The combination drug of sulbactam (SBT) with cefoperazone (CP2) in the ratio of 1: 1, demonstrated marked synergy of antibacterial activities to S. aureus, E. coli carrying R (bla) plasmids, P. mirabilis, P. vulgaris, P. morganii, and B. fragilis, and moderate synergy against the clinical isolates of S. marcescens, Citrobacter and E. cloacae. Since CPZ-resistant strains were rare in S. pyogenes and S. epidermidis, the synergy of SBT and CPZ was not clear in those microbes. Little synergy was also observed in clinical isolates of P. aeruginosa.
Inactivation of β-lactamase continued for 60 min after the depletion of SBT if P. vulgaris had been pretreated with more than 10 μg/ml of the inhibitor. When S. aureus and P. vulgaris producing the type Ic β-lactamase were inoculated simultaneously in a medium containing the MIC of CPZ to S. aureus, the antibiotic was destroyed soon and both microbes started regrowth. However, the combination of SBT in the same concentration of CPZ prevented the destruction of CPZ and the regrowth of both microbes.

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It was confirmed that β-lactamase-inhibitors that can manifest a synergy of antibacterial activities with β-lactamase-susceptible β-lactams are limited to those possessing an activity of permanent inactivation of the enzymes. Since sulbactam (SBT) inactivated the types of Ic, II, III (TEM), IV, and V (OXA) β-lactamases strongly and the type Ia enzyme moderately, a combination of SBT with cefoperazone (CPZ) showed marked antibacterial activities against P. vulgaris, P. cepacia, B. fragilis, E. coli carrying R (bla) plasmids, Klebsiella, and P. mirabilis. The activity of SBT to inactivate the type III β-lactamase, however, was weaker than that of clavulanic acid (CVA) in some extent. The combined drug exhibited some synergies to Serratia marcescens also, because of inactivation of the type Ia enzyme.
SBT competed for penicillin-binding proteins of Escherichia coli and Staphylococcus aureus with more than 25 μg/ml, resulting in stronger cell-lysis if combined with CPZ.

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We studied the in vitro antibacterial effects of the combination of cefoperazone (CPZ) and sulbactam (SBT), a β-lactamase inhibitor, on clinical isolates of various pathogenic bacteria, i. e., Staphylococcus, Streptococcus faecalis, Hemophilus influenzae, Enterobacteriaceae, glucose non-fermenting Gram-negative rods and Bacteroides.
1) Except for Gram-positive cocci and H. influenzae, a combination effect was evident with all bacterial isolates, especially those with higher MIC's against CPZ, and the antibacterial activity of CPZ was enhanced by the addition of SBT.
2) Some of the isolates were also examined for the production of β-lactamase. Against most of the β-lactamase producing bacteria, the antibacterial activity of CPZ was enhanced by the addition of SBT.
3) In these experiments, the combination effect of CPZ and SBT was greater with the inoculum size of 10⁸ CFU/ml compared to that of 10⁶ CFU/ml.

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The activity of sulbactam as a β-lactamase inhibitor, when combined with cefoperazone, was studied in a variety of bacteria.
Sulbactam by itself has little antibacterial activity against most bacteria, and thus cannot be used alone as a therapeutic agent. However, it has strong activity to inhibit β-lactamases.
When sulbactam and cefoperazone were combined in a ratio of 1:1, marked synergistic activity was obtained against E. coli, K. pneumoniae, Proteus, and B. fragilis.
Sulbactam exhibited strong inhibitory activity against β-lactamases of types 2 to 5 by Richmond's classification, and weak activity against type 1 β-lactamase.
In experimental infections in mice, excellent protective effects were obtained against E. coli, P. vulgaris, and a mixed infection of B. fragilis and E. coli with the combination of sulbactam and cefoperazone, even though neither sulbactam nor cefoperazone was effective by itself.

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In vitro antibacterial activity of sulbactam (SBT), a β-lactamase inhibitor, in combination with cefoperazone (CPZ), was investigated with the following results.
1) When tested against the various bacterial strains maintained in our laboratory, the antibacterial activity of SBT by itself was weak, with MICs of more than 25 μg/ml against all strains tested. SBT, when combined with CPZ in a ratio of 1:1, did not affect the MIC of CPZ against CPZ-sensitive strains but lowered the MIC of CPZ against CPZ-resistant strains of Escherichia coli, Proteus vulgaris, Citrobacter, etc. at an inoculum size of 10⁸ cells/ml.
2) Synergistic effects of SBT in combination with CPZ against clinical isolates of Staphylococcus aureus, E. coli, Klebsiella pneumoniae, and P. vulgaris were examined by the checker board dilution method. At an inoculum size of 10⁸ cells/ml, marked synergistic effects were obtained with the-combination, while at an inoculum size of 10⁶ cells/ml the synergistic effects tended to be obscured because the bacteria were sensitive to CPZ.
3) The mode of the antibacterial activity of SBT in combination with CPZ was studied with CPZ-resistant S. aureus, E. coli, K. pneumoniae, and P. vulgaris. At the concentrations in which the respective drugs alone showed only bacteriostabc activity, the combined drugs showed marked bactericidal activity, thus confirming the synergistic effect of the two drugs.
4) Morphological changes of E. coli in the presence of SBT were examined with phase-contrast microscopy. At SBT concentrations close to the MIC, the bacteria became extremely elongated and filamentous in shape.
5) SBT showed strong affinity to penicillin binding proteins 2, 3 and lA in E. coli K-12.

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Antibacterial activity of sulbactam (SBT) in combination with cefoperazone (CPZ) against anaerobes was evaluated in vitro and in vivo.
SBT, when combined with CPZ, cefazolin (CEZ), or amoxicillin (AMPC), showed excellent antibacterial activity against anaerobic Gram-negative rods such as Bacteroides fragilis. The combination of SBT and CPZ in a 1:1 ratio had antibacterial activity equal or superior to cefmetazole (CMZ) against anaerobic Gram-negative rods including B. fragilis and Bacteroides thetaiotaomicron, and the activity was bactericidal.
In experimental infection models with mice, the combination of SBT and CPZ showed excellent in vivo antibacterial activity. In addition, the incidence of Clostridium difficile, one of the causative agents of diarrhoea observed after antibiotic administration, was markedly reduced by the combination, compared with the single administration of each drug.

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The in vitro antibacterial activity of CPZ against bacteria resistant to CPZ was markedly increased by the addition of Sulbactam (SBT), while the antimicrobial activity of SBT was generally weak, except for its powerful activity against species of N. gonorrhoeae and A. calcoaceticus. The combination of SBT and CPZ in the ratio of 1:1 displayed the marked synergy against β-lactamase-producing strains of E. coli, K. pneumoniae, Proteus spp. and B. fragilis. This synergetic effect was also observed in other species of Enterobacteriaceae, P. aeruginosa and Staphylococcus spp.
The degree of synergetic effect of SBT and CPZ against various species was closely related to the affinity of SBT to the β-lactamase produced by the bacterial strains. The bactericidal activity of CPZ was also potentiated by the addition of SBT.
The in vitro and in vivo antibacterial activities of various ratios of SBT and CPZ were compared using CPZresistant E. coli, K. pneumoniae, Proteus spp. and B. fragilis, and the most effective ratio in in vitro was found to be between 1:4 and 4:1, while the ratio between 1:8 and 2:1 was most effective against experimental infections in mice.
The simultaneous administration of SBT and CPZ to the mice infected with various CPZ-resistant bacteria demonstrated higher survival rate of mice than that by CPZ administration alone, and the administration of SBT 60 min. prior to that of CPZ showed full survival without lowering of the survival rate of mice.

