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.     

Antimicrobial activity of sulbactam/cefoperazone. Comparison with other new cephems

Antimicrobial activities of sulbactam/cefoperazone (SBT/CPZ) against 50 fresh clinical isolates of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter spp., Serratia marcescens, Proteus mirabilis, Proteus vulgaris and Pseudomonas aeruginosa were compared to those of CPZ, Cefotiam (CTM), Cefotaxime (CTX) and Latamoxef (LMOX). Minimal inhibitory concentrations (MIC's) of SBT and CPZ mixed in a ratio of 1:1 were determined by the dilution method using Mueller-Hinton agar and expressed by absolute concentrations of CPZ. Antimicrobial activities of SBT/CPZ against principally penicillinase (PCase) producing bacteria, i.e., S. aureus, E. coli, K. pneumoniae, P. mirabilis, were superior to those of CPZ alone. The presence of SBT in concentrations around 0.39 approximately 1.56 micrograms/ml clearly enhanced CPZ's antimicrobial activities against these PCase producing strains. The synergistic antimicrobial effects of SBT in combination with CPZ were less pronounced against principally cephalosporinase (CEPase) producing bacteria, i.e., C. freundii, Enterobacter spp., S. marcescens, P. vulgaris, and P. aeruginosa, and exerted with SBT at concentrations around 3.13 approximately 12.5 micrograms/ml. Comparative antimicrobial activities indicated by MIC80's of tested agents showed that SBT/CPZ had more stable activities against bacteria ranging from Gram-positive to Gram-negative bacteria than CTM, CTX and LMOX. MIC's of SBT/CPZ were higher than 25 micrograms/ml against 8% of S. aureus, 18% of C. freundii, 10% of Enterobacter spp., 26% of S. marcescens, 2% of P. vulgaris, and 18% of P. aeruginosa. These resistant strains against which the addition of SBT showed no synergism, may possess other mechanism of resistance than beta-lactamase production. It is concluded that the presence of CPZ resistant strains is an actual current problem and not an imaginary future problem, and that the number of resistant strains against other new cephems which have different chemical structure from CPZ is increasing. When these present bacteriological environments are considered, the appearance of SBT/CPZ in the clinical practice is timely and meaningful.     

Comparison of in vitro antibacterial activities of new cephems against clinical organisms (isolated between June 1983 and January 1984)

We compared the in vitro antibacterial activities of ceftizoxime (CZX), cefotaxime (CTX), cefmenoxime (CMX), cefoperazone (CPZ), ceftazidime (CAZ), latamoxef (LMOX) and cefotetan (CTT) against 2,729 strains of 11 organisms freshly isolated from 10 medical institutions in Japan between June 1983 and January 1984 and obtained the following results: Against S. pyogenes, LMOX and CTT, which have the methoxy group at the 7 position, were less active than the other drugs. LMOX inhibited 80% of S. pyogenes at 0.78 micrograms/ml; CTT, at 1.56 micrograms/ml; but CZX and CTX inhibited 100% at 0.025 micrograms/ml or lower; CMX, at 0.05 micrograms/ml; and CPZ and CAZ, at 0.20 micrograms/ml. Against H. influenzae, E. coli, K. pneumoniae, P. mirabilis and indole-positive Proteus, these test antibiotics, especially CZX, CTX and CMX, which have the aminothiazolyl methoxyimino group, were potently active. Against S. marcescens CZX and CAZ were more active than the other drugs and against P. aeruginosa CAZ was more active than the other drugs. The test organisms did not tend to acquire resistance to these cephems when our results were compared with the results obtained at the development period.     

