Antibacterial activities of new cephems against clinically isolated organisms (author's transl)

The antibacterial activities of cefotaxime (CTX), cefoperazone (CPZ), ceftizoxime (CZX), cefmenoxime (CMX), latamoxef (LMOX), cefotiam (CTM), cefazolin (CEZ), gentamicin (GM) and cefsulodin (CFS) were investigated. All causative organisms were isolated from patients with urinary tract infections treated in Tokai University Hospital. The results were as follows. 1) The MICs of CMX, CTX, and CZX against most of clinically isolated strains of E. coli, K. pneumoniae, Indole (-) Proteus sp. were 0.1 microgram/ml and lower. And then CTM, LMOX and CPZ showed similar antibacterial activities. 2) LMOX and GM showed potent antibacterial activities against C. freundii which was considered to be causative organisms of infections in rare cases. 3) Against S. marcescens, CMX, CTX, CZX, and LMOX showed very potent antibacterial activities. 4) Against P. aeruginosa, CFS, GM and CPZ showed moderate antibacterial activities. 5) Against Enterobacter sp., GM and CMX showed potent antibacterial activities.     

Fundamental and clinical studies on ceftazidime in the field of pediatrics

Fundamental and clinical studies were carried out on ceftazidime ( CAZ ), a new cephalosporin, in the field of pediatrics. 1. Antimicrobial activity MICs of CAZ were determined for clinical isolates of 24 strains of S. aureus, 15 of S. pyogenes, 8 of H. influenzae, 22 of E. coli, 20 of K. pneumoniae, 18 of P. mirabilis, 3 of P. morganii, and 21 of P. aeruginosa, and compared with those of the control drugs, i.e. CEZ, CXM, CMZ, CTX, LMOX and CMX. For P. aeruginosa, CPM, CFS and GM were also employed as the control drugs. CAZ was as active as CTX, LMOX and CMX, its MICs distributing in the range not higher than 0.10 microgram/ml for H. influenzae, 0.78 microgram/ml for E. coli, 0.39 microgram/ml for K. pneumoniae, 0.10 microgram/ml for P. mirabilis, and 0.10 microgram/ml for P. morganii in all the strains. Against P. aeruginosa, CAZ showed MICs in the range between 0.39 and 3.13 micrograms /ml, which showed activity higher than that of CTX, LMOX , CPM, CMX and GM, and comparable to that of CFS. Against S. pyogenes, CAZ was as active as all the control drugs except for LMOX , its MICs for all strains tested being 0.20 microgram/ml or below. Against S. aureus, CAZ was slightly more active than LMOX , but less active than the other control drugs, its MICs being relatively high ranging from 6.25 to 50 micrograms/ml. 2. Pharmacokinetics After a one-shot intravenous injection of CAZ 20 mg/kg, serum levels and urinary excretion were studied in 3 children aged 6 to 9 years, and CSF levels were determined in 2 children aged 6 to 7 years with aseptic meningitis. The mean serum levels of CAZ were 85.3 micrograms/ml at 1/4 hour, 53.3 micrograms/ml at 1/2 hour, 32.0 micrograms/ml at 1 hour, 16.1 micrograms/ml at 2 hours, 5.3 micrograms/ml at 4 hours, and 2.0 micrograms/ml at 6 hours, with the mean half-life of 1.18 hours. The mean urinary levels were 9,700 micrograms/ml at 0 to 2 hours, 803 micrograms/ml at 2 to 4 hours, 540 micrograms at 4 to 6 hours, and the mean urinary recovery rate during the first 6 hours was 83.9%. The CSF levels at 1 hour after intravenous injection were 0.44 microgram/ml in acute stage and 0.10 to 0.22 microgram/ml in convalescent stage. 3. Clinical study Thirty-one pediatric patients with bacterial infections were treated with CAZ , and the clinical efficacy, bacteriological response, and side effects were evaluated.(ABSTRACT TRUNCATED AT 400 WORDS)     

In vitro antibacterial activity of various cephems against clinical isolates from complicated urinary tract infections

In vitro antibacterial activity of several cephems (CEZ as the first generation (group A); CTM and CMZ as the second generation (group B); CMX, CPZ, LMOX, CTX and CZX as the third generation (group C)) against 8 species, each of 54 strains, of Gram-negative clinical isolates from complicated urinary tract infection was compared by determination of the MICs. The following results were obtained: The most sensitive drugs against each species in MIC80; CTX (MIC80 0.20 microgram/ml) against E. coli, CMX (1.56 microgram/ml) against K. pneumoniae, LMOX (0.39 microgram/ml) against P. mirabilis, LMOX (0.78 microgram/ml) against Indole (+) Proteus, CMX and CPZ (50 micrograms/ml) against E. cloacae, CMX and LMOX (50 micrograms/ml) against C. freundii, CMX (3.13 micrograms/ml) against S. marcescens and CPZ (25 micrograms/ml) against P. aeruginosa The most sensitive drugs against each species in MICS100; CMX (MIC100 3.13 micrograms/ml) against E. coli, CMX (6.25 micrograms/ml) against K. pneumoniae, CTX (0.78 microgram/ml) against P. mirabilis, LMOX (1.56 microgram/ml) against Indole (+) Proteus, CPZ (100 micrograms/ml) against E. cloacae, CMX (100 micrograms/ml) against C. freundii, CMX (12.5 microgram/ml) against S. marcescens and CPZ (50 micrograms/ml) against P. aeruginosa. In each species, the group C were most sensitive followed by those of the group B. Many isolates were highly resistant to the group A (especially in C. freundii, S. marcescens and P. aeruginosa).     

