ORIGINAL ARTICLE Scand J Infect Dis 29: 503-508, 1997

lmipenem/cilastatin (1.5 g daily) versus Meropenem (3.0 g daily) in Patients with Intra-abdominal Infections: Results of a Prospective, Randomized, Multicentre Trial ANTONIO BASOLI, EMANUELE ZARBA MELI, PAOLO MAZZOCCHI, VINCENZO SPERANZA and STUDY GROUP* From the Department of Surgery, Clinica Chirurgica II, Universitd degli Studi “La Sapienza”, Policlinico Umberto I., Rome, Italy

An open-label prospective, randomized, parallel molticentre study was undertaken to compare the efficacy and tolerability of 1.5 g/day intravenous imipenem/cilastatin with 3 g/day intravenous meropenem in the treatment of intra-abdominal infections. A total of 287 patients were enrolled; 201 patients, divided between the 2 treatment groups, were evaluable. Clinical outcome, bacteriological outcome, untoward microbiological effects, and clinical and laboratory adverse experiences were evaluated. 98%) of patients receiving imipenem/cilastatin therapy were cured, with 96% showing eradication of infection. 95% of those on meropenem were cured, with 98% showing eradication. These differences in clinical and bacteriological outcome between the 2 treatments were not statistically significant. Two patients receiving imipenem/cilastatin and 5 receiving meropenem had untoward microbiological effects. There was a 0.7% frequency (11139 patients) of possibly or probably drug-related clinical or laboratory adverse experiences with imipenem/cilastatin and a 2.7% frequency (41148) with meropenem. The mean time to defervescence was significantly less for patients in the imipenem/cilastatin treatment group than for those receiving meropenem. This study shows that 1.5 g/day of imipenem/cilastatin is equivalent to 3.0 g/day meropenem in clinical and bacteriological outcome, as well as in incidence of side effects.

A . Basoli, MD, Clinica Chivuugica II, Uniueusita degli Studi, “La Sapienza”, Policlinico Umbevto I., Viale del Policlinico, 1-00161 Rome, Italy

INTRODUCTION

Intra-abdominal infections following a perforation of the gastrointestinal tract are a common problem in surgery and often result in a high mortality, which can be over 60% in patients with secondary organ failure (1 -3).

Besides mandatory surgical drainage, an adequate sup- port of the patient’s vital systems and an appropriate antimicrobial therapy, usually started immediately on an empirical basis, well before results of cultures and suscepti- bilities are known, are also very important (4, 5).

The microorganisms involved frequently include Gram- negative and Gram-positive aerobes, mainly Escherichia coli, Streptococcus faecalis, Klebsiella spp., Proteus spp. and Enterobacter spp., and anaerobes such as Bacteroides

* E. Lezoche, M. Guerrieri (Ancona); D. Marrano, F. Minni (Bologna); S.M. Giulini, F. Nodari (Brescia); G. Brotzu, P. Loddo (Cagliari); F. Latteri, G. Scuderi; G. Rodolico, L. Cavallaro (Catania); I. Donini, A. Sortini (Ferrdra); F. Tonelli, S. Spini (Firenze); C. Natale, V. Musto (Foggia); A. Vio, G. Verdecchia, D. Morgdgni (Forli); L. Mariani (Grosseto); A. Montefusco, E. Gerosa; G. Tiberio, A. Nardone (Milano); F. Mazzeo, G. Benassai (Napoli); D. D’Amico, A. Tropea (Padova); M. Piervittori (Peru- gia); S. Becelli, M. Cazzaniga, F. Stagnitti; F. Crucitti, F. Pacelli; A. Gargiulo; G. Panichi, R. Di Rosa; R. Porzio, U. Lombardi; V. Stipa, P. Chirletti (Roma); D. De Anna, I. Pisano (Sassari); S. Armenio, E. Salvestrini (Siena); A. Baglioni, G. Iafrate (Sora); F. Donadio, L. Paron; A. Saccia, P. Di Girolamo (Torino).

fragilis, Bacteroides spp., Peptostreptococcus spp. and Clostridium spp. (3, 6).

