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The antibacterial activity of cefmetazole (CMZ) against clinical isolates from 15 medical institutions all over Japan was evaluated yearly for two years from June 2000 to March 2002 and compared with that of other parenteral beta-lactams, cefazolin (CEZ), cefotiam (CTM), sulbactam/cefoperazone (SBT/CPZ), and flomoxef (FMOX). In the first surveillance from June 2000 to March 2001, 575 isolates of 13 species were tested, and 548 isolates of the same 13 species were tested in the second surveillance from April 2001 to March 2002. In these surveillances spanning two years, the MIC90s of CMZ against the bacterial species tested hardly differed. Changes in percent resistance of each species to CMZ (MIC of CMZ > or = 32 micrograms/mL) were as follows: methicillin-susceptible Staphylococcus aureus (MSSA, 0%-->0%), methicillin-resistant Staphylococcus aureus (MRSA, 73%-->87%), Staphylococcus epidermidis (19%-->32%), other coagulase-negative Staphylococcus spp. (other CNS, 13%-->18%), Escherichia coli (4%-->1%), Klebsiella pneumoniae (3%-->4%), Klebsiella oxytoca (0%-->0%), Proteus mirabilis (2%-->2%), Proteus vulgaris (14%-->7%), Morganella morganii (7%-->0%), Providencia spp. (17%-->0%), Peptostreptococcus spp. (0%-->0%), Bacteroides fragilis (10%-->11%), and other Bacteroides spp. (79%-->88%). The change in percent resistance of MRSA, S. epidermidis, other CNS, and other Bacteroides spp. tended to increase. In addition, the percent resistance of B. fragilis was 10%. It is necessary to pay much attention to the trends observed in these species. Compared to other drugs tested, against MSSA, the activity of CMZ was inferior to that of CEZ, CTM, and FMOX and superior to that of SBT/CPZ. Against MRSA, S. epidermidis, and CNS, the tested drugs exhibited little activity. Against Gram-negative bacteria, the activity of CMZ was almost superior to that of CEZ and CTM, and inferior to that of FMOX. Against B. fragilis and other Bacteroides spp., the activity of CMZ was almost superior to that of CEZ and CTM, and comparable to or inferior to that of SBT/CPZ and FMOX. No remarkable changes in the activity of CMZ were observed in this study compared with studies conducted before CMZ was launched. This result suggests that CMZ still maintains potent activity.

The in vitro antibacterial activities of cefozopran (CZOP), an agent of cephems, against various clinical isolates obtained between 1996 and 2001 were yearly evaluated and compared with those of other cephems, oxacephems and carbapenems. A total of 3,245 strains in 32 species of Gram-negative bacteria were isolated from the clinical materials annually collected from January to December, and consisted of Moraxella subgenus Branhamella catarrhalis, Escherichia coli, Citrobacter freundii, Citrobacter koseri, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter cloacae, Serratia marcescens, Proteus mirabillis, Proteus vulgaris, Morganella morganii, Providencia spp. (P. alcalifaciens, P. rettgeri, P. stuartii), Pseudomonas aeruginosa, Pseudomonas putida, Burkholderia cepacia, Stenotrophomonas maltophilia, Haemophilus influenzae, Acinetobactor baumannii, Acinetobactor lwoffii, Bacteroides fragilis group (B. fragilis, B. vulgatus, B. distasonis, B. ovatus, B. thetaiotaomicron), and Prevotella spp. (P. melaninogenica, P. intermedia, P. bivia, P. oralis, P. denticola). CZOP possessed stable antibacterial activities against M. (B.) catarrhalis, E. coli, C. freundii, C. koseri, K. pneumoniae, K. oxytoca, E. aerogenes, E. cloacae, S. marcescens, P. mirabilis, P. vulgaris, M. morganii, Providencia spp., P. aeruginosa, and A. lwoffii throughout 6 years. The MIC90 of CZOP against those strains were consistent with those obtained from the studies performed until the new drug application approval. On the other hand, the MIC90 of CZOP against H. influenzae yearly obviously increased with approximately 64-time difference during the study period. The MIC90 of cefpirome, cefepime, and flomoxef against H. influenzae also yearly tended to rise. The present results demonstrated that CZOP had maintained the antibacterial activity against almost Gram-negative strains tested. However, the decrease in antibacterial activities of CZOP against B. cepacia, and H. influenzae was suggested.

MICs of piperacillin, sulbactam/cefoperazone, minocycline (MINO), gentamicin, amikacin, flomoxef, ceftazidime, cefozopran, cefsulodin and imipenem were determined, against 189 clinical isolated strains of glucose non-fermentative Gram-negative Rods (NFGNR; Acinetobacter baumannii (44), Alcaligenes faecalis (5), Alcaligenes xylosoxidans (25), Burkholderia cepacia (12), Chryseobacterium indologenes (23), Chryseobacterium meningosepticum (9), Pseudomonas fluorescens (8), Pseudomonas putida (12), Stenotrophomonas maltophilia (51). Most species of these NFGNR show resistance to many antibiotics tested. Among the antibiotics used in this study, the only antibiotic effective against all species of NFGNR tested is MINO. The spectrums of antibacterial activities of various antibiotics determined by MICs may be useful in preliminary test for identification of these NFGNR.

In vitro activities of sulopenem, a novel parenteral penem, was compared with those of imipenem, flomoxef, cefuzonam, cefoperazone and sulbactam/ampicillin against 66 reference strains (19 genera, 61 species) and 392 recent clinical isolates of anaerobic bacteria and fastidious aerobic bacteria. Sulopenem had a very broad spectrum against anaerobic bacteria. In general, this compound was active against anaerobic reference strains with MICs of < or = 0.78 micrograms/ml, while being the least active against Bifidobacterium spp. and less active than imipenem against Lactobacillus spp. Sulopenem was more active against Bacteroides fragilis isolates than imipenem and had the highest activities against Bacteroides thetaiotaomicron, Prevotella intermedia, Porphyromonas gingivalis, Fusobacterium spp. and Peptostreptococcus spp. among the antibiotics tested. Sulopenem was not hydrolyzed by oxyiminocephalosporinase type 1 produced by B. fragilis GAI-0558, GAI-7955 and GAI-10150 and its stability was comparable to imipenem. Its susceptibilities to hydrolysis by a metallo-beta-lactamase from B. fragilis GAI-30144 was less than imipenem. Sulopenem (120 mg/kg, 3 times a day for 4 days) was as effective as imipenem/cilastatin against a mixed intraabdominal mice infection due to E. coli and B. fragilis. Sulopenem (20 mg/kg twice a day for 5 days) did not induce an overgrowth of Clostridium difficile in the caecum of mice.