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 (1986). I. Susceptibility distribution

Susceptibilities to various antibacterial and antibiotic agents of bacterial strains isolated from urinary tract infections at 8 hospitals in Japan from July to October in 1986 are summarized as follows. 1. Enterococcus faecalis was susceptible to sulfamethoxazole/trimethoprim (ST) and imipenem (IPM) with MIC90s of 0.78 and 1.56 microgram/ml. Minocycline had the strongest activity against Staphylococcus aureus; the MICs for all strains tested were lower than 0.39 microgram/ml. The MIC80s of dicloxacillin, and arbekacin (HBK) were 0.20 and 0.78 microgram/ml, respectively. Among the cephems, the MIC80 of flomoxef was 25 micrograms/ml, whereas those of cefmenoxime (CMX) and cefotiam (CTM) were 50 micrograms/ml. 2. Escherichia coli was most susceptible to ofloxacin (OFLX) among the oral antibacterial and antibiotic agents tested. OFLX showed the minimum inhibitory concentration against 90% (MIC90) of the 274 strains of E. coli tested to be lower than 0.10 microgram/ml. The antibacterial activities of the third generation cephems such as CMX and latamoxef (LMOX) were the strongest among the injectable antibiotics tested. The MIC90s of CMX and LMOX were lower than 0.10 and 0.20 microgram/ml, respectively. CTM and cefmetazole, the second generation cephems, were also highly active against E. coli with MIC90s of 0.39 and 1.56 micrograms/ml, respectively. 3. Among the oral antibacterial and antibiotic agents tested, OFLX was the most active against Klebsiella pneumoniae. Its MIC90 was 0.78 microgram/ml. Among the injectable antibiotics tested, CMX was the strongest with an MIC90 of 0.20 microgram/ml; MIC90 of CTM and LMOX were 0.39 microgram/ml. 4. The tested antibacterial and antibiotic agents were generally less active against Citrobacter freundii than against other bacteria. The MIC80 of OFLX was 0.39 microgram/ml. Gentamicin (GM) and ST were slightly active against C. freundii. Among the cephems, CMX had the MIC80 of 25 micrograms/ml. 5. Enterobacter cloacae was less susceptible to the cephems tested. OFLX, GM, and mecillinam were active against this bacteria with MIC80s of 0.78, 0.78 and 1.56 micrograms/ml, respectively. 6. Among the oral antibacterial and antibiotic agents and penicillins examined, piperacillin (PIPC) was the most active against Proteus mirabilis. Its MIC90 was 0.39 microgram/ml. Those of sulbenicillin, cefaclor, ampicillin, OFLX, and ST were 0.78, 0.78, 1.56, 3.13 and 3.13 micrograms/ml, respectively. CMX was highly active against P. mirabilis with an MIC90 of less than or equal to 0.10 microgram/ml; LMOX followed with an MIC90 of 0.20 microgram/ml among the injectable antibiotics tested. CTM was also active against this bacterium; the MIC90 was 0.39 microgram/ml. 7. The antibacterial and antibiotic agents were generally only slightly active against Proteus vulgaris.(ABSTRACT TRUNCATED AT 400 WORDS)     

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)     

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.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (1997). I. Susceptibility distribution

