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498 Sulbactam/Cefoperazone Versus Cefotaxime for the Treatment of Moderate-to-Severe Bacterial Infections: Results of a Randomized, Controlled Clinical Trial Li Jia-tai, Lu Yuan, Hou Jie, Chen Yi-fang, Miao Jing-zhi, Jia Yu-xia, Hou Jun, Zhang Xiu-zhi, Chen Dong-ke, Hu Wen-zhi, Li Li-jin, Liu De-meng, Wang Zhe, Wu Jin, Gu Jun-ming, Wang Hui-ling, Zhang Yi-ling, and Sun Ling From the Institute of Clinical Pharmacology, Beijing Medical University, and Beijing Hospital, Beijing; 2nd Affiliated Hospital, Tian Jin Medical University, Tian Jin; and 2nd Affiliated Hospital, Da Lian Medical University, Da Lian, People's Republic of China We conducted a randomized, open-label, controlled, multicenter study to compare sulbactam/ cefoperazone with cefotaxime in terms of efficacy and safety for the treatment of hospitalized patients with moderate-to-severe bacterial infections. More than two-thirds of the pathogens recovered from these patients produced /3-lactamase. Two hundred-seven (88.1%) of the 235 patients enrolled completed the study and were included in the efficacy and safety evaluations. One hundred-three patients received sulbactam/cefoperazone (2-4 g/d) administered in evenly divided doses every 12 hours by a 30-minute intravenous drip; 104 patients received cefotaxime (6-12 g/d) administered in evenly divided doses every 6 or 8 hours by a 30-minute intravenous drip. The overall efficacy rates (i.e., cure or markedly improved) were 95% for the sulbactam/cefoperazone group and 90% for the cefotaxime group (P = .186), whereas the bacterial eradication rates were 85% for the sulbactam/cefoperazone group and 81% for the cefotaxime group (P = .467). Both drug regimens were well tolerated. Sulbactam/cefoperazone is effective and safe for the treatment of moderate-tosevere bacterial infections caused mainly by /3-lactamase—producing organisms. Sulbactam/cefoperazone (Sulperazon; Pfizer Inc., New York) is a synergistic antimicrobial combination with marked in vitro antibacterial activity against a broad spectrum of organisms [1]. Sulbactam is a /3-lactamase inhibitor that can irreversibly inhibit several bacterial penicillinases and cephalosporinases produced by a variety of bacteria [2]. When combined with a /3-lactam antibiotic, sulbactam can enhance the activity of enzyme-resistant antibiotics [1-4]. The combination of sulbactam/ampicillin has been widely used in the treatment of bacterial infections. When combined with cefoperazone, sulbactam inhibits f3-lactamase -producing isolates and thus significantly improves cefoperazone's activity against gram-negative resistant bacilli, including highly resistant Enterobacteriaceae [4]. The activity of cefoperazone against Staphylococcus aureus is greater than that of other third-generation cephalosporins, and this activity is further strengthened when cefoperazone is combined with sulbactam. The "Guidelines for the Clinical Research of Antimicrobial Agents" of the Ministry of Public Health, People's Republic of China, were followed in the conduct of this study. This article is part of a series of papers presented at a satellite symposium to the Western Pacific Congress on Chemotherapy. The symposium was entitled "An Update on Cephalosporin Resistance and the Role of Sulbactam/ Cefoperazone" and was held in Manila in December 1994. Reprints or correspondence: Dr. Li Jia-tai, Institute of Clinical Pharmacology, Beijing Medical University, Beijing, People's Republic of China. Clinical Infectious Diseases 1997; 24:498-505 © 1997 by The University of Chicago. All rights reserved. 