Synergistic enhancement of the in vitro antimicrobial activity of imipenem combined with cephalosporins against methicillin-resistant Staphylococcus aureus (MRSA) has been reported. In order to investigate which cephalosporin is more effective in enhancing the activity of imipenem against MRSA, the in vitro antimicrobial activities of imipenem, cefazolin, cephalothin, cefotiam, cefamandole and cefoperazone, alone and in combination, against methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA were assessed. Using the checkerboard Mueller-Hinton agar dilution method, strong synergy was found in 97% to 100% of MRSA strains for imipenem and all tested cephalosporins except cefoperazone; fractional inhibitory concentration (FIC) indices were < or = 0.5. Among the cephalosporins studied, cefamandole most markedly increased the activity of imipenem against MRSA, followed, in order of decreasing effect, by cefotiam, cephalothin, cefazolin, and cefoperazone. The synergistic effect of imipenem combined with cefamandole or cefotiam was confirmed using the broth dilution method with 2% of NaCl.

We studied the combined effect of fosfomycin (FOM) with sulbactam/cefoperazone (SBT/CPZ) on clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA, 246 strains) and Pseudomonas aeruginosa (190 strains) in vitro. In ratio of mixed serum concentration of antibiotics at three hours after intravenous administration, the combination of FOM with SBT/CPZ and alone of arbekacin showed over 90% in cumulative percentage of MIC against MRSA and P. aeruginosa. The effect of the combination of FOM and SBT/CPZ was observed in MRSA strains of > 16 micrograms/ml of SBT/CPZ MIC and > 256 micrograms/ml FOM MIC. As well as in P. aeruginosa strains, the effect of the combination of FOM and SBT/CPZ was observed in strains of > 16 micrograms/ml of SBT/CPZ MIC and < 256 micrograms/ml FOM MIC, but it was not remarkable in strains of > 256 micrograms/ml FOM MIC. These results suggests that the combination treatment of FOM and SBT/CPZ may be effective for mixed infection of MRSA and P. aeruginosa.

Pseudomonas aeruginosa has been a major bacterial partner when MRSA (Methicillin-resistant Staphylococcus aureus) is isolated clinically. Hence, we studied the in vitro combined effect of fosfomycin (FOM) plus sulbactam/cefoperazone (SBT/CPZ) against mixed infections of MRSA and P. aeruginosa. The combined effect of FOM plus SBT/CPZ was observed through an FIC index using the checkerboard method, log reduction of colony counts on the time killing curve, and morphological changes observed using scanning electron micrography. Under serum concentration at 3 hours after administration in consider of pharmacokinetics, the combination effect was also evaluated. Furthermore, we evaluated a time-lag combination therapy in which FOM is administered 60 minutes before SBT/CPZ administration for mixed infections. Synergistic effects of FOM plus SBT/CPZ were clearly observed against mixed infections of MRSA and P. aeruginosa. Log reduction of colony counts on the time killing curve seemed to be an appropriate indicator in the evaluation of synergistic effects.

Effects of sulbactam/cefoperazone (SBT/CPZ) on the host-parasite relationship were studied using an established mouse macrophage cell line. Since SBT inactivates some types of beta-lactamase strongly, a combination of SBT with CPZ shows marked antibacterial activities against the bacteria producing beta-lactamases. In addition, sub-MIC levels of SBT/CPZ made Escherichia coli more susceptible to bactericidal activity of macrophage. This study provides evidence that SBT/CPZ works in partnership with host defense mechanism against bacterial infections in clinical situations.

We evaluated combined effects of sulbactam/cefoperazone (SBT/CPZ) with each of imipenem/cilastatin (IPM), cefuzonam, flomoxef, amikacin (AMK) and tobramycin (TOB) against 324 clinical strains. Through this study, we obtained the following results. 1. Against Serratia marcescens and Enterobacter cloacae, good synergism was obtained by combining SBT/CPZ with IPM, AMK, or TOB. 2. Against Pseudomonas aeruginosa, good synergism was obtained by combining SBT/CPZ with AMK or TOB. 3. When SBT/CPZ was used in combination with IPM, antagonism was observed among about 45% of strains of P. aeruginosa.

A study was done on the combined actions of an aminoglycoside, isepamicin (ISP), and 3 beta-lactam antibiotics (cefoperazone (CPZ), latamoxef (LMOX) and imipenem/cilastatin sodium (IPM/CS] against clinical isolates of Pseudomonas aeruginosa, Serratia marcescens and Klebsiella pneumoniae. Minimal inhibitory concentrations of individual antibiotics were compared first. ISP and IPM/CS had strong antibacterial activities against all 3 bacterial species while the antibacterial activities of CPZ against P. aeruginosa and S. marcescens, and that of LMOX against P. aeruginosa were much weaker than those of IPM/CS or ISP. Fractional inhibitory concentration indices determined by the checker-board dilution method were compared next. ISP, when used in combination with beta-lactam antibiotics (CPZ, LMOX, or IPM/CS), showed synergistic or additive effect on most strains of the all 3 species, the combination of ISP and CPZ being most effective. Although less effective, synergistic or additive effects were also observed with the combinations of 2 beta-lactam antibiotics (CPZ and IPM/CS, LMOX and IPM/CS). Time course experiments demonstrated that ISP combined with CPZ had bactericidal activities against all 3 bacterial species at concentrations at which the respective drug alone showed only bacteriostatic activity.

Antimicrobial activities of sulbactam (SBT) with ampicillin (ABPC) or with cefoperazone (CPZ), in other words, the effects of SBT, an beta-lactamase inhibitor, against beta-lactamase producing strains of clinical isolates, were studied using microdilution broth method. 1. beta-Lactamase producing strains such as Staphylococcus aureus, Branhamella catarrhalis, Haemophilus influenzae, Escherichia coli and Klebsiella pneumoniae decompose benzylpenicillin (PCG) which is one of substrates of the acid-metry disc method and show a strong reaction, while they do not decompose cefazolin (CEZ), another substrate, showing no or weak reaction. Thus, it is suspected that beta-lactamases produced by these organisms are mainly penicillinase (PCase). MIC-distributions of ABPC and CPZ against these clinical isolates which seemed to produce PCase shifted to lower MIC ranges with MIC's reduced to 1/4 or below when 0.025 to 0.39 microgram/ml of SBT was added. 2. It appears that beta-lactamase produced by Proteus vulgaris may be oxyiminocephalosporinase (CXase), because P. vulgaris showed strong reaction on CEZ, but moderate reaction on PCG in the acid-metry disc method. MIC-distribution of ABPC and CPZ against P. vulgaris shifted to a lower range with MIC's of 1/4 or below when 0.20 to 0.39 microgram/ml of SBT was added. 3. All the test strains of Pseudomonas aeruginosa showed strong reaction on CEZ but only 56% of the test strains showed reaction on PCG. It appears that the beta-lactamases which showed strong reaction on CEZ is cephalosporinase and is encoded in chromosome, while those beta-lactamase that showed strong reaction on PCG is encoded in a plasmid which was acquired secondarily by P. aeruginosa. MIC-distribution of CPZ against P. aeruginosa shifted to a lower range with MIC values of 1/2 or below with the addition of SBT at 1.56 micrograms/ml. 4. It appears that the synergy of SBT with ABPC or with CPZ against the PCase or CXase producing strains may occur in the presence of SBT at a concentration far less than that reported previously.