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Actue, subacute and chronic toxicities of sulbactam (SBT), a new β-lactamase inhibitor, and SBT/CPZ were evaluated in Sprague-Dawley rats or ICR mice.
The acute intravenous LD₅₀ of SBT or SBT/CPZ were estimated to be greater than 6000mg/kg in rats and mice.
In the subacute intravenous toxicity tests, all rats treated with SBT (30, 100, 300, 600, 1200mg/kg) or SBT/CPZ (300/300, 600/600mg/kg) for 1 month were well tolerated, and non-toxic dose of SBT is considered to be 100mg/kg. The higher dose levels (300, 600, 1200mg/kg) of SBT produced slight increases of the liver and cecum weights and a deposition of glycogen-like droplets in the hepatic cell cytoplasm withotit any functional abnormality and morphological lesions. SBT/CPZ groups, however, showed less degree of deposition than those of SBT groups, and the combination groups had no evidence of increase in liver weight.
In the chronic toxicity test, the rats treated intraperitoneally with SBT (25, 50, 250, 500mg/kg), CPZ (250, 500mg/kg) or SBT/CPZ (250/500, 500/250, 500/500mg/kg) for 6 months were well tolerated and the results were comparable to those in the subacute toxicity tests. The non-toxic dose in the chronic intraperitoneal toxicity test with SBT is considered to be 50mg/kg, and SBT did not enhance the toxicity when combined with CPZ.

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Reproduction studies of sulbactam (SBT) and SBT/CPZ were conducted in Sprague-Dawley rats. Doses employed in these studies were 500, 250 and 50 mg/kg of SBT, and 500/500mg/kg of SBT/CPZ.
1) Fertility and general reproductive study
Male rats were treated intraperitoneally with SBT or SBT/CPZ for 62 days prior to mating and females were treated intravenously from 14 days prior to mating to day 7 of gestation. The reproductive performance parameters such as the rates of copulation and pregnancy in the SBT or SBT/CPZ groups were comparable to those of controls. No drug-related external, visceral or skeletal malformations were observed in the fetuses from the dams sacrificed on day 21 of gestation.
2) Teratological study
Pregnant rats were treated intravenously with SBT or SBT/CPZ from day 7 to day 17 of gestation. No drugrelated external, visceral or skeletal malformations of the fetuses were found. The parturition and nursing ability of the dams and the growth, viability, behavioral and reproductive performance of F₁ offsprings of SBT or SBT/CPZ groups were comparable to those of controls. No drug-related external malformations were noted in any of the F₂, fetuses.
3) Peri-and postnatal study
Pregnant rats were treated intravenously with SBT or SBT/CPZ from day 17 of gestation to day 21 of the postparturition. A slight decrease of survival rates of the pups at day 4 after birth in the groups treated with 500mg/kg of SBT or 500/500mg/kg of SBT/CPZ was found, but no significant decrease was noted thereafter. The postnatal development, fertility of offspring (F₁) and development of F₂ fetuses in the treated groups were comparable to those of controls.

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General pharmacological properties of sulbactam (SBT) and SBT/CPZ were examined.
1. When mice were intravenously treated with SBT at 2, 000mg/kg or SBT/CPZ at1, 000/1, 000mg/kg, there were no significant effects on spontaneous motor activity, motor coordination, grip strength, electroshock-induced convulsion or nociceptive response.
2. In anesthetized dogs, slight and transient increases in respiratory rate and blood pressure were noted after intravenous injection of SBT at 500mg/kg or SBT/CPZ at 500/500mg/kg. There were no effects of SBT and SBT/CPZ on atrial rate or contractile force of isolated guinea pig atria.
3. Intravenous injection of SBT at 2, 000mg/kg or SBT/CPZ at 1, 000/1, 000mg/kg had no effects on pupil size in mice, gastric secretion in Shay rats and nictitating membrane contraction in anesthetized cats.
4. No significant effects of SBT or SBT/CPZ were found in isolated smooth muscle preparations, except for slight increase in spontaneous motility of isolated rabbit ileum at a high concentration of SBT/CPZ (10^-3/10^-3g/ml).
5. In saline loaded-rats, no significant influences on urine volume or urinary electrolytes excretion were noted with SBT at 1, 000mg/kg or SBT/CPZ at 1, 000/1, 000mg/kg (i. v.), but slight increases in urine volume and urinary Na⁺ excretion were observed with SBT at 2, 000mg/kg.

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Pharmacokinetics of the combination of sulbactam (SBT) and cefoperazone (CPZ) administered intravenously or subcutaneously to mice, rats and dogs were compared with those of SBT alone. The following results were obtained:
1) The serum levels of SBT and CPZ after intravenous administration of SBT/CPZ were higher in dogs than in rats. Their serum half lives were 20 and 21 minutes in rats, and 30-35 and 42-46 minutes in dogs, respectively. Serum levels of SBT and CPZ reached a peak 15 to 30 minutes after subcutaneous administration of the combination to mice, and then declined in parallel. The serum half lives of both drugs were about 20 minutes.
2) The tissue levels of drugs after intravenous administration of SBT/CPZ to rats were highest in the kidney, followed by the liver, serum and lung. After subcutaneous administration of SBT/CPZ to mice, SBT concentration was highest in the kidney, followed by the serum, lung and liver, and CPZ levels were highest in the liver, followed by the kidney, serum and lung in this order.
3) After intravenous administration of SBT/CPZ, SBT was predominantly recovered in the urine in mice, rats, and dogs. The urinary and fecal recoveries of CPZ were approximately 17% and 35% in rats, and 64% and 20% in dogs, respectively. Biliary recovery in rats was about 1% for SBT and about 54% for CPZ. Therefore, it seems that the major route of excretion for SBT was the urine and for CPZ the bile in rats and urine in dogs. The pharmacokinetics of SBT after administration of SBT alone were not different from those after administration of a combination of SBT/CPZ.
4) No active metabolite of SBT and CPZ was detected in rat urines by means of TLC-bioautography.
5) The extent of serum protein binding of SBT on coexisting of SBT and CPZ was about 20% for human and dog sera, 16% for rabbits and 56% for rats. That of CPZ was 77-93% in these animals.

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Concentrations of sulbactam (SBT) and cefoperazone (CPZ) in body fluids and tissues following an intravenous administration of the combination of SBT/CPZ were measured by microbiological assay, gas chromatography (GC) and gas chromatograph-mass spectrometry (GC-MS).
CPZ could be determined by a standard agar-diffusion microbiological assay using Micrococcusluteus ATCC 9341 without any influence of co-existing SBT. SBT was microbiologically assayed by using a β-lactamase producing strain, Escherichia coli 603, in the presence of subinhibitory concentrations of CPZ (150μg/ml in the medium). These microbiological assay methods of SBT and CPZ revealed good sensitivity; 1.6 and 0.4μg/ml, respectively, with wide range linearity.
In addition, low concentration of SBT in biological specimens was determined by GC and GC-MS with a fairly good detection limit of 0.5μg/ml and 0.05μg/ml in the serum, respectively. The concentration of SBT in biological specimens determined by the GC method showed a good correlation with those obtained by microbiological assay method.
SBT and CPZ were stable in human serum and urine at-20°C over a period of 21 days.

