Results of a Multicenter Trial ComparingImipenem/Cilastatin to Tobramycin/Clindamycinfor Intra-abdominal Infections

JOSEPH S. SOLOMKIN, M.D.,* E. PATCHEN DELLINGER, M.D.,t NICOLAS V. CHRISTOU, M.D., PH.D.,*and RONALD W. BUSUTTIL, M.D., PH.D.§

We designed a multicenter study to compare tobramycin/clin-damycin to imipenem/cilastatin for intra-abdominal infections.We included the Acute Physiology and Chronic Health Evalu-ation (APACHE II) index of severity and excluded patientswithout established infection. Two hundred ninety patients wereenrolled, of whom 162 were evaluable. Using logistic regressionto analyze both outcome at the abdominal site of infection andoutcome as mortality, we found a significant correlation for bothwith APACHE II score (p < 0.0001 for both). Next we analyzedthe residual effect of treatment assignment and found a significantimprovement in outcome for imipenem/cilastatin-treated patients(p = 0.043). The differences in outcome were explained by ahigher failure rate for patients with gram-negative organismsfor tobramycin/clindamycin-treated patients (p = 0.018). Thiswas reflected in a significantly higher incidence of fasciitis re-quiring reoperation and prosthetic fascial replacement. Maximumpeak tobramycin levels were analyzed for 63 tobramycin/clin-damycin patients harboring gram-negative organisms. For fail-ures the maximum peak was 6.4 ± 1.9 gg/mL, and time to max-imum peak was 4.6 ± 5.2 days. For successes the maximumpeak was 6.1 ± 1.7 Mg/mL, occurring at 3.8 ± 2.6 days. Thisstudy supports inclusion of severity scoring in statistical analysesof outcome results and supports the notion that imipenem/ci-lastatin therapy improves outcome at the intra-abdominal siteof infection as compared to a conventionally prescribed amino-glycoside-based regimen.

I NTRA-ABDOMINAL INFECTIONS harboring a mixedaerobic and anaerobic flora are significant treatmentproblems. The overriding importance of early op-

erative intervention prevents precise preoperative bacte-riologic evaluation; adjunctive antibiotic therapy therefore

Supported by a grant from Merck Sharp and Dohme Research Lab-oratories. West Point, Pennsylvania.

Presented in part at the Interscience Conference on AntimicrobialAgents and Chemotherapy, New York, NY, October 4-7, 1987; and inabstract form at the 4th European Congress of Clinical Microbiology inNice, France, April 19, 1989.

Address reprint requests to Joseph S. Solomkin, M.D., University ofCincinnati College of Medicine, Department of Surgery, ML #558, 231Bethesda Ave., Cincinnati, OH 45267.

Accepted for publication November 29, 1989.

From the Departments of Surgery, University of CincinnatiCollege of Medicine, and the Veterans AdministrationMedical Center, Cincinnati, Ohio*; the Department of

Surgery, Harborview Medical Center, University ofWashington School of Medicine, Seattle, Washingtont; the

Department of Surgery and Microbiology, McGill University,Montreal, Quebec, Canadat; and the Department of Surgery,

University of California, Los Angeles School of Medicine,Los Angeles, California§

must be directed toward a broad range of potentially in-fecting aerobic and anaerobic organisms.' The spectrumof antibacterial activity provided by aminoglycosides incombination with clindamycin or metronidazole has beenconsidered ideal for the anticipated flora of intra-abdom-inal sepsis. The notable antimicrobial properties of ami-noglycosides against Enterobacteriaceae and Pseudo-monas include rapid killing of dividing and nondividingorganisms, dose-dependent killing, a postantibiotic effect,and infrequent development of resistance with ther-apy.2' These factors have been accepted as reasons forthe preferred use of aminoglycosides for life-threateninggram-negative infections.5 In line with these perceptions,comparative trials of antibiotic therapy for intra-abdom-inal infection generally have used aminoglycoside-basedregimens as control therapy.6The renal and auditory toxicities of aminoglycosides

and the need for serum level monitoring to ensure ther-apeutic efficacy in the face of concurrent changes in dis-tributive volumes has stimulated the development of lesstoxic agents with roughly similar gram-negative spec-tra.7'9 The fact that some of these newer agents may en-gender resistance on therapy for Pseudomonas aeruginosaand Enterobacter species has led to considerable debateas to their appropriate role in clinical practice.'0"'A precise definition of the clinical efficacy of antibiotic

