Tuberculosis (TB) is still the greatest single infectious cause of mortality worldwide. However, powerful new anti-TB drugs with new mechanisms of action have not been developed in the last over thirty years. It is expected that development of new effective anti-TB drugs will bring us various outcomes such as shortening the total treatment duration, improvement of the treatment completion ratio, prevention and treatment of multidrug-resistant tuberculosis (MDR-TB) and reducing overall medical expenditures. A new anti-TB drug needs to show good pharmacokinetic distribution and permeation into lung tissue and cells. Furthermore, it is also desired that novel candidate exhibits the potent bactericidal activity both against exponential and stable phases of Mycobacterium tuberculosis in vivo. In addition, it is ideal thatthe novel agent possesses a narrow antimicrobial spectrum targeting only the Mycobacterial species. Nitroimidazopyran is the center of attention in the world today as a most potent drug candidate for TB. Its leading compound, PA-824, is being developed in clinical trial phase I. PA-824 has two mechanisms; inhibitions of the biosynthesis of protein and cell wall lipid of M. tuberculosis. It exhibits bactericidal activity against both replicating and static M. tuberculosis. It also shows potent bactericidal activity against MDR-M. tuberculosis. Among new rifamycin derivatives, rifalazil (KRM-1648) the most promising drug candidate, is being developed in clinical trial phase II. Rifalazil demonstrates potent long-acting oral activity against M. tuberculosis both in animal models and humans. Gatifloxacin (GFLX) and moxifloxacin (MXFX), 8-methoxy-fluoroquinolone representatives, show bactericidal activity against replicating M. tuberculosis both in vitro and in murine tuberculosis models. ABT-773 and HMR-3647, ketolide compound representatives possess potential bactericidal activity against Mycobacterium avium-intracellulare complex (MAC) in vitro, but these ketolide compounds are ineffective against macrolide-resistant MAC strains. Caprazamycin-B (CPZ-B) is a promising novel antibiotic recently developed in Japan, which was isolated from Streptomyces species. In contrast to current anti-TB drugs, CPZ-B has a novel chemical structure with specific bactericidal activity against Mycobacterial species, especially M. tuberculosis including MDR strains and MAC isolates. CPZ-B inhibits cell wall biosynthesis of Mycobacteria, and exhibits moderate therapeutic efficacy that is dose size dependent in a murine pulmonary tuberculosis model. Any cytotoxicity is not observed in preceding animal experiments. “The Global Alliance for TB Drug Development (GATB)”, formed organization under a WHO initiative, started funding pharmaceutical companies to develop the novel agents for TB. GATB recently set up a new project, “Aerosolized new drug in DDS”. It has a potentially promising scope for developing new anti-TB drugs and managing chemotherapy as well.

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We studied resistance to β-lactum agents in 329 strains of Enterobacteriaceae detected in blood cultures in the 10 years between 1991 and 2000. Drug sensitivity tests showed good sensitivity (MIC₉₀:≤0.5g/mL) in third-generation cephem and in carbapenem to Escherichia coli and Klebsiella pneumoniae. We found relatively good sensitivity of fourth-generation cephem (the sensitivity of third-generation cephem was slightly lower) and carbapenem to Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens. For all Enterobacteriaceae, meropenem was the lowest (MIC₉₀:≤0.12μg/mL). Resistance among bacterial species using ceftazidime was the highest in E. cloacae (50.5%). Double-disk synergy tests (DDST) were positive in 19 strains and 2-mercapto propionic acid tests (2-MP) were positive in 5 strains. As resistance genes, the extended spectrum β-lactamase (ESBL)-producing gene, CTX-M 1/3, was detected in 18 of 19 strains. The metallo β-lactamase (MBL)-producing gene was detected in 5 strains which were IMP-1. In K. pneumoniae detected in 1991, the presence of SHV ESBL-producing bacteria was confirmed. A clinical background survey showed a high incidence of serious conditions such as malignant tumors and cerebrovascular diseases as underlying diseases, and IVH catheters had been inserted in all patients. Clinical symptoms were improved after administration of carbapenem and aminoglycosides in patients with ESBL-producing bacteria infection, and by administration of aztreonam in patients with MBL-producing bacteria infection.

