In the 1980s, the abuse of third-generation cepharosporins caused problems of MRSA and many other related problems in Japan, where no standard guidelines exist for surgical infection therapy or postoperative infection prophylaxis Although antibiotic use for surgical prophylaxis is quite common, no indications in insurance use are cited in Japan. For medical economy and prevention of hospital infection and accidents, such standard guidelines are urgently needed. I propose a draft guideline on perioperative antibiotic, and discuss related problems.

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Bactericidal activity of levofloxacin was compared to that of cefcapene against Haemophilus influenzae isolated in 1998. Levofloxacin and cefcapene were bactericidal against ampicillin-susceptible strain at a concentration of 1 and 4 times the MIC, but only levofloxacin was bactericidalagainst β-lactamasenegative and ampicillin-resistant H. influenzae luenzae (BLNAR). Significant morphological alteration was not observed after levofloxacin treatment, while filamentous cells appeared after cefcapene treatment of the ampicillin-susceptible strain. BLNAR changed to filamentous without drug exposure, so we analyzed the amino acid sequence of the gene encoding penicillin-binding protein (PBP) 3. We found 6 substitutions in PBP 3, suggesting that PBP 3 alteration was a cause of the lack of bactericidal activity of cefcapene.

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We studied the influence of ceftizoxime alapivoxil (CZX-AP), a new prodrug oral cephem agent, on intestinal bacterial flora in gnotobiotic mice inoculated with 4 bacterial strains. We administered 20mg/kg of CZX-AP once daily for 5 consecutive days to mice inoculated with bacterial strains, Escherichia coli Hokken M, Enterococcus facealis Hokken M, Bacteroides fragilis GKP 0001 and Bifidobacterium breve YIT 4006. We found a decrease in E. coli, but no change in the other 3 bacteria. We also found a decrease in the number of viable E. coli in the contents of each part of the digestive tract (stomach, upper intestine, middle intestine, lower intestine, colon) 4 hours after the last dose was administered, but no change in the other 3 bacteria. This agrees with results we found on changes in the number of fecal flora. All specimens from the stool or digestive tract contents tested forβ-lactamase activity before and after drug administration were positive. The minimum inhibitory concentration (MIC) of ceftizoxime (CZX), the active moiety of CZX-AP we used, with inoculum size of 106CFU/mL, was 0.005μg/mL for E. coli, 12.5μg/mL for E. facealis, 3.13μg/mL for B. fragilis and 12.5μg/mL for B. breve. We found no MIC increase concomitant to drug administration for any bacterial strains.

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Annual changes in susceptibility of biapenem (BIPM), a new injectable carbapenem, against 1, 032clinical strains (14 species) including Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Pseudomonas aeruginosa, etc., were determined by agar dilution. Strains were isolated from patients in the Nagasaki University Hospital from January 1994 to December 1996. Comparison of annual changes of MIC₅₀ and MIC₉₀ against S. aureus including methicillin-resistant strains, S. pneumoniae including penicillin-resistant strains, Streptococcus pyogenes, Enterococcus faecalis, E. coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Acinetobacter baumannii, and Moraxella catarrhalis did not show increased resistance. Staphylococcus epidermidis and Serratia marcescens showed a slight increase in carbapenem-resistant strains, judging from MIC₅₀. Although P. aeruginosa also showed an increase in carbapenem-resistant strains by the comparison of MIC₉₀, the tendency toward BIPM resistance against this species was lower than those of other carbapenems. Among Haemophilus influenzae isolated in 1996, some strains were resistant strains toβ-lactams including carbapenems, so we must note this tendency.

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Acute otitis media is one of the most common upper respiratory infection diseases in childhood. The most common organisms causing it are Streptococcus pneumoniae and Haemophilus influenzae. In children, the nasopharynx is the carrier focus for upper respiratory infection diseases such as acute otitis media, and S.pneumoniae and H. influenzae colonize the nasopharynx. We studied the changes in nasopharyngeal carriage of S. pneumoniae and H. influenzae before and after amoxicillin (AMPC) and cefditoren-pivoxil (CDTR) therapy using a polymerase chain reaction to detect penicillin-binding protein genes and macroride-resistant genes, with the following results:
1. In 25 cases, 18 showed S. pneumoniae only, 4 H. influenzae only, and 3 detected cases. In the 18 having only S. pneumoniae, 2 consisted of a different type of S. pneumoniae. In 23 strains of S. pneumoniae, 2 were penicillin-susceptible S. pneumoniae (PSSP), 4 penicillin intermediate-resistant S. pneumoniae (PISP), and 17 penicillin-resistant S. pneumoniae (PRSP). In the 7 strains of H. influenzae, 3 were β-actamase-negative ampicillin-susceptible H. influenzae (BLNAS) and 4β-lactamase-negative ampicillin-resistant H. influenzae (BLNAR).
2. All PSSP and PISP were removed from the nasopharynx with AMPC, but in PSSP, PRSP was detected in all cases after AMPC therapy, In the 17 strains of PRSP recognized initially, 2 were removed from the nasopharynx with AMPC therapy, 4 changed to other strain types with AMPC therapy, and of the 11 strains remaining, 3 new strains appeared. With CDTR (9mg/kg/day) therapy, 2 strains were removed and 16 remained. With CDTR (18mg/kg/day) therapy, 1 strain changed to another type, and 1 new strain appeared. Ultimately, 17 strains remained, but only 9 existed from the beginning.
3. All 3 BLNAS strains were removed from the nasopharynx with AMPC, CDTR (9mg/kg/day), and CDTR (18mg/kg/day) therapy. During these therapies, however, 3 BLNAS appeared and only 1 strain ultimately remained in the nasopharynx. All 4 BLNAR strains were removed from the nasopharynx with AMPC, with 3 new strains appearing and CDTR (18mg/kg/day), with 2 new strains appearing. One strain ultimately remained in the nasopharynx. All strains recognized initially were removed.
4. No relationship was seen between S. pneumoniae and H. influenzae remaining in the nasopharynx and results of acute otitis media therapy. But it was recognized the tendencies that in the good result cases the rate of the removal of the bacteria from the beginning were high and all of them removed with AMPC and in the poor result cases the removal of the bacteria from the beginning were not high and bacteria from the beginning changed to the different bacteria which had different pattern of the resistant genes.

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In developing a vancomycin (VCM) dosage regimen, we assessed the prediction accuracy of VCM serum concentration using population pharmacokinetic parameters in 30 patients and by the Bayesian method in 12 patients (April, 1997-July, 2000). The use of population pharmacokinetic parameters appropriately estimated the serum VCM concentration as judged by the mean prediction error (ME;-0.75μg/mL), mean absolute prediction error (MAE; 3.21μg/mL), and root mean squared prediction error (RMSE; 3.97μg/mL) at troughs (n=30), and ME 2.71μg/mL, MAE 4.59μg/mL, and RMSE 5.24μg/mL at peaks (n=26). Prediction accuracy worsened, however, after about 9 days of VCM treatment due to a decrease in VCM clearance during therapy. Predictive performance by the Bayesian method was ME-3.30μg/mL, MAE 3.90μg/mL, and RMSE 4.93μg/mL at troughs (n=12), and ME 1.67μg/mL, MAE 5.73μg/mL, and RMSE 7.48μg/mL at peaks (n=11). The adequacy of the dosage determined by the Bayesian method was good for patients whose VCM half-life estimated from observed concentrations was less than 1.25 times the mean population half-life. For patients whose estimated half-life was more than 1.45 times of the mean population pharmacokinetic parameter, the prediction error was high. The dosage regimen for patients in this group thus requires careful adjustment.

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