1058-4838/97/2403 — 0031$02.00 Similar synergism is evident in the activity of this combination against anaerobes [5-7]. We conducted the present clinical trial to evaluate sulbactam/ cefoperazone vs. the third-generation cephalosporin cefotaxime in terms of efficacy and safety in hospitalized patients with moderate-to-severe bacterial infections caused predominantly by 0-lactamase-producing strains. This cooperative study was performed from May 1993 to April 1994 at four sites in the People's Republic of China: the Institute of Clinical Pharmacology, Beijing Medical University, and Beijing Hospital, Beijing; Tian Jin Medical University, Tian Jin; and Da Lian Medical University, Da Lian. Patients and Methods Study design. This randomized, open-label, parallel-group, controlled, multicenter trial was designed to compare sulbactam/cefoperazone with cefotaxime in terms of efficacy and safety for treating hospitalized patients with moderate-to-severe bacterial infections. Before randomization, patients were stratified according to the site of infection (e.g., upper or lower respiratory tract, urinary tract, or skin and soft tissue) so as to ensure equal distribution of patients in the active treatment (sulbactam/cefoperazone) and control (cefotaxime) groups. Diagnostic criteria were stipulated in advance. The study design stipulated that at least 80% of patients had to have positive pretreatment bacterial cultures and that at least 50%-66% of the isolated pathogens had to be /3-lactamase positive. Patients. Hospitalized male and female patients between the ages of 14 and 65 years were eligible for inclusion in the CID 1997;24 (March) Sulbactam/Cefoperazone vs. Cefotaxime 499 Table 1. Scores for the severity of infection in hospitalized patients who received sulbactam/cefoperazone or cefotaxime. Type of infection, clinical variable Respiratory infection* Mental status Normal Moderately disoriented Severely disoriented Chills Gastrointestinal symptoms Fever Temperature, ---38°C Temperature, >38°C Elevated WBC count Lymph node tenderness Pharyngalgia Congestion of pharynx or tonsil Peritonsillar pyoid secreta Aphagia Cough Cough with yellow sputum Thoracalgia Dyspnea Pulmonary percussion dullness Pulmonary rale (dry/moist) Radiographic findings Caurse lung markings Pulmonary infiltration Urinary tract infections Mental status Normal Moderately disoriented Severely disoriented Score 0 1 2 2 2 2 2 2 1 2 1 2 2 2 1 2 0 Type of infection, clinical variable Chills Fever Temperature, -.._.38°C Temperature, >38°C Elevated WBC count Urination (frequent, precipitant, or painful) Aching back Lumbago Urethral pyoid secreta Tenderness of lower abdomen Pain on percussion of kidney area Urinary protein (+ ++ +) Urinalysis Presence of WBCs Presence of WBCs and RBCs Surgical infection Elevated WBC count Lymph node tenderness Fever Focal flushing, swelling, warmth, and pain Secreta Size of wound <5 X 5 cm >5 X 5 cm Depth of wound Epidermis Dermis Subcutaneous Score 2 1 2 2 11 1 2 2 2 2 2 2 2 2 2 2 2 3 1 2 * Severity scores were as follows: mild, moderate, 7-10; severe, I. Severity scores were as follows: mild, -.7; moderate, 8-11; severe, For each symptom that was present. Severity scores were as follows: mild, 3-6; moderate, 7-11, severe, study if their clinical signs and symptoms as well as their laboratory test results were in accordance with diagnostic criteria for moderate-to-severe bacterial infections and if they had not received effective antimicrobial treatment within 48 hours of study enrollment. The scoring for assessment of moderateto-severe infections of the respiratory tract or urinary tract and of surgical infections is shown in table 1. Patients were excluded from the study if they had a history of hypersensitivity to penicillins or cephalosporins; other significant allergies; severe cardiac, hepatic, renal, or hematopoietic system abnormalities; or terminal cancer. Patients were also excluded if they had previously received treatment with either sulbactam/cefoperazone or cefotaxime; had received any other