Study on the drug sensitivity of multiple drug-resistant Staphylococcus aureus

Of clinically isolated Staphylococcus aureus showing resistance to multiple drugs among penicillins (PCs), cephem antibiotics (CEPs), aminoglycosides (AGs), minocycline (MINO) and fosfomycin (FOM), 64 strains were selected for the determination of MIC. Twenty-one drugs were used for the determination of MIC, with ampicillin (ABPC), cloxacillin (MCIPC), cephalothin (CET), cefazolin (CEZ), cefotiam (CTM), cefuroxime (CXM), cefamandole (CMD), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX), cefmetazole (CMZ), cefoxitin (CFX), latamoxef (LMOX), cefotetan (CTT), cefoperazone (CPZ), gentamicin (GM), dibekacin (DKB), tobramycin (TOB), amikacin (AMK), MINO, and FOM. MIC80 of each drug at 10(6) CFU/ml were: ABPC, MCIPC, CEZ, CTM, CXM, CTX, CZX, CMX, CFX, LMOX, CTT, CPZ, GM, DKB and TOB greater than 100 micrograms/ml; CET 50 micrograms/ml; CMD and AMK 25 micrograms/ml; CMZ 12.5 micrograms/ml; FOM 6.25 micrograms/ml; and MINO 0.78 micrograms/ml. The ratio of highly resistant strains with MIC greater than 100 micrograms/ml at 10(6) CFU/ml varied according to drug, and a difference tended to be seen in the degree of influence by resistant factors reflected upon MIC, e.g. drugs for which a high resistance of more than 50% was confirmed were ABPC, CXM, CZX, LMOX and TOB, and 20 approximately 30% MCIPC, CTM, CTX, CMX and CFX. MIC on MCIPC which has a correlation of structural activity with methicillin correlated with cephems (CEPs) resistance to a high degree, but many of the so-called new CEPs showed resistance even to the strains with a low MIC on MCIPC. It was assumed that CEPs resistant strains have multiple drug resistant factors based on the fact that such strains showed multiple drug resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antibiotic susceptibility of bacteria isolated from surgical infections (first report)

In vitro activities of several antimicrobial agents against bacterial pathogens isolated from patients with primary and postoperative infections were investigated in 1982 and 1983. Antimicrobial agents examined were as follows: sulbenicillin (SBPC), piperacillin (PIPC), cephalothin (CET), cefazolin (CEZ), cefmetazole (CMZ), cefotiam (CTM), cefoperazone (CPZ), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX), latamoxef (LMOX), lincomycin (LCM), gentamicin (GM) and amikacin (AMK). Specimens for bacterial isolation included plus, fluid drawn by centesis, or bile. Blood samples of septicemia were excluded. The antimicrobial activities of these drugs were determined by the agar plate dilution method of the Japanese Society of Chemotherapy. There were 123 strains obtained in the 1982 survey and 252 strains in the 1983 survey. Little or no differences were seen in frequencies of isolation between the isolates of principal species in 1982 and those in 1983. Isolation frequencies of pathogens in primary infections were, in an order of decreasing frequency, E. coli (25.6%), anaerobes (21.1%), Streptococcus sp. (14.3%), Staphylococcus sp. (11.3%); in postoperative infections, Streptococcus sp. was most frequent (28.6%), followed by Pseudomonas sp. (17.6%), anaerobes (12.6%), E. coli (10.9%), Staphylococcus (10.1%). Against S. aureus, CEZ, CTM, LCM and GM had similar degree of activity with CET being somewhat more active. CMX was the most active drug among the third generation cephems tested against S. aureus. No strain was CTM, CEZ, and LCM-resistant at the same time. Over 90% of E. coli, were sensitive to CTX, CZX and CMX, inhibited by 0.10 microgram/ml, while E. coli were slightly less susceptible to CPZ and LMOX. Penicillins were not very active against K. pneumoniae, and only 60% of K. pneumoniae were inhibited by PIPC at concentrations of 12.5 micrograms/ml. Third generation cephems, CTX, CMX and CZX, proved highly active against K. pneumoniae; over 90% of K. pneumoniae was inhibited by CTX, CMX and CZX at a concentration of 0.10 microgram/ml. About 60% of P. aeruginosa was inhibited by 3.13 micrograms/ml of PIPC and GM but was resistant to SBPC. This survey should be very useful for the selection of an appropriate drug for prophylaxis if the frequencies of incidences of pathogens in postoperative infections are taken into account in selecting the most active antibiotic agent(s) against the most frequent genus, genera and species of pathogens.     

