Targeting renal OATs to develop renal protective agent from traditional Chinese medicines: Protective effect of Apigenin against Imipenem-induced nephrotoxicity.

Imipenem (Imp) is a widely used broad-spectrum antibiotic. However, renal adverse effects limit its clinical application. We previously reported that organic anion transporters (OATs) facilitated the renal transport of Imp and contributed its nephrotoxicity. Natural flavonoids exhibited renal protective effect. Here, we aimed to develop potent OAT inhibitors from traditional Chinese medicines (TCMs) and to evaluate its protective effect against Imp-induced nephrotoxicity. Among 50 TCMs, Tribuli Fructus, Platycladi Cacumen, and Lycopi Herba exhibited potent inhibition on OAT1/3. After screening their main components, Apigenin strongly inhibited Imp uptake by OAT1/3-HEK293 cells with IC50 values of 1.98 ± 0.36 µM (OAT1) and 2.29 ± 0.88 µM (OAT3). Moreover, Imp exhibited OAT1/3-dependent cytotoxicity, which was alleviated by Apigenin. Furthermore, Apigenin ameliorated Imp-induced nephrotoxicity in rabbits, and reduced the renal secretion of Imp. Apigenin inhibited intracellular accumulation of Imp and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells (rPTCs). Apigenin, a flavone widely distributed in TCMs, was a potent OAT1/3 inhibitor. Through OAT inhibition, at least in part, Apigenin decreased the renal exposure of Imp and consequently protected against the nephrotoxicity of Imp. Apigenin can be used as a promising agent to reduce the renal adverse reaction of Imp in clinic.

Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia.

To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients.

[Convulsive liability of an oral carbapenem antibiotic, tebipenem pivoxil].

Tebipenem pivoxil (TBPM-PI), the first oral carbapenem antibiotic both in Japan and abroad, was examined on its convulsive liability. We used ICR male mice and Sprague-Dawley male rats to examine the pro-convulsive effect and anticonvulsive effect of TBPM-PI and its active metabolite, TBPM. (1) When mice were treated with TBPM-PI (30-1000 mg/kg, p.o.) or TBPM (10-300 mg/kg, i.v.), no convulsion was noted at any dose level. When rats were treated with TBPM (300 mg/kg, i.v.), no convulsant effects were noted in electroencephalography or behavioral observation. In intraventricular injection of TBPM in mice, clonic convulsion was observed in 7/10 animals at 100 microg but no effect at 30 microg. On the other hand, the administration of 10/10 microg imipenem/cilastatin (IPM/CS) resulted in clonic convulsion in all animals and tonic convulsion in 3/10 animals, and 4/10 animals died. The administration of 100 microg meropenem did not cause any effects. (2) When mice were co-administered with pentylenetetrazole (45 mg/kg: maximum dose level at which no convulsion is induced) and TBPM-PI (30-300 mg/kg, p.o.) or TBPM (300 mg/kg, i.v.), convulsion enhancing effect was not noted. On the other hand, the co-administration of pentylenetetrazole with IPM/CS (300/300 mg/kg, i.v.) enhanced a convulsive effect of pentylenetetrazole. (3) When mice were treated with TBPM-PI (30-300 mg/kg, p.o.) or TBPM (100 mg/kg, i.v.), inhibitory effect was not noted on convulsions induced by electrostimulation, pentylenetetrazole or strychinine. In conclusion, there were no pro-convulsive effects or anticonvulsive effect in the oral administration of TBPM-PI or intravenous administration of TBPM. Pro-convulsive effect was observed in the intraventricular injection of TBPM as in the case of other carbapenem antibiotics, but such action was weaker than that in IPM/CS administration. Accordingly, the risk of occurrence of convulsion related to TBPM-PI administration was low compared to IPM/CS administration, and TBPM-PI was considered to be less potential to induce convulsions in clinical use.

An unusual cause of seizures during subarachnoid anesthesia in a patient undergoing transurethral resection of the prostate: a case report.