The frequencies of isolation and susceptibilities to antimicrobial agents were investigated on 560 bacterial strains isolated from patients with urinary tract infections (UTIs) in 9 hospitals during the period of June 1997 to May 1998. Of the above bacterial isolates, Gram-positive bacteria accounted for 29.3% and a majority of them were Enterococcus faecalis. Gram-negative bacteria accounted for 70.7% and most of them were Escherichia coli. Susceptibilities of several isolated bacteria to antimicrobial agents were as followed; 1. Enterococcus faecalis Ampicillin (ABPC) showed the highest activity against E. faecalis isolated from patients with UTIs. Its MIC90 was 1 microgram/ml. Imipenem (IPM) and vancomycin (VCM) were also active with the MIC90s of 2 micrograms/ml. The others had low activities with the MIC90s of 16 micrograms/ml or above. 2. Staphylococcus aureus including MRSA VCM and arbekacin (ABK) showed the highest activities against both S. aureus and MRSA isolated from patients with UTIs. The MIC90s of them were 1 microgram/ml. The others except minocycline (MINO) had low activities with the MIC90s of 32 micrograms/ml or above. More than a half of S. aureus strains (including MRSA) showed high susceptibilities to gentamicin (GM) and MINO, the MIC50s of 0.25 microgram/ml or 0.5 microgram/ml. 3. Enterobacter cloacae IPM showed the highest activity against E. cloacae. The MICs for all strains were equal to or lower than 1 microgram/ml. The MIC90s of ciprofloxacin (CPFX) and tosufloxacin (TFLX) were 1 microgram/ml, the MIC90s of amikacin (AMK) and ofloxacin (OFLX) were 4 micrograms/ml, the MIC90 of GM was 16 micrograms/ml. Among E. cloacae strains, those with low susceptibilities to quinolones have decreased in 1997, compared with those in 1996. But the other drugs were not so active in 1997 as 1996. 4. Escherichia coli All drugs except penicillins were active against E. coli with the MIC90s of 8 micrograms/ml or below. Particularly, flomoxef (FMOX), cefmenoxime (CMX), cefpirome (CPR), cefozopran (CZOP), IPM, CPFX and TFLX showed the highest activities against E. coli with the MIC90s of 0.125 microgram/ml or below. 5. Klebsiella pneumoniae K. pneumoniae was susceptible to almost all the drugs except penicillins. Carumonam (CRMN) had the strongest activity with the MICs for all strains equal to or lower than 0.125 microgram/ml. FMOX, CPR, CZOP, CPFX and TFLX were also active with the MIC90s of 0.125 microgram/ml or below. The MIC90s of quinolones had changed into a better state in 1997, compared with those in 1996. 6. Proteus mirabilis Almost all the drugs except ABPC and MINO showed high activities against P. mirabilis. CMX, ceftazidime (CAZ), latamoxef (LMOX), CPR, cefixime (CFIX), cefpodoxime (CPDX) and CRMN showed the highest activities against P. mirabilis. The MICs of them for all strains were equal to or lower than 0.125 microgram/ml. CPFX and TFLX were also active with the MIC90s of 0.125 microgram/ml or below. 7. Pseudomonas aeruginosa The MIC90 of GM was 8 micrograms/ml, the MIC90s of AMK, IPM and meropenem (MEPM) were 16 micrograms/ml. The others were not so active against P. aeruginosa with the MIC90s of 32 micrograms/ml or above. The MIC90s of quinolones had changed into a lower state in 1997, compared with those in 1996. 8. Serratia marcescens IPM showed the highest activity against S. marcescens. Its MIC90 was 2 micrograms/ml. GM was also active with the MIC90 of 4 micrograms/ml. The MIC90s of the others were 16 micrograms/ml or above. The MIC50s of CRMN was 0.125 microgram/ml or below, the MIC50s of CPR and CZOP were 0.25 microgram/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)     

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 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%.     

Fundamental and clinical evaluation on ceftriaxone in the pediatric field

Fundamental and clinical evaluation on ceftriaxone (Ro 13-9904, CTRX) was performed. CTRX was compared with CEZ, CMZ, CTX and LMOX in the antibacterial activity against the clinical isolates such as S. aureus, E. coli, P. mirabilis, K. pneumoniae and S. marcescens. Against S. aureus, the MIC of CTRX ranged from 0.2 to greater than 100 micrograms/ml with a peak of 3.13 micrograms/ml, showing that CTRX was almost equal to CTX in activity, slightly superior to LMOX and much inferior to CMZ and CEZ, although some strains were not susceptible to CEZ. Against the intestinal strains of E. coli, K. pneumoniae and P. mirabilis, the MIC distribution of CTRX was similar to that of CTX and LMOX while CTRX showed the MIC as high as 3.13 micrograms/ml or above against 44% of all strains including the beta-lactamase producing strains of E. coli and K. pneumoniae, indicating a slight tendency of their becoming resistant. The MIC peaks against E. coli, K. pneumoniae and P. mirabilis were less than or equal to 0.1, 0.39 and less than or equal to 0.1 microgram/ml, respectively. As to S. marcescens which is drawing attention as a causative agent for infections inside of hospitals or those among young infants, CTRX inhibited 84% of the strains at 3.13 micrograms/ml, showing a definite superiority to CEZ and CMZ and a slight superiority to CTX and LMOX. The serum concentration after a single intravenous injection with 40 mg/kg reached a mean peak of 168.8 micrograms/ml at the first blood sampling (at 30 minutes) and gradually decreased to 137.5 micrograms/ml at 1 hour, 30.9 micrograms/ml at 6 hours, 12.6 micrograms/ml at 12 hours and 3.8 micrograms/ml at 24 hours, while the half-life time was 6.0 hours. The comparison of the serum level by 1 hour intravenous drip infusion between the dosage groups of 20 mg/kg and 40 mg/kg revealed that the former group reached a peak of 85.4 micrograms/ml at the termination of drip while the latter's peak was 176.6 micrograms/ml observed during the drip (30 minutes after the initiation of drip). The respective levels of the 2 groups were 15.4 and 32.1 micrograms/ml at 6 hours, 5.1 and 15.0 micrograms/ml at 12 hours, and 1.6 and 4.1 micrograms/ml at 24 hours, indicating a distinct dose-response 2 hours after the initiation of drip administration. The half-life times were 4.9 and 6.2 hours, respectively, which are the longest among the cephalosporins presently being developed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Antibacterial activities of monobactams against fresh clinical isolates