Laboratory and clinical studies on ceftazidime in the field of pediatrics

Laboratory and clinical studies on ceftazidime ( CAZ ), a new cephem antibiotic, were carried out in the field of pediatrics. The results were as follows: Antibacterial activities of CAZ against clinically isolated strains of S. pneumoniae, H. influenzae, E. coli and P. aeruginosa were compared with those of cefotaxime (CTX), ceftizoxime (CZX), latamoxef ( LMOX ), cefoperazone (CPZ) and cefmetazole (CMZ), and also with cefsulodin (CFS) and gentamicin (GM) against P. aeruginosa. Against S. pneumoniae and H. influenzae, CAZ was almost as active as CTX, CZX and CPZ. Against E. coli, it was almost as active as CTX, CZX and LMOX . Against P. aeruginosa, it was almost as active as CFS and GM. Serum concentrations and urinary excretion rates after intravenous bolus injection of CAZ at doses of 20 mg/kg and 10 mg/kg for 5 minutes in each 2 cases (4 cases in total) were determined. The mean serum concentrations of CAZ were 78.9 and 52.0 micrograms/ml at 15 minutes, 38.5 and 27.4 micrograms/ml at 1 hour, and 6.5 and 4.8 micrograms/ml at 4 hours, with serum half-lives (T 1/2) of 1.39 and 1.80 hours respectively. Mean cumulative urinary excretion rate within 6 hours after administration was 84.6%. In a patient with chronic renal failure, serum half-life was 3.22 hours and urinary excretion rate within 6 hours was 22.8% (after intravenous bolus injection of CAZ at a dose of 10 mg/kg). CAZ was administered at a dose of 55.5 mg/kg by intravenous bolus injection to a child with purulent meningitis. The levels of CAZ in the cerebrospinal fluid (CSF) at 1 hour after administration were 2.7-38.9 micrograms/ml with CSF/Serum ratios of 3.2-28.8%. Forty-two pediatric patients with various bacterial infections (pyelonephritis 14, tonsillitis 1, bronchopneumonia 3, pneumonia 17, purulent meningitis 1, bacteremia 2, SSSS 1, enterocolitis 3) were treated with CAZ at a daily dose of 49-222 mg/kg t.i.d. or q.i.d. (as a rule 60 mg/kg t.i.d.). The efficacy rate was 97.6% clinically and 97.8% bacteriologically. No adverse reactions were observed except 1 case with mild diarrhea. Abnormal laboratory findings were also only mild; eosinophilia in 1, slight elevation of GOT in 5 and that of GOT & GPT in 3 cases. These results indicate the usefulness of CAZ in the treatment of bacterial infections in children.     

Comparison of in vitro activity of first, second and third generation cephem antibiotics against various pathogens isolated from clinical materials in 1983

In vitro susceptibilities of 3,286 strains of various pathogens isolated from clinical materials in 1983 to various cephem antibiotics were studied using the Showa disk diffusion test. The following antibiotics were evaluated: cephalexin (CEX), cephalothin (CET), cefazolin (CEZ), cefotiam (CTM), cefoxitin (CFX), cefmetazole (CMZ), cefotaxime (CTX), cefoperazone (CPZ), ceftizoxime (CZX), cefmenoxime (CMX) and latamoxef (LMOX). S. aureus: Susceptible strains to CET, CEZ, CTM, CFX and CMZ with MIC less than 15 micrograms/ml accounted for 93, 75, 93, 70 and 96% of the strains tested, while those to CTX, CPZ, CZX, CMX and LMOX for 89, 65, 61, 86 and 62%, respectively. Susceptible strains to CEX at MICs less than or equal to 20 micrograms/ml were 60%. Prevalence of bacterial resistance to CEX and CEZ, which have been used extensively, was greater than that to CET, CTM or CMZ, showing a bimodal distribution of MICs. The third generation cephems studied, in general, also showed bimodal distributions of MICs. S. pyogenes: All strains studied were susceptible to CET, CTX, CPZ, CZX, CMX and LMOX at MICs less than or equal to 15 micrograms/ml. However, susceptible strains to CEZ, CTM, CFX and CMZ accounted for 95, 95, 80 and 90%, respectively, while those to CEX at MICs less than or equal to 20 micrograms/ml for 79%. S. pneumoniae: At MICs less than 3 micrograms/ml, all strains were susceptible to all cephem antibiotics tested. S. faecalis: Only a very few strains were susceptible to these antibiotics. E. coli, K. pneumoniae and Proteus spp.: Susceptible strains of E. coli and K. pneumoniae to CEX at MICs less than or equal to 20 micrograms/ml accounted for 80 and 81% of the strains tested, while those of indole negative and positive Proteus for 69 and 4%, respectively. Strains of E. coli susceptible to CET, CEZ, CTM, CFX and CMZ at MICs less than or equal to 15 micrograms/ml were 78 to 96%, while those to CTX, CPZ, CZX, CMX and LMOX were 94 to 100%. Those of K. pneumoniae to these 2 groups of antibiotics were 81 to 95% and 94 to 100%, respectively. Susceptible strains of indole negative Proteus to the former group were 81 to 93% and those to the latter were 100%.(ABSTRACT TRUNCATED AT 400 WORDS)     

