Data on new drug effectiveness and safety is limited at approval because it is based on clinical trials limited by the number of patients, combination drugs, complications, patients age, etc. Once new drugs are marketed, serious adverse reactions not found in clinical trials may arise due to the rapid increase in the number of patients and clincal diversification from clinical trials. We evaluated “Early Postmarketing Phase Vigilance (EPPV)” enacted Oct. 1, 2001, by amendment of Good Postmarketing Surveillance Practices (GPMSP) of Drugs in December 2000.

View full abstract

Change in the sensitivity of clinical isolates to cefepime (CFPM) and injectable cephalosporin was studied by collecting samples in a survey over 3 successive periods. In the first survey, 20 species including 597 strains were isolated from clinical materials during 3 months from May to July 1996. Twenty species including 523 strains were collected during 5 months from May to September 1998 in the second survey, and 20 species including 551 strains were collected in 12 months from January 2000 to January 2001 in the third survey. MIC distributions of cefepime and other tested drugs in each test strain isolated in the third survey should tends similar to those in test strains isolated in the first and 2 surveys. MIC₉₀ of tested drugs in Streptococcus pneumoniae and Haemophilus influenzae were higher in the third survey than in the first 2 surveys. The antibacterial activity of each drug to gram-negative bacteria in the third survey was equivalent to those in the first 2 surveys. Several strains of Escherichia coli and Klebsiella pneumoniae had MIC of 100, μg/mL for ceftazidime in the second or third survey. Pseudomonas aeruginosa isolates were susceptible to cefepime, cefozopran, ceftazidime and imipenem/cilastatin. These were same in all surveys. An imipenem/cilastatin and other drug-resistant strain was isolated from Serratia marcescens in the first survey. The susceptibility of strains against tested antibiotics showed no change in any survey. CFPM has low selection in drug resistance because it has potent antibacterial activity against gram-positive and negative bacteria and is stable in β-lactamase produced from various species.

View full abstract

The antibacterial activity of (-) epigallocatechin gallate (EGCg), purified from green tea was studied using 9 reference strains and 49 clinical isolated strains of Streptococcus pneumoniae. The MIC₉₀ of EGCg against S. pneumoniae was 250μg/mL. The concentration of EGCg having antibacterial activity is equal to a daily consumable concentration of tea. The time-killing assay showed that a concentration of 500μg/mL of EGCg showed marked killing activity against l×10⁴mL of bacteria (initial bacterial count) within 5 hours. However, 250 or 125μg/mL of EGCg killed only moderate numbers of bacteria and remaining bacteria spread again later. To these remaining bacteria, EGCg at concentrations below the MIC was added 6 hours later. In these cases, remaining viable bacteria were killed using only half the MIC of EGCg. We studied the bactericidal effects of EGCg combinad with benzylpenicillin (PCG) using 11 strains of penicillin-resistant S. pneumoniae (PRSP). Combing PCG with 14 the MIC of EGCg the concentration of PCG (0.06μg/mL) that kills penicillin-sensitive strains now also killed highly penicillin-resistant strains. Analysis of penicillin-resistant genes in PRSP by polymerase chain reaction (PCR) showed 8 penicillin binding protein (PBP) 2 B class B strains but no PBP 2 B class A strain, indicating that the combined antibacterial effect of penicillin and EGCg on PRSP was obtained regardless of the resistance acquisition mechanism.