study drug within 4 weeks of study enrollment; or had severe or potentially lethal infections requiring more potent antibiotic treatment. Pregnant or lactating women also were excluded, as were any patients who might die of any condition within 48 hours of enrollment. A patient who began randomized treatment could be withdrawn from the study if (1) a bacterial culture was negative after the patient had received a 72-hour course of antimicrobial therapy; (2) the isolated pathogen was resistant to both study drugs; (3) the patient had a hypersensitivity reaction or other severe adverse reaction to treatment that precluded the evaluation of efficacy; (4) the patient's symptoms worsened or there was no significant improvement in the patient's condition after 72 hours of therapy; and/or (5) the patient had received any additional antibiotic therapy during the trial. Drugs. Sulbactam/cefoperazone (1:1 ratio) was given at a dosage of 2-4 g/d in equally divided doses every 12 hours by 30-minute intravenous drip. Cefotaxime was given at a dosage of 6-12 g/d in equally divided doses every 6-8 hours by 30minute intravenous drip. Each agent was prepared in 1-g doses that were dissolved in 50-100 mL of normal saline or 5% glucose solution. Evaluation criteria. The efficacy and safety of the study drugs were evaluated on the basis of changes in maximum body temperature, clinical signs and symptoms, and (when applicable) findings on chest radiographs and other objective methods. Clinical laboratory tests (e.g., urinalysis, hematology, 500 CID 1997;24 (March) Li et al. and tests of hepatic and renal function) were performed at baseline, on days 3 and 4 during therapy, at the end of treatment, and on day 7 after treatment was completed. All clinical findings, including any changes in laboratory test results, were classified as definitely drug related, possibly drug related, possibly non—drug related, definitely non—drug related, or unevaluable. Pathogens were isolated, cultured, and identified at baseline, during therapy, at the end of therapy, and 5 to 7 days after therapy was discontinued. However, for patients with urinary tract infections, including gonorrhea, urine was cultured at baseline; 24, 48, and 72 hours after the start of therapy; at the end of therapy; and 5-7 days after therapy was discontinued. Disk susceptibility tests were performed on pretreatment isolates with use of sulbactam/cefoperazone, cefoperazone, cefotaxime, amoxicillin/clavulanic acid, and ticarcillin/clavulanic acid. The nitrocefin procedure was used to identify 0-lactamase —producing strains. Bacteriologic effectiveness at the end of therapy was graded as follows: "eradication" (all pathogens were eradicated), "partial eradication" (one of the original pathogens was eradicated), "persistence" (none of the original pathogens was eradicated), "eradication with colonization" (a new pathogen was isolated at the end of therapy, but the patient did not have any associated signs and symptoms), and "superinfection" (a new pathogen was isolated, and there were associated signs and symptoms). The overall bacterial clearance rate for each treatment group was defined as the proportion of the total number of isolates present before therapy that were eradicated at the end of therapy. Overall efficacy was graded on the basis of a combination of clinical observations (e.g., changes in signs and symptoms of infection), bacteriologic response, and changes in laboratory test results and was rated as "cure," "marked improvement," "improvement," or "failure." A grade of cure required resolution of all signs and symptoms of infection, eradication of the pathogens, and normal laboratory test results. Marked improvement was graded as improvement in relation to any three of the above four criteria, whereas a grade of improvement required improvement