In vitro antimicrobial activity of various antibiotics against Haemophilus influenzae isolated from clinical specimens in 1983

In vitro susceptibilities of 73 strains of Haemophilus influenzae isolated from clinical specimens in 1983 to various antibiotics were studied. The following antibiotics were evaluated; ampicillin (ABPC), piperacillin (PIPC), cefotaxime (CTX), cefoperazone (CPZ), ceftizoxime (CZX), cefmenoxime (CMX), latamoxef (LMOX), tetracycline (TC), doxycycline (DOXY), minocycline (MINO), chloramphenicol (CP) and erythromycin (EM). Susceptible strains to ABPC and PIPC with MICs less than 3 micrograms/ml were 80.3 and 84.1%, respectively. With this break point of MIC, all strains showed susceptibility to CPZ, CZX, and CMX, but resistant strains were observed in 1.5% against CTX and LMOX. Susceptible strains to TC, DOXY and MINO at MICs less than 2 micrograms/ml were 86.3, 80, and 87.7%, respectively. Those to CP at MICs less than or equal to 4 micrograms/ml and to EM at MICs less than or equal to 1 microgram/ml were 86.2 and 71.9%.     

The antibacterial activity of new cephem antibiotics against clinical isolates. A comparison of the antibacterial activity of cefotaxime with 6 other antibiotics

During the period from May through July 1981, a comparative study was carried out on the antibacterial activities of cefotaxime (CTX) and ceftizoxime (CZX), cefoperazone (CPZ), latamoxef (LMOX), cefotiam (CTM), cefmetazole (CMZ) and cefazolin (CEZ). CTX and these other cephem antibiotics were tested against fresh clinical isolates which had been obtained from clinical materials by the laboratories of 14 participating medical institutions. 1. The clinical isolates were obtained from various clinical materials in the following decreasing order: urine, sputum and pus/discharge; 85.7% of the isolates came from these materials. 2. Concerning the sources of each species of clinical isolates, it was found that P. aeruginosa was isolated from the greatest number -9- of different clinical materials. This was followed by E. coli and E. cloacae, each isolated from 8 different clinical materials, and C. freundii and E. aerogenes, each found in 7 different clinical materials. 3. In relation to S. pyogenes, S. agalactiae and S. pneumoniae, CTX showed the best antibacterial activity; the second most potent antibiotic was CZX. CMZ and LMOX were found to show relatively high MIC values for those species. Against S. aureus, CEZ showed the best antibacterial activity, but 3 resistant strains had MICs of greater than 100 micrograms/ml. 4. With regard to Gram-negative bacteria, CTX and CZX showed the best antibacterial activities for all of the species, except for P. aeruginosa. These were followed, in order, by LMOX and CPZ. Compared with these 4 antibiotics, CTM, CMZ and CEZ were found to have inferior antibacterial activities against these bacteria. In relation to P. aeruginosa, the peak of the MIC distribution for CPZ was 6.25 micrograms/ml, and this was the best antibacterial activity detected with the various antibiotics tested. This was followed by CTX (25 micrograms/ml) LMOX (25 micrograms/ml) and CZX (50 micrograms/ml). CTM had an MIC of 100 micrograms/ml for 1 strain, and MICs of greater than 100 micrograms/ml for all of the other strains of P. aeruginosa, indicating them to be resistant to this antibiotic. All of the strains were resistant to CMZ and CEZ, showing MICs of greater than 100 micrograms/ml. 5. For each of the tested antibiotics, no correlation was found between the MIC and the serogroup for either P. aeruginosa or S. marcescens.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from urinary tract infections (1985). I. Susceptibility distribution