We evaluated relationships between production of beta-lactamase and their resistances to beta-lactams, effect of sulbactam (SBT), a beta-lactamase inhibitor, against beta-lactam resistant strains, and combined effect of sulbactam/cefoperazone (SBT/CPZ) with other antibiotics against multi-resistant strains. Through these studies, we obtained the following results. 1. Most of the strains resistant to beta-lactams were beta-lactamase producers. 2. Relationships between the production of beta-lactamase and their resistances to beta-lactams indicate that their resistances generally were the highest in producers of both penicillinase (PCase) and cephalosporinase (CEPase), moderate in producers of either PCase or CEPase, and the lowest in beta-lactamase non-producers. Most of highly-resistant strains of MRSA appeared to be beta-lactamase non-producers though some exceptions were observed among methicillin-resistant Staphylococcus aureus (MRSA), Serratia marcescens and Pseudomonas aeruginosa. 3. SBT showed good effect against PCase producers, moderate effect against producers of both PCase and CEPase, little effect against CEPase producers, and no effect against beta-lactamase non-producers. 4. Results of combined effect of SBT/CPZ with other antibiotics indicated that good synergism was obtained by combining SBT/CPZ with fosfomycin (FOM) or piperacillin against multi-resistant strains of Proteus spp., Enterobacter cloacae, and S. marcescens, by combining SBT/CPZ with ceftazidime (CAZ) or FOM in methicillin-sensitive S. aureus and by combining SBT/CPZ with CAZ in P. aeruginosa. 5. Better synergism was obtained with the higher concentrations of antibiotics.

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.

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.

Susceptibilities of 372 strains of bacteria to cefotaxime (CTX) were determined based on the inhibition zone diameter obtained by the single-disc method. Four categories were assessed. Susceptibility of clinical isolated to CTX and 3 other antibiotics. Against most strains, CTX showed higher antibacterial activity than other drugs in the low concentration, especially for S. aureus, S. pneumoniae, S. agalactiae, E. coli and P. morganii. Susceptibility of strains isolated from different clinical materials. CTX showed the highest antibacterial activity against most strains isolated from pus, blood and cerebrospinal fluid and showed higher activity against strains isolated from other materials, too. Susceptibility of clinical isolates in 7 different fields. CTX was shown to have uniformly higher antibacterial activity than other drugs against isolates from such fields as internal medicine, pediatrics, surgery, urology, obstetrics & gynecology, dermatology and otorhinolaryngology. CTX showed the highest antibacterial activity in dermatology. Susceptibility of all clinical isolates. CTX showed the highest antibacterial activity against isolated pathogenic 352 strains (except for P. aeruginosa of 20 strains).

Efficacy and safety of sulbactam/cefoperazone (SBT/CPZ) was studied on gynecological infections. The results obtained are as follows: In the treatment of 31 cases of gynecological infections, the clinical efficacy of SBT/CPZ was assessed as excellent in 9 cases and effective in 22 cases. As for the bacteriological effects of SBT/CPZ, clinically isolated organisms were completely (100%) eradicated. In comparison with MICs of CPZ, SBT/CPZ was found to show a combined effect on Gram-negative and Gram-positive organisms in the order mentioned, but this effect was not observed against anaerobes. The combined effect of SBT/CPZ on beta-lactamase producing bacteria was also investigated in the same manner. As a result, SBT/CPZ was found to exert a combined effect on beta-lactamase strains of S. aureus, S. epidermidis, E. coli, B. catarrhalis and B. fragilis. The laboratory tests performed before and after administration of SBT/CPZ revealed rise in GOT and GPT values in 1 case, GPT values in 2 cases and eosinophil in 1 case. However, these rises were all mild and required no particular measures.

As indexes for administration of cefoperazone (CPZ) in the treatment of gyneco-obstetrical infections, sensitivities to CPZ of important pathogenic organisms and CPZ concentrations in the exudate of the pelvic dead space were determined, and a pharmacokinetic analysis was made on the results. Sensitivities to CPZ were determined for freshly isolated organisms from gynecological material consisting of 227 strains of 7 aerobic bacteria and 70 strains of 1 anaerobic bacterium, in a total of 297 strains. MIC80 values of CPZ against E. coli, K. pneumoniae, P. aeruginosa, E. cloacae, C. freundii, S. aureus, S. epidermidis and B. fragilis were 0.39, 0.78, 6.25, 25, 50, 12.5, 12.5 micrograms/ml and 6.25 micrograms/ml, respectively. On the whole, these activities are relatively superior to those of other antibiotics. CPZ concentrations in the exudate of the pelvic dead space and their changes with time after 2 g single dose by drip infusion were Cmax 93.89 micrograms/ml, Tmax 1.53 hours, T 1/2 4.33 hours and AUC 759.4 hr X micrograms/ml. After 1 g single dose, they were Cmax 37.7 micrograms/ml, Tmax 3.2 hours, T 1/2 2.78 hours and AUC 339.2 hr X micrograms/ml. Similarly, after 2 g single dose intravenously, they were Cmax 111.02 micrograms/ml, Tmax 0.761 hours, T 1/2 6.22 hours and AUC 1,083.9 hr X micrograms/ml, and after 1 g single dose, they were Cmax 29.1 micrograms/ml, Tmax 2.65 hours, T 1/2 4.82 hours and AUC 296.9 hr X micrograms/ml. Similarly, after 2 g single dose intramuscularly, they were 39.4 micrograms/ml, Tmax 2.70 hours, T 1/2 8.19 hours and AUC 584.7 hr X micrograms/ml, and after 1 g single dose, they were Cmax 26.4 micrograms/ml, Tmax 5.79 hours, T 1/2 5.53 hours and AUC 435.7 hr X micrograms/ml. As indicated, there were noted dose-dependent responses and the kinetics of CPZ exudate concentrations varied with the administration routes. Whatever the dose level and the administration route were, CPZ exudate concentrations covered MIC80 values against important clinical isolates for 10 to 12 hours. This suggests that we can well expect of the antibacterial activity of this drug by any of these administration routes and dosages on the intrapelvic lesions.