in relation to any two of the four criteria. Failure was defined as persistence or worsening of clinical signs and symptoms after 72 hours of treatment. The overall efficacy rate was defined as the proportion of patients in each treatment group who were considered to be cured or whose conditions had markedly improved. Statistical methods. The matched-pairs t-test was used for the analysis of quantitative data, and the x 2 test was used for the analysis of qualitative data. Fisher's exact test was used to calculate P values, the percentage of total clinical isolates that were susceptible to the treatment, the bacterial clearance rate, and the rate at which enzyme-producing bacteria were recovered. Results Patient characteristics. A total of 235 patients were enrolled at four centers, 28 (11.9%) of whom were withdrawn Table 2. Demographic and clinical characteristics of hospitalized patients who received sulbactam/cefoperazone or cefotaxime for moderate-to-severe bacterial infections. Variable Mean age (y) ± SD Mean weight (kg) ± SD No. (%) with indicated site of infection Respiratory tract Urinary tract Skin, soft tissue, other No. (%) with moderate-to-severe cases Mean duration (d) of treatment ± SD Mean total dose (g) given ± SD No. (%) of patients with fever before treatment Mean duration (d) of fever ± SD No. (%) of patients with an elevated WBC count before treatment Mean duration (d) of elevated WBC count ± SD Sulbactam/ cefoperazone (n = 103) Cefotaxime (n = 104) 48± 15 62± 10 64-99 64±99 44 (43) 37 (36) 22 (21) 93 (90) 10 ± 2.8 39 -± 17 51 (49) 33 (32) 20 (19) 94 (90) 9.8 ± 2.9 39 -± 13 78 (76) 4.2 ± 2.5 75 (72) 4.4 ± 2.8 52 (50) 53 (51) 6.6 -± 3.1 3.1 6.2±3.1 NOTE. P > .05 for the comparison of data between the two groups. from the study before beginning treatment. Of these 28 patients, 25 were withdrawn because of negative bacterial cultures, and three were withdrawn because their isolates were resistant to the two study drugs. No patients were withdrawn because of persistence or worsening of signs and symptoms or the occurrence of adverse reactions within 72 hours of initiation of treatment. The demographic and clinical characteristics of the 207 patients who completed the study and were included in the efficacy and safety evaluations are shown in table 2. One hundredthree patients were treated with sulbactam/cefoperazone, and 104 were treated with cefotaxime. Ninety-six (46%) of the 207 patients had respiratory infections (predominantly pneumonias), 70 (34%) had urinary tract infections (primarily pyelonephritis), and 42 (20%) had skin and/or soft-tissue infections or other bacterial infections. There were no significant differences between treatment groups with respect to demographic or other baseline characteristics. Efficacy. A total of 76 (74%) of the 103 patients treated with sulbactam/cefoperazone were cured (i.e., all signs and symptoms resolved, the pathogens were eradicated, and laboratory test results normalized), whereas 69 (66%) of the 104 patients treated with cefotaxime were cured (P = .243) (table 3). The overall efficacy rate (i.e., cure plus marked improvement) for the sulbactam/cefoperazone group was 95%, and that for the cefotaxime group was 90%; there were no statistically significant differences between the groups (P = .186). The overall efficacy rates, by type of infection, were as follows: sulbactam/cefoperazone and cefotaxime were 93% and 88%, respectively, for respiratory infections (P = NS); 100% 501 Sulbactam/Cefoperazone vs. Cefotaxime CID 1997;24 (March) Table 3. Clinical efficacy of sulbactam/cefoperazone vs. cefotaxime for the treatment of moderate-to-severe bacterial infections in hospitalized patients. Cefotaxime*t (n = 104) Sulbactam/cefoperazone* t (n = 103) Site, type of infection Respiratory tract Unilateral or bilateral pneumonia