regimens for intra-abdominal infection has been ham-

581

SOLOMKIN AND OTHERS

pered by several problems relating to study design. 2 Sam-ple sizes often have been too small to detect significantdifferences and cases of peritoneal contamination or in-flammation from traumatic bowel, acutely perforatedgastroduodenal ulcers, appendicitis, and cholecystitis havebeen included for evaluation in some studies. Patientcharacteristics such as age, background diseases, and se-

verity of acute illness are of considerable importance indetermining outcome but have not been used in analyzingdata from controlled trials.'3To circumvent these difficulties, we recently proposed

stricter enrollment criteria and the use of severity scoringfor patients enrolled in therapeutic trials to allow more

precision in intergroup comparisons.'4"15 We suggesteduse of the Acute Physiology and Chronic Health Evalu-ation (APACHE II) system.'6 This system assesses threeelements: (1) an Acute Physiology Score composed ofroutine hemodynamic, hematologic, blood gas, and serum

chemistry data; (2) age; and (3) a chronic health evaluationencompassing diseases such as renal failure requiringmaintenance dialysis, cirrhosis, lung or heart diseasesymptomatic at rest, and immunosuppressive therapy.This system was developed to analyze mortality for pa-

tients receiving medical-surgical intensive care and in thissetting has been explored and refined.'7-20 We conducteda retrospective study that supported use of this system.2'We now report the results ofa prospective, randomized

multicenter trial intended to examine the utility of theproposed study design in a comparison of an aminogly-coside (tobramycin) plus clindamycin versus imipenem/cilastatin. Imipenem is a carbapenem with a spectrum ofactivity encompassing the gram-positive, facultative gram-negative, and anaerobic organisms encountered in mixedflora intra-abdominal infections.22'23 This agent sharescertain properties with aminoglycosides, including killingof nondividing organisms, a postantibiotic effect, and ac-

tivity in the presence of B-lactamase-mediated resistanceto third-generation cephalosporins.24 26 Imipenem is sup-plied with cilastatin. Cilastatin inhibits a renal dipeptidasethat otherwise inactivates imipenem by producing an openlactam metabolite.27 Previously we reported a single-centerstudy comparing imipenem/cilastatin with gentamicinplus clindamycin in which we encountered a high rate ofnephrotoxicity and considerable resistance of P. aerugi-nosa to gentamicin.28 For this reason we chose tobramycinfor the current study.

Methods

The study was conducted from February 1, 1985 toDecember 31, 1986. Elements of this protocol are de-scribed elsewhere. 5 The study protocol was approved bythe relevant institutional review boards and written in-

formed consent to participate was obtained from all pa-tients.

Patients 18 years ofage or older with history and phys-ical findings suggestive of established intra-abdominal in-fection were eligible for inclusion. Patients not expectedto survive 48 hours, receiving maintenance dialysis, or

having a history of anaphylactic or urticarial reaction toB-lactam antibiotics were excluded.29 Patients receivingimmunosuppressive therapy for transplantation also were

excluded.Patients were assigned to one of two randomization

lists based on APACHE II scores of less than 15 and 15or more. The protocol allowed patient entry either beforeoperative intervention or after operation if no intraoper-ative or postoperative antibiotics were administered.Randomization procedures varied for each center in re-

gards to timing of study enrollment in relation to oper-

ation. For the Cincinnati, Seattle, and Los Angeles cases,

patients were randomized before operation. The patientsat McGill were taken to the operating room having re-

ceived one dose ofcefazolin and then randomized follow-ing operative confirmation of active infection. Writtenconsent was obtained before randomization.

Imipenem/cilastatin was administered as 500-mg in-travenous doses every 6 hours. Tobramycin was givenintravenously at 1.5 mg/kg with dosing interval initiallyadjusted for serum creatinine. The tobramycin dose andinterval then were adjusted to achieve target peak levels.6 ug/mL and trough levels between 1 and 2 gg/mL.Clindamycin was administered intravenously at 600 mgevery 6 hours. Ifthe initial cultures revealed gram-positiveorganisms believed to be resistant to study therapy, theprotocol allowed addition of vancomycin. Eleven tobra-mycin/clindamycin-treated patients received vancomycinbeginning 2 or more days after operation while one imi-penem/cilastatin patient was so treated.Complete blood counts, urinalyses, prothrombin and

partial thromboplastin times, multichannel chemistries,blood gas analyses, cultures, and disk susceptibility were

performed by each center's clinical laboratories.30 Mini-mum inhibitory concentrations were determined by agardilution using the University of Cincinnati Clinical Mi-crobiology Laboratories as the reference center."