In order to provide broad-spectrum coverage, antimicro- bial therapy has often consisted of a combination of 2 or even 3 antibiotics, but some of these combinations can cause serious side effects, such as nephro- or oto-toxicity, promote proliferation of resistant organisms, and can be relatively expensive compared to appropriate monotherapy (7, 8).

Imipenem/cilastatin, the prototype carbapenem p-lactam antibiotic, has been shown to have unusually broad-spec- trum antibacterial activity against aerobic and anaerobic Gram-negative and Gram-positive bacteria (9- 11). Com- pared to different antibiotic combinations, monotherapy with imipenem/cilastatin has been shown to be highly effec- tive in the treatment of intra-abdominal infections (9, 12).

The action of meropenem, also a carbapenem (13, 14), has been shown in vitro to be similar to that of imipenem/ cilastatin against a broad spectrum of pathogens, and has been reported to have comparable efficacy and safety profi- les in 2 recent clinical trials. In one trial, the dosage was 3.0 g/day of meropenem vs. the same dose of imipenem/cilas- tatin in mild to severe intra-abdominal infections (15). In the other trial 1.5 g/day of meropenem vs. the same dose of imipenem/cilastatin was studied in moderately severe infec- tions (16).

This study was designed to compare the clinical efficacy, safety and tolerability of therapy using 1.5 g/day of intra-

0 1997 Scandinavian University Press. ISSN 0036-5548

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Scand J Infect Dis 29 504 A . Busoli et ul.

venous imipenem/cilastatin and 3.0 g/day of intravenous meropenem in the treatment of serious complicated intra- abdominal infections. The imipenem/cilastatin dosage of 1.5 g/day was chosen based on the product circular and numerous previous clinical trials. The meropenem dosage was chosen not only because the product circular recom- mends that 3 g/day be administered in the treatment of peritonitis, but also because of the in vivo treatment impli- cations of the significantly greater activity of imipenem/ cilastatin as compared to meropenem against enterococci (17). In fact, imipenem/cilastatin has an MIC90 of 2 pg/ml against S. faecalis (18) which is a level maintained in plasma after an administration of a 500 mg i.v. infusion for about 4 h (19), whereas meropenem with a MIC90 against S. faecalis of 8 pg/ml (18), maintains this plasma level after a n administration of a 1 g i.v. infusion for less than 3 h (20).

MATERIALS AND METHODS Study sample Patients included were 2 18 y of age, with intra-abdominal infec- tions extending beyond the organ wall, characterized as serious (requiring hospitalization), complicated (requiring surgical inter- vention within 24 h of diagnosis/enrolment in the study), and mild to moderate in severity (not life-threatening).

All pre-study evaluations were made in the 24-h period prior to initiation of study-drug therapy, patients were stratified according to the severity of disease, as determined by the APACHE I1 score (4, 21), and then randomized sequentially into the 2 treatment groups.

After a diagnosis at enrolment based on history, complete medical and physical examinations, and laboratory evaluation, patients were required to present with either an oral temperature 2 38T, or a WBC 2 10.5 x IO’/mm, with symptoms and physical findings (e.g. abdominal tenderness and pain) and radiological, ultrasonic or radionuclide (if performed) changes consistent with intra-abdominal infection.

Microorganisms, isolated from an intraperitoneal source from all patients, were cultured and tested for in vitro susceptibility to the study antibiotics.

Excluded were patients with traumatic bowel perforation requir- ing surgery within 12 h, perforation of gastroduodenal ulcers requiring surgery within 24 h, or other intra-abdominal processes in which the primary aetiology was unlikely to be infectious. Also excluded were patients who had undergone a percutaneous drainage procedure rather than a surgical procedure.

Those patients who had not received previous antibiotic therapy or who had received only a single dose of systemic antibiotics within the 48-h period immediately prior to consideration for enrolment in the study were considered candidates if the infection required a change in the antibiotic regimen or if specimens from the infection site were cultured and found to be susceptible to the study antibiotics.