The results of determinations of sensitivities of bacterial strains to various antibiotics are summarized as follows: 1. Against Escherichia coli, ofloxacin (OFLX) showed the strongest activity among oral antibacterial and antibiotic agents. Its MIC90 was below 0.10 micrograms/ml. The next strongest activity was found in mecillinam (MPC), cefaclor (CCL) and pipemidic acid (PPA); MIC90's of these agents 3.13 micrograms/ml. Cefotiam (CTM), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX) and latamoxef (LMOX) had MIC90 below 0.39 micrograms/ml. MIC90's of cefmetazole (CMZ) and cefoperazone (CPZ) were 1.56 micrograms/ml. Aztreonam (AZT) and carumonam (CRMN) in the monobactam group showed strong activities with MIC90's at 0.20 micrograms/ml. 2. Although Klebsiella pneumoniae had a strong resistance to ampicillin (ABPC) and showed relatively low sensitivities to other oral antibacterial and antibiotic agents, OFLX maintained high activity against this species and showed MIC90 of 0.39 micrograms/ml. Among injectable antibiotics, third generation cephems showed the strongest activity to this species with MIC90 of CZX below 0.10 micrograms/ml, of CTX and CMX 0.20 micrograms/ml, and of LMOX 0.78 micrograms/ml. MIC90 of CPZ was 6.25 micrograms/ml, which was the same as those of cefazolin (CEZ) and cefoxitin (CFX). CTM had similar MIC90 to LMOX, namely, 1.56 micrograms/ml. MIC90 of CMZ was 3.13 micrograms/ml. Monobactams AZT and CRMN showed strong activities to this species; their MIC90's were below 0.10 micrograms/ml and 0.20 micrograms/ml. 3. Although Citrobacter freundii generally exhibited low sensitivities to antibacterial and antibiotic agents examined, it showed high sensitivity to OFLX, at MIC80 of 0.78 micrograms/ml. This species showed low sensitivities to MPC, nalidixic acid (NA), PPA, and sulfamethoxazole-trimethoprim (ST). Among injectable antibiotics, LMOX and CMX had activities against this species; namely, MIC80's were 6.25 and 3.13 micrograms/ml, respectively. Among monobactams, AZT showed MIC80 of 12.5 micrograms/ml, and CRMN had that of 6.25 micrograms/ml. 4. Against Enterobacter cloacae, the strongest antibacterial activity was found with OFLX which had MIC90 of 0.39 micrograms/ml. A relatively strong activity was seen with MPC. MIC80 of MPC was 1.56 micrograms/ml. Except to CTM, this species had poor sensitivities to injectable first and second generation cephems, and their MIC80's were over 200 micrograms/ml. MIC80 of CTM was 25 micrograms/ml.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from urinary tract infections (1985). III. Secular changes in susceptibility

Sensitivities to antimicrobial agents of Escherichia coli, Klebsiella spp., Citrobacter spp., Enterobacter spp., Proteus spp., Pseudomonas aeruginosa and Serratia marcescens isolated from infected patients were evaluated and compared according to the types of their infections, i.e., simple and complicated urinary tract infections with or without indwelling catheter. There were no apparent decreases in the sensitivity of E. coli isolated from patients with simple urinary tract infections. When data obtained in 1982-1985 were summarized, it was found that a new quinoline derivative, ofloxacin (OFLX), showed the strongest activity among oral antimicrobial and antibiotic agents. This agent inhibited 100% of bacterial growth at MIC of 1.56 micrograms/ml. The next strongest activity was found with mecillinam (MPC) which showed 89.3% growth inhibition at the same concentration. Cefaclor (CCL) also showed 84.9% growth inhibition at the same concentration. When sensitivities of E. coli isolated from patients with complicated urinary tract infections with or without indwelling catheter to first and second generation cephems were determined, cefotiam (CTM), which inhibited 88.9%: 91.4% bacterial growth at MIC of 0.39 micrograms/ml, had the strongest activity among CTM, cefazolin (CEZ), cefoxitin (CFX) and cefmetazole (CMZ). Among third generation cephems, including cefmenoxime (CMX), latamoxef (LMOX), ceftizoxime (CZX), cefotaxime (CTX) and cefoperazone (CPZ), the strongest activity was observed with CZX, and the agent having the next strongest activity was CMX. LMOX and CPZ showed relatively low activities. Carumonam (CRMN) and aztreonam (AZT), monobactams, showed strong activities against E. coli. As for Klebsiella spp., activities of pencillins against these strains were low. When activities of oral cephems (cephalexin (CEX) and CCL) and of a quinoline derivative OFLX against these strains were determined, OFLX showed strong activity; i.e., the growth of Klebsiella spp. isolated from complicated urinary tract infections was inhibited at 87.2%: 82.1% at MIC of 0.20 micrograms/ml.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative studies of antimicrobial agents against causative organisms isolated from urinary tract infections (1982). III. Secular changes in susceptibility

In vitro susceptibilities have been investigated against several species isolated from patients with simple and complicated urinary tract infections (UTI) during 1980-1982. Antimicrobial activities of the third generation cephems against E. coli isolated from patients with complicated UTI were found to decrease slightly in 1982. And those against Klebsiella spp. isolated from patients with simple and complicated UTI were also found to decrease similarly. Against P. mirabilis, all the drugs tested have showed relatively potent activities and slight changes in the susceptibility. The marked decrease of susceptibility against Citrobacter spp. isolated from UTI have been found even in the third generation cephems. Especially, Citrobacter spp. exhibited a greater degree of resistant to CZX and CPZ. Strains of P. aeruginosa were on the whole susceptible to the drugs tested, CFS, GM, TOB and AMK, inhibiting 50-80% of the strains tested at 1.56 micrograms/ml. CTX, CZX and CMX seemed most effective against S. marcescens among the third generation cephems, inhibiting 50-90% of the strains tested at 3.13 micrograms/ml.     