View full abstract

We studied the antibacterial effect of NM 394, the active ingredient of prulifloxacin (PUFX), a prodrug synthetic quinolone, on relatively recently isolated drug-resistant bacteria from clinical specimens in vitro. Quinolone, third-generation cephem, and carbapenem are antibacterial drugs designed not to be affected by drug resistance controlled by the transposable gene that caused problems in 1960-1979. After clinical use of third-generation cephem drugs having a wide antibacterial spectrum, MRSA isolation appeared to rise. Around 1995, Escherichia coli and Klebsiella pneumoniae producing extended-spectrum β-lactamases (ESBLs) that hydrolyze even third-generation cephem drugs were isolated in Japan. Carbapenem hydrolyzing Pseudomonas aeruginosa and Serratia marcescens, penicillin-resistant Streptococcus pneumoniae (PRSP), vancomycin-resistant Enterococcus faecalis (VRE), β-lactamase nonproducing ampicillin (ABPC)-resistant Haemophilus influenzae (BLNAR), etc., have also caused problems. NM 394 produced an antibacterial effect on 28 cephem-resistant P. aeruginosa isolates, 43 levofloxacin (LVFX)-resistant P. aeruginosa isolates, and 52 carbapenem-resistant P. aeruginosa isolates at MIC₅₀ of 0.5, 32 and 0.5, μg/mL. This effect was equivalent or superior to that of control drugs norfloxacin (NFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX), fleroxacin (FLRX), sparfloxacin (SPFX), and levofloxacin (LVFX). MIC₉₀ of NM 394 against 24 cephem-resistant E. coli isolates and 28 ESBLs-producing E. coli isolates was 0.03 and 1μg/mL, showing antibacterial activity stronger than that of NFLX, CPFX, TFLX, FLRX, SPFX, or LVFX. MIC ₉₀ of NM 394 against 24 ESBLs-producing K pnenumoniae, 32β-lactam drug-resistant H. influenzae isolates, 17 LVFX-resistant E. faecalis isolates, 18 LVFX-resistant Enterococcus faecium isolates, 30 ABPC-resistant Enterobacter cloacae isolates, and 20 ABPC-resistant S. marcescens isolates was 2, ≤ 0.015, 32, 32, 1, and 2, μg/mL, and NM 394 exhibited antibacterial activity equivalent or superior to 6 other new quinolone drugs. MIC90 of NM 394 against 27 PRSP isolates was 0.5μg/mL, and activity was equivalent to that of LVFX but inferior to that TFLX and of SPFX. Strong antibacterial activity of NM 394 was shown in short-time bactericidal effect on P. aeruginosa and E. coli, and activity was strong comparied to that of CPFX, TFLX, and LVFX.

View full abstract

Extended-spectrum β-lactamase producing Enterobacteriaceae other than Escherichia coli and Klebsiella spp., especially AmpC β-lactamase producing organisms, were examined from January to June 2000; 903 isolates were isolated from 6 hospitals in Kinki, Japan. Of these, 88 isolates (9.7%) which MICs of cefotaxime (CTX) and/or ceftazidime (CAZ) were 16≥μg/mL, were tested by the modified double-disk synergy test (mDDST) using cepepime (CFPM), CTX, and CAZ disks. We found that 10 (1.1%) of 88 isolates were positive by mDDST, and CFPM-disk was more detectable disk than the other 2 disks.The percentage of mDDST positive isolates in 6 hospitals was 0 to 2.9%. ESBL gene types were MEN-1-derived (Enterobacter cloacae (4), Citrobacter freundii (3), Serratia marcescens (1)) and Toho-1 derived (C. freundii (1), Proteus mirabilis (1)). ESBL-producing isolates from the same hospital were differently cloned using random amplification of polymorphic DNA (RAPD) analysis, enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR), and phenotypical analysis (serotype, antibiogram and biotype).

View full abstract

Between September 1999 and August 2001, we studied serotypes, mutation of penicillin-binding protein (PBP) genes, and antimicrobial susceptibilities of 11 strains of Streptococcus pneumoniae isolated from liquor or blood in children. Diseases were pneumonia in 7, meningitis in 2, pneumonia with acute otitis media in 1, and arthritis in 1. Patients ranged from 5 months to 4 years of age. Prevalent serotypes were 5 strains of type 6 and 2 of type 23. One and 8 strains were penicillin-resistant (MIC ≥ 2.0μg/mL) and intermediate (MIC 0.1-1.0μg/mL). The mutation of 3 genes (pbp 1 a, pbp 2 x, and pbp 2 b) was seen in 3 isolates, that of 2 genes (pbp 2 x and pbp 2 b) in 2, and pbp 2 x alone in 6. The MIC₉₀S of ampicillin was 1.0μg/mL, cefotaxime 1.0μg/mL, ceftriaxone 1.0μg/mL, panipenem ≤0.06μg/mL and vancomycin 0.5μg/mL.

View full abstract