A 73-year-old, ASA I patient scheduled for transurethral resection of the prostate under subarachnoid anesthesia received, prior to the beginning of the surgery, intravenous imipenem/cilastatin 1 g for a urinary infection with multiresistant Escherichia coli. The patient developed seizures during the surgical procedure. Central nervous toxicity of imipenem/cilastatin might have been the cause of the seizures. After appropriate management, the patient recovered well and was discharged without complications. The differential diagnosis between systemic toxicity of local anesthetics and imipenem-related seizures is discussed.

Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study.

OBJECTIVE: Doripenem is an investigational carbapenem with broad-spectrum activity against gram-negative and gram-positive pathogens, including multidrug-resistant strains, commonly responsible for ventilator-associated pneumonia (VAP). This large, phase III study compared doripenem with imipenem for the treatment of ventilator-associated pneumonia. DESIGN: Prospective, multicenter, parallel randomized, active-controlled, open-label study. SETTING: Intensive care units. PATIENTS: Adults (N = 531) who met clinical and radiologic criteria for ventilator-associated pneumonia. INTERVENTIONS: Patients were stratified by duration of mechanical ventilation (< 5 vs. > or = 5 days), severity of illness (Acute Physiology and Chronic Health Evaluation II score < or = 15 vs. > 15), and geographic region and then randomly assigned to doripenem 500 mg every 8 hrs via a 4-hr intravenous infusion or imipenem 500 mg every 6 hrs or 1000 mg every 8 hrs via 30- or 60-min intravenous infusions, respectively, for 7-14 days. MEASUREMENTS AND MAIN RESULTS: The primary efficacy end points were the clinical cure rates in the clinical modified intent-to-treat (cMITT) and clinically evaluable populations. Doripenem was noninferior to imipenem (lower boundary of 95% confidence interval around the difference between treatments > or = -20%). Clinical cure rates were 68.3% (doripenem) and 64.2% (imipenem) in the clinically evaluable and 59.0% (doripenem) and 57.8% (imipenem) in the cMITT populations. In patients with Pseudomonas aeruginosa, clinical cure was 80.0% (doripenem) and 42.9% (imipenem) (p not significant); microbiological cure was 65.0% (doripenem) and 37.5% (imipenem). Only 18% (5 of 28) of P. aeruginosa isolates had minimum inhibitory concentration > or = 8 microg/mL at baseline or following therapy in the doripenem arm compared with 64% (16 of 25) in the imipenem treatment group (p = .001). Clinical cure rate was higher with doripenem than imipenem at higher Acute Physiology and Chronic Health Evaluation II scores and older ages. Doripenem was generally well tolerated. CONCLUSIONS: In this large, phase III study of patients with ventilator-associated pneumonia, a 4-hr intravenous infusion of doripenem was clinically efficacious and therapeutically noninferior to imipenem.

The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data.

This pooled analysis includes 2 phase 3, double-blind trials designed to evaluate the safety and efficacy of tigecycline, versus that of imipenem-cilastatin, in 1642 adults with complicated intra-abdominal infections. Patients were randomized to receive either tigecycline (initial dose of 100 mg, followed by 50 mg intravenously every 12 h) or imipenem-cilastatin (500/500 mg intravenously every 6 h) for 5-14 days. The primary end point was the clinical response at the test-of-cure visit (12-42 days after therapy) in the co-primary end point microbiologically evaluable and microbiological modified intent-to-treat populations. For the microbiologically evaluable group, clinical cure rates were 86.1% (441/512) for tigecycline, versus 86.2% (442/513) for imipenem-cilastatin (95% confidence interval for the difference, -4.5% to 4.4%; P < .0001 for noninferiority). Clinical cure rates in the microbiological modified intent-to-treat population were 80.2% (506/631) for tigecycline, versus 81.5% (514/631) for imipenem-cilastatin (95% confidence interval for the difference, -5.8% to 3.2%; P < .0001 for noninferiority). Nausea (24.4% tigecycline, 19.0% imipenem-cilastatin [P = .01]), vomiting (19.2% tigecycline, 14.3% imipenem-cilastatin [P = .008]), and diarrhea (13.8% tigecycline, 13.2% imipenem-cilastatin [P = .719]) were the most frequently reported adverse events. This pooled analysis demonstrates that tigecycline was efficacious and well tolerated in the treatment of patients with complicated intra-abdominal infections.