Comparative studies of antimicrobial agents against causative organisms isolated from urinary tract infections (1984). I. Susceptibility distribution

Our research group was engaged for 3 years (1979-1981) in a study on sensitivities to antibiotics of 4 bacterial groups including representative pathogenic bacteria found in cases of urinary tract infections; i.e. E. coli, Klebsiella spp., Citrobacter spp., and Proteus spp. Since 1982, all the bacterial strains isolated by our group from patients with urinary tract infections and deemed by doctors in charge as pathogens were sent to the Laboratory of Clinical Pathology of Juntendo University, where they were refixed and subjected to MIC determination. This is the third year of the new study. E. coli was detected most frequently from patients with urinary tract infections and the detection frequency was 28% (323/1,153) this year (1984), whereas it was 35.3% (304/860) last year, showing a 7% decline from last year to this year. E. faecalis was next frequent organism (12.7% or 147/1,153) followed by P. aeruginosa (10.8% or 124/1,153). This order, however, was reversed from last year. Other pathogens, in a decreasing order of isolation frequencies following the above three, were as follows: Proteus spp. (9.5% or 109/1,153), S. marcescens (6.2% or 71/1,153), S. epidermidis (5.4% or 62/1,153), K. pneumoniae (4.9% or 56/1,153), Enterobacter spp. (2.4% or 28/1,153) and Citrobacter spp. (2.3% or 27/1,153). The results of the determination of the sensitivity of bacterial strains to the antibiotics are described below. Of all the oral antibacterial and antibiotic agents used against E. coli, mecillinam (MPC), cefaclor (CCL) and pipemidic acid (PPA) proved to have high antibacterial potency, and their MIC90 (the concentration to inhibit growths of 90% of the objective bacteria) was 3.13 micrograms/ml. The MIC90's of cefotiam (CTM), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX) and latamoxef (LMOX) were less than 0.39 microgram/ml. The MIC90's of cefmetazole (CMZ) and cefoperazone (CPZ) were invariably 1.56 micrograms/ml. K. pneumoniae was not sensitive to ampicillin (ABPC) and did not show much sensitivity to other oral antibacterial and antibiotic agents also. Of all the injectable preparations of antibiotics, cephem antibiotics of the third generation showed the most potent antibacterial effects against K. pneumoniae, and their MIC90's were lower than 0.10 microgram/ml for CZX, 0.20 microgram/ml for CTX, 0.39 microgram/ml for CMX, and 0.78 microgram/ml for LMOX, while MIC90's of CPZ was 6.25 micrograms/ml, which was equal to that of CMZ. The MIC90 of CTM was 0.78 microgram/ml which was identical to that of LMOX.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparison of antibacterial potencies of oral and parenteral antibiotic preparations against Escherichia coli, Klebsiella, Citrobacter, and Proteus isolated from urinary tract infections (3: 1981). 2. Changes in bacterial sensitivities

Since 1979 the antibacterial activity of antibiotics against E. coli, Klebsiella, Citrobacter and Proteus isolated from patients with urinary tract infections has been investigated. The serious transition of susceptibilities of E. coli and Klebsiella could not be recognized in these antibiotics (MPC, ABPC, NA, PPA, CEX, CEZ, CTM, CMZ and CFX). However, a few resistant organisms against the third generation's antibiotics (CTX, CMX, CZX, LMOX and CPZ) have already been appeared, we have to observe these results, continuously.     

Fundamental and clinical studies on cefuzonam in the field of pediatrics

Fundamental and clinical studies on cefuzonam (L-105, CZON), a newly semisynthesized cephem antibiotic, were carried out in the field of pediatrics and the following results were obtained. Antibacterial activities of CZON against clinically isolated strains of Staphylococcus aureus, S. epidermidis, Streptococcus pneumoniae, S. pyogenes, Escherichia coli, Klebsiella pneumoniae, Haemophilus parainfluenzae and H. influenzae were compared with those of cefmenoxime (CMX), latamoxef (LMOX), cefoperazone (CPZ), cefmetazole (CMZ), cefotiam (CTM) and cefazolin (CEZ). CZON was nearly as active as CEZ against S. aureus and S. epidermidis and superior to other antibiotics against other Gram-positive cocci. Against Gram-negative rods, CZON was as active as CMX and superior to other 5 antibiotics compared. Serum concentrations and urinary excretion rates after intravenous bolus injection of CZON at doses of 10 mg/kg, 20 mg/kg and 40 mg/kg for 5 minutes in 1, 5 and 4 cases, respectively, were determined. Mean serum concentrations of CZON at these dose levels were 11.0, 43.8 and 111.5 micrograms/ml at 15 minutes, 2.4, 10.3 and 30.3 micrograms/ml at 1 hour and 0.17, 0.72 and 1.28 micrograms/ml at 4 hours, with serum half-lives of 1.79, 0.88 and 1.19 hours, respectively. Mean cumulative urinary excretion rates within 6 hours after administration were 47.9, 56.3 and 40.3%, respectively. Thirty-four pediatric patients with various bacterial infections (tonsillitis 2, acute bronchitis 1, pneumonia 14, pyothorax 1, sepsis 1, suppurative lymphadenitis 1, UTI 13 and enteritis 1) were treated with CZON at a daily dose of 40-94 mg/kg t.i.d. or q.i.d.. The overall clinical efficacy rate was 94.1%. No adverse reactions were observed except 2 cases with mild diarrhea. Abnormal laboratory findings were also mild; slight elevation of GOT and GPT in 2, eosinophilia in 1 and thrombocytosis in 1. These results clearly indicate the usefulness of CZON in the treatment of bacterial infections in children.     