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Sulbactam (SBT)/Cefoperazone (CPZ) is a formulation consisting of one part of SBT, a new β-lactamase inhibitor, and one part of CPZ. The antibacterial activity of SBT/CPZ was investigated against 139 strains of clinical isolates of E.coli, Klebsiella sp., Rmirabilis, P.morganii and S. marcescens using CPZ as a control drug. The activity of SBT/CPZ was superior to that of CPZ slightly. A cross over pharmacokinetic study CPZ with and without SBT were carried out in 6 healthy volunteers. The peak serum concentration of CPZ without SBT was 252μ/ml after 5 minute 2g dose administration. The levels was 113.8μ/ml after 1 hour and 9.9μg/ml after 6 hours. The half-life of the drug was calculated to be 1.7 hour. The blood level curve of CPZ with SBT was as same as that of CPZ without SBT. On the other hand, the peak serum concentration of SBT administered lg dose was 128.7μg/ml after 5 minutes and 23.5μg/ml after 1 hour (T/2: 1.2 hour). The urinary excretion rate of CPZ was ca 25% and that of SBT was 85.2% within 8 hours after administration.
Twenty three patients with various infections were treated with lg twice a daily of SBT/CPZ for 7-26 days. The clinical response was excellent in 14 cases, good in 5, fair in one and failure in 3. Overall the efficacy rate was 82.6%. As to the side effect, chest in-comfortability in intravenous injection was occured one patient, and no abnormal laboratory findings were observed.

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To evaluate the clinical efficacy of sulbactam/cefoperazone the treatment was made with the drug in 19 patients including 5 with pneumonia, 2 with acute cystitis, 6 with chronic cystitis, 3 with acute pyelonephritis and 3 with chronic pyelonephritis. Response was excellent in 1 patient, good in 14, poor in 3.
There were seven cefoperazone resistant bacteria produced a lot of β-lactamase. However, these bacteria were sensitive to the drug of sulbactam/cefoperazone. Five out of these cefoperazone resistant bacteria were vanished following the treatment of sulbactam/cefoperazone, 1 diminished and 1 persisted. The patients infected by these cefoperazone resistant bacteria responded clinically excellent in 1 patient, good in 5 and poor in 1 to sulbactam/cefoperazone.
Side effect noted was exanthema in 1 patient. Laboratory abnormalities were observed as slight elevation of GOT in 1 patient and slight elevation of serum creatinine in 1.

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In vitro antimicrobial activity of Sulbactam/Cefoperazone (SBT/CPZ) which has a composition of 1:1 of Cefoperazone (CPZ) and Sulbactam (SBT), a potent inhibitor of many β-lactamases, was examined by a broth dilution method with Dynatech MIC 2000 system. Also, therapeutic efficacy of Sulbactam/Cefoperazone in the treatment of patients with respiratory tract infections was evaluated.
The minimum inhibitory concentrations (MICs) of Sulbactam/Cefoperazone were compared with those of Cefoperazone, Cefmetazole (CMZ), Cefazolin (CEZ), Cefsulodin (CFS) and Piperacillin (PIPC) against following 20 strains each of clinical isolates; Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa. Reductions in the MICs of Cefoperazone in the presence of Sulbactam were marked for penicillinase-producing strains of Escherichia coil, Klebsiella pneumoniae, Enterbacter cloacae and Pseudomonas aeruginosa, but less extent for cephalosporinase-producing strains of Serratia marcescens.
Sulbactam/Cefoperazone was given to a total of 12 patients by an intravenous drip infusion. The subjects examined consisted of four patients each of acute pneumonia, infection associated with bronchiectasis and infection associated with lung cancer. A daily dose of the drug given was 2 grams in 11 patients and 4 grams in one patient. Clinical response to the treatment with the drug was excellent in five patients, good in five patients and poor in two patients. Following eight potential pathogens were recovered from the sputum of these patients at the start of the treatment with the drug; four strains of Haemophilus influenzae, one strain each of Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae and Acinetobacter calcoaceticus. All of them, including three strains which has β-lactamase activity, were eradicated during the treatment with the drug. Transient diarrhea was observed in three patients among these 12 patients and in one patient among three patients with diarrhea, transient anemia and eosinophilia was complicated but returned to normal after the cessation of the drug.

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Sulbactam/Cefoperazone was administered to 16 cases (biliary tract infections 5 cases, two of them with bacteremia; respiratory tract infections 5 cases; urinary tract infections 4 cases). They received a daily dose of 2-4g of Sulbactam/Cefoperazone by intravenous injection over a period of 3-5 or 60 minutes once or twice daily. Two cases were excluded from the evaluation of clinical effect (Case 10 was proved not to be a infectious disease, and Case 16 was prophylactic chemotherapy). Clinical effects of 14 cases were excellent in 10 cases (4 cases of biliary tract infections, 3 cases of respiratory tract infections, 3 cases of urinary tract infections), good in 3 cases (one case of biliary tract infection, 2 cases of respiratory tract infections), and fair in one case of urinary tract infection. Among 16 cases treated with this drug, diarrhea was observed in 4 cases (the drug was discontinued in Case 12). Other serious adverse effects were not observed.
Serum and/or urine levels of sulbactam and cefoperazone were studied in 13 cases during the therapy with Sulbactam/Cefoperazone. Elevation of serum levels and prolongation of serum half-life of sulbactam correlated with the degree of renal dysfunction, and. those of cefoperazone correlated more with the degree of hepatic dysfunction than with the degree of renal dysfunction. Urinary excretion of cefoperazone increased in patients with hepatic dysfunction, but that of sulbactam and cefoperazone decreased in parallel with the degree of renal dysfunction. Dosage modification of Sulbactarn/Cefoperazone is necessary in patients with hepatic and/or renal dysfunction.

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A clinical administration of sulbactam/cefoperazone was conducted with eleven patients who were suffering from various infections. Sulbactam/cefoperazone was used intravenously one gram twice a day in ten patients and 2 grams twice a day in one. The results of the administration were as follows:
1. In eight patients of respiratory tract infection (four patients with pneumonia, two with chronic bronchitis, one with acute bronchitis and one with pyothorax) clinical effects of sulbactam/cefoperazone were all good except two cases (one case with pneumonia and one with acute bronchitis) with Mycoplasma infection.
2. In two cases with biliary tract infection, the therepeutic effects of sulbactam/cefoperazone were excellent in one, and good in one.
3. Sulbactam/cefoperazone obtained good effect in one patient with cystitis caused by Citrobacter.
4. No side effect was found, but elevation of titer of GOT, GPT were observed in two cases.