Randomized, double-blind, multicenter trial comparing clinafloxacin with imipenem as empirical monotherapy for febrile granulocytopenic patients.

In a double-blind, multicenter trial, 541 febrile granulocytopenic patients were randomized to receive either intravenous (iv) clinafloxacin (200 mg every 12 h) or i.v. imipenem (500 mg every 6 h) as empirical monotherapy. More baseline pathogens were susceptible to clinafloxacin (259 [99%] of 262 organisms) than to imipenem (253 [95%] of 265; P=.03). Initial favorable clinical response rates for clinafloxacin (88 [32%] of 272 patients) and imipenem (89 [33%] of 269) were similar. After addition of other antimicrobial agents, overall response rates were 259 (95%) of 272 for clinafloxacin and 251 (93%) of 269 for imipenem. During the study, only 13 clinafloxacin (5%) and 18 imipenem (7%) recipients died. Both drugs were generally well tolerated. Drug-related skin rash occurred more often with clinafloxacin (11% vs. 6%; P=.07), whereas nausea (2% vs. 5%; P=.16), Clostridium-difficile-associated diarrhea (3% vs. 8%; P=.02), and seizures (0% vs. 2%; P=.06) occurred more often with imipenem. These results suggest that clinafloxacin and imipenem have similar efficacy as empirical monotherapy in febrile granulocytopenic patients.

Clinical and economic evaluation of subsequent infection following intravenous ciprofloxacin or imipenem therapy in hospitalized patients with severe pneumonia.

A recent multicentre clinical study evaluated the safety and efficacy of i.v. ciprofloxacin therapy compared with imipenem-cilastatin in hospitalized patients with severe pneumonia. Monotherapy with i.v. ciprofloxacin was at least equivalent to imipenem in terms of bacteriological eradication and clinical response. In a single-centre, retrospective, post-therapy evaluation of persistent and subsequent infection, the incidence of gram-negative infections and associated costs were compared. The main elements of the economic analysis included costs of additional antimicrobial therapy and hospitalization. Thirty-two patients were randomized into the study, of whom 27 were efficacy-valid. The 13 patients randomized into the ciprofloxacin group were not significantly different from the 14 patients in the imipenem group in terms of clinical parameters. Clinical cure occurred in ten of 13 patients (77%) in the ciprofloxacin group and in seven of 14 (50%) in the imipenem group. Bacteriological eradication was achieved in 11 of 13 (85%) ciprofloxacin-treated and eight of 14 (57%) imipenem-treated patients. Five of 13 (38%) patients in the ciprofloxacin group and nine of 14 (64%) in the imipenem group experienced persistent or subsequent infection requiring post-treatment antimicrobials. In these five ciprofloxacin patients, three had cultures with gram-positive organisms only and two had cultures with both gram-positive and gram-negative organisms. In the nine imipenem-treated patients requiring post-study antimicrobials, all had gram-negative bacteria and three also had gram-positive organisms. The incidence of subsequent gram-negative infection in the two groups (15% vs 64%) was significantly different (P < 0.05). Pseudomonas aeruginosa was isolated from seven patients in the imipenem group but only one in the ciprofloxacin group (P < 0.05). Subsequent costs for post-therapy antimicrobials and hospital stay while receiving study and post-study drug therapy were evaluated; the cost per patient cure was US$29,000 for ciprofloxacin and US$76,000 for imipenem. Initial treatment of severe pneumonia with ciprofloxacin resulted in significantly less subsequent gram-negative infection and was associated with substantially lower curative costs.

Empiric therapy of sepsis in the surgical intensive care unit with broad-spectrum antibiotics for 72 hours does not lead to the emergence of resistant bacteria.