Fundamental and clinical studies on imipenem/cilastatin sodium in the pediatric field

Fundamental and clinical studies were performed on a newly developed carbapenem antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791), and results were summarized as follows. The antibacterial activity of MK-0787 at an inoculum of 10(6) cells/ml against strains of S. aureus which were sensitive or resistant to cefazolin (CEZ), E. coli, P. mirabilis, K. pneumoniae, S. marcescens and P. aeruginosa were determined and compared with activities of ceftazidime (CAZ), CEZ, cefmetazole (CMZ), ceftizoxime (CZX), latamoxef (LMOX), cefamandole (CMD), cefoperazone (CPZ), cefsulodin (CFS) and piperacillin (PIPC). The peak MIC of MK-0787 was less than or equal to 0.024 micrograms/ml against S. aureus, which were sensitive or resistant to CEZ, 0.10 micrograms/ml against E. coli, P. mirabilis, or K. pneumoniae, 0.39 micrograms/ml against S. marcescens and 1.56 micrograms/ml against P. aeruginosa. The antibacterial activity of MK-0787 against these bacteria was, on the whole, superior to that of CAZ, CEZ, CMZ, CZX, LMOX, CMD, CPZ, CFS or PIPC. The pharmacokinetics of MK-0787/MK-0791 was studied in 10 children at dose levels of 10 mg/10 mg/kg and 20 mg/20 mg/kg by a 30-minute intravenous drip infusion. Maximum serum levels of MK-0787, at dose levels of 10 mg/10 mg/kg and 20 mg/20 mg/kg were 41.6 micrograms/ml and 72.9 micrograms/ml, respectively, at the end of infusion and 0.1 micrograms/ml at 6 hours, respectively, after drip infusion. The half-life of both dose levels was 0.9 hour. Mean peak serum levels of MK-0791, at dose levels of 10 mg/10 mg/kg and 20 mg/20 mg/kg, were 49.7 micrograms/ml and 87.0 micrograms/ml, respectively, with half-life of 1.1 and 0.6 hour, respectively. Urinary recovery rates of MK-0787 for 6 hours at dose levels of 10 mg/10 mg/kg and 20 mg/20 mg/kg, were 47.8-82.7% and 25.5-78.0%, respectively, and of MK-0791 for 6 hours were 51.7-93.4% and 40.3-94.4%, respectively. Twenty-four patients, including 1 with purulent meningitis, 1 with septicemia, 1 with pyothorax, 10 with bronchopneumonia, 7 with pyelonephritis and 4 with infections of cutaneous soft tissue were treated with MK-0787/MK-0791 at dose levels of over 100 mg/100 mg/kg/day with purulent meningitis and septicemia and 28.8 mg/28.8 mg-72.8 mg/72.8 mg/kg/day with other infections. The clinical response in all patients was excellent or good.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evaluation of cefuzonam in the pediatric field

Cefuzonam (L-105, CZON) was studied in pediatric infections. A summary of the results it as follows: For recently isolated Staphylococcus aureus strains, Peak MICs of CZON were distributed between 0.39 and 0.78 micrograms/ml showing a greater susceptibility of S. aureus to CZON than to cefoperazone (CPZ), latamoxef (LMOX), and cefmenoxime (CMX). Peak MICs of CZON for Escherichia coli were 0.10-0.20 micrograms/ml, similar to those of CPZ, LMOX, and CMX. Ampicillin (ABPC)-resistant strains were also susceptible to CZON. MICs for Salmonella were similar to those for E. coli. Peak MICs of CZON for Vibrio parahaemolyticus were 0.20-0.39 micrograms/ml. The susceptibility of the bacteria to CZON was far greater than to ABPC, and was similar to CPZ, LMOX, and CMX. With 20 mg/kg drip infusion, serum concentrations reached their peaks at the end of administration with values of 20.6-68.7 micrograms/ml, which decreased to 0.43-1.70 micrograms/ml after 2 hours. Half-lives of CZON in serum were 0.68-1.2 hours. With 50 mg/kg drip infusion, serum concentrations reached their peaks at the end of administration with levels of 69.0-82.0 micrograms/ml, and at after 2 hours 1.85-3.45 micrograms/ml. Thus, an apparent dose response was observed. Half-lives of CZON in serum were 0.63-0.99 hours. Urinary recovery rates in 6 hours were 39.9-80.5%. A total of 44 cases of 10 different types of acute pediatric infections was treated by CZON intravenous drip infusion as the main therapeutic procedure. The efficacy rate was 93.2%, and the compound was effective on purulent infections, acute urinary tract infection, etc. with pathogens such as ABPC-resistant S. aureus, E. coli, and Enterococcus faecalis. Dosage levels per day were 50 to 80 mg/kg in most cases. In infections with S. aureus (8 strains), Streptococcus pneumoniae (3 strains), E. faecalis (1 strain), Haemophilus parahaemolyticus (1 strain), Haemophilus parainfluenzae (2 strains), Haemophilus influenzae (11 strains), Bordetella pertussis (1 strain), E. coli (3 strains), a total of 30 strains, bacterial elimination was noted with an exception of 1 strain of S. aureus. The compound was used for 4 to 15 days, but side effects observed clinically were only 1 case of diarrhea and 1 case of thrombocytosis.     