Also excluded were the following patients: lactating or pregnant; with a history of allergy, hypersensitivity, or any severe reaction to the study antibiotics or to any of the components of these prod- ucts; with rapidly progressive or terminal illness; with a history or presence of severe hepatic or renal disease (e.g. creatinine clearance 10 .5 ml/min/1.73 m2); with a concomitant infection that would interfere with evaluation of response to the study antibiotics. Participation in any other clinical study involving antibiotics,

previous participation in this study at any time or the inability of the patient or legal representative to provide written informed consent for any reason, were grounds for exclusion.

Patients requiring concomitant administration of probenecid, cisplatin, carboplatin, or neuromuscular blocking agents (unless the patient was on mechanical ventilation) were also excluded.

Trial design This open-label, prospective, randomized, parallel clinical study of serious complicated intra-abdominal infections was conducted in 20 centres, with a planned enrolment of at least 100 patients in each of two treatment groups.

Patients were randomized to receive either i.v. imipenem/cilas- tatin (500 mg q8h) or meropenem (1000 mg q8h) for at least 5 days. Dosages were modified for patients with impaired renal function (creatinine clearance 1 7 0 ml/min/1.73 mZ) or body weight <70 kg.

Patients requiring concornitant antibiotic therapy, who devel- oped concomitant nonsusceptible infections in other sites, or re- quiring additional surgery within 24 h of the initial surgery, were to be withdrawn from the study. In addition, patients with infec- tions caused by microorganisms not susceptible to the study antibi- otics were withdrawn from the study. Safety and tolerability were assessed in all patients who received the study antibiotic regimen.

Patients were evaluated at 7-10 days after cessation of all antibiotic therapy to ascertain the presence or absence of an infectious process.

Clinical and laboratory measurements Patient examinations were conducted daily. Laboratory studies, including a CBC with WBC and differential, platelet count, serum glucose, BUN, and serum creatinine were performed at the start and the end of the study, at the post-treatment follow-up, or more frequently as clinically indicated. Prothrombin time, liver function studies, serum electrolytes and urinalysis were performed as clini- cally indicated and at the discontinuation of intravenous study- drug therapy. During antibiotic therapy, blood, urine and speci- mens from other clinically relevant intra-abdominal sites were obtained for repeat culture and susceptibility testing when clini- cally indicated and at the end of antibiotic study-drug, unless there was no material available to culture and/or no clinical evidence of infection.

Evaluable patients were classified into three groups according to the clinical outcome: cure (no signs or symptoms of infection and no further antimicrobial therapy); failure (indicating no improve- ment, infection progression or death due to infection); or late failure (indicating recurrence between cessation of antibiotics and follow-up).

Bacteriologic outcome, defined on the basis of culture and susceptibility testing of specimens obtained at the end and at least 7-10 days after discontinuation of the study-drug therapy, was categorized in evaluable patients as eradicated, relapsed, persistent or persisted acquiring resistance.

Susceptibility testing was performed according to the standard accepted disk sensitivity criteria and zone diameters for the two antibiotics were: imipenem - susceptible 2 16 mm, intermediate 14-15 mm, resistant 1 1 3 mm; meropenem - susceptible 214 mm, intermediate 11-13 mm, resistant 510 mm. For anaerobes the susceptibility was evaluated by broth dilution using a break- point concentration of 4 pg/ml, able to inhibit the growth of all anaerobes tested.

Data analysis Treatment groups were compared using a Pearson xZ test or Fisher’s exact test. Statistical significance was declared at the 0.05 level. All tests were two-sided. Two-sided 95% confidence intervals

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Scand J Infect Dis 29 Imipenem/cilastatin versus rneropenem 505

Table I. Reasons for patient exclusion ,from study (n = 86)

Imipenem/cilastatin Meropenem

Reason

No primary pathogen isolated 37 (97.4%) 44 (91.6%) 81 (94.1) Primaiy pathogen resistant in 0 (O.OY0) 2 (4.2%) 2” (2.3)

No specimen available 1 (2.6%) 0 (O.O‘%) 1 (1.2) Protocol violator 0 (0.0%) 1 (2.1%) I b (1 .2) Adverse experiences 0 (0.0%) 1 (2.1%) 1‘ (1.2) Total 38 (lOO.OY0) 48 (1 00.0%) 86 (IOO.O%!)

vitro to assigned therapy

a Enterococcus faecium resistant to both antibiotics; Pseudomonas aeruginosa resistant to assigned meropenem treatment. bAge <18 y. Hyperbilirubinaemia, possibly related to meropenem, after 3 days of treatment.

were calculated for the difference in efficacy parameters between the two groups.