To interpret of the cefoperazone (CPZ) disc susceptibility test, a 4 category system is used in Japan, but a 3 category system is used in the U.S.A. and Europe. In the 4 category interpretation system of Showa CPZ disc the following classification is used: ( ) MIC less than or equal to 3 micrograms/ml, (++) MIC greater than 3 approximately 15 micrograms/ml, (+) MIC greater than 15 approximately 60 micrograms/ml, (-) MIC greater than 60 micrograms/ml. In the 3 category system the classification used is as follows: susceptible MIC less than or equal to 16 micrograms/ml, moderately susceptible MIC greater than 16 approximately 32 micrograms/ml, resistant MIC greater than 32 micrograms/ml, or susceptible MIC less than or equal to 32 micrograms/ml, moderately susceptible MIC greater than 32 approximately 64 micrograms/ml, resistant MIC greater than 64 micrograms/ml, depending on dose levels, 1 or 2 g. Reliability of the CPZ disc susceptibility test in estimating approximate MICs by classifying the test results into 4 categories was studied using discs containing 1, 2, 5, 10, 30 and 75 micrograms. The MICs were determined using the agar dilution method at an inoculum level of 10(6) CFU/ml. A good negative correlation was observed between inhibitory zone diameters and MICs, showing reliability of the test using these discs. The results obtained with discs containing 30 or 75 micrograms of CPZ were well categorized into the 4 groups mentioned above. Some strains of Pseudomonas aeruginosa and Enterococcus faecalis, however, showed false positive results. When different break points of inhibitory zone diameters than those used for other bacteria were used for P. aeruginosa, and E. faecalis was excluded from the test, an excellent correlations were obtained. With 30 or 75 micrograms discs, it was unable to subclassify strains against which MICs of CPZ were below 3 micrograms/ml. However, with discs containing 1 to 10 micrograms, it was possible to separate the strains against which MICs were less than 0.5 microgram/ml. The fact that most frequent values of MICs of CPZ against Escherichia coli, Klebsiella pneumoniae, Proteus spp., Haemophilus influenzae, Streptococcus pyogenes etc. were less than 0.5 microgram/ml supports the usefulness of low dose discs. According to recently ongoing concepts on the pharmacokinetics of antibiotics and their penetration into tissues and inflammatory fluids, serum protein binding appear to be one of the important determinants of drug distribution in the body. Only free, unbound drug molecules can readily pass through capillary pores into tissue fluids except into hepatic biliary system.(ABSTRACT TRUNCATED AT 400 WORDS)

Bacteriological and clinical effect of a newly developed SBT/CPZ in the treatment for pediatric patients was assessed by a study group consisting of 15 institutions. The results were as follows. Antibacterial effect Susceptibility studies were performed with 93 clinical isolates. The MIC of SBT/CPZ was one-tube inferior or almost similar to that of CPZ in susceptible organisms. In CPZ-resistant organisms at the inoculum of 10(8) cells/ml, however, SBT/CPZ was much superior to CPZ on the basis of the MIC. When the MIC of SBT/CPZ was compared to that of CPZ in 27 strains which have high beta-lactamase-producing activity, it was found that many of CPZ-resistant organisms were susceptible to SBT/CPZ. Serum concentration and urinary excretion The serum concentrations of SBT and CPZ were 33.2 micrograms/ml, respectively at 15 minutes after 20 mg/kg SBT/CPZ was administered by intravenous bolus injection, and those of SBT and CPZ, 51.0 micrograms/ml and 108.3 micrograms/ml, respectively following 40 mg/kg SBT/CPZ therapy. The serum concentrations of CPZ were 2.1-2.4 times as high as those of SBT. The concentrations were dose-related. The half-lives of SBT and CPZ following 20 mg/kg SBT/CPZ administration were 0.94 hour and 1.50 hours, respectively, and those following 40 mg/kg SBT/CPZ were 0.95 hour and 1.53 hours, respectively. There was no significant difference between 20 mg/kg and 40 mg/kg administrations. When compared between SBT and CPZ, CPZ had slightly longer half-lives. At the termination of 1 hour drip infusion of 20 mg/kg SBT/CPZ, the serum concentrations of SBT and CPZ were 16.7 micrograms/ml and 40.1 micrograms/ml, respectively. In the case of 40 mg/kg, the levels of SBT and CPZ were 38.6 micrograms/ml and 94.9 micrograms/ml, respectively. The concentrations were found to be dose-related as were following intravenous bolus injections. The SBT half-lives obtained after 20 mg/kg and 40 mg/kg SBT/CPZ administrations were 1.39 hours and 0.89 hour, respectively; those of CPZ, 2.00 hours and 1.44 hours, respectively. The highest urinary concentration occurred 0-2 hours after intravenous bolus injections of 20 mg/kg or 40 mg/kg SBT/CPZ. Urinary excretion of SBT over 6 hours was 60.0% and 67.7%, and that of CPZ, 21.2% and 25.0%, indicating higher urinary excretion for SBT. When 20 mg/kg SBT/CPZ or 40 mg/kg was administered over 1 hour by drip infusion, urinary excretion became the highest at 1-3 hours after administration. Urinary excretion of SBT over 7 hours following 20 mg/kg and 40 mg/kg SBT/CPZ was 68.8% and 80.3%, respectively, and that of CPZ, 24.4% and 27.3%. The results were similar to those observed following intravenous bolus injections.

Clinical and bacteriological efficiencies of cefoperazone (CPZ) in 19 serious infections associated with hematological malignancy were studied. CPZ was clinically effective in 13 cases (68.4%). Excellent effects were obtained in 3 cases (15.8%), good effects in 7 cases (36.8%) and fairly good effects in 3 cases (15.8%). The rate of clinical effectiveness by CPZ was not dependent on neutrophils number in peripheral blood. Bacteriological effectiveness to isolated organisms in 15 cases was obtained in 9 cases (60%). Clinically significant serum concentrations of CPZ persisted over 6 hours after injection (1 g/l hour, d.i.v.). In comparative study of MIC against clinically isolated P. aeruginosa, CPZ was superior to other cephalosporins. Adverse reactions were not significant except for 3 cases with abnormalities of hepatic function.