Distribution and changes in the susceptibility of bacteria isolated from clinical samples. III

This report presents data concerning in vitro activity of antimicrobial agents against Citrobacter freundii, Enterobacter spp., Serratia marcescens and Proteus vulgaris isolated from patients with complicated urinary tract infections and against Pseudomonas aeruginosa isolated from surgical wounds with postoperative infection and exudate from superficial abscesses. There was a marked increase of resistant strains of C. freundii, Enterobacter spp. and S. marcescens to penicillins, CEPs or GM. The isolates of these species obtained in 1983 showed MIC values of 100 micrograms/ml or more for the so-called new CEPs (CTX, CMX, CZX, LMOX and CPZ). The P. vulgaris isolates exhibited an increasing incidence of strains resistant to penicillins, and data on P. vulgaris isolates in 1983 indicated increase of strains resistant to CEPs. GM-resistant organisms were also noted to be increasing among the isolate of this species. The analysis did not reveal any appreciable change with calendar years among P. aeruginosa in respect of frequency of strains resistant to SBPC or CEPs (except CPZ). The data obtained in 1983, however, showed an indication of increasing incidence of organisms resistant to CPZ and GM. The increasing tendency of emergence of organisms resistant to new CEPs designed to expand activity against C. freundii, Enterobacter spp., S. marcescens and P. vulgaris, observed among the isolates of these species is considered probably to be the consequence of bacterial selective acquisition of R plasmid that carry drug resistant genes against CEPs. These are exactly reflected in the present data obtained in studies initiated in 1981 when the new CEPs became commonly prescribed in the daily clinics. It is concluded, accordingly, that organisms of these species resistant to CEPs have been increasing throughout the country.     

In vitro susceptibility of Escherichia coli and Klebsiella sp. to antibiotics

A nationwide susceptibility survey of clinical isolates of Escherichia coli and Klebsiella pneumoniae initiated in 1980 was continued for the 8th consecutive year. A total of 4,421 strains of E. coli and 2,825 strains of K. pneumoniae isolated mainly from urine, sputum and pus, were obtained from 69 hospitals throughout Japan during the 2 years (1986-1987). MICs were determined using the agar plate dilution method (Mueller-Hinton agar, BBL) with inoculation of 10(8)CFU/ml bacteria. Antibiotics tested in this survey were 2 penicillins, 7 cephems and 2 aminoglycosides. Most of the strains of the two species of bacteria were susceptible to ceftizoxime (CZX), cefotetan (CTT), latamoxef (LMOX), cefotiam (CTM) and cefmetazole (CMZ) and also gentamicin (GM) and netilmicin (NTL) were active against both species of bacteria. About 90% of the E. coli strains were inhibited at a concentration of 0.20 micrograms/ml of CZX, 0.39 micrograms/ml of LMOX, 0.78 micrograms/ml of CTT, 1.56 micrograms/ml of CTM or NTL, or 3.13 micrograms/ml of CMZ or GM. Most of the strains were resistant to ampicillin (ABPC) and piperacillin. For the strains of K. pneumoniae, similar results were obtained. Yearly changes in susceptibility of E. coli and K. pneumoniae were not obvious with ABPC, cefazolin, CMZ or GM. No significant differences were observed during 1986-1987 in susceptibilities of the isolates of both species of bacteria due to different clinical specimens. These results suggest that the 2nd and the 3rd generation cephems and aminoglycosides, alone or in combination, may be efficacious in treating infections due to E. coli and K. pneumoniae.     

Distribution and changes in the susceptibility of bacteria isolated from clinical samples. II

In vitro activity of antimicrobial agents such as ABPC, SBPC, MPC, CEZ, CTM, CMZ, CTX, CMX, CZX, LMOX, CPZ, CFS and GM against major clinical isolates, S. aureus, S. pyogenes, E. coli, K. pneumoniae, P. mirabilis, C. freundii, Enterobacter spp., S. marcescens, P. vulgaris and P. aeruginosa, was examined. In this paper, we will report the susceptibility of S. aureus, S. pyogenes, E. coli, K. pneumoniae and P. mirabilis during a three-year period, 1981 to approximately 1983. CEZ- and GM-resistant S. aureus has markedly increased and occupied 24% and 18%, respectively, in 1983. CMZ and CFS have showed potent activity against CEZ-resistant S. aureus. It seems that the abuse of third generation-cephems and new oral cephalosporins is closely related with the increase of cephems-resistant S. aureus. The penicillin- and cephem-resistant strains of S. pyogenes could not be found in our study. Quite a few strains of E. coli, K. pneumoniae and P. mirabilis are resistant to penicillins, and also there is no appreciable change in susceptibility. Some strains of E. coli, K. pneumoniae and P. mirabilis showed low susceptibility to CPZ, but all strains showed high susceptibility and no change in susceptibility to third generations, and these strains showed no tendency to decrease in susceptibility to GM.