RESULTS

Patient characteristics A total of 287 patients were enrolled in the study at 20 centres and 201 were evaluable; 101 were randomized to imipenem/cilastatin and 100 to meropenem. The mean age of patients in both treatment groups was 54.4 y ranging from 19 to 90 y in the imipenemicilastatin group and from 20 to 92 y in the meropenem group. Evaluable patients included 113 men and 88 women, with a ratio of 58:43 (M:F) in the imipenemlcilastatin group and a ratio of 55 : 45 in the meropenem group.

Reasons for exclusion and primary diagnosis for evalu- able patients are shown in Tables I and 11.

Table 11. Primary diagnosis of evaluable patients

Infection

Peritonitis Diffuse

Appendicitis Biliary tract Bowel Stomach

Appendicitis Cholecystitis Diverticulitis

Abscess Crohn’s disease

Local

with perforation, fistula, abscess

Other disease

Total

~~

Imipenem/ cilastatin Meropenem Total

n n (“YO) n (%I)

48 22

3 18 5

36 11 11 14 5 5

I 101

41.5 45.8

6.3 31.5 10.4 35.6 30.5 30.5 39.0

5.0 5.0

6.9

100.0

43 43.0 20 46.5

3 7.0 14 32.5 6 14.0

45 45.0 19 42.2 16 35.6 10 22.2 4 4.0 4 4.0

4 4.0

100 100.0

91 45.2 42 46.1 6 6.6

32 35.2 11 12.1 81 40.3 30 31.0 21 33.4 24 29.6 9 4.5 9 4.5

11 5.5

201 100.0

The 2 groups were well matched for concomitant dis- eases, present in nearly half of the evaluable patients, the most common being heart and lung disorders and neo- plasms.

The distribution of patients, divided into low-, moderate- and high-risk groups, according to the APACHE I1 scores, is summarized in Table 111.

Clinical outcomes 99 patients (98%) in the imipenem/cilastatin treatment group and 95 patients (950/0) in the meropenem treatment group were cured; the differences in cure rate were not statistically significant.

The average time of defervescence and duration of ther- apy were significantly shorter in the imipenem/cilastatin group compared to the meropenem group.

Study results are summarized in Table IV.

Bacteriological outcomes 165 pathogens were isolated from the 101 evaluable pa- tients receiving imipenem/cilastatin and were: 59.4% Gram- negative and 24.8% Gram-positive aerobes, 1 1 .O% Gram- negative and 4.8% Gram-positive anaerobes. 153 pathogens were isolated from the 100 evaluable patients receiving meropenem and were: 61.5% Gram-negative and 29.4%) Gram-positive aerobes, 8.5% Gram-negative and 0.6% Gram-positive anaerobes. All but one of the pathogens isolated from evaluable patients assigned to the meropenem group were susceptible to imipenem/cilastatin, while 10 isolates (of which 6 were enterococci) from the imipenem/ cilastatin group were resistant to meropenem (Table V).

97 patients (96o/u) in the imipenem/cilastatin group and 98 (98%) in the meropenem group experienced infection eradication. These numbers were statistically equivalent.

Untoward microbiological effects involving organisms not associated with the original infection occurred in two patients treated with imipenem/cilastatin. Cultures were identified as Acinetobacter lwoffi and Staphylococcus epi- dermidis in one patient and Enterobacter cloacae and Staphylococcus aureus in the other.

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Scand J Infect Dis 29 506 A . Basoli et al.

