Since its establishment in 1946, the Japanese Society of Chemotherapy (JSC) has contributed greatly to encouraging research and progress in chemotherapy through extensive exchange and dissemination of information in the field. One such activity in which the JSC has been and currently is involved is the development of synthetic antibacterial agents from nalidixic acid and pipemidic acid, leading to new quinolones. In 1962, nalidixic acid, the first agent of what to day are referred to as old quinolones, was discovered as an antibibacterial active against gram-negative bacteria. Since then, a series of old quinolones have been developed, but they have certain drawbacks, such as narrow antibiotic spectra, low recovery in urine, and relatively easy biotransformation. Subsequent work led to the birth of a new era with the introduction of norfloxacin as the first new quinolone in Japan in 1984 and then in many other countries throughout the world. This particular agent features clear differences from old quinolones in structure and activity, including the introduction of a fluorine atom into the prototype nucleus, resulting in much more potent antibacterial activity against gram-negative bacteria and a broad antibacterial spectrum covering even gram-positive bacteria. These features have led to extended indications for norfloxacin, to upper respiratory tract infections and superficial suppurative diseases, in addition to those of the old quinolones, urinary tract infections, intestinal infections, and otorhinological infections. Based on clinical studies planned and organized by JSC, a number of new quinolones have subsequently been developed, including ofloxacin. However, no drugs other than norfloxacin have yet been approved for pediatric use. The adverse reaction of arthropathy (joint and cartilage damage) predicted from studies in young animals have never materialized in clinical use. However, unexpected reactions, such as CNS reactions and phototoxicity, have been reported in clinical studies or post-marketing surveillance of the new quinolones. In this context, a newer quinolone, gatifloxacin is expected to reduce phototoxicity on the basis of recent studies. The JSC should continue to provide improved chemotherapeutic treatments required by our patients in the coming millennium through better understanding and public education in regard to infectious diseases as well as developing promising antibacterial agents, and for this same purpose, the JSC should also continue its extensive activities, including journal publishing, conferences and workshops, and interdisciplinary studies with related societies.

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WQ-3034 and HSR-903 are newly synthesized fluoroquinolones with potent antimicrobial activity against common gram-positive cocci. We assessed the in vitro activity of WQ-3034 and HSR-903 against Mycobacterium tuberculosis (MTB) and Mycobacterium avium complex (MAC) by using levofloxacin (LVFX), ciprofloxacin (CPFX), sparfloxacin (SPFX), gatifloxacin (GFLX), and sitafloxacin (STFX) as reference drugs. First, the MICs of all of these drugs were determined by the agar dilution method with 7H11 medium. The MICs at which 50% and 90% of the test MTB strains were inhibited (MIC₅₀ and MIC₉₀, respectively) by the test quinolones were: rifampicin (RFP)-susceptible MTB, STFX (0.1, 0.2μg/mL)≤GFLX (0.1, 0.39μg/mL)≤SPFX (0.2, 0.39μg/mL)<LVFX (0.39, 1.56μg/mL)≤WQ-3O34≅HSR-903≅CPFX (0.78, 1.56μg/mL); RFP-resistant MTB, STFX≅GFLX (0.39, 1.56 μg/mL)<SPFX (1.56, 3.13μg/mL)≤WQ-3034 (1.56, 6.25μg/mL)<LVFX (3.13, 6.25μg/mL)≤HSR-903 (3.13, 25μg/mL)≅CPFX (6.25, 12.5 μg/mL). On the other hand, the MIC₉₀ and MIC₉₀ of the test quinolones for MAC isolates were: RFP-susceptible MAC, STFX≅GFLX (6.25, 6.25μg/mL)<SPFX≅HSR-903 (12.5, 12.5μg/mL)<WQ-3034≅LVFX≅CPFX (25, 25μg/mL); RFP-resistant MAC, STFX≅SPFX (1.56, 1.56μg/mL)<GFLX≅WQ-3034>HSR-903≅CPFX (3.13, 3.13μg/mL)<LVFX (6.25, 6.25μg/mL). Second, we compared the antimicrobial activity of the test drugs against the MTB 93062 strain residing in the Mono Mac 6 macrophage cell line (MM6-Mφs) and the A-549 type II alveolar cell line (A-549 cells). When the drugs were added at the blood C_max, progressive killing or inhibition of the MTB residing in MM6-Mφs and A-549 cells was observed in the order: SPFX LVFX>WQ-3034>CPFX. The efficacy of all of the quinolones against intracellular MTB was significantly lower in the A-549 cells than in the MM6-M-s. WQ-3034, HSR-903, and LVFX at their MIC caused growth inhibition of intramacrophage MTh Kurono strain in the order: WQ-3034>HSR-903>LVFX. These findings indicate that the anti-MTB and anti-MAC activity of WQ-3034 is greater than that of CPFX and comparable to that of LVFX, while the activity of HSR-903 is somewhat greater than or comparable to that of CPFX. It thus appears that an increase in the activity of a given quinolone against gram-positive cocci does not necessarily mean increased activity of that drug against MTB organisms. Third, we examined the activity of WQ-3034 and HSR-903 alone and in combination with other antimycobacterial drugs against extracellularly growing MAC. The activity of these quinolones was reduced by combination with either clarithromycin or RFP but significantly potentiated by combination with isoniazid.