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Sulbactam, a new β-lactamase inhibitor, was an irreversible inhibitor of several bacterial penicillinase and cephalosporinase. Clinical effects on combination of sulbactam and cefoperazone (SBT/CPZ) were investigated and following results were obtained.
SBT/CPZ was administrated by intravenous drip infusion to 6 patients of RTI, 9 patients of UTI, 1 patient of BTI. And 2 grams of SBT/CPZ was administrated twice a day for 4 to 21 days. Clinical efficacy rate was 63% in 16 patients. As side effects, diarrhea was observed in 1 patient, and neutropenia was observed in other 1 patient.

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We injected bolusly sulbactam 1000mg to 5 healthy male volunteers for the first time in Japan and after 1 week sulbactam 1000mg and cefoperazone 1000mg simultaneously. No abnormal findings of sings or symptoms, physical examinations and laboratory tests were observed after each injection.
A hundred and four μg/ml of peak serum level was obtained 5 minutes after injection of sulbactam 1000mg and was 0.564g/ml 6 hours after injection. Urinary level of sulbactam after 0-1 hour was 9, 820μg/ml and 98.8% of dose was excreted in urine, until 12 hours.
Serum level of cefoperazone after two drug administration was higher than that of sulbactam and prolonged.Urinary excretion of cefoperaozne for 24 hours was 29.3%.
Urinary level until 6 hours of sulbactam was higher than that of cefoperazone, but cefoperaozne was higher than sulbactam after 6 hours in urine.

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SBT/CPZ were combined drug of sulbactam, a p-lactamase inhibitor, and cefoperazone at a ratio of 1 to 1.
Susceptibilities of following clinical isolates to SBT/CPZ, cefoperazone and sulbactam were determined; Escherichia coli, indole positive Proteus, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Citrobacter freundii. Antibacterial activities were enhanced by combining sulbactam and cefoperazone, especially in 10⁶ cells/ml inoculation or to cefoperazone resistant isolates.
SBT/CPZ were intravenously administered to 12 patients at a daily dose of 2-4g for 4-18 days; 3 septicemias, 3 respiratory tract infections, 4 urinary tract infections, 1 cholecystitis and 1 peritonitis. Clinical results were excellent in 1, good in 5, fair in 4, poor in 1, inevaluable in 1. No side effects or laboratory abnormalities were noticed.

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We did 6-times-administration trials of Sulbactam 1g/Cefoperazone 1g by intravenous drip infusions to 6 healthy volunteers. Drip infusions were done twice a day for 3 days.
In laboratory data, 2 volunteers had a few abnormal data before the trial. These data became normal during the trial in one case, and were stationary after the trial in the other. No abnormal data caused by this trial were recognized.
Disulfiram-like reaction was recognized in 5 volunteers who drank next day after the trial. No other side effect was recognized after 6-times-administrations of Sulbactam/Cefoperazone.
The peaks of serum concentration of both drugs were at the end of drip infusions, and those values were almost equal in each administrations. At 7 hours after drip infusions, Sulbactam serum levels were trace and Cefoperazone levels were about 4.5μg/ml. Urinary recovery ratio of 0-8 hours of Sulbactam was 90-95%, and that of Cefoperazone was about 25%. Any accumulation was not recognized after 6-times-administrations.

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A combination drug of sulbactam/cefoperazone were intravenously administered to 7 patients at a daily dose of 2g divided in two for 5-4 days. Sex were male 2, female 5. Age were 66-90 years. Diagnosis were chronic pyelonephritis 4, chronic cystitis 1, pneumonia 2. Causative organisms were P. rettgeri 2, P. mirabilis1, E. coli 1, P. mirabils, E. coli 1, unknown 2.
All organisms of urinary tract infection were good 5, fair 1, unevaluable 1. Fever and exanthema in 2, Al-P elevation in 1 were observed. They were not related to the drug.

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Sulbactam/Cefoperazone (SBT/CPZ) was administered to 10 patients with respiratory tract infections, who had responded poorly to treatment with other antibiotics, at dose level of 1 g twice daily by drip infusion. The overall clinical effectiveness rate was 70%(7/10).
One of the two patients with chronic bronchitis who had poorly responded to Cefoperazone was responded with good result to the combination drug. Causative organism of the non-responded case was identified as E. coil, that produced β-lactamase highly and was resistant to cefoperazone (MIC: 100μg/rill).
Neither subjective adverse reactions nor abnormal laboratory findings related to the drug were observed.
Thus, it is suggested that SBT/CPZ is a useful drug for the treatment of RTI, especially chronic complicated lower respiratory tract infections, and further evaluation in this field, for instance transfer of the drug to pulmonary tissue, would be worthwhile.

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Sulbactam (penicillanic acid sulfone) is a chemically stable β-lactamase inhibitor, which.synergistically increase the activity of β-lactam antibiotics against β-lactamase-producing gram-positive and gram-negative microorganisms.
Cefoperazone is a new piperazine cephalosporin derivative which has a broad spectrum of antibacterial activity particularly against Pseudomonas aeruginosa. A 1:1 mixture of sulbactum and cefoperazone displays marked antimicrobial activity.
Sulbactam/cefoperazone was used in the treatment of infectious disease: 4 cases of pneumonia, 3 cases of chronic bronchitis, 2 cases of bronchiectasis and one case of subacute bacterial endocardits.
The age of the patients ranged 34 to 79 years (mean age 61.4 years) and there were 7 males and 3 females.
Sulbactam/cefoperazone was administered intravenous drip infusion. The dose of this drug was 1.0g 12 hourly and the duration of the treatment varied from 8 to 32 days (mean total dose 31.8 g).
Clinical responses were excellent in 3 cases, good in 6 cases and poor in 1 case. The effects of this drug against 4 cases of pneumonia were excellent in 2 and good in 2. In 3 cases of chronic bronchitis, 2 were good and one case was poor, in 2 cases of bronchiectasis 2 cases were good. SBE was excellent.
No significant adverse reaction was found clinically and no abnormality in laboratory findings.

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Bacteriological and clinical effects of a new β-lactamase inhibitor, sulbactam (SBT), in combination with cefoperazone (CPZ) at a ratio of 1: I were investigated.
The sensitivities of 101 strains of clinically isolated Gram-negative rods were measured against SBT/CPZ combination in comparison with CPZ, CMZ and CEZ.
MIC's of SBT/CPZ against E. coli (41 strains) ranged between 0.1-100μg/ml with the peak MIC of 0.2-0.4μg/ml, which were superior to those of CEZ and CMZ, but equal to or 1 tube higher than those of CPZ most strains. Against Klebsiella (20 strains), MIC's of SBT/CPZ were distributed between < 0.1-25μg/ml with thepeak at 0.4μg/ml, which were superior to those of CEZ and CMZ, but equal to those of CPZ. Against P. aeruginosa (20 strains), MIC's of SBT/CPZ were distributed between 0.4-100μg/ml with the peak at 6.4 μg/ml, and mostly equal to or 1 tube higher than those of CPZ.
Clinically, the SBT/CPZ was administered at a dose of 1-2g twice a day for 14-31 days by either dripinfusion or i.v. bolus to 7 patients; 5 cases of pneumonia and 1 case each of cholangitis and gingivitis. The overall efficacy was: excellent, 1; good, 5; poor, 1. No side effect was observed, but some laboratory abnormalities were detected in 4 cases, two of which had no clear causal relationship with the drug administration. Among the others, the increase of GOT and eosinophils was observed in one case, and the increase of GOT and GPT was observed in another. However, the increases in both cases were transient and mild.