Table 111. APACHE II score according to treatment: evaluable patients

Imipenem/cilastatin Meropenem Total

Apache I1 score n ( Y O ) n (“h) n (“h) ~

5 10 81 (80.2%) 85 (85.0%) 166 (82.6%) > I 0 5 2 0 20 (1 9.8%) 13 (1 3 .0%) 33 (16.4%) > 20 0 (0.0%) 2” (2.0%) 2 (1 .0%) Mean Apache I1 score 6.4 5.9 6.1

* One patient scored 21 and another 22.

Untoward microbiological effects occurred in 5 patients treated with meropenem. The first patient was infected with S. epidermidis, the second with E. coli, the third with S. cohnii, the fourth with S. epidermidis, the fifth with B. fragilis. There was no significant difference in untoward microbiological effects between the treatment groups.

Safety All 287 patients who received study medication, 138 in the imipenem/cilastatin group and 144 in the meropenem group, were evaluated for clinical and laboratory adverse experiences. One patient in the imipenem/cilastatin group experienced a facial “butterfly” erythema and one patient in the meropenem group experienced an erythematous wheal considered as probably drug-related. Another 3 pa- tients in the meropenem group experienced adverse events or complication considered possibly drug-related, such as: one case of epigastralgia, pyrosis, sweating; one case of hyperbilirubinemia and one case of surgical wound suppu- ration. There was no difference in incidence of adverse experience between the 2 treatment groups.

DISCUSSION

The results of this study indicate that both 1.5 g/day imipenem/cilastatin and 3.0 g/day meropenem, with dosages adjusted according to patient weight and creatinine clearance rate, are efficacious in the treatment of serious complicated intra-abdominal infections. The number of patients with favourable clinical outcomes was nearly iden- tical, with no significant difference between the two treat- ment groups. The results of this trial are consistent with previously obtained results (1 5, 16).

In the present study, the majority of the clinically evalu- able patients were comparable in terms of their underlying pathology, although there was a higher proportion of pa- tients presenting with severe disease (APACHE I1 score > 10) in the imipenem/cilastatin group though statistical significance was not reached. High APACHE I1 scores have been cited as the main reason for failure to cure intra-ab- dominal infections (21).

The in vitro activity of imipenem/cilastatin is broader than that of most other antibiotics, and includes most of the clinically important pathogens. The spectrum of meropenem is similar, although imipenem/cilastatin has

shown greater activity against Gram-positive microbes while meropenem tends to be more potent against some Gram-negative organisms (22). The bacteriological out- come was not significantly different for patients in the 2 treatment groups, with eradication of the infecting organ- isms occurring in over 96% of all patients. In the 4 patients (4/101) who experienced bacteriological persistence after treatment with imipenem/cilastatin, the organisms were known to be susceptible to the treatment in vitro. Persis- tence of S. aureus and E. coli infections occurred, respec- tively, in 2 patients (2/100) in the meropenem group. It is noteworthy, however, that at the commencement of treat- ment with imipenem/cilastatin, 10 pathogens sensitive to imipenem/cilastatin were completely resistant to mero- penem and that of the 17 Enterococcus species sensitive to imipenem/cilastatin 6 were resistant to meropenem. This data is particularly relevant since treatment of these infec- tions is often started on an empirical basis.

Each treatment was found to have a good safety and tolerability profile. One patient (0.7%)) in the imipenem/ cilastatin group experienced facial erythema which was probably treatment-related, while 4 patients (2.70/0 fre- quency) in the meropenem treatment group experienced adverse effects that were possibly or probably drug-related.

Our results demonstrated no significant differences in the tolerability profiles and were consistent with those reported by Norrby et al. (23) in a recent review of the side effects of these 2 carbapenems. No seizures were reported in our study, although patients with known CNS abnormalities were not excluded. No seizures were reported in the com- parative randomized trial also, where the dosage of imipenem/cilastatin was 3 g/day (15).

Although imipenem/cilastatin was administered at half the dosage of meropenem, both the time to defervescence and the required treatment time were significantly less for the imipenem/cilastatin group. Previous results have sug- gested that the mean treatment duration using these 2 therapies was similar, 5.1 days in the imipenem/cilastatin group and 5.4 days in the meropenem group (16).

