Basic chemotherapy was developed by R. Koch and his disciples, who promoted causal treatment in infectious disease, and by L. Pasteur and others. Shibasaburo Kitasato, a disciple of R. Koch, developed serotherapy using antitoxin against tetanus. P. Ehrlich, another Koch disciple, discovered salvarsan in cooperation with Sahachiro Hata. The discovery of penicillin by A. Fleming and its “rediscovery” by H. Florey, E. Chain, and others led to rapid advances in chemotherapy, especially in the treatment of infection. The development of antibacterials in Japan started with the discovery of kanamycin by Hamao Umezawa. Japanese researchers have played a major role in the development of new quinolones and contributed greatly by expanding the indication of macrolide to DPB, a chronic pulmonary disease. Unfortunately, the spread of drug-resistant bacteria, such as MRSA, PRSP, and VRE, and multiple-drug-resistant Pseudomonas aeruginosa, has become a serious concern, calling for more controlled use of antibacterials and better control of nosocomial infection control. Other problems include the emergence of new infections, such as SARS, and the threat of bioterrorism. With infections becoming increasingly complex, now is the time to return to the starting point of chemotherapy and develop new methods using new gene exploration and the analysis of pathogenic factors not present when chemotherapy first started.

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In vitro inetractions between vancomycin (VCM) and cefpirome (CPR), cefoselis (CFSL), cefepime (CFPM), or cefozopran (CZOP) were studied using the micro-dilution checkerboard technique in 102 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). All strains were isolated from blood samples obtained from patients admitted to Jichi Medical School between 1999 and 2000. Out of 102 strains, synergism or an additive action was observed in 77 strains (75.5%) treated with VCM plus CPR, 82 strains (80.4%) treated with VCM plus CFSL, 81 strains (79.4%) treated with VCM plus CFPM, and 76 strains (74.5%) treated with VCM plus CZOP. The fractional inhibitory concentration (FIC) indexes for VCM plus each of the four cephems were between 0.67 and 0.75. Antagonism was not observed in any of the VCM-plus-any cephem combinations. Treatment with a combination of VCM and a fourth-generation cephem, such as CPR, CFSL, CFPM or CZOP, produces synergistic or additive effect and should be considered for the treatment of MRSA infections.

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We compared the efficacy of cefditoren pivoxil (CDTR-PI) to that of cefcapene pivoxil (CFPN-PI), cefpodoxime proxetil (CPDX-PR), amoxicillin/clavulanic acid (AMPC/CVA), amoxicillin (AMPC), and levofloxacin (LVFX) in a mouse model of mixed infection pneumonia with Streptococcus pneumoniae and Haemophilus influenzae. The efficacy of CDTR-PI was dose-dependent in the model f pneumonia cased by mixed infection with penicillin-sensitive S. pneumoniae and β-lactamase negative ampicillin (ABPC)-resistant H. influenzae (BLNAR). The efficacy of CDTR-PI against PSSP in the model was comparable to that of other β-lactam antibiotics tested and superior to that of LVFX. The efficacy of CDTR-PI against BLNAR was superior to that of CPDX-PR and AMPC and comparable to that of CFPN-PI and AMPC/CVA. The efficacy of CDTR-PI against ABPC-sensitive H. influenzae was comparable to that of CFPN-PI and CPDX-PR but inferior to that of LVFX. CDTR-PI has showed balanced therapeutic efficacy against both S. pneumoniae and H. influenzae. This suggests that CDTR-PI has the potential for clinical use against mixed infections with S. pneumoniae and H. influenzae including BLNAR.