The disulfiram-like reactions following the treatment of cephem antibiotics with methyltetrazolethiol moiety (latamoxef (LMOX) and cefoperazone (CPZ) was studied by using large (500 mg/kg) and small (50 mg/kg) doses of the drugs. Normal and fatty liver rats were injected intraperitoneally with the cephem antibiotics. After overnight fasting blood samples were obtained following an administration of 20% ethanol (2g/kg). Blood ethanol and acetaldehyde concentrations, and liver acetaldehyde dehydrogenase activity were determined. Blood ethanol concentration upon the small dose was similar to that obtained upon the large dose in both groups of normal and fatty liver rats. Blood acetaldehyde concentration upon the large dose was higher than that upon the small dose; 2-fold increase in normal rats and 2.6-4.7-fold increase in fatty liver rats were observed after administering LMOX, while 3.7-fold increase in normal rats and 5-5.7-fold increase in fatty liver rats upon administering CPZ. Additionally, liver acetaldehyde dehydrogenase activity (Enzyme 1) observed upon the large dose was lower than that observed upon the small dose; the degree of reduction was 33% in normal and 19% in fatty liver rats upon the administration of LMOX, while 37% in normal and 45% in fatty liver rats upon the administration of CPZ.

Fundamental and clinical studies were carried out on sulbactam/cefoperazone (SBT/CPZ) in the field of pediatrics. The following results were obtained: A total of 185 clinical isolates that had been stocked at our department was employed to determine the minimum inhibitory concentrations (MICs) of SBT/CPZ against various bacterial species. SBT/CPZ showed strong antibacterial potency against E. coli, Salmonella, Klebsiella and P. mirabilis, and relatively strong potency against S. marcescens, P. aeruginosa and S. aureus. Antibacterial potency of SBT/CPZ was stronger than that of CPZ alone against E. coli, and it also showed strong activity against strains of Salmonella, S. marcescens and S. aureus, moderately or highly resistant to CPZ. SBT/CPZ was administered by intravenous bolus infusion to pediatric patients to determine the serum concentrations of SBT and CPZ. At a dose of 10 mg/kg the mean serum levels of SBT and CPZ were as follows; 17.8 micrograms/ml, 40.7 micrograms/ml at 15 minutes and 0.3 microgram/ml at 6 hours, respectively. The half-lives of SBT and CPZ in the serum were 1.05 hours and 1.76 hours, respectively. Similarly, at a dose of 20 mg/kg the mean serum levels of SBT and CPZ were; 31.9 micrograms/ml, 81.0 micrograms/ml at 15 minutes and 0.5 microgram/ml, 6.1 micrograms/ml at 6 hours, and the half-lives were 1.00 hour and 1.72 hours, respectively. At a dose of 40 mg/kg, only 1 case was determined. The serum levels of SBT and CPZ were 34.4 micrograms/ml, 74.8 micrograms/ml at 30 minutes and 0.2 microgram/ml at 6 hours, and the half-lives were 0.78 hour and 1.38 hours, respectively. SBT/CPZ was drip-infused intravenously over a period of 1 hour, and the serum concentrations of SBT and CPZ were determined. At the dose of 10 mg/kg or 20 mg/kg, the peak serum levels of SBT and CPZ were observed at 1 hour or at the end of drip infusion. At a dose of 10 mg/kg the mean serum levels of SBT and CPZ were 14.4 micrograms/ml, 33.7 micrograms/ml at 1 hour and 1.4 micrograms/ml, 4.6 micrograms/ml at 7 hours, respectively. The half-lives was 1.86 hours for SBT and 2.23 hours for CPZ, respectively. Similarly at a dose of 20 mg/kg, the mean serum levels of SBT and CPZ were, 22.2 micrograms/ml, 34.6 micrograms/ml at 1 hour and 0.5 microgram/ml, 2.8 micrograms/ml at 7 hours, and the half-lives was 1.17 hours and 1.75 hours, respectively. The urinary recovery rate was determined for the 6 hours period after administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Sulbactam/cefoperazone (SBT/CPZ) is a preparation containing CPZ and SBT, an inhibitor of beta-lactamases, at the ratio 1:1. The reliability of the SBT/CPZ disc susceptibility test in estimating approximate values of MICs and the utilization of the test in the evaluation of proper administrative doses were studied using 365 strains of clinical isolates. The antimicrobial activity of SBT/CPZ was stronger than that of CPZ alone. This increase in the antimicrobial activity due to the addition of SBT was well observed in the disc diffusion susceptibility test and MIC values. The MIC80 of SBT/CPZ against Staphylococcus aureus was 12.5 micrograms/ml, while that of CPZ alone was 50 micrograms/ml. MIC80s of SBT/CPZ against Escherichia coli, Pseudomonas aeruginosa, Serratia marcescens and Enterobacter aerogenes were smaller than those of CPZ, and were 0.20, 12.5, 25 and 3.13 micrograms/ml, respectively. However, MIC80s of SBT/CPZ against Staphylococcus epidermidis, Klebsiella pneumoniae, Proteus mirabilis and Proteus vulgaris were not changed compared to those of CPZ alone, and MIC80s were 6.25, 0.20, 0.78, and 0.78 micrograms/ml, respectively. The reliability of the SBT/CPZ disc diffusion susceptibility test in the quantitative estimation of antimicrobial activities was well demonstrated using commercialized 8 mm diameter discs (Showa) and 6 mm diameter discs prepared in this laboratory, both of which contained 30 micrograms of CPZ and 30 micrograms of SBT. These disc susceptibility test results were well correlated with MICs, hence the SBT/CPZ disc susceptibility test should be useful for the estimation of approximate MIC values. To interpret results of the Showa SBT/CPZ disc test, the following 4 category classification was used: (¿) MIC less than or equal to 3 micrograms/ml, (¿ 3 micrograms/ml less than MIC less than or equal to 15 micrograms/ml, (¿15 micrograms/ml less than MIC less than or equal to 60 micrograms/ml, (-) MIC greater than 60 micrograms/ml. In both 6 and 8 mm diameter disc tests, when uniform break points of inhibitory zone diameter were similarly applied to all strains isolated clinically, some strains of S. aureus, E. faecalis, and P. aeruginosa, brought false positive (susceptible) results showing slightly greater inhibitory zone diameters compared to MICs. However, if different break points against P. aeruginosa as indicated in this study were applied and E. faecalis was excluded from the test, excellent results were obtained in the quantitative estimation of MICs. Antimicrobial activities of antibiotic agents have been reported to be reduced by serum protein binding.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Incidences of methicillin-resistant strains of Staphylococcus (MRS) have been increasing because of the extensive uses of cephalosporins and semisynthetic beta-lactamase-resistant penicillins. Most of these strains are known to be resistant to beta-lactam antibiotics due to their production of penicillinases and mutated penicillin-binding proteins. Our recent clinical isolates of MRS were also suspected to be this type because of their temperature sensitive resistance to methicillin. We studied in vitro antibiotic activity of cefuzoname (CZON) a cephalosporin developed against Staphylococcus, against these MRS in comparison with those of the representative cephalosporins, cefazolin (CEZ), cefamandole (CMD), cefotiam (CTM), cefoperazone (CPZ) and cefpiramide (CPM). It was found that CZON was the most active against MRS among these cephalosporins under normal body temperatures as well as at lower temperatures.