BACKGROUND: It is our practice to treat suspected sepsis with imipenem/cilastatin and gentamicin (IMP/GENT) for 72 hours while awaiting culture results. We wanted to determine if this practice engenders antimicrobial resistance. METHODS: Review of prospectively collected data regarding use of IMP/GENT and microbial sensitivity to imipenem/cilastatin during the first and last 7 months of a 19-month study period (October 1, 1995, to April 30, 1997). RESULTS: The susceptibility of appropriate organisms to imipenem/cilastatin was 76% in the early period and 80% in the late period (p = 0.42). Pseudomonas aeruginosa was more susceptible in the late period (88 vs. 62%; p = 0.007). Resistance to gentamicin (30% early vs. 21% late; p = 0.02) and representative cephalosporins (cefoxitin, 52% early vs. 61% late; p = 0.35; ceftazidime, 26% early vs. 23% late; p = 0.76) did not develop during the study period. The incidence of fungemia was the same in both periods (4 of 467 admissions vs. 3 of 599 admissions; p = 0.48). CONCLUSION: This protocol did not lead to the emergence of resistant bacteria.

Randomized comparison of sulbactam/cefoperazone with imipenem as empirical monotherapy for febrile granulocytopenic patients.

In a prospective, randomized, controlled trial, we compared sulbactam/cefoperazone with imipenem as empirical monotherapy for febrile, granulocytopenic patients; 101 patients received sulbactam/cefoperazone (2 g/4 g every 12 hours) and 102 patients received imipenem (500 mg every 6 hours). Documented infections were present in 40% of patients treated with sulbactam/cefoperazone (40 of 101) and in 39% of patients receiving imipenem (40 of 102). The number of pretherapy gram-positive pathogens (52 isolates) was twice the number of pretherapy gram-negative pathogens (26 isolates). The overall favorable clinical response rates for sulbactam/cefoperazone (91 of 103 patients, or 88%) and imipenem (84 of 104 patients, or 81%) were similar. Both drugs were generally well tolerated. However, diarrhea occurred more often in patients treated with sulbactam/cefoperazone (31 of 101 patients, or 31%, vs. 15 of 102 patients, or 15%; P = .007), while seizures developed only in patients receiving imipenem (0 of 101 patients vs. 3 of 102 patients, or 3%). Superinfections developed in 16% of patients in both study groups but were infrequently caused by beta-lactam-resistant gram-negative bacilli (two cases with sulbactam/cefoperazone therapy and six cases with imipenem). These results support the efficacy and safety of either sulbactam/cefoperazone or imipenem as empirical monotherapy for febrile granulocytopenic patients.

Cost-effectiveness of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients.

A cost-effectiveness analysis was performed following a double-blind, randomized study of ampicillin/sulbactam (A/S) versus imipenem/cilastatin (I/C) for the treatment of limb-threatening foot infections in 90 diabetic patients. There were no significant differences between the treatments in terms of clinical success rate, adverse-event frequency, duration of study antibiotic treatment, or length of hospitalization. Costs of the study antibiotics, treatment of failures and adverse events, and hospitalization were calculated. Mean per-patient treatment cost in the A/S group was $14,084, compared with $17,008 in the I/C group (P = .05), primarily because of lower drug and hospitalization costs and less-severe adverse events in the A/S group. Sensitivity analyses varying drug prices or hospital costs demonstrated that A/S was consistently more cost-effective than I/C. Varying the clinical success rate for each drug revealed that I/C would have to be 30% more effective than A/S to change the economic decisions.

A comparison of imipenem/cilastatin with the combination of cefuroxime and metronidazole in the treatment of intra-abdominal infections.

515 patients with intra-abdominal infection participated in an open randomized comparative multicenter trial in order to compare the efficacy, safety, and tolerance of imipenem/cilastatin with cefuroxime/metronidazole. 258 patients (mean age 56 years) received imipenem/cilastatin 1.5-2.0 g/day, and 257 patients (mean age 54 years) received cefuroxime 3.0-4.5 g/day plus metronidazole 1.0-1.5 g/day for at least 3 days. 130/161 evaluable patients (80.8%) receiving imipenem/cilastatin and 124/145 evaluable patients (85.5%) receiving cefuroxime/metronidazole were clinically cured. The microbiological response was favorable in 86.9% in the imipenem/cilastatin group and in 90.8% in the cefuroxime/metronidazole group. The two treatment groups were similar with respect to median time to defervescence which was 4 days. The median duration of treatment was 6 days and the median time to discharge from hospital was 9 days in both groups. Drug-related adverse reactions were observed in 14 patients receiving iminpenem/cilastatin and in 8 patients receiving cefuroxime/metronidazole. 19 patients in the imipenen/cilastatin group and 12 patients in the cefuroxime/metronidazole group died. No correlation was found between the deaths and the study drugs. The present study shows that intra-abdominal infections can be treated successfully with imipenem/cilastatin as well as with cefuroxime/metronidazole.