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We studied susceptibility testing isepamicin (ISP) of aminoglycosides and antibacterials for gramnegative rod resistance to β-lactams isolated from blood. MICs of 14 antibacterial agents, aminoglycosides, and β-lactams against gram-negative rods. Bacterial strains were 50 clinical isolates, 9 of Escherichia coli, 10 of Proteus mirabilis, 3 of Providencia stuartii, 3 of Enterobacter aerogenes, 9 of Enterobacter cloacae, 10 of Serratia marcescens, 3 of Pseudomonas aeruginosa, 1 of Klebsiella oxytoca, 1 of Morganella morganii, and 1 of Citrobacter freundii. MICs of ISP ranged from 1 to≥256μg/mL. MIC₅₀ was 4μg/mL and MIC. was 16μg/mL. Our results suggest that ISP is an effective antibacterial agent against β-lactam resistance from blood.

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The 6, 692 samples used in this study were sent to our laboratory by 187 medical institutions participating in the Community-Acquired Bacterial Infections Working Group between 1998 and 2000 in Japan. Acute otitis media (n=1, 425), acute upper respiratory tract infection (n=961), and acute bronchitis (n=390) were prevalent in 4, 030 cases, duplicates excluded. We also included 175 pneumonia cases in this study. The proportion of Haemophilus influenzae isolates in all cases was about 34%. The prevalence of H. influenzae isolates peaked in those aged 1 year and gradually decreased with age until children entered school. In contrast, average prevalence in adults was 10%. We conducted molecular-level epidemiological studies for 1, 408 strains using PCR to identify resistant genes in H. influenzae. Our 4 sets of primers are as follows:(i) p6 gene of p6 membrane protein, (ii) TEM-1 type β-lactamase gene (bla), (iii) normal PBP 3 gene (ftsI), and (iv) mutational ftsI gene detected in β-lactamase-nonproducing ampicillin (ABPC) resistant H. influenzae (BLNAR). H. influenzae strains were classified into 6 types based on PCR:(i)β-lactamase-nonproducing ABPC-susceptible strains (BLNAS; n=826) with no any resistant genes, (ii) TEM-1 type β-lactamase-producing ABPC resistant strains (BLPAR; n=81), (iii)β-lactamase-nonproducing and low-level ABPC-resistant strains (Low-BLNAR;n=352) possessing Asn -526→Lys-526 amino acid substitution, (iv) BLNAR strains (n: 109) possessing Asn-526→Lys-526 and 3 amino acids substitutions detected around the Ser-Ser-Asn conserved motif, (v)β-lactamase-producing amoxicillin-clavulanate resistant strains (BLPACR-I; n=36) possessing TEM-1 and Low-BLNAR resistant genes, and (vi)β-lactamase-producing amoxicillin-clavulanate resistant strains (BLPACR II: n=4) possessing TEM-1 and BLNAR resistant genes. ABPC MIC₉₀s in Low-BLNAR was 2μg/mL and in BLNAR was 8μg/mL. Susceptibility of oral and intravenous cephalosporins MICs to these resistant strains apparently decreased more than that of ABPC and meropenem. In oral cephalosporins, only cefditoren MIC₉₀ was excellent<1μg/mL against BLNAR. BLNAR increased significantly from 3.2% in 1998, 6.6% in 1999, and 13.5% in 2000. Insufficient serum concentrations after oral cephalosporins prescribed for immunological immature pediatric patients accelerate the increase of BLNAR strains. Selection of proper antibiotics based on rapid, accurate bacteriological examinations, and Hib vaccination against H. influenzae must be taken to prevent resistant microorganisms from increasing.