The in vitro antibacterial activities of cefoperazone (CPZ) against clinical isolates including various beta-lactamase-producing strains were studied and compared with those of cefotiam (CTM). CPZ had a broad spectrum against Gram-negative and Gram-positive bacteria. Especially, CPZ showed apparently more potent antibacterial activities than CTM against Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa. However, CPZ was less active than CTM against Staphylococcus aureus and Proteus mirabilis. The stability and affinity of CPZ for various types of beta-lactamase were also studied. CPZ was more resistant to hydrolysis by typical cephalosporinase (CSase) and cefuroximase (CXase) than CTM, but was less stable to penicillinase (PCase). CPZ often showed higher affinity to beta-lactamases than CTM. The study for the inducer-activity revealed that CPZ hardly induced CSase production in E. cloacae and Proteus vulgaris while CTM highly induced in both strains. CPZ was more active against CSase-producers than CTM, especially against strains which inducibly produced the enzyme. It was speculated that this activity was responsible for the superior stability to CSase and low inducer-activity for CSase production.

Sulbactam (SBT) in a novel beta-lactamase inhibitor from Pfizer and combined with cefoperazone (CPZ) ina 1:1 ratio (SBT/CPZ). Fundamental and clinical studies on SBT/CPZ were executed. The antibacterial activity of SBT/CPZ was compared with those of SBT, CPZ and CEZ against clinical isolates of S. aureus and E. coli which were not susceptible to CEZ. SBT alone did not show any activity against S. aureus, MICs against all strains were over than 100 micrograms/ml on the inoculations of undiluted and 100-fold diluted specimen. CPZ showed MICs over than 100 micrograms/ml against approximately 70% of the isolates on the undiluted inoculation, and on the 100-fold diluted inoculation, the MIC50 and MIC70 were 12.5 micrograms/ml and 100 micrograms/ml, respectively. SBT/CPZ showed better activity than CPZ by 2-8 folds against the strains highly resistant to CPZ; the MIC50 on the undiluted inoculation was 50 micrograms/ml. Against E. coli, the characteristic of SBT/CPZ was shown more clearly. The MICs of CPZ were over than 100 micrograms/ml against approximately 70% of the isolates on the undiluted inoculation, but SBT/CPZ showed MIC50 at 25 micrograms/ml. On the 100-fold diluted inoculation, SBT/CPZ was 4 approximately 8-fold superior than CPZ against strains on which MICs of CPZ were over than 12.5 micrograms/ml. Serum levels were determined by a bolus intravenous injection and by intravenous drip infusion of 10, 20, 40 mg/kg of SBT/CPZ. When administered by a bolus injection, the peak level was seen at 30 minutes in most patients: 8.7, 14.7 or 27.0 micrograms/ml of SBT and 30.1, 42.5 or 76.4 micrograms/ml of CPZ were detected with the 3 different doses. These levels were dose-dependent, and decreased slowly to 0.3, 0.3 or 0.3 micrograms/ml of SBT and 2.9, 2.8 or 3.3 micrograms/ml of CPZ at 6 hours after administration. Half-lives were 1.39, 1.20 or 0.98 hour for SBT and 1.77, 1.59 or 1.42 hours for CPZ. The same 3 doses were given by intravenous drip infusion. The peak levels obtained at the end of infusion (1 hour after initiation of infusion) were 15.3, 14.4 or 43.2 micrograms/ml for SBT and 33.4, 38.2 or 104.2 micrograms/ml for CPZ, respectively. The levels were somewhat low in 20 mg/kg group. After the end of infusion, these levels decreased fairly rapidly, and after 6 hours almost the same levels of 0.4, 0.5 or 0.3 micrograms/ml for SBT and 1.4, 3.9 or 3.3 micrograms/ml for CPZ were detected.(ABSTRACT TRUNCATED AT 400 WORDS)

Microbiological, pharmacokinetic and clinical studies on sulbactam/cefoperazone (SBT/CPZ) were carried out in the field of pediatrics. Antimicrobial activity The MIC80 of SBT/CPZ was 6.25 micrograms/ml for clinically isolated 24 strains of S. aureus (24 beta-lactamase producing strains), 0.39 micrograms/ml for 17 strains of S. pyogenes, 3.13 micrograms/ml for 24 strains of E. coli (22 beta-lactamase producing strains), 3.13 micrograms/ml for 22 strains of K. pneumoniae (22 beta-lactamase producing strains), 1.56 micrograms/ml for 22 strains of P. mirabilis and 0.20 microgram/ml for 15 strains of H. influenzae (13 beta-lactamase producing strains). In comparison with CPZ in respect to the MIC, SBT/CPZ exhibited synergistic effect on 31 strains out of 81 beta-lactamase producing strains (included 6 strains of S. aureus, 9 of E. coli, 5 of K. pneumoniae and 11 of H. influenzae) which was scarcely observed against 43 non-beta-lactamase producing strains. Absorption and excretion Serum levels and urinary excretion of SBT/CPZ were studied in 7 children aged 5 to 12 years. The mean serum concentration of SBT at 15 minutes following a single intravenous injection of 10 mg/kg of SBT/CPZ was 14.2 micrograms/ml and that of CPZ was 30.4 micrograms/ml. The mean urinary recovery rates at 6 hours following the intravenous injection were 57.8% and 18.3%, respectively. The mean serum concentrations of SBT and CPZ after 1-hour infusion of 10 mg/kg of SBT/CPZ were 10.9 micrograms/ml and 17.6 micrograms/ml, respectively. The urinary recovery rates of SBT and CPZ at 7 hours after the infusion were 100.0% and 27.7% on average, respectively. The mean serum levels of SBT and CPZ at 15 minutes after a single intravenous injection of 20 mg/kg of SBT/CPZ were 25.6 micrograms/ml and 66.0 micrograms/ml, respectively and urinary elimination until up to 6 hours were 72.5% on average for SBT and 21.1% for CPZ. Clinical study SBT/CPZ was used for the treatment of a total of 20 pediatric patients aged 1 month to 14 years to evaluate its clinical effectiveness, bacteriological efficacy and adverse effects. The clinical efficacy in 6 patients with acute pneumonia, 3 with staphylococcal scalded skin syndrome, 2 each with acute purulent tonsillitis and acute pyelonephritis, 1 each with acute purulent lymphadenitis, acute sinusitis, acute bronchitis, peritonitis and acute enteritis was judged to be excellent in 15 cases and good in 3 cases with an efficacy ratio of 100%. The clinical efficacy in 6 patients whose infections were caused by beta-lactamase producing strains was judged to be excellent in all the cases.(ABSTRACT TRUNCATED AT 400 WORDS)

The combined actions of sisomicin (SISO), gentamicin (GM) and cefmenoxime (CMX), ceftizoxime (CZX), cefoperazone (CPZ), cefotetan (CTT) against S. marcescens IFO-3735 and P. aeruginosa IFO-12689 were investigated. The results were summarized as follows. The synergistic effect of the combinations of SISO-CMX, SISO-CZX, SISO-CPZ, SISO-CTT, GM-CMX, GM-CZX, GM-CPZ and GM-CTT using the checker board dilution method on S. marcescens IFO-3735 and P. aeruginosa IFO-12689 were found. Especially the minimum FIC index value of combination of SISO-CTT and GM-CTT were rather low as 0.14 and 0.13, respectively and these synergistic effect was remarkably strong on S. marcescens IFO-3735. With the killing kinetic method, all combinations tested showed the synergistic effect in both bacteria.