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We studied the detection rates of β-lactam antibiotic induced vancomycin (VCM)-resistant MRSA (BIVR) in MRSA isolated from clinical materials from September to December 2002 at 15 medical institutions participating in the Kyushu Resistant-Organism Test Network and the combined effects of glycopeptides and carbapenems against 70 strains of MRSA including BIVR by the checkerboard method. We found that (1) 36 (9%) of the 404 strains of MRSA isolated in medical institutions were identified as BIVR;(2) the detection rates of BIVR classified by clinical sample were highest in puncture fluid samples (29%, 2/7 strains); followed in descending order by tube samples 15%, 3/20 strains); bedsore samples (14%, 3/21 strains); and blood samples (13%, 2/16 strains);(3) the following combined effects of antibiotics against 70 strains of MRSA were obtained as an FIC index: VCM+imipenem (IPM) (mean FIC index: 0.53), VCM+panipemem (PAPM) (0.50), VCM+meropenem (MEPM) (0.51), teicoplanin (TEIC) +IPM (0.23), TEIC+PAPM (0.25), and TEIC+MEPM (0.26). Combined effects were favorable in these combinations. Marked synergistic effects (FIC index:≤0.25) were: VCM+IPM: 0%; VCM+PAPM: 5.7%; VCM+MEPM: 1.4%; TEIC+IPM: 64.3%; TEIC + PAPM: 42.9%; and TEIC+MEPM: 44.3%. In a study of the combined effects synergistic and additive effects of antibiotics against BIVR (26 strains) and non-BIVR (44 strains), We found no marked differences between combined effects against BIVR and against non-BIVR. These results indicate that combined effects of glycopeptides and IPM, PAPM, or MEPM were favorable but the enhancement of antibacterial activity by the combination of TEIC and carbapenems was markedly superior to that by the combination of VCM and carbapenems.

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Based on the solution-dilution MICs recommended by the Japan Society of Chemotherapy, we assessed the activity of antibacterial agents against urinary isolates of 1, 582 strains of 12 uropathogenic species obtained in 2002 from outpatients and patients hospitalized at Fujita Health University Hospital. Methicillin-resistant strains accounted for 50% of Staphylococcus aureus and Staphylococcus epidermidis. The most common species isolated was Enterococcus faecalis (16.3%). Much difference existed in resistance to antibacterial agents between enterococcal species, Enterococcus faecium being the most resistant. Escherichia coli accounted for over 50% of the 1, 151 gram-negative bacillus strains. The proportion of new quinolons (NQ)-resistant E. coli strains was 15O, and these 25 strains (4.4%) were suspected of producing extended-spectrum β-lactamase (ESBL). ESBL-producing strains with NQresistance accounted for 80%. Over 90% of Klebsiella pneumoniae was susceptible to all agents. The distribution of antipseudomonal agent activity against Pseudomonas aeruginosa indicated a decrease in the number of multiresistant strains and an increase in strains susceptible to all agents. Some difference existed in resistance to antibacterial agents between Proteus species. No ESBL-producing or multiresistant strains were isolated among Serratia marcescens. Our results suggest problems in which enterococcal species with resistance increase in gram-positive cocci and ESBL-producing and NQresistant strains are detected in gram-negative bacilli.

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A 56-year-old man was diagnosed as advanced gastric cancer. He underwent distal gastrectomy and Billroth II reconstruction. Combined resection was conducted as far as possible for invasion into the pancreas head and transverse mesocolon observed during surgery. Pathology revealed poorly differentiated adenocarcinoma, pT4 pN2 M 0 p Stage III B. Respite postoperative adjuvant chemotherapy consisting of 5 FU and cisplatin (CDDP), tumor marker increased and stricture was seen at the transverse colon, which suggested cancer recurrence by postoperative dissemination. Elevation of GOT and GPT made us hesitate the administration of TS-1 for a week. After 1 week, TS-1 was given to improve further liver function, though the suspension of the agent worsened. The symptoms of anorexia and general fatigue became also improved after one course of 5-day of administration and 2-day of suspension by TS-1. Six courses of chemotherapy were followed by bypass operation to the transverse colon obstruction. After 9 courses of chemotherapy altogether, the general condition became poor, so the treatment became palliative care. The patient died 17 months after the diagnosis of cancerous peritonitis. The oral administration of TS-1 is possible in outpatient clinic though hesitated due to the side effects. This patient could survive long for 455 days after 9 courses consisting of 5-day administration and 2-day suspension. The chemotherapy should not be hesitated in case when the elevation of GOT and GPT appears to be due to cancer.

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