Antibacterial activities of monobactam antibiotics (carumonam (CRMN) and aztreonam (AZT] against Gram-negative bacilli isolated from inpatients in the latter half of 1987 were investigated using penicillin (PC: piperacillin (PIPC], cephems (CEPs: ceftazidime (CAZ), cefotaxime (CTX), latamoxef (LMOX), cefsulodin (CFS], carbapenem (imipenem (IPM] and pyridonecarboxylic acids (norfloxacin (NFLX) and ofloxacin (OFLX] as reference antibiotics. A total of 400 strains of 13 species, i.e. Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Pseudomonas aeruginosa and Haemophilus influenzae, were used as test strains. 1. CRMN and AZT, both monobactam antibiotics, were roughly comparable in their activities and no resistant strain to these antibiotics were found among isolates of E. coli, Klebsiella spp., Proteus spp., M. morganii, P. rettgeri or H. influenzae and few resistant strains were observed among isolates of S. marcescens. On the other hand, isolates of C. freundii, Enterobacter spp. and P. aeruginosa included rather numerous strains resistant to the monobactam antibiotics. Among these cases, whereas R strains, i.e. resistant strains showing MICs greater than or equal to 50 micrograms/ml, accounted for a large proportion of strains resistant to PC and CEPs, I strains, i.e. intermediately resistant strains showing MICs between 12.5 and 25 micrograms/ml, accounted for a large proportion of strains resistant to the monobactam antibiotics. 2. Strains resistant to PIPC, a PC, were detected with high and more or less uniform frequencies over the entire spectrum of the isolates examined. 3. Antibacterial activities of CEPs varied against different bacterial species. While strains resistant to CTX, CAZ and LMOX were commonly detected with high frequencies among isolates of C. freundii, Enterobacter spp. and S. marcescens, large percentages of LMOX-resistant strains of C. freundii and Enterobacter spp. were of the I type. CTX-resistant strains were also found among isolates of P. vulgaris and M. morganii. Proportions of CEP-resistant strains of P. aeruginosa were 28% for CFS and 12% for CAZ. 4. No or few strains among the isolates of 13 species investigated were resistant to IPM, a carbapenem antibiotic, which showed the most stable antibacterial activity, but it was less active than monobactam antibiotics and CEPs against Klebsiella spp., P. mirabilis and H. influenzae.(ABSTRACT TRUNCATED AT 400 WORDS)     

Post-marketing surveillance of antibacterial activities of cefozopran against various clinical isolates--II. Gram-negative bacteria