To 6 cases of children in 2 groups of 3 each, newly developed sulbactam/cefoperazone (SBT/CPZ) was given at 20 and 40 mg/kg by intravenous bolus injection, respectively, and the serum and urinary concentrations and recoveries of SBT and CPZ were determined. To 1 case of purulent meningitis, this drug was given at 40 mg/kg by intravenous bolus injection, and the cerebrospinal fluid and serum concentrations of SBT and CPZ were determined. Susceptibility tests to SBT/CPZ and CPZ of total 289 strains were conducted; Gram-positive cocci tested consisted of 26 S. aureus strains, 20 S. pyogenes strains and 21 S. pneumoniae strains, and Gram-negative bacilli consisted of 24 H. influenzae strains, 22 E. coli strains, 26 K. pneumoniae strains, 24 E. cloacae strains, 21 E. aerogenes strains, 19 Citrobacter sp. strains, 20 S. marcescens strains, 23 P. mirabilis strains, 23 indole-positive Proteus sp. strains and 20 P. aeruginosa strains. SBT/CPZ was given to total 43 cases at a mean daily dosage of 80.4 mg/kg, in 3 or 4 divided doses (6 cases in 3 and 37 cases in 4), 1 case receiving the drug by drip infusion over 30 minutes (in 3 divided doses) and all the other 42 cases by intravenous bolus injection, for 7 days on an average. They consisted of 2 cases of tonsillitis, 1 case of otitis media, 1 case of otitis media associated with mastoiditis, 30 cases of pneumonia, 1 case of suspected septicemia, 1 case of purulent meningitis, 5 cases of urinary tract infection, 1 case of purulent lymphadenitis and 1 case of submaxillaritis. And the clinical and bacteriological effects were evaluated. Also, side reactions and laboratory examinations for abnormal values due to administration of this drug were made on 47 cases including 4 drop-outs. The following results were obtained: After administration of this drug to 2 groups of 3 children each at 20 and 40 mg/kg by intravenous bolus injection, mean serum concentrations of both SBT and CPZ reached the peaks in 5 minutes; SBT levels were 60.9 and 124.7 micrograms/ml for the 2 groups and CPZ levels were 105.0 and 214.1 micrograms/ml, respectively. In either group, CPZ levels were 1.7 times as high as SBT levels, and there was observed a dose-response in both. In the 20 mg/kg group, mean half-lives of SBT and CPZ were 0.96 and 1.24 hours, respectively, and in the 40 mg/kg group, they were 1.01 and 1.32 hours, CPZ values tending to be longer.(ABSTRACT TRUNCATED AT 400 WORDS)

Sulbactam/cefoperazone (SBT/CPZ) was evaluated in the treatment of pediatric patients to have the following results: Peak serum concentrations which occurred just after the drip infusion of 20 mg/kg SBT/CPZ were 36.4 micrograms/ml and 8.6 micrograms/ml for CPZ and SBT, respectively. The half-life of CPZ was 1.91 hours, and that of SBT, 0.97 hour. Following the 40 mg/kg drip infusion, the peak serum concentration of CPZ was 79.1 micrograms/ml, and that of SBT, 27.0 micrograms/ml. The half-lives were 1.99 hours for CPZ, and 1.07 hours for SBT, respectively. In 6 hours after drip infusion of 20 mg/kg and 40 mg/kg 21.7, 37.0% of CPZ and 41.6, 85.6% of SBT were excreted in urine. Daily doses of about 50-90 mg/kg SBT/CPZ were administered by intravenous or drip infusion to 26 pediatric patients with acute infections such as lacunar tonsillitis, bronchitis, bronchopneumonia, suppurative diseases caused by Staphylococcus (staphylococcal scalded skin syndrome), purulent parotitis, cervical lymphadenitis, phlegmon and acute UTI related with ABPC/CPZ resistant beta lactamase producing E. coli. SBT/CPZ demonstrated the bacteriological effect on all the causative organisms. The clinical efficacy was also confirmed with the efficacy rate of 88.5%. No side effects were observed in all the cases though transient eosinophilia developed in 2 patients.

Sulbactam/cefoperazone (SBT/CPZ) was administered intravenously to 9 patients with respiratory infections (H. influenzae 6 cases, pathogens unknown 3 cases), 2 patients with urinary tract infection (E. coli and C. freundii; both cases had VUR), and 1 patient with staphylococcal bacteremia. In these causative bacteria, 5 strains (H. influenzae 3, E. coli 1 and S. aureus 1) were beta-lactamase producers. Bacteriological efficacy (eradication rate) was complete (9/9, 100%) and clinical efficacy was also complete (12/12, 100%). In comparison with CPZ alone, MICs of SBT/CPZ against beta-lactamase producing bacteria were superior. Although mild side effect was observed in 1 case (eosinophilia), no other severe form of adverse reaction were encountered. It was concluded that SBT/CPZ was an useful antibiotic for the treatment of pediatric bacterial infections, especially caused by beta-lactamase (penicillinase) producing bacteria.

Clinical effectiveness of cefoperazone (CPZ) was studied for 46 elderly patients with respiratory infections. 1. Clinical efficacy rate of CPZ was 80.6% (29/36). 2. Adverse reactions occurred in 2 patients as systemic rush and fever. Laboratory abnormalities were observed in 5 patients. These included elevation of transaminase value. 3. The serum concentration of CPZ at 12 hours after administration of 2 g CPZ was not reflected in creatinine clearance and total bilirubin, and those 2 values appeared to have little effects on CPZ excretion. 4. The administration of CPZ at 4 g/day for less than 3 weeks had no effects on the renal function. As a result of this study, CPZ was found to have little undesirable effect on renal functions and to be a useful drug for the treatment of respiratory infections in elderly patients.