The results of the study indicate that both these antibi- otics are effective and well tolerated in the treatment of moderate to severe intra-abdominal infection, and are good choices for monotherapy given their broad spectrum of activity and low probability for development of cross-resis-

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Scand J Infect Dis 29 Imipenemlcilastatin versus meropenem 501

Table IV. Summary of mean results f o r evaluable patients (n = 201)

Outcome Imipenem/cilastatin ( n = 101)

Meropenem (n = 100) p value

Dosage (mean) 1.40 g/day 2.86 g/day -

Clinical outcome 98% cured -2.7% + 2.0%* 95% cured -2.7% ns

Bacteriological outcome 96% eradication -2.4% + 2.4%* 98% eradication -2.4%) ns

Time to defervescence (mean) 1.83 days 0.0-4.4 days* 2.46 days 0.0-7.0 days* 0.046 Duration of treatment (mean) 6.7 days 5.0-10.5 days* 7.2 days 5.0-12.4 days* 0.019

+2.7%*

+ 2.0%*

* 95% confidence interval.

tance (22). Imipenem has the advantage of being combined with cilastatin, which has been shown to possess nephro- protective properties (24, 25) and of a significantly greater activity against enterococci. Since imipenem/cilastatin was clinically efficacious at half the dosage of meropenem and

required a shorter duration of treatment, it appears that treatment with imipeneni/cilastatin may be more cost-effec- tive. It would be worthwhile to compare the overall treat- ment expenses for patients receiving imipenem/cilastatin with that for patients receiving meropenem.

Table V. Initial susceptibility of organisms to study-drug

Imipenem/cilastatin Meropenem evaluable patients evaluable patients

Meropenem Imipenem/cilastatin Imipenem/cilastatin Meropenem

S S R S S R

Gram-positive aerobes Streptococcus faecalis 11 11 - 11 8 3 Other enterococci 5 4 1 6 3 3 Streptococcus bovis 2 2 - - - -

Viridans streptococci 9 9 - 10 8 2 Staphylococcus aureus 12 12 - 5 5 -

Coagulase-negative staphylococci 6 6 - 8 8 -

- - - Others 1 1 -

Gram-negative aerobes Escherichia coli Klebsiella spp." Proteus spp. Morganella ~ p p . ~ Pseudomonas spp. Enterobacter spp. Citrobacter freundii Serratia marcescens Others

Anaerobes Bacteroides spp. Clostridium spp. Prevotella spp. Fusobacterium spp. Peptostreptococcus spp. Eubacterium spp. Others

54 11 6 6 8 5 2 2

59 13 I

6 5 2

-

6

Total 153 151 1 165 154 10

S = susceptible, R = resistant. a One intermediate to meropenem.

One intermediate to imipenem.

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508 A . Busoli et al. Scand J Infect Dis 29

REFERENCES 1. Meakins JL, Solomkin JS, Allo MD, Dellinger EP, Howard

RJ, Simmons RL. A proposed classification of intra-abdomi- nal infections. Arch Surg 1984; 119: 1372-8.

2. Nichols RL. Intraabdominal infections: An overview. Rev Infect Dis 1985; 7 (Suppl 4): S709-15.

3. Levison ME, Bush LM. Peritonitis and other intra-abdominal infections. In: GL Mandell et al., editors. Principles and prac- tice of infectious diseases. New York: Churchill Livingstone, 1990, p. 636-70.

4. Bohnen JMA, Mustard RA, Oxholm SE, Schouten BD. APACHE I1 score and abdominal sepsis - A prospective study. Arch Surg 1988; 123: 225-9.

5. Geroulanos SJ. Antibiotics and the abdomen. Curr Opin Infect Dis 1994; 7 (Suppl 1): S17-22.

6. Kager L, Nord CE. Imipenem/cilastatin in the treatment of intraabdominal infections: A review of worldwide experience. Rev Infect Dis 1985; 7 (Suppl 3): S518-21.

7. Wilson SE. Carbapenem: monotherapy in intra-abdominal sepsis. Scand J Infect Dis Suppl 1995; 96: 28-33.

8. Condon RE, Walker AP, Sirinek KR, White PW, Fabian TC, Nichols RL, Wilson SE. Meropenem versus tobramycin plus clindamicyn for treatment of intraabdominal infections: results of a prospective, randomized, double-blind clinical trial. Clin Infect Dis 1995; 21: 544-50.