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Sulbactam/Cefoperazone, a new antibiotic formulation consisting of sulbactam plus cefoperazone, was administered to 7 patients with various infections diseases, which were failed to be cured with cephems or aminoglycosides. Sulbactam/Cefoperazone was given by I. V. D. infusion at a daily dose of 2-4g for 5-21 days. Clinical efficacy was excellent in 1, good in 4, fair in 1 and poor in 1 case.
No adverse effect was observed.

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The MIC of cefoperazone alone (CPZ) and that of its combination with sulbactam (SBT/CPZ) were compared against clinical isolates of E. coli, K. pneumoniae, E. cloacae, E. aerogenes, C. freundii, S. marcescens, and P. aeruginosa. At an inoculum of 10⁶ CFU/ml, SBT/CPZ showed superior MICs against all CPZ resistant organism of the clinical isolates. Clinical evaluation of SBT/CPZ was performed in 5 cases of pneumonia, 2 of bronchopneumonia complicated infection of old pulmonary tuberculosis, 2 of acute cholesystitis, 1 of biliary infection after cholesystectomy, and 1 of septicemia, in totally 12 cases. The dose of 1 or 2g b. i. d. was administered intravenously by the direct infusion or by the drip infusion for 4 to 16 days. Clinical efficacy was observed in 11 cases out of 12 cases: excellent in 3 cases, good in 8 cases and fair in one case. Organisms such as S. pneumoniae, H. influenzae, K. pneumoniae, S. aureus, E. coli and E. aerogenes were identified in 6 cases; all of the organisms were not detected after the administration of SBT/CPZ. Transient increases in Al-P, GOT and GPT were found in 2 cases but none of the subjective or objective side effects (rash, diarrhea etc.) were observed.

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Clinical study was made on sulbactam/cefoperazone, a new β-lactamase inhibitor combined with a new cephem.
The results were as follows.
1) Sulbactam/Cefoperazone was found effective in 50% of 22 patients with respiratory tract infection.
2) Sulbactam/Cefoperazone was found effective in 44.4% of 18 patients with lower airway infection.
3) Sulbactam/Cefoperazone was found effective in 75% of 4 patients with pneumonia.
4) H. influenzae, which were isolated in each sputum of seven patients, were totally eradicated with thisdrug, but for six patients with P. aeruginosa infection, this drug was not effective.
5) Sulbactam/Cefoperazone caused eosinophilia in one case and leukopenia in one case but these findingswere alleviated rapidly following cessation of the drug. In another one case, this drug caused antabuselike effect after his taking alcohol. But this symptom disappeared completely in about three hourswithout any medical treatment.

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The susceptibility of 50 strains of multiresistant S. aureus to Sulbactam/Cefoperazone (SBT/CPZ) was determined. The MIC₅₀ (MIC which inhibits 50% of the strains tested) was 25μg/ml, which was almost equal to that of Cefoperazone.
Eleven patients were treated with SBT/CPZ and 10 were feasible for evaluation. Six patients (each one of septicemia, bronchiolitis and chronic cystitis, and three of biliary tract infection) responded satisfactorily, including a patients with a large solitary pyogenic liver abscess, which disappeared completely after regimen of 4g a day of SBT/CPZ for 2 weeks.

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The clinical efficacy of the combination of a new β-lactarnase inhibitor, sulbactam (SBT), with CPZ (1:1) was evaluated in 15 patients aged 37-83 years with respiratory tract infection (6 cases) and with urinary tract infection (9 cases). A daily does of this drug was 2-4 g by intravenous injection twice a day and duration of SBT/CPZ combination (1:1) therapy was for 4 to 14 days.
The results were as follows.
1. Clinical response to SBT/CPZ combination (1:1) therapy of respiratory tract infection was good in 2 cases, fair in 2 cases, poor in 2 cases and that of urinary tract infection was excellent in 4 cases and good in 5 cases. Efficacy rate was 73.3%.
2. As a side effect, eosinophilia (3267/mm³) was transiently shown in one case and elevation of GOT & GPT was shown in other one case.
However, it was reversible, and no other side effects were observed.

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Antibacterial activity, pharmacokinetics and clinical efficacy of SBT/CPZ were investigated, with the following results.
1. Antibacterial activities of SBT/CPZ against clinically isolated S.aureus, E. coli, K. pneumoniae, P. mirabilis and P. aeruginosa, each 50 strains, were about equal to those of CPZ. However, the sensitivity of the strains among E. coli, K. p neumoniae and P. mirabilis with MICs of more than 3.13-6.25μg/ml to CPZ was augmented by SBT/CPZ, demonstrating the usefulness to add the β-lactamase inhibitor.
2. SBT/CPZ 2g, was administered to 2 cases of respiratory tract infection by drip-infusion for 2 hours, and blood levels of each drug were monitored. The peak values were observed at the end of drip-infusion, and were 131.6 and 141.2μg/ml for CPZ, 58.2 and 60.3μg/ml for SBT, respectively.
The ratio of CPZ to SBT in blood was approximately 2: 1.
3. Three patients, one each of Klebsiella pneumonia, P. aeruginosa pulmonary abscess and chronic pyelonephritis, were treated with SBT/CPZ.
For the patient with Klebsiella pneumonia, SBT/CPZ at 2g/day was ineffective, but by increasing the does to 4.0g/day marked improvement was observed. For the patient with P. aeruginosa pulmonary abscess to whom CPZ was ineffective, the treatment with SBT/CPZ at 4g/day brought on a good result. In a case of chronic pyelonephritis caused by Klebsiella, the treatment with SBT/CPZ at 4.0g/day, but not 2.0g/day, resulted in improvement. From the above results, the dose of SBT/CPZ at 4.0g/day will be adequate for the treatment of relatively severe cases.
No adverse reactions or abnormal values of clinical chemistry by SBT/CPZ were observed.

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The authors report on the results of their clinical investigations of SBT/CPZ, a β-lactamase inhibitor sulbactam (SBT) and cefoperazone (CPZ) in combination.
The antibacterial activity of SBT/CPZ was compared to those of CPZ alone and SBT alone in a total of 178 clinically isolated strains of S. aureus, S. faecalis, E. coil, Citrobacter, Klebsiella, Enterobacter, Serratia, Proteus and P. aeruginosa.
SBT/CPZ exhibited greater antibacterial activity against S. aureus, S. faecalis, E. coli, Serratia, Proteus and P. aeruginosa than CPZ alone, while no clear antibacterial activity of SBT was noticed against gram positive and negative bacteria.
SBT/CPZ was then administered to a total of 18 patients, among whom there were 11 cases of respiratory tract infections (RTI), 1 case of septicemia and 6 cases of urinary tract infections (UTI).
Results obtained were good in 9 (81.8%) out of 11 RTI cases, good in the sole case of septicemia and good in 5 (83.3%) out of 6 UTI cases.
As adverse reactions and abnormal laboratory findings diarrhea were observed in 3 out of 18 patients and GPT elevated in 1.
These adverse reactions, however, returned to normal after the completion of administration.

