In 1997 the “New GCP Guideline” was published. In the following year, the “Guideline for the Clinical Evaluation of Antimicrobial Drugs” was issued which addressed all the issues about conventional clinical trials and also used Western guidelines as references. However, development of clinical trials in Japan has considerably lagged behind contributed by a growing difficulty in getting patient consent to participation, a draconian enforcement of stricter protocol compliance and an increase in dropouts stemming from protocol violations. Antimicrobial development is ebbing in Japan and product launch has dramatically decreased in the last five years beginning in 1996.Also, time required for comparison studies is increasing every year. Conducting clinical trials in Japan is getting more and more difficult in recent years, which has led to the upsurge of bridging studies that use extrapolated foreign data. The Japanese Society of Chemotherapy (JSC) has set up the Bridging Study Committee and hammered out its view on the subject. Standardization of disease names or creation of comparison lists is a pressing need to straighten out the adaptable disease classification issue. Repository of unnecessary cases is really unnecessary. What weneed to do now is make efforts to create an environment where clinical trials can be conducted with much less impediment and without imprudently having resort to bridging studies. A strong industry-regulatory cooperation with JSC at the core is key to providing impetus to antimicrobial development in Japan.

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Active infection control measures began being taken in geriatric wards starting in October 1991. MICs of 148 strains (nasal cavity 72, pharynx 44, and sputum 32) of Staphylococcus aureus were determined for 14 antimicrobial agents, isolated from Aino Memorial Hospital patients between August 1995 and August 1996. The frequency of methicillin-resistant S. aureus (MRSA) was 62.5% in the nasal cavity, 79.5% in the pharynx, and 93.7% in the sputum, suggesting that most strains of S. aureus remain resistant to β-lactam agents such as cephems, penicillins, and carbapenems. The frequency of strains susceptible to minocycline (MIC≤6.25μg/mL) was 61.1% in the nasal cavity, 54.5% in the pharynx, and 25.0% in the sputum. An increase in susceptible strains was brought by reinforcing infection control, including limiting the use of minocycline since 1987. No strains were highly intermediately or resistant to vancomycin. The frequency of strains with an MIC of 3.13μg/mL to vancomycin was 19.4% in the nasal cavity and 20.5% in the pharynx. No such strains were isolated from the sputum. Most strains (90.6%) in the sputum revealed an MIC of 1.56 μg/mL, suggesting the need to follow up MICs of S. aureus to vancomycin carefully in the future.

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Synergy between arbekacin (ABK) and antibacterial agents against 206 clinical isolated MRSA from blood cultures was evaluated using checkerboad. The MICs of ABK, imipenem/cilastatin (IPM/CS), levofloxacin (LVFX), cefepime (CFPM), flomoxef (FM0X), cefazolin (CEZ), cefotiam (CTM), sulbactam/ampicillin (SBT/ABPC), imipenem/cilastatin (IPM/CS), minocycline (MINO), fosfomycin (FOM), levofloxacin (LVFX), cefmetazole (CMZ), teicoplanin (TEIC), and vancomycin (VCM) were assayed. The MICs of ABK against 206 strains of MRSA ranged from 0.25 to 4μg/mL. Partial synergy between ABK and IPM/CS or levofloxacin (LVFX) was observed (FIC indices were 0.85 and 0.89). In combination with ABK, MIC of IPM/CS and LVFX were much smaller than that of ABK alone. These findings suggest that ABK combined with IPM or LVFX may have therapeutic benefits against MRSA.

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A cost analysis on the use of oseltamivir treatments for patient with infuenza was performed, and the economic impact of an oseltamivir treatment program was estimated. We developed a decision tree with the occurrence of pneumonia as endpoints to compare two strategies in otherwise healthy adult patients with an influenza-like illness: an oseltamivir group and a non-oseltamivir group. The basic analysis was performed from the payers' perspective, but additional analyses were also conducted in which the productivity losses associated with influenza were considered. The parameters used in the analysis were extrapolated from a random-controlled Japanese study on the use of oseltamivir and references to published data. The expected medical cost per patient was 14, 100 yen and 14, 412 yen for the oseltamivir group and non-oseltamivir group, respectively. The expected cost including production loss was 56, 654 yen and 63, 485 yen for the oseltamivir group and non-oseltamovir group, respectively. We also conducted a sensitivity analysis on the parameters used in our model and calculated threshold values. Furthermore, we estimated that the use of oseltamovir would result in a nationwide healthcare cost savings of between 1.1 billion and 3.4 billion yen.

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We studied susceptibility testing to isepamicin (ISP) of aminoglycosides and antibacterials for IMP-1 metallo β-lactamase producing gram-negative rods. MICs of 14 antibacterial agents against IMP-1 metallo β-lactamase producing gram-negative rods were studied. Bacterial strains were 50 of 6 microbial species clinically isolated, 19 of Pseudomonas aeruginosa, 20 of Serratia marcescens, 2 of Escherichia coli, 5 of Klebsiella pneumoniae, 2 of Enterobacter aerogenes and 2 of Enterobacter cloacae. The 14 antibacterial agents used were ISP, gentamicin, amikacin, tobramycin, dibekacin, piperacillin, cefoperazone, ceftazidime, cefotaxime, cefminox, cefpirome, imipenem, sulbactam/cefoperazone and aztreonam. Microbroth dilution was used. MIC values of ISP against IMP-1 producers were widely distributed between 0.25 and ≥256μg/mL, but 28 of 50 strains (56%) were ≤ 8 μg/mL. Our results suggest that ISP is an effective antibacterial against IMP-1 metallo β-lactamase producing bacteria.

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A 50-year-old man with MRSA septicemia due to infective endocarditis was treated using therapy combining vancomycin (VCM) with rifampicin (RFP) and sulfamethoxazole/trimethoprim (ST). He was admitted to our hospital with a diagnosis of acute pneumococcal meningitis in February 2000. In mid March, he had a high grade fever and MRSA was isolated from the blood. The isolated MRSA was susceptible to VCM and arbekacin (ABK). Intravenous VCM administration was started. MRSA bacteremia continued even after 3 weeks of VCM therapy. Subsequent combination therapy with intravenous ABK and sulbactam/ampicillin also failed to eradicate the organism from the blood. In mid April, transthoracic echocardiography revealed vegetation, suggesting infective endocarditis. Antibacterial therapy was immediately changed to intravenous VCM with both oral RFP and ST. After 10 days of aggressive antibiotic treatment, the blood culture was negative, and after 3 months, the outcome was a successful. This case emphasizes the efficacy of therapy combining RFP and ST in addition to VCM in a case of severe MRSA infection, especially involving infective endocarditis.

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