9. Balfour JA, Bryson HM, Brogden RN. Imipenem/cilastatin: An update of its antibacterial activity, pharmacokinetics and therapeutic efficacy in the treatment of serious infections. Drugs 1996; 51: 99-136.

10. Kropp H, Gerckens L, Sundelof JG, Kahan FM. Antibacterial activity of hipenem: The first thienamycin antibiotic. Rev Infect Dis 1985; 7 (Suppl 3): S389-410.

11. Norby SR. Imipenem/cilastatin - rationale for a fixed combi- nation. Rev Infect Dis 1985; 7 (Suppl 3): S446-51.

12. Solomkin JS, Dellinger EP, Christou NV, Busuttil RW. Re- sults of a multicenter trial comparing imipenem/cilastatin to tobramycin/clindamycin for intra-abdominal infections. Ann Surg 1990; 212: 581-91.

13. Jones RN, Aldridge KE, Allen SD, Barry AL, Fuchs PC, Gerlach EH, Pfaller MA. Multicenter in vitro evaluation of SM-7338, a new carbapenem. Antimicrob Agents Chemother 1989; 33: 562-5.

14. Visser MR, Hoepelman IM, Beumer H, Rozenberg-Arska M, Verhoef J. Comparative in vitro antibacterial activity of the new carbapenem meropenem (SM-7338). Eur J Clin Microbiol Infect Dis 1989; 8: 1061-4.

15. Geroulanos SJ, and the Meropenem Study Group. Mero- penem versus imipenem/cilastatin in intra-abdominal infec- tions requiring surgery. J Antimicrob Chemother 1995; 36 (Suppl A): 191-205.

16. Brismar B, Malmborg AS, Tunevall G, Lindren V, Bergman L, Mentaing LO, et al. Meropenem versus imipenem/cilastatin in the treatment of intra-abdominal infections. J Antimicrob Chemother 1995; 35: 139-48.

17. Harabe E, Kawai Y, Kanazawa K, Otsuki M, Nishino T. In vitro and in vivo antibacterial activities of meropenem, a new carbapenem antibiotic. Drugs Exp Clin Res 1992; 18: 37-46.

18. Edwards JR. Meropenem: a microbiological overview. J An- timicrob Chemother 1995; 36 (Suppl A): 1-17.

19. Norrby SR, Bjornegird B, Feber F, Jones KH. Pharmacoki- netics of imipenem in healthy volunteers. J Antimicrob Chemother 1983; 12 (Suppl D): 109-24.

20. Kelly HC, Hutchison M, Haworth SJ. A comparison of the pharmacokinetics of meropenem after administration by intra- venous injection over 5 min. and intravenous infusion over 30 min. J Antimicrob Chemother 1995; 36 (Suppl A): 35-41.

21. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE 11: A severity of disease classification system. Crit Care Med 1985; 13: 818-29.

22. White R, Friedrich L, Burgess D, Warkentin D, Bosso J. Comparative in vitro pharmacodynamic of imipenem and meropenem against Pseudomonas aeruginosa. Antimicrob Agents Chemother 1996; 40: 904-8.

23. Norrby SR, Newel1 PA, Faulkner KL, Lesky W. Safety profile of meropenem: international clinical experience based on the first 3125 patients treated with meropenem. J Antimicrob Chemother 1995; 36 (Suppl A): 207-23.

24. Toyoguchi T, Nakagawa Y, Watanabe H. Nephrotoxicity and drug interaction of vancomycin (1). Folia Pharmacol Jpn 1996; 107: 53-66.

25. Markewitz A, Hammer C, Pfeiffer M, Zahn S, Drechsel J, Reichenspurner H, Reichart B. Reduction of cyclosporine-in- duced nephrotoxicity by cilastatin following clinical heart transplantation. Transplantation 1994; 57: 865-70.

Submitted April 7, 1997; accepted July 8, 1997

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