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Sulbactam/Cefoperazone was administered to 11 episodes of 10 patients with respiratory tract infection.
The clinical effectiveness was good in 10 and fair 1. The clinical effective rate was 91%.
The causative organisms were able to isolate in 10 episodes: Haemophilus influenzae; 7 episodes, Streptococccus pneumoniae+Haemophilus influenzae; 1 episode and Staphylococcus aureus; 2 episodes. These organisms didn't yield after administration of sulbactam/cefoperazone without two episodes isolated β-lactamase produced Staphylococcus aureus. As side effects, two cases showed slight elevation of GOT and GPT, and one case showed slight elevation of Creatimine in serum.

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Sulbactam/Cefoperazone was applied to the treatment of ten patients with respiratory infections.
The drug administered intravenously, 2-4g/day, divided into two doses, for the period of four to fifteen days.
The results were as follows, excellent in one case, good in six cases, ineffective in three cases. Effectiveness rate was 80%.
No side effects were observed.

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We investigated the bacteriological and clinical effects of a new formulation, Sulbactam/Cefoperazone, in which cefoperazone was combined in a ratio of 1: 1 with Sulbactam, a β-lactamase inhibitor developed by Pfizer Inc., USA, and obtained the following results.
1. The peak values of MIC distributions of Sublactam/Cefoperazone against clinical isolates are 1.56μg/ml for S. aureus, 0.78-1.56μg/ml for E. coli, 0.2μg/ml for K. pneumoniae, 0.78μg/ml for P. mirabilis, 0.39μg/ml for P. vulgaris, and 6.25μg/ml for P. aeruginosa, respectively. While no effects of the combination of cefoperazone with sulbactam were obvious against S. aureus, E. coli and P. aeruginosa, the antibacterial activities of Sulbactam/Cefoperazone against K. pneumoniae, P. mirabilis and P. vulgaris were superior to those of cefoperazone alone, demonstrating the synergistic effects of the combination against these species.
2. Sulbactam/Cefoperazone was administered by drip infusion at 1-3g, twice daily for 2 to 27 days to a total of 7 patients, 4 cases of respiratory tract infections, 2 cases of septicemia and 1 case of infected diabetic gangrene. The clinical efficacy was effective in 3 cases, ineffective in 2 cases and 2 cases in inevaluable. Transient aggravation of liver functions were observed in 2 cases.

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Basic and clinical studies were made on a new combination of the drugs, SBT/CPZ, i.e. Cefoperazone (CPZ) and sulbactam (STB) 1:1.
The results obtained were as follows:
1) Antibacterial activity in vitro:
The activity of SBT/CPZ was found to be much more active against gram-negative bacilli, especially against Proteus (both indole positive and negative species) and Serratia than CPZ alone. The MIC of Oralone were 25-50μg/ml against most of the gram negative bacilli.
2) Distribution in the rat's body:
100mg/ml of SBT/CPZ was administered intramuscularly to rats, and the tissue concentrations of each drug were serially estimated: SBT and CPZ showed similar pharmakinetic patterns. The order of their tissue concentrations were liverkidnies>blood>lungs>spleen>muscles.
3) Clinical trials
Eight patients with various complicated infections were treated with 2-4g SBT/CPZ per day by drip infusion: One of them turned out to be myeoplasmic pneumoniae and was excluded from the evaluation. Good responses were obtained in 4 our of the 7 cases, while one of the other three patients, having ulcerative stomatitis, showed bacterial substitution by the treatment.
As to the side effects, a drug fever occured in one of the cases after seven days treatment. No abnormal laboratory findings were observed.

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Fundamental and clinical studies were carried out on Sulbactam/Cefoperazone (SBT/CPZ), new injectable antibiotics composed of a mixture of Cefoperazone (CPZ) and Sulbactam, a new 13-lactamase inhibitor, equally. And the following results were obtained.
1) Antimicrobial activities of SBT/CPZ against CPZ resistant E. coli and Indole positive proteus were superior to those of CPZ alone. But there was no combination effect on MICs for S. aureus
In Klebsiella spp., S. marcescens, Proteus mirabilis and Pseudomonas spp. only a little improvement of activity was observed, and the lowest MICs against Acinetobacter spp. was observed in SBT alone.
The peak serum concentrations of CPZ and SBT, after a drip infusion of 1.0g of SBT/CPZ for one hour were 112.4μg/ml and 26.3μg/ml respectively. And the proportion of serum levels of SBT and CPZ were 1: 4.3 at the peak, 1: 3.6 at 2 hours and 1: 9.3 at 4 hours after start of infusion. The urinary excretions rate up to 6 hours after start of infusion were 10.3%(CPZ) and 40.7%(SBT) respectively.
A total of 16 patients (14 with respiratory and 2 with urinary tract infections) were treated with 2.0-4.0g daily dose of SBT/CPZ for 2-15 days. Clinical efficacy was evaluated as good in 7, fair in 2, poor in 6 and unassessable in 1. The overall efficacy rate was therefore 46.7%.
No subjective side effect was observed, but in clinicalaboratory data, slight and transient increasings of transaminase and Al-p was observed in 2 patients after the treatments.

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Antimicrobial activities of sulbactam/cefoperazone combination (SBT/CPZ) were compared with that of CPZ against the clinically isOlated strains, such as S. aureus, S. epidermidis, S. pneumoniae, α-Streptococcus, S. faecalis, E. coli, Shigella, Salmonella, K. pneumoniae, K. oxytoca, Citrobacter, Enterobacter, Serratia, P. vulgaris, P.mirabilis, P.morganii, P. rettgeri, Rinconstans, H. influenzae, V. parahemolyticus, A. calcoaceticus, Flavobacterium, P. aeruginosa, P. cepack and P. maltophilia.
Except the strains of P. vulgaris and A.calcoaceticus, SBT/CPZ showed similar activity to CPZ. Though SBT/CPZ also showed much stronger activity against A. calcoaceticus than other cephems tested, the merit of combination of sulbactam and CPZ was obscure, because of the strong activity of sulbactam against the strain.
SBT/CPZ was administered to 7 cases of respiratory tract infections (5 cases of bronchopneumonia, one case of lung abscess and one case of chronic bronchitis) and each one case of septicemia, urinary tract infection and FUO. With the exception of the case of septicemia, SBT/CPZ showed good results clinically and bacteriologically.
As for the side effects of the drug, no marked ones were observed.

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Laboratory and clinical studies were performed on Sulbactam/Cefoperazone, containing a new β-lactamase inhibitor, Sulbactam (SBT), and Cefoperazone (CPZ).
MICs of SBT/CPZ were determined with 10⁶ cells/ml against the clinical isolates derived from in-patients of our clinic. Percentages of strains susceptible to 12.5μg/ml or less were S. aureus 82%, Sfaecalis 3%, E. coli 95%, K. pneumoniae 91%, Enterobacter sp. 85%, S. marcescens 63%, Proteus sp. 96%, Citrobacter sp. 53%, Salmonella and Shigella sp. 100%, P. aeruginosa 79%, other Pseudomonas sp. 50%. These percentages were almost the same as CPZ alone. But some CPZ-resistant strains were slightly become to sensitive. These strains were all positive on the acidmetry disk and chromogenic cephalosporin (87/312) disk test.
Six patients with respiratory tract infection, 3 with biliary tract infection, 4 with bacteremia, and 1 with skin abscess were treated with SBT/CPZ at a dose of 2-6g for 2-55days. Clinical responses were excellent in 2, good in 5, fair in 3, poor in 2, and unknown in 2 patients, efficacy ratio being 58%. No side effect were observed. But, elevation of GOT/GPT and eosinophilia were seen in 3 and a patient, respectively.

