than 0.025μg/mL. Tobramycin showed the most potent antibacterial activity against P. aeruginosa, with an MIC₉₀ of 1.56μg/mL. On regression analysis, positive correlations were observed between MICs of MEPM and imipenem (IPM), MEPM and panipenem (PAPM), and IPM and PAPM against tested strains, with correlation coefficients ranging between 0.602 and 0.966.

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Cefoselis (CFSL; trade name: Wincef^®), a new injectable cephem with intensified antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), besides the antimicrobial activity of the third injectable cephem, was marketed in Japan beginning in September, 1998. It was recommended for use with patients with a predisposition or susceptibility to acquiring infections or those refractory to other antibiotic treatment. However, central nervous system symptoms, such as convulsions and disorders of consciousness, were encountered in 64 out of about 40, 000 patients (estimation from the amount sold) who received it within the first 4 months after launching. These symptoms were not predicted from the results of clinical and non-clinical studies up to the time of new-drug approval, and analysis of the background of these patients indicated that these symptoms occurred predominantly in patients with lowered renal functions, such as those with severe renal impairment including dialysis patients and the elderly (in particular, 75 years of age or older). Among those patients with central nervous system symptoms and normal renal function, other factors were present, such as anamnesis of cerebral infarction, cerebral hemorrhage, brain tumor, convulsions, or meningitis, or a predisposition to convulsions. Although the usual administration of Wincef^® is intravenous drip infusion of 0.5-1g/time twice daily, the daily amount administered to most of the patients with central nervous system symptoms was 1g uid in the case of dialysis patients, and 1g bid in the case of other patients. Symptoms occurred 4-5 days after the start of administration in most cases, and most symptoms occurred within one week. Cefoselis is a drug of the kidney-elimination type, as are most existing cephems, and the elimination half-life in blood may be prolonged by renal impairment. Most of these patients with adverse drug reactions had lowered renal function, so it is presumed that central nervous system symptoms occurred due to the transfer of cefoselis into the brain through the blood brain barrier (BBB) or the blood liquid barrier (BLB), as a result of the persistence of high blood concentration following consecutive administration. With respect to the mechanism of action of cefoselis in the brain, reports which indicate the involvement of the β-aminobutyric acid (GABA) receptor or the N-methyl-D-aspartate (NMDA) receptor have been published, but the details remain unclear. For further promotion of appropriate use of this drug, clarification of the risk factors for the occurrence of central nervous system symptoms is needed, for which clarification of the transferability of this drug into the brain, and its mechanism of action, is necessary.

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