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Between September 1998 and December 2001, we retrospectively studied clinical manifestation and treatment in 22 children, aged from 7 months to 9 years, with Yersinia enterocolitica infection. The most common symptoms in patients less than 3 years old were fever (92%) and diarrhea (69%), and those in patients 3 or more years old were abdominal pain (89%) and diarrhea (78%). Seventeen patients were treated with antibiotics: oral fosfomycin in 9, intravenous cefotaxime in 5, oral cefditoren-pivoxile in 2, and oral norfloxacin in 1. Clinical symptoms improved within 3 days in 15 patients except for 2 treated with fosfomycin. It took 14 days to 20 days for clinical symptoms to improve in 3 patients less than 2 years old, who were not treated with antibiotics. Antimicrobial susceptibility was determined with ampicillin, cefditoren, fosfomycin, clarithromycin, norfloxacin, piperacillin, gentamicin, ceftazidime, imipenem, and sulbactam/cefoperazone in 22 strains isolated from the stool of patients. Norfloxacin showed the highest antibacterial activity with MIC₉₀ of 0.1μg/mL in oral antibiotics, and imipenem showed the highest with MIC₉₀ of 0.5μg/mL or less in nonoral antibiotics.

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We conducted a Use-Results Surveillance study of Farom ^® tablet (faropenem, FRPM) in the first four years after its launch in 1997, covering 19, 375 cases at 2, 826 institutions nationmide. Of these, safety analyzed in 17, 303 and efficay in 16, 324 excluding inappropriate cases for reasons such as the cases given FRPM off the specified surveillance period. Results were as follows.
1. The incidence of adverse events associated with the use of FRPM (including abnormal laboratory findings) was 2.96%(512 cases), lower than 5.75%(127 of 2, 207 cases) in premarketing studies. Major adverse event were gastrointestinal disorders at 2.38%(412 cases) including diarrhoea and loose bowels (2.1%); skin and appendages disorders at 0.24%(42 cases) including rash. The incidence of diarrhoea and stools loose was lower compared with the reported in premarketing studies. Any symptoms were mild, and resolved by early termination of use. A higher incidence of adverse drug reactions were observed in patients with hypersensitive predisposition and those given 900mg/day of FRPM. We confirmed that adverse drug reactions to less than three days of medication starts.
2. FRPM efficacy exceeded 85.0% for all indication, similar to those observed in premarketing studies.

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We evaluated the accuracy of Bayesian dosing for vancomycin (VCM). Prospectively collected serum concentration data was evaluated retrospectively in 12 patients who had 2 steady-state peak and trough serum VCM concentrations obtained in routine therapeutic drug monitoring from April 1995 to July 2000. The predictive performance of the method using a 1-point trough level was compared to that using 2-point trough and peak levels. In predicting subsequent peak and trough VCM serum concentrations, the predictive accuracy of the Bayesian method using only the trough level did not differ significantly from that using both trough and peak levels. At the trough level (n=12), mean prediction error (ME) was-4.08μg/mL, mean absolute prediction error (MAE) was 4.44μg/mL, and root mean squared prediction error (RMSE) was 5.42μg/mL. At the peak level (n=11), ME was 2.87μg/mL, MAE was 7.04μg/mL, and RMSE was 8.89μg/mL for the 1-point method. The corresponding ME for the 2-point method was -3.30μg/mL, MAE was 3.90μg/mL, and RMSE was 4.93μg/mL at the trough level (n=12), and at the peak level (n=10), 0.57μg/mL for ME, 5.03μg/mL for MAE, and 6.74μg/mL for RMSE. The difference in accuracy was less than 1μg/mL at the trough level, and less than 3μg/mL at the peak level. These results indicate that therapeutic drug monitoring of only trough levels after initial VCM dosing determined by Moellering nomography would satisfactorily achieve desired serum VCM concentrations by using a Bayesian method for individualizing VCM dosage.

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