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The influence of 7 antibiotics on immunoglobulin (Ig) secretion by human B cells and lymphocyte growth was investigated in vitro. Highly purified human peripheral B cells were cultured with anti-CD 3 activated mitomycin C-treated T cells in the presence or absence of antibiotics. Ig content in supernatants was analyzed by specific sandwich ELISA and cellular growth by a rapid colorimetric method. Erythromycin, clarithromycin, fosfomycin, tobramycin, and amikacin had no apparent effect on IgG secretion. Grepafloxacin did not affect IgG secretion at 1μg/mL or lower concentrations, whereas IgG secretion in the presence of 5μg/mL or higher concentrations was inhibited significantly. Compared to grepafloxacin, ofloxacin did not influence IgG secretion and failed to induce suppression at a concentration of 1 or 5μg/mL. Antibiotics other than grepafloxacin did not affect cellular growth. Grepafloxacin, however, significantly inhibited cellular growth at a concentration of 5gg/mL. These observations suggest that among the 7 antibiotics we studied, only grepafloxacin may modify humoral immune defense. Note that grepafloxacin induced immunomodulation at clinically attainable concentrations.

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The increase in ampicillin-resistant Haemophilus influenzae isolates, especially β-lactamase nonproducing ampicillin-resistant (BLNAR) strains, is a growing problem in Japan. This species is a cause of communitacquired respiratory infection. We compared the activity of oral third-generation cephems, which are frequently administered to patients with respiratory inection against ampicillin-resistant H. influenzae organisms using murine bronchopneumonia caused by ampicillin-susceptible, β-lactamaseproducing and BLNAR strains. After each drug was administered at 20mg/kg twice a day for 3 days, we compared degrees to which viable bacteria in infected tissues was reduced using 7 β-lactams. In general, the efficacy in mice treated with cefpodoxime proxetil, cefditoren pivoxil, and cefcapene pivoxil was better than that of those treated with cefdinir, cefaclor, faropenem and ampicillin. The in vitro activity of cefditoren against the 3 infectious organisms was strongest among these drugs and that of cefcapene was the same or a slightly less than cefditoren, while that of cefpodoxime was one-quarter or less than these 2 drugs. These results suggest that the drug efficacy in a murine infection model may depend upon MIC and protein binding percent and drug pharmacokinetics in the infected tissues.

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The collagen gel droplet embedded culture drug sensitivity test (CD-DST) was applied to 19 patients with esophageal cancer (13 primary tumors, 12 metastatic tumors, and 13 biopsy specimens). Evaluable rates by CD-DST were 85% for primary tumors, 92% for metastatic tumors, and 69% for biopsy specimens. Growth rates of esophageal cancer for 7 days of culture were significantly higher than those of gastric cancers (7.33 vs 2.68). Chemosensitivities of primary tumors were: cisplatin 45%, 5-fluorouracil 45%, mitomycin C 40%, adriamycin 20%, and etoposide 18%. The percentage of multidrug-resistant tumors in esophageal cancers was lower than in gastric cancers (27% vs 67%). There were significant correlations between chemosensitivities (T/C ratios) of primary tumors and those of metastatic tumors. There was no difference between the effects of 5-fluorouracil by exposure condition to the drug. In 3 of 4 patients who had measurable lesions, clinical responses to chemotherapy were predictable by CD-DST.

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