Chronic bronchitis (acute attack) Acute bronchitis Bronchiectasis, concurrent infection Acute tonsillitis Acute nasal sinusitis Pyothorax Total Urinary tract Acute pyelonephritis Chronic pyelonephritis (acute attack) Acute cystitis Gonococcal urethritis Acute prostatitis Kidney stone, concurrent urinary infection Total Skin, soft tissue, other sites Wound infection Furuncle, carbuncle, or abscess Tinea pedis, secondary infection Infection complicating other skin diseases Erysipelas Mastadenitis Pelvic inflammation Celiac infection Intracranial infection Septicemia Cholecystitis Total No. of cases Cure Marked improvement Improvement No. of cases Cure Marked improvement Improvement 34 23 8 3 33 18 10 5 6 1 3 1 3 10 4 6 2 3 2 1 1 2 2 2 51 28 17 6 18 12 4 2 4 8 1 2 3 7 1 1 1 1 33 24 6 1 4 3 1 1 3 2 4 3 2 1 1 1 2 1 1 1 1 2 1 20 1 2 1 17 1 1 1 1 44 28 13 23 19 4 2 10 2 10 1 1 1 37 32 4 3 5 3 4 4 3 2 3 1 1 3 1 5 1 1 1 3 1 1 1 2 1 22 2 1 1 16 1 4 2 2 1 * Seventy-six (74%) of 103 patients in the sulbactam/cefoperazone group were cured vs. 69 (66%) of 104 in the cefotaxime group (P = .243). t The overall efficacy rates (cure plus marked improvement) for the two groups were 98 (95%) of 103 patients in the sulbactam/cefoperazone group and 94 (90%) of 104 in the cefotaxime group (P = .186); there were no treatment failures in either group. and 91%, respectively, for urinary and reproductive tract infections (P = .061); and 91% and 95%, respectively, for skin and soft-tissue infections (P = NS). One hundred seventy-eight pathogens were isolated from the 207 patients before treatment was started (table 4). The overall rate of positivity was 86%, which exceeded the protocolstipulated rate of Of the 178 strains isolated (most commonly from sputum), 85 were recovered from patients in the sulbactam/cefoperazone group, and 93 were recovered from patients in the cefotaxime group (table 4). As might be expected for hospitalized patients with moderate-to-severe infections, the pathogens most commonly isolated from the patients in this study were Escherichia coli (49 [28%] of 178 isolates), Klebsiella species (22 [12%]), S. aureus (22 [12%]), and Pseudomonas species (21 [12%]). One hundred seventy-six of the 178 isolates were tested for susceptibility; none was resistant to sulbactam/cefoperazone or cefotaxime, while 12 (7%) were resistant to cefoperazone alone, 98 (56%) were resistant to amoxicillin/clavulanic acid, and 17 (10%) were resistant to ticarcillin/clavulanic acid (table CID 1997; 24 (March) Li et al. 502 Table 4. Identification and sources of pretreatment bacterial isolates recovered from hospitalized patients who received sulbactam/cefoperazone or cefotaxime. Cefotaxime Sulbactam/cefoperazone Sputum Pus Blood Urine Swab Total Sputum Pus Blood Urine Swab Total Escherichia coli Klebsiella species Enterobacter cloacae Enterobacter aerogenes 0 7 3 2 0 0 1 0 Other Enterobacteriaceae Citrobacter species Serratia species Proteus species Acinetobacter species Pseudomonas species 0 1 0 0 4 7 1 0 0 0 0 4 1 0 1 0 0 0 0 0 0 0 Haemophilus influenzae Hafnia alvei 0 1 Other glucose nonfermenters Enterobacter agglomerans Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus hemolyticus 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 20 9 4 1 1 1 0 2 5 14 0 1 2 2 12 5 3 0 13 6 3 1 1 2 2 3 4 3 0 0 1 0 1 3 4 0 0 0 0 0 0 0 2 2 0 0 0 0 6 1 0 0 0 0 15 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 23 0 1 0 0 1 0 1 0 1 0 0 0 0 3 0 0 0 0 1 30 0 0 0 0 0 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 2 29 13 7 3 1 2 2 3 6 7 3 0 0 1 10 2 3 0 0 1 93 Pathogen Group D enterococci Neisseria gonorrhoeae Total 0 0 2 0 0 1 1 1 7 0 0 0 2 3 2 0 0 0 17 2 0 0 0 0 0 2 1 3 0 0 0 0 4 1 0 1 0 0 0 0 1 0 1 0 35 0 0 17 0 0 2 1 0 31 0 0 0 2 0 85 0 0 44 0 Table 5. Susceptibility testing results for isolates recovered from