As a post-marketing surveillance, the in vitro antibacterial activities of cefozopran (CZOP), an agent of cephems, against various clinical isolates were yearly evaluated and compared with those of other cephems, oxacephems, carbapenems, monobactams, and penicillins. Changes in CZOP susceptibility among bacteria were also evaluated with the bacterial resistance ratio calculated from the breakpoint MIC. Twenty-five species (4,154 strains) of Gram-negative bacteria were isolated from the clinical materials annually collected from 1996 to 2001, and consisted of Moraxella (Branhamella) catarrhalis, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Serratia liquefaciens, Citrobacter freundii, Citrobacter koseri, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia spp., Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas putida, Acinetobacter baumannii, Acinetobacter Iwoffii, Burkholderia cepacia, Stenotrophomonas maltophilia, Bacteroides fragilis group, and Prevotella/Porphyromonas. CZOP preserved its antibacterial activity against M. (B.) catarrhalis (MIC90: 4 micrograms/mL) and showed comparable activity to carbapenems against H. influenzae (MIC90: 1 microgram/mL). The antibacterial activity of CZOP against E. coli was preferable (MIC90: 0.125 microgram/mL) and comparable to those of cefpirome (CPR), cefepime (CFPM), and imipenem (IPM). The MIC90 of CZOP against K. pneumoniae and K. oxytoca was 1 and 0.25 microgram/mL, respectively. The MIC90 of CZOP against E. cloacae increased during 6 years (32 to 128 micrograms/mL). The antibacterial activity of CZOP against E. aerogenes was preferable (MIC90: 1 microgram/mL). The antibacterial activities of CZOP against S. marcescens and S. liquefaciens were relatively potent (MIC90: 0.5 and 0.25 microgram/mL) and comparable to those of CPR, CFPM, and carumonam. CZOP preserved comparable antibacterial activity to CPR against C. freundii and C. koseri (MIC90: 8 and 0.125 micrograms/mL). The MIC90 of CZOP against P. mirabilis, P. vulgaris, and M. morganii was 0.25, 16, and 2 micrograms/mL, respectively. The antibacterial activity of CZOP against Providencia spp. was moderate (MIC90: 64 micrograms/mL). The antibacterial activity of CZOP against P. aeruginosa was the most potent (MIC90: 16 micrograms/mL) among the test agents and comparable to those CFPM, IPM, and MEPM. CZOP had low activity against P. fluorescens and P. putida (MIC90: 128 micrograms/mL). The antibacterial activity of CZOP against A. baumannii was comparable to those of ceftazidime (CAZ), CPR and CFPM (MIC90: 32 micrograms/mL) and against A. lwoffii was moderate (MIC90: 64 micrograms/mL). Most of the test agents including CZOP had low antibacterial activity against B. cepacia, S. maltophilia, and B. fragilis group. The MIC90 of CZOP against Prevotella/Porphyromonas was 64 micrograms/mL. Bacterial cross-resistance ratio between CZOP and other agents was low in most of the species, ranging from 0.0 to 15.1%. In non-glucose fermentative bacteria, however, the bacterial cross-resistance ratio between CZOP and CFPM, CAZ, CPR, or IPM was high, being 36.8%, 28.0%, 38.7%, or 31.1%, respectively. In conclusion, the 6-year duration study suggested that the antibacterial activity of CZOP against E. cloacae possible decreased, but against other Gram-negative bacteria was consistent with the study results obtained until the new drug application approval.     

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.     

Bacterial and clinical studies on imipenem/cilastatin sodium in urological infection

Antibacterial activities of imipenem (MK-0787), cefazolin (CEZ), cefmenoxime (CMX) and cefoperazone (CPZ) were measured by using an agar dilution method against 243 strains of bacteria isolated from the patients with urinary tract infections. The MIC80 of MK-0787 against S. epidermidis, E. faecalis, E. coli, K. pneumoniae, E. cloacae, S. marcescens, P. mirabilis, P. vulgaris and P. aeruginosa was less than or equal to 0.10, 3.13, less than or equal to 0.10, 0.20, 0.78, 1.56, 3.13, 3.13 and 6.25 micrograms/ml, respectively. MK-0787 was more active than CEZ, CMX and CPZ against all bacterial species except Proteus spp. Imipenem/cilastatin sodium (MK-0787/MK-0791) 500 mg/500 mg two times a day for 5 days was given to 31 cases of chronic complicated urinary tract infections and a case of acute prostatitis. Overall clinical effectiveness rate judged by the criteria proposed by the Japanese UTI committee in 22 cases of chronic complicated urinary tract infection treated with MK-0787/MK-0791 was evaluated to be 86% including excellent in 6 cases, moderate in 13 cases and poor in 3 cases. As side effects, 2 cases encountered eruption or anorexia. Abnormal laboratory findings were observed in 6 cases.     