[Use of imipenem in the treatment of patients with surgical infection]. / Primenenie imipenem dlia lecheniia bol'nykh s khirurgicheskoi infektsiei.

The efficacy of thienam, a product of Merck, Sharp and Dohme (USA) composed of imipenem and cylastatin was studied in the treatment of 52 patients with surgical infection. In 48 and 4 patients the drug was used therapeutically and prophylactically respectively. When the drug was used therapeutically the recovery and improvement were observed in 41 out of 44 patients (93.2 per cent), 4 patients being excluded from the treatment group because of adverse reactions such as hyperthermia and skin eruption. When the drug was used prophylactically the recovery and improvement were stated in all the 4 patients. The pathogens were eradicated in the wound in 40 patients (91 per cent). 114 clinical isolates were tested and the imipenem resistance was detected only in 6.5 per cent of the Staphylococcus aureus strains, in 20 per cent of the Pseudomonas aeruginosa strains and in 50 per cent of the P. mirabilis and P. vulgaris strains. All the isolates of Escherichia coli, Enterobacter, Acinetobacter and Citrobacter were susceptible or moderately susceptible to imipenem.

Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group.

Intravenously administered ciprofloxacin was compared with imipenem for the treatment of severe pneumonia. In this prospective, randomized, double-blind, multicenter trial, which included an intent-to-treat analysis, a total of 405 patients with severe pneumonia were enrolled. The mean APACHE II score was 17.6, 79% of the patients required mechanical ventilation, and 78% had nosocomial pneumonia. A subgroup of 205 patients (98 ciprofloxacin-treated patients and 107 imipenem-treated patients) were evaluable for the major efficacy endpoints. Patients were randomized to receive intravenous treatment with either ciprofloxacin (400 mg every 8 h) or imipenem (1,000 mg every 8 h), and doses were adjusted for renal function. The primary and secondary efficacy endpoints were bacteriological and clinical responses at 3 to 7 days after completion of therapy. Ciprofloxacin-treated patients had a higher bacteriological eradication rate than did imipenem-treated patients (69 versus 59%; 95% confidence interval of -0.6%, 26.2%; P = 0.069) and also a significantly higher clinical response rate (69 versus 56%; 95% confidence interval of 3.5%, 28.5%; P = 0.021). The greatest difference between ciprofloxacin and imipenem was in eradication of members of the family Enterobacteriaceae (93 versus 65%; P = 0.009). Stepwise logistic regression analysis demonstrated the following factors to be associated with bacteriological eradication: absence of Pseudomonas aeruginosa (P < 0.01), higher weight (P < 0.01), a low APACHE II score (P = 0.03), and treatment with ciprofloxacin (P = 0.04). When P. aeruginosa was recovered from initial respiratory tract cultures, failure to achieve bacteriological eradication and development of resistance during therapy were common in both treatment groups (67 and 33% for ciprofloxacin and 59 and 53% for imipenem, respectively). Seizures were observed more frequently with imipenem than with ciprofloxacin (6 versus 1%; P = 0.028). These results demonstrate that in patients with severe pneumonia, monotherapy with ciprofloxacin is at least equivalent to monotherapy with imipenem in terms of bacteriological eradication and clinical response. For both treatment groups, the presence of P. aeruginosa had a negative impact on treatment success. Seizures were more common with imipenem than with ciprofloxacin. Monotherapy for severe pneumonia is a safe and effective initial strategy but may need to be modified if P. aeruginosa is suspected or recovered from patients.

[Thienam (imipenem/cilastatin) as an agent for empirical antibiotic therapy]. / Tienam (imipenem/tsilastatin) kak sredstvo émpiricheskoi antibiotikoterapii.