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Sulbactam, a new β-Jactamase inhibitor and cefoperazone combination (SBT/CPZ) was administered to 20 cases of RTI patients. SBT/CPZ was administered 1-4g twice a day by drip infusion for 5-47 days. Clinical efficacy was excellent in 4, good in 7, poor in 5, and no response in 4 patients, and overall clinical efficacy rate was 55%. Causative organisms were isolated in 15 patients out of 20 patients. Bacteriological effects were obtained in 8 patients. Diarrhea and nausea were noted in each one patient and elevation of Al-P was noted in 2 patients.

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Clinical study on sulbactam/cefoperazone (combined ratio 1: 1) was investigated in 25 patients with respiratory tract infections, and following results were obtained.
Clinical effects were Excellent in 19, Good in 5 and Poor in 1 patient and overall efficacy rate was 96%.
Bacteriological effects were investigated in 17 clinical isolated organisms and bacteriological efficacy rate was 88.2%.
During therapy drug fever and eosinophilia were observed in one patient.

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Laboratory and clinical studies on SBT/CPZ, a novel antibiotic which combine a broad-spectrum cephalosporin antibiotic, cefoperazone and a β-lactamase inhibitor, sulbactam developed by Pfizer Co. Ltd., were carried out and the results were as follows.
1) Antibacterial activity:
Minimum inhibitory concentrations (MICs) of SBT/CPZ against a total of 240 strains isolated from various specimens (Staphylococcus aureus 25, Citrobacter freundii 27, Enterobacter aerogenes 26, Enterobacter cloacae 27, Proteus rettgeri 7, Proteus inconstans 20, Proteus morganii 27, Escherichia coli 27, Klebsiella aerogenes 27, Serratiii marcescens 27) were compared with those of CPZ and SBT. MICs50 of SBT/CPZ against most of these organisms other than Serratia marcescens were somewhat inferior to those of CPZ. MICs100 of SBT/CPZ against Escherichia coli, Citrobacter freundii and Proteus species were superior to those of CPZ. SBT alone showed no remarkable antimicrobial activity against most of these organisms.
2) Serum and sputum levels in patients with chronic respiratory tract infections:
SBT/CPZ was administered by intravenous drip infusion at a dose of 2g to four patients. The peak serum levels were 71-130μg/ml for CPZ and 20-58μg/ml for SBT at the termination of infusion and the peak sputum levels were 5.67mu;g/ml for CPZ and 8.8μg/ml for SBT.
3) Clinical results:
Twenty patients with respiratory tract infections (chronic bronchitis 3, bronchiectasis 7, pulmonary cyst 2, pneumonia 6, lung abscess 1, pleuritis 1) were treated with SBT/CPZ by intravenous drip infusion at a dose of 1-2g once or twice a day for 7-14 days and over all efficacy rate was 80%. Adverse reaction was noted in one case with slight elevation of S-GOT and S-GPT.

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MICs of cefoperazone, alone and combination with the β-lactamase inhibitor sulbactam, was tested against inocula 10⁶ colony-forming units of respiratory pathogenic Branhamella catarrhalis per ml. Of 47 strains tested, all strains required 0.05-3.13μg of cefoperazone per ml and 0.1->100μg of sulbactam per ml for growth inhibition. Synergy occured with the combination of sulbactam and cefoperazone and the growth of all strains was inhibited by the presence of 0.013-0.78μg of the mixture per ml.
Serum and sputum concentrations were measured in two patients with chronic bronchiolitis and the sputum excretion rate (=peak sputum concentration÷peak serum concentration×100%) was calculated. The sputum excretion rate of cefoperazone was 1.9-3.0% and that of sulbactam was 1.6%, and from these results we suspected that both intravenous cefoperazone and sulbactam were excreted through the bronchi.
Nine patients with respiratory infections and a patients with renal infection were treated with sulbactam/cefoperazone intravenously. S. pneumoniae, H. influenzae, B. catarrhalis and M. morganii were disappeared from these patients and they were all improved. Watery diarrhea developed in one female patient with pneumonia, but subsided with no therapy.

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We compared M.I.C.'s of cefoperazone (CPZ) with those of sulbactam/cefoperazone (SBT/CPZ)(1: 1 combination) in 205 clinical isolates. Of those 205 isolates, 33 showed M.I.C.'s of CPZ equal to or more than 25μ/ml.
No differences were found in the antimicrobial activities against S. aureus, Salmonella and P. mirabilis which were not resistant isolates. Of the 14 P. aeruginosa isolates, although one with more than 100μg/ml M.I.C. for CPZ showed 50μg/ml M.I.C. for the combined SBT/CPZ, the member of isolates with M. I. C.'s equal to or less than 12.5μg/ml were the some in the two groups. In most isolates of E. coli, Klebsiella, Enterobacter and Citrobacter, M.L.C.'s of SBT/CPZ were one or two orders smaller than these of CPZ. Remarkably an isolate of E. coli with more than 100μg/ml M.I.C. for CPZ was inhibited by 6.25μg/ml of SBT/CPZ. These synergistic effects were not observed in indol-positive Proteus nor in S. inarcescens.
Present study did not reveal a clear synergism between SBT and CPZ except one CPZ resistant E. coli probably due to the fast that few isolate highly resistant to CPZ were included. We want to evaluate the SBT/CPZ combination further by collecting more CPZ resistant isolates.

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Cefoperazone, a cephalosporin which inhibits most Enterobacteriacae, Pseudomonas aeruginosa and Staphylococcus aureus, is hydrolyzed by some β-lactamases. Combination drug of cefoperazone with β-lactamase inhibitor, sulbactam (SBT) for parenteral use, was administered to 18 hospitalized patients with infectious diseases: 6 with biliary tract infection, 6 with acute appendicitis, 2 with gastric ulcer, 1 with acute panperitonitis due to intestinal obstruction, 1 with necrosis of right lower leg due to arterial obstruction, 1 with cervical lymph cyst and 1 with fistula ani. Sulbactam/Cefoperazone (SBT/CPZ) in a dose of 1g was given by intravenous administration before or during operation. Tissue specimens of different sites were taken from the surgically removed organs. Samples of bile and purulent ascites were subsequently taken at intervals. SBT concentration was determined according to a cup bioassay method with Escherichia coil 603 (β-lactamase producing, CPZ high resistant) as the test organism. CPZ concentration was determined by bioassay with Micrococcus luteus ATCC 9341 as the test organism.
Concentrations of CPZ in the common duct bile increased quickly and reached high level, about 2, 000μg/ml and declined very slowly. In the cases of acute appendicitis and patients with purulent ascites, it is very interesting thing that SBT concentrations in ascites and appendix wall at the early time after SBT/CPZ injection, were higher than CPZ concentrations and CPZ concentration was higher than SBT concentration at 10 to 30 minutes after injection. The concentrations of SBT and CPZ in the infected tissues were higher than those in none infected tissues.
SET and CPZ concentrations in purulent ascites, common duct bile, gall bladder bile, gall bladder wall, infected appendix wall, pus in abscess and other infected tissues were observed higher than the MIC of CPZ and SBT/CPZ against Escherichia coil and Klebsiella pneumoniae bacilli, after 1 g of SBT/CPZ intravenous administration.
Sulbactam/Cefoperazone therefore will be a useful drug when used for chemotherapy of abdominal infectious diseases.