hospitalized patients with bacterial infections. No. of isolates with indicated susceptibility Sulbactam/ cefoperazone Ticarcillin/ clavulanic acid Amoxicillin/ clavulanic acid Cefotaxime Cefoperazone Pathogen S I R S I R S I R S I R S I R Pseudomonas species Klebsiella species Escherichia coli Enterobacter cloacae Acinetobacter species Serratia species Enterobacter aerogenes 20 21 42 1 1 6 0 1 0 1 0 1 0 0 0 0 0 0 0 3 0 2 0 16 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19 16 35 10 5 2 1 2 1 4 0 2 3 3 1 5 15 5 0 1 130 1 5 11 1 3 0 1 0 2 1 1 0 0 0 0 0 6 0 2 0 34 1 1 2 0 3 0 2 0 0 0 0 0 0 0 0 1 1 1 0 0 12 9 14 40 8 9 1 1 2 1 4 0 2 3 3 1 4 13 6 0 0 121 12 8 8 3 2 1 3 0 2 1 1 0 0 0 0 2 9 0 2 1 55 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 7 12 0 6 1 1 0 0 1 0 0 0 3 1 4 14 6 2 1 61 3 3 5 2 0 0 1 0 1 0 0 1 0 0 0 1 0 0 0 0 17 16 12 31 9 5 1 2 2 2 4 1 1 3 0 0 1 8 0 0 0 98 19 17 33 5 8 1 2 2 1 2 0 2 3 3 1 4 18 6 1 1 129 1 4 12 1 3 0 1 0 0 3 0 0 0 0 0 0 3 0 1 0 29 1 1 3 5 0 1 1 0 2 0 1 0 0 0 0 2 0 0 0 0 17 Other Enterobacteriaceae Citrobacter species Proteus species 11 10 2 3 2 2 5 Hafnia alvei 1 Other glucose nonfermenters 2 3 3 Enterobacter agglomerans Haemophilus influenzae Neisseria gonorrhoeae Staphylococcus epidermidis Staphylococcus aureus Streptococcus pneumoniae Group D enterococci Streptococcus hemolyticus Total No. of highly susceptible pathogens over total no. of pathogens (%) 1 6 19 6 0 1 160 160/176 (91) 130/176 (74) 121/176 (69) 61/176 (35) 129/175 (74) NOTE. For the comparison between the sulbactam/cefoperazone and cefoperazone groups, P = .002; for the comparison between the sulbactam/cefoperazone and cefotaxime groups, P = .001. S = highly susceptible; I = intermediately susceptible; R = resistant. CID 1997;24 (March) Sulbactam/Cefoperazone vs. Cefotaxime 503 Table 6. Identification of enzyme-producing bacterial strains recovered from hospitalized patients with moderate-to-severe infections who received sulbactam/cefoperazone or cefotaxime. Sulbactam/cefoperazone* Pathogen Escherichia coli Pseudomonas species Klebsiella species Citrobacter species Enterobacter cloacae Acinetobacter species Enterobacter aerogenes Enterobacter agglomerans Other Enterobacteriaceae Proteus species Serratia species Haemophilus influenzae Hafnia alvei Cefotaximet Total no. of strains of indicated pathogen No. positive for fi-lactamase No. negative for /3-lactamase 20 14 9 17 11 7 3 3 2 1 1 4 5 4 4 1 1 2 2 2 2 12 4 3 8 2 Total no. of strains of indicated pathogen 2 1 Other glucose nonfermenters Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus hemolyticus Group D enterococci 2 4 2 3 28 8 13 2 6 6 3 No. positive for fi-lactamase No. negative for fi-lactamase 22 5 10 2 5 4 3 6 3 3 3 1 3 1 10 2 3 1 2 2 1 3 1 7 3 2 3 2 NOTE. P = .601 when the sulbactam/cefoperazone group was compared with the cefotaxime group. * Of a total of 84 strains, 60 (71%) were positive for /3-lactamase. t Of a total of 90 strains, 61 (68%) were positive for /3-lactamase. 5). Of the susceptible isolates, 160 (91%) were highly susceptible to sulbactam/cefoperazone, whereas only 121 (69%) were highly susceptible to cefotaxime. This difference between groups was statistically significant (P = .001). The difference between the rates of susceptibility to sulbactam/cefoperazone and to cefoperazone alone (130 [74%] of 176) was also statistically significant (P = .002). As noted earlier, the nitrocefin procedure was used to identify 0-lactamase—producing strains among 174 clinical isolates (table 6). Sixty (71%) of 84 strains recovered from patients in the sulbactam/cefoperazone group and 61 (68%) of 90 strains recovered from patients in the cefotaxime group produced 0lactamase; these numbers exceeded the study design requirement that two-thirds of the isolates be /3-lactamase positive. The difference between