The in vitro activity and beta-lactamase stability of cefodizime (HR 221), a new cephalosporin, were compared with those of other cephem antibiotics. HR 221 was highly active against Gram-negative bacteria. The compound inhibited growth of all tested Haemophilus influenzae strains at 0.10 microgram/ml and showed strong activity even against penicillin-resistant Neisseria gonorrhoeae strains, but it was less effective against Pseudomonas aeruginosa than the other antibiotics tested. Against Gram-positive bacteria, HR 221 showed 100% inhibition of growth of Streptococcus pneumoniae at 0.39 microgram/ml, and it was slightly less active against Staphylococcus aureus (MIC90:12.5 micrograms/ml) than other antibiotics such as cefotaxime (CTX). The bactericidal activity of HR 221 against E. coli was dose-related and comparable to that of CTX, cefoperazone and latamoxef. The bactericidal activity of the compound at medium concentrations simulating human serum levels was higher than that of CTX and cefmetazole, and no cell regrowth was noted after beta-lactamase-induced inactivation of the compound. HR 221 was stable to most drug-inactivating enzyme preparations from various bacterial species.

Sulbactam/Cefoperazone (SBT/CPZ) have been used in clinical infusion at ratios of 1:1 and 1:2 in Japan and U.S.A., respectively. After an administration of these drugs as a 1:1 parenteral formulation, the ratio of levels of CPZ and SBT in blood was 1:1/4 to 1:1/5 for 1 to 2 hours, whereas the ratio of free, unbound drug levels was 1:1.4 to 1:1.5. In urine these drugs were excreted at a ratio between 1:1 and 1:4 during 6 hours after the infusion. Antimicrobial interaction studies using various combinations of CPZ and SBT were performed to obtain information with respect to the effect of SBT on the antimicrobial activity of CPZ in vivo and the most appropriate ratio of these drugs for the in vitro test system. Antimicrobial activities were determined using the agar dilution method and the disk diffusion susceptibility test. SBT increased the activity of CPZ against various clinical isolates tested except Enterococcus faecalis. CPZ-SBT at a fixed ratio of 1:1/5 significantly increased the antimicrobial activity of CPZ, resulting in decreases in MIC values and increases in disk inhibitory zone diameters. These drugs at ratios 1:1 to 1:3 maximized the synergistic enhancement of the activity. Therefore, a fixed ratio between 1:1/5 and 1:1 would be appropriate for the in vitro antimicrobial test system using either the agar dilution method or the disk susceptibility test. Based on pharmacokinetic data for CPZ and SBT, results of the present study on antimicrobial activity would support that the parenteral formulation of CPZ-SBT at the fixed ratios of 1:1 and 2:1 for the intravenous infusion used in Japan and U.S.A., respectively, are appropriate. The effect of SBT on the activity of CPZ was more marked against clinical isolates with greater production abilities of beta-lactamase than against those with less production abilities. SBT/CPZ, however, exerted a synergistic effect against methicillin-resistant Staphylococcus aureus without beta-lactamase production. The MIC80 of SBT/CPZ (1:1) against various clinical isolates with 10(6) CFU/ml inoculum size were as follows: S. aureus 12.5 micrograms/ml, Staphylococcus epidermis 3.13 micrograms/ml, and E. faecalis 50 micrograms/ml. Those of Gram-negative bacilli were: Escherichia coli 0.20 microgram/ml, Klebsiella pneumoniae 0.20 micrograms/ml, Proteus mirabilis 0.78 microgram/ml, Proteus vulgaris 0.78 microgram/ml, Pseudomonas aeruginosa 12.5 micrograms/ml, Serratia marcescens 25 micrograms/ml, Enterobacter spp. 3.13 micrograms/ml, Citrobacter spp. 12.5 micrograms/ml and Acinetobacter spp. 0.78 microgram/ml.

Aztreonam (AZT), which has a newly developed and synthetic structure belonging to the group of monobactams, possesses excellent antibacterial activity against a broad range of Gram-negative bacteria (including the beta-lactamase producing strains). Antibacterial activities of AZT were examined and compared with those of 5 antibiotics (cefoperazone (CPZ), latamoxef (LMOX), cefotaxime (CTX), cefmetazole (CMZ) and cefsulodin (CFS) against 296 strains of clinical isolates. The evaluation of antibacterial activities was determined with the inhibition zone diameter obtained by the single disc method. The results can be summarized by three categories as follows: 1. Susceptibility of clinical isolates to AZT and other antibiotics AZT and other 3rd-generation antibiotics (CPZ, LMOX, CTX) showed excellent antibacterial activities against most strains. Especially AZT was more active against Enterobacter cloacae and Serratia marcescens than reference drugs. Against Pseudomonas aeruginosa, the activity of AZT was similar to that of CFS. AZT showed as excellent activity against P. aeruginosa as CFS. 2. Susceptibility of strains isolated from different clinical materials and different clinics AZT showed the highest antibacterial activity against the clinical isolates from sputum, pharynx, urine, pus, bile, puncture fluid, blood and others. AZT exhibited the most potent activity against isolates in the 7 clinics we tested. 3. Susceptibility of strains isolated from inpatients and outpatients AZT demonstrated the highest antibacterial activity (the rate of susceptibility: 87.0%) against strains obtained from inpatients (except for P. aeruginosa). The activity of AZT (81.4%) against P. aeruginosa was as active as that of CFS (81.4%), and it was the highest in all drugs. Antibacterial activity of these antibiotics against bacteria was rated as follows: AZT greater than LMOX greater than CPZ greater than CTX greater than CMZ AZT showed the highest antibacterial activity (100%) against strains isolated in all the materials and at all the clinics tested of outpatients. Antibacterial activity of these antibiotics against isolates from outpatients was rated as follows: AZT greater than CPZ greater than LMOX greater than CTX greater than CMZ.

Clinical trials were carried out with sulbactam/cefoperazone (SBT/CPZ) (combination ratio of 1:1) in pediatric infections. Results were as follows. The mean half-lives of SBT and CPZ in the serum following intravenous injection of SBT/CPZ were about 0.7 and 1.2 hours, respectively. Urinary excretions of SBT and CPZ within 6 hours after intravenous injection of SBT/CPZ were 81.9% and 28.1%, respectively. SBT/CPZ was administered to 33 pediatric patients with various infection; 18 respiratory tract infections, 12 urinary tract infections and 3 Salmonella enterocolitis. The overall efficacy rate was 87.9%. In particular, 7 of 8 urinary tract infections caused by beta-lactamase producing organisms were improved after administration of SBT/CPZ. Diarrhea in 8 and soft stool in 3 of 33 patients occurred, and slight elevation of GOT/GPT was observed in 2 patients.