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Cefoperazone, a third generation cephalosporin which inhibits most Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus, is hydrolysed by some penicillinase type of ft-lactamase. Combination drug of cefoperazone (CPZ) with β-lactamase inhibitor Sulbactam (SBT), Sulbactam/Cefoperazone (SBT/CPZ) for parenteral use, was administered to 31 patients with infectious diseases. They were 4 out-patients and 27 hospitalized patients, 15 females and 16 males, from 7 to 78 years old, including 8 with biliary tract infection, 10 with acute peritonitis (7 with acute appendicitis, 2 with post-operative peritonitis after gastrectomy due to gastric ulcer and 1 with panperitonitis due to intestinal obstruction), and 11 with infectious diseases of skin and soft tissues (2 with slight infection of out-patients, 6 with serious infection of legs due to arterial obstruction, and 3 others), and out-patients of acute appendicitis of 2 cases (not operated).
SBT/CPZ in a dose of 1 to 2 g was given by intravenous injection or intravenous drip infusion once or twice a day for 3 to 20 days. The clinical efficacy obtained was excellent in 8 cases, good in 20 cases, fair in 3 cases and poor in none (efficacy rate was 90.3%). Clinical adverse effect was not recognized.
Therefore, Sulbactam/Cefoperazone may be a useful drug for surgical infections.

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A combination drug of sulbactam/cefoperazone (a ratio of 1: 1) was administered to 13 patients with surgical infections and 11 patients after gastrectomy. 1-2g of sublactam/cefoperazone diluted in 100ml of physiological saline was infused intravenously in 30 minutes, once or twice daily for 4-16 days. Total doses per patient ranged from 8 to 64g.
Clinical response in 13 surgical infecitions were: good in 6, fair in 2 and poor in 5 patients. No post operative infections were observed in the eleven patients who were administered the drug after gastrectomy.
Sulbactam and cefoperazone concentrations in peritoneal exudate after gastrectomy were measured in 10 patients, 3 patients given 2g/day and 7 patients 4g of sulbactam/cefoperazone. Sulbactam concentrations in exudate were on the average 2.3/4/ml on the 1st day, 2.9μg/ml on the 2nd day and 2.6 μg/ml on the 3rd day in the 2g administration group, whereas they were 6.1 μg/ml on the 1st, 4.4μg/ml on the 2nd and 4.6 μg/ml on the 3rd day in the 4g administration group.
Cefoperazone concentrations in exudate were about 4μg/ml by 2g and 12-15μg/ml by 4g administration of sulbactam/cefoperazone. Considering the good excretion into peritoneal exudate and excellent antibacterial activity of sulbactam/cefoperazone, this drug could be expected to inhibit bacterial growth in peritoneal exudate.
A systemic skin eruption appeared in a patient on the 15th day of prophylactic use, which was considered to be related to the drug. Four days after the discontinuation of the drug, the eruption disappeared. No other adverse reactions nor abnormal laboratory findings related to the use of the drug were observed.

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Microbiologic, pharmacokinetic and clinical efficacy studies were carried out on Sulbactam/Cefoperazone (SBT/CPZ).
The drug proved to possess a broad antimicrobial spectrum similar to cefoperazone, however with stronger antimicrobial activity against β-lactamase producing cefoperazone resistant strains. But the combination did not exhibit increased activity against S. marcescens or P. aeruginosa.
Its antimicrobial activity against cefoperazone resistant clinical isolates of S. epidermidis, E. coli, K. pneumoniae, and E. cloacae was excellent although it was less active than cefoperazone againt cefoperazone susceptible strains.
SBT/CPZ was administered intravenously at a does of 2.0g to three healthy male volunteers and serum and urine levels were determined by HPLC and GC-MS. Mean peak serum levels were 65.5μg/ml for SBT and 150.7μg/ml for CPZ 5 minutes after administration. Mean peak urine levels were 6697μg/ml for SBT and 14611μg/ml for CPZ at 1 hour, and the urinary recovery rates were 60.2% for SBT and 17.9% for CPZ over the first 10 hours.
Pharamacokinetic parameters were calculated using a two-compartment open model. Serum half-lives were 0.78 hours for SBT and 1.57 hours for CPZ. AUC values were 52.1 hr.μg/ml for SBT and 208.6 hr.μg/ml for CPZ.
Analysis of human urine by TLC and bioautography demonstrated that neither SBT nor CPZ were metabolized to another antimicrobial active form in the body.
Following intramuscular administration of 40 mg/kg to SD rats, high levels of SBT were observed in descending order in the kidney, liver, lung and serum, and CPZ in the kidney, liver, serum and lung.
SBT/CPZ was effective in two cases of surgical infections including intra-abdominal abscess and respiratory tract infection. Side effects were not observed.

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Fundamental and clinical studies of cefoperazone in combination with β-lactamase-inhibitor, sulbactam (SBT/CPZ) was performed in the surgical field, and following results were obtained.
1) Antibacterial activity of SBT/CPZ
Bacterial activity of cefoperazone, alone and in combination with sulbactam, was tested against inocula of 10⁶ colony-forming units of clinical isolates of E. coli, K. pneumoniae and P. aeruginosa. Against two of 2 cefoperazone-resistant strains of E. coli, and 2 of 2 straines of Klebsiella, cefoperazone in combination with sulbactam could have good activities.
Although, against P. aeruginosa, no infulence of sulbactam on the activity of cefoperazone could be found.
2) Biliary excretion
The biliary excretion of cefoperazone was high level, although sulbactam was low level. The recovery-rate of sulbactam until 6 hours after 2.0gr (i.v.) of SBT/CPZ was ranged from 0.10% to 0.15%.
3) Clinical results
SBT/CPZ was administered to 17 cases with surgical infection and clinical results were excellent in 1 case, good in 13, fair in 2 and unknown in 1. No adversed reaction could be found.

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Sulbactam (penicillanic acid sulfone), a new β-lactamase inhibitor, in combination with cefoperazone, was investigated on clinical effectiveness and side effects.
Sulbactarn/Cefoperazone was given to 30 patients with various surgical infections including 13 cases of localized peritonitis, 1 case of infections cholangitis, 6 cases of thoracic empyema, 5 cases of postoperative wound infection, 3 cases of septicaemia and 2 cases of erysipelas.
The results obtained were “excellent” in 13, “good” in 13, “poor” in 4 and efficacy rate was 86.7%.
Side effects were not observed except elavated values of GOT, GPT and Al-p in 5 cases, eosinophilia in 3 cases.

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