The clinicobacteriological efficacy and tolerance of thienam (imipenem/cylastatin) were studied in the empirical therapy of 38 patients with severe purulent inflammatory diseases of various localization i.e. pneumonia, lung abscesses, pyothorax, peritonitis, abdominal abscesses, meningitis and brain abscesses. The treatment of all the patients with the drug was started before the data on the bacteriological investigation were available. Although the infections and the general state of the patients were extremely severe, the therapy with thienam proved to be efficient in 31 out of 35 cases (88.6 per cent) subjected to the drug efficacy estimation. The bacteriological diagnoses with respect to 24 out of 38 patients (64.7 per cent) were available later: 93.6 per cent of the isolates was sensitive to imipenem. The antimicrobial activity of imipenem against 254 clinical isolates assayed by the method of serial dilutions exceeded that of the majority of the currently used antimicrobial drugs, including aminoglycosides, 3rd generation cephalosporins and ureldopenicillins. The tolerance of thienam was good. Only in 4 out of 38 patients it was necessary to use some other drugs because of the side effects. Therefore, the use of the thienam is advisable as a drug of empirical monotherapy in patients with severe infections of the respiratory organs, abdominal cavity and central nervous system.

The antimicrobial activity of imipenem/cilastatin and its treatment in critical ill patients with polymicrobial and mixed infection.

The antimicrobial activity of imipenem/cilastatin (IPM/CS) was determined for a broad spectrum of 7,157 organisms isolated from the Clinical Microbiology Laboratory of Chang Gung Memorial Hospital, Linkou Medical Center, between April 1 and June 30, 1988. Ninety eight point one percent of 4,389 gram negative aerobes, 95.8% of 2391 gram positive rods, and 95.9% of 507 anaerobes, were shown to be sensitive to IPM/CS. Ninety nine point two percent of 837 Pseudomonas aeruginosa isolates were sensitive to this antibiotic. This study also disclosed that this agent was much more active against Pseudomonas aeruginosa than any other tested aminoglycosides (gentamicin, amikacin, netilmicin) or third generation cephalosporins (cefotaxime, latamoxef, ceftazidime). Twelve critically ill patients with polymicrobial and mixed infection were recruited into this trial. All patients received IPM/CS 500 mg intravenously every six hours except one patient with poor renal function had 250 mg every six hours. The average duration of therapy was 12.5 days. All patients were evaluated according to the selection criteria. IPM/CS achieved favorable clinical response in 83.7 percent. The antibiotic was well tolerated. One patient discontinued treatment because of jaundice. One patient had superinfection of fungemia. The results suggested that IPM/CS is very useful in the treatment of patients with mixed infections due to gram positive, gram negative, and anaerobic bacteriae, even when empirical therapy with other antibiotics fails.

Piperacillin-tazobactam versus imipenem-cilastatin for treatment of intra-abdominal infections.

In order to compare the clinical and microbiological efficacies and safety of piperacillin plus tazobactam with those of imipenem plus cilastatin, 134 patients with intra-abdominal infections (73 patients with appendicitis) participated in an open randomized comparative multicenter trial. A total of 40 men and 29 women (mean age, 53 years; age range, 18 to 92 years) were enrolled in the piperacillin-tazobactam group and 40 men and 25 women (mean age, 54 years; age range, 16 to 91 years) were enrolled in the imipenem-cilastatin group. The patients received either piperacillin (4 g) and tazobactam (500 mg) every 8 h or imipenem and cilastatin (500 mg each) every 8 h. Both regimens were given by intravenous infusion. A total of 113 patients were clinically evaluable. Of 55 patients who received piperacillin-tazobactam, 50 were clinically cured, while 40 of 58 patients in the imipenem-cilastatin group were clinically cured. The differences were significant (Wilcoxon test; P = 0.005). There were 4 failures or relapses in the piperacillin-tazobactam group and 18 failures or relapses in the imipenem-cilastatin group. The microorganisms isolated were eradicated in similar proportions in the two patient groups. Adverse reactions, mainly gastrointestinal disturbances and nausea, were noted in 13 patients who received piperacillin-tazobactam and in 14 patients who received imipenem-cilastatin. Results of the present study show that piperacillin-tazobactam is effective and safe for the treatment of intra-abdominal infections.