the treatment groups was not statistically significant (P = .601) The overall bacterial clearance rates for the sulbactam/cefoperazone group and the cefotaxime group at the end of treatment were 85% and 81%, respectively; no statistically significant difference was observed between groups (table 7). Safety. Both drug treatments were well tolerated. Overall, 17 (8.2%) of 207 patients had generally mild, drug-related adverse reactions; 8 (7.8%) of 103 patients in the sulbactam/ cefoperazone group had reactions, and 9 (8.7%) of 104 in the cefotaxime group had reactions (P = .831) (table 8). Treatment was not discontinued because of side effects or death for any patient in either group. One case of rash was reported in the sulbactam/cefoperazone group, whereas one case of nausea and three cases of phlebitis were reported in the cefotaxime group. Laboratory abnormalities were reported for seven patients in the sulbactam/cefoperazone group and five patients in the cefotaxime group. Discussion The results of this randomized, controlled, multicenter trial indicate that 1 or 2 grams of sulbactam/cefoperazone (1:1 ratio), dissolved in 50-100 mL of normal saline or in 5% glucose solution and given every 12 hours by a 30-minute intravenous drip, is effective for treating infections of the respiratory tract, urinary tract, and skin and/or soft tissues as well as other moderate-to-severe bacterial infections in hospitalized patients. There were no statistically significant differences between sulbactam/cefoperazone and the control agent, cefotaxime, with regard to clinical efficacy or bacterial clearance. These findings are consistent with the results reported in other clinical trials [8-11]. For example, the results of a multicenter clinical trial conducted by Hara et al. [8] and published in 1985 showed no significant difference between sulbac- 504 CID 1997;24 (March) Li et al. Table 7. Bacterial clearance rates among hospitalized patients who received sulbactam/cefoperazone or cefotaxime. Cefotaximet Sulbactam/cefoperazone* Pathogen Escherichia coli* Klebsiella species Enterobacter cloacae Enterobacter aerogenes Other Enterobacteriaceae Citrobacter species Serratia species Proteus species Acinetobacter species Pseudomonas species Haemophilus influenzae Hafnia alvei Other glucose nonfermenters Enterobacter agglomerans Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus hemolyticus Group D enterococci Neisseria gonorrhoeae Total no. of strains No. (%) eradicated 20 9 4 1 1 1 0 2 5 14 0 1 2 2 12 5 3 1 2 0 17 (85) 7 (78) 4 (100) 1 (100) 1 (100) 1 (100) 0 2 (100) 4 (80) 9 (64) 0 1 (100) 2 (100) 1 (50) 11 (92) 5 (100) 3 (100) 1 (100) 2 (100) 0 No. persisting No. causing superinfections 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total no. of strains No. (%) eradicated No. persisting No. causing superinfections 29 13 7 3 1 2 2 3 6 7 3 0 0 1 10 2 3 0 0 1 24 (83) 8 (62) 7 (100) 1 (33) 1 (100) 2 (100) 1 (50) 3(100) 5 (83) 4 (57) 3 (100) 0 0 0 10 (100) 2 (100) 3 (100) 0 0 1 (100) 2 4 0 1 0 0 1 0 1 3 0 0 0 0 0 0 0 0 0 0 2 1 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 NOTE. P = .467 when the sulbactam/cefoperazone group was compared with the cefotaxime group. * Of 85 strains isolated, 72 (85%) were eradicated. t Of 93 strains isolated, 75 (81%) were eradicated. Among patients from whom E. coli was isolated, there was one case of reinfection in the sulbactam/cefoperazone group and one case of relapse in the cefotaxime group. Table 8. Adverse reactions among hospitalized patients with bacterial infections who received sulbactam/cefoperazone or cefotaxime. Reaction Clinical adverse reaction Rash Nausea Phlebitis Laboratory abnormalities Elevated alanine aminotransferase level Elevated alanine aminotransferase and alkaline phosphatase levels Elevated alanine aminotransferase and aspartate