Evaluation of latamoxef in neonates

Basic and clinical studies were carried out on latamoxef (LMOX) in relation to the use of this antibiotic in the treatment of infections in newborn infants. The results were as follows. The MICs of LMOX were determined for various clinical isolates of Gram-negative bacteria: 22 strains of E. coli, 18 strains of K. pneumoniae, 4 strains of K. oxytoca, 19 strains of P. mirabilis, 4 strains of P. vulgaris, 5 strains of P. morganii and 3 strains of C. freundii and 60 strains of H. influenzae. The MIC distributions against all of these strains for each species were 0.1, 0.2, 0.1, 0.2, 0.1, 0.1, 6.25 and 0.78 microgram/ml or less, respectively. The antibacterial activity of LMOX against all of these Gram-negative isolates was thus found to be excellent. For 38 strains of P. aeruginosa, the MIC distribution was from 6.25 to 200 micrograms/ml; accordingly, although this antibiotic does show antibacterial activity against this microbe, it is not very potent. As Gram-positive bacteria, 28 clinical isolates of S. pyogenes and 34 strains of S. aureus were tested; their respective MIC distributions were 0.39--1.56 micrograms/ml and 3.13--25 micrograms/ml. Therefore, it is clear that the antibacterial activity of LMOX against these Gram-positive bacteria is not as good as against the above-mentioned Gram-negative species. LMOX was injected intravenously as a one-shot dose of 20 mg/kg to 5 newborn infants (ranging in age from 0 to 13 days) and to 2 suckling infants (49 and 60 days of age), and then the concentration of the drug in the serum was monitored with time. The mean serum concentrations in the newborn group at various times were as follows: 38.5 micrograms/ml at 0.5 hour, 31.6 micrograms/ml at 1 hour, 26.9 micrograms/m l at 2 hours, 17.8 micrograms at 4 hours and 15.5 micrograms/ml at 6 hours. For the 2 suckling infants, the mean values at those same time points were 30.5, 23.9, 16.3, 7.4 and 4.0 micrograms/ml. In addition the value for the mean serum half-life was 4.46 hours in the newborn infant group and 1.96 hours in the suckling infant group. The urinary recovery rate was 32.3% in the newborn infant group and 49.7% in the suckling infant group during 6 hours or 8 hours.(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)     

Laboratory and clinical studies of sulbactam/cefoperazone in the pediatric field

The authors have carried out the laboratory and clinical studies of sulbactam/cefoperazone (SBT/CPZ) and obtained the following results. The antibacterial activities of SBT/CPZ against the clinical isolates of S. aureus, E. coli, K. pneumoniae, E. cloacae, E. aerogenes, S. marcescens, P. aeruginosa were measured by the plate dilution method with inoculum size of 10(6) cells/ml. The susceptibility distribution of S. aureus to SBT/CPZ ranged from 0.39 to 6.25 micrograms/ml, and the peak of distribution was 1.56 micrograms/ml. The peak of susceptibility distribution of K. pneumoniae was 0.20 microgram/ml, and the distribution of E. coli and E. aerogenes ranged from 0.10 to 12.5 micrograms/ml and that of S. marcescens, from 0.2 to 25 micrograms/ml. The growth of 80.8% of P. aeruginosa was inhibited at the concentration of 12.5 micrograms/ml. The distribution of E. cloacae ranged from 0.1 to 50 micrograms/ml. For pharmacokinetic study, SBT/CPZ was given in a single dose of 20 mg/kg by drip infusion for 1 hour in 2 children and 40 mg/kg by drip infusion for 1 hour in 1 children. With drip infusion of SBT/CPZ, the peak serum level were 17.8/43.9 micrograms/ml, 21.8/75.5 micrograms/ml on completion of the infusion, respectively. SBT/CPZ was effective in 14 cases out of 16 cases with clinical effect. No side effect was observed except for eosinophilia in 1 case.     

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.