aminotransferase levels No. who received sulbactam/ cefoperazone with indicated reaction No. who received cefotaxime with indicated reaction 0 0 0 5 1 3 4 0 1 NOTE. The rate of adverse reactions was 7.8% in the sulbactam/cefoperazone group and 8.7% in the cefotaxime group (P = .831). tam/cefoperazone and cefotaxime with regard to efficacy and safety in 56 patients with respiratory tract infections. Although most of the patients in the present study had lower respiratory tract infections, only 3 (1.7%) of the 178 isolated pathogens were Haemophilus influenzae, and only 6 (3.4%) were Streptococcus pneumoniae. While this finding may appear paradoxical, our study population consisted primarily of patients with moderate-to-severe nosocomial infections that were most frequently caused by gram-negative rods, —70% of which produced 41-lactamase. The results of disk susceptibility tests in our trial showed that none of the strains were resistant to sulbactam/cefoperazone or cefotaxime, whereas 12 (6.9%) of 176 strains were resistant to cefoperazone alone. Moreover, 91% of the strains were highly susceptible to sulbactam/cefoperazone, as compared with 74% that were highly susceptible to cefoperazone alone (P = .002). These observations are consistent with the observations from other studies [1, 2, 4, 12] and suggest that the addition of the enzyme inhibitor sulbactam enhances the antibacterial activity of cefoperazone against resistant, 0-lactamase —producing strains. The potential clinical benefit of the combination of sulbactam/cefoperazone is supported by the results of another clinical trial [9] in which sulbactam/cefoperazone was found to be significantly more effective than cefoperazone alone in the treatment of urinary tract infections. CID 1997; 24 (March) Sulbactam/Cefoperazone vs. Cefotaxime In our trial, both regimens were well tolerated. Clinical adverse reactions and laboratory abnormalities occurred in only 17 (8.2%) of the 207 patients. The adverse reaction rates for sulbactam/cefoperazone and cefotaxime were both low (7.8% and 8.7%, respectively) and did not differ significantly in incidence. The results of this study demonstrate that the combination of sulbactam/cefoperazone is effective and safe when used to treat hospitalized patients with a variety of moderate-to-severe bacterial infections, the majority of which are caused by 0-lactamase—producing organisms. Acknowledgments The authors thank Pfizer Pharmaceuticals, Ltd. (Da Lian, China) for providing sulbactam/cefoperazone and Hoechst, Inc. for providing cefotaxime. References 1. Jones RN, Barry AL, Thornsberry C, Wilson HW. The cefoperazonesulbactam combination. In vitro qualities including 0-lactamase stability, antimicrobial activity, and interpretive criteria for disk diffusion tests. Am J Clin Pathol 1985; 84:496-505. 2. English AR, Retsema JA, Girard AE, Lynch JE, Barth WE. CP-45,899, a /3-lactamase inhibitor that extends the antibacterial spectrum of /3-lactams: initial bacteriological characterization. Antimicrob Agents Chemother 1978; 14:414-9. 505 3. Jones RN, Barry AL. Cefoperazone: a review of its antimicrobial spectrum, /3-lactamase stability, enzyme inhibition, and other in vitro characteristics. Rev Infect Dis 1983; 5 (suppl):S108-26. 4. Fass RJ, Gregory WW, D'Amato RF, Matsen JM, Wright DN, Young LS. In vitro activities of cefoperazone and sulbactam singly and in combination against cefoperazone-resistant members of the family Enterobacteriaceae and nonfermenters. Antimicrob Agents Chemother 1990; 34:2256-9. 5. Barry AL, Jones RN. In vitro activities of ampicillin-sulbactam and cefoperazone-sulbactam against oxacillin-susceptible and oxacillin-resistant staphylococci. Antimicrob Agents Chemother 1990; 34:1830-2. 6. Clark RB, Bartell MA, Chan EL, Dalton HP. 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