Patients were evaluated for outcome of therapy if (1)they were 18 years of age or older and adequate consentwas obtained; (2) an intra-abdominal focus of establishedinfection was documented by operative intervention or

by a radiographically controlled drainage procedure; (3)cultures of the site of infection were positive for bacteria;(4) nonprotocol antibiotics were not administered aftercultures of the intra-abdominal site of infection were ob-tained unless the patient suffered an adverse reaction, an

extra-abdominal infection, or a failure at the abdominal

582 Ann. Surg. * November 1990

IMIPENEM FOR INTRA-ABDOMINAL INFECTIONS

site. Patients undergoing operation within 12 hours ofinjury for traumatic bowel perforation, within 24 hoursfor perforations of gastroduodenal ulcers, and patientswith simple acute cholecystitis or nonperforated appen-dicitis were excluded.Outcome evaluations were performed for (1) the local

intra-abdominal infectious process and (2) hospitalization.Patients were considered nonevaluable if they did notsurvive 48 hours or longer. Patients surviving longer than48 hours but less than 7 days were considered treatmentfailures.

Patients were considered treatment successes ifthe ini-tial course of study-driven therapy and the initial inter-vention resolved the intra-abdominal infectious processand if no infectious wound complications occurred.1'521If more than one intervention was required to cure thepatient of his/her intra-abdominal infection and the initialprocedure was considered inadequate, the patient wasconsidered nonevaluable. An operation was consideredinadequate if all communications between the gastroin-testinal tract and the peritoneal cavity were not closed.

Patients who received additional antibiotics for noso-comial infections started 5 or more days from study entrywere scored on the day these agents were begun. Patientswith evidence of resolved intra-abdominal sepsis at thistime and whose subsequent clinical courses were free ofrecurrent intra-abdominal infection were scored as suc-cesses.

Statistical Elements

Previous studies demonstrated a failure rate ofapprox-imately 25% with certain aminoglycoside/clindamycin-based regimens.' We chose a sample size that would detecta 50% difference in treatment outcome with an a value

583of 0.05 and ,B value of 0.20.32 This gave us a sample sizeofapproximately 90 cases per treatment arm. We expecteda nonevaluability rate of30% and therefore chose a samplesize of 300 patients.

Logistic regression analysis ofAPACHE II scores versusfailures or deaths was performed using the StatisticalPackage for the Social Sciences (SPSS, Inc., Chicago, IL).Other statistical tests included chi square testing and Stu-dent's t test.

Results

Two hundred ninety patients were entered in the trial.One hundred twenty-eight patients were considered to benot evaluable for reasons outlined in Table 1, yielding anexclusion rate of 44%. The most common reason for ex-clusion was absence of intra-abdominal infection at theinitial operative procedure. This group included 17 withnonperforated appendicitis, 32 with small bowel or colonicnoninfectious inflammatory or obstructive disease, 5 withacute cholecystitis, 3 with pancreatitis, 5 with suspectedpostoperative infection, and 10 with no disease found.The four deaths in patients with no intra-abdominal

infection occurred in patients with intestinal strangulation.The average APACHE II score for this group was 27.5.The single death without operative intervention occurredin a patient found to have hemorrhagic pancreatitis. Fivedeaths occurred within 48 hours of study entry. One pa-tient had clostridial sepsis and died before exploration,and the other four had diffuse peritonitis from entericsources. The average APACHE II score in this group was28.4. Two elderly patients with acutely perforated duo-denal ulcers died of irreversible shock. One additionalpatient excluded because of acute renal failure with cre-atinine of 5.2 on admission to the study died after oper-

TABLE 1. Reasons for Exclusion of 128 Patients*

Tobramycin/ Imipenem/Reason Total Clindamycin Cilastatin

Intervention performed but no infection found 72 40 (3) 32 (1)No intervention performed 18 8 10 (1)Survival < 48 hours 5 1 (1) 4 (4)Enteric perforation from trauma < 12 hours or

from gastroduodenal ulcer <24 hours 20 9 (1) 11 (1)Medication errors 3 1 2 (1)Candida infection with no bacterial

copathogens 2 1(1) INonadmissible infection 4 1 3Inadequate initial operation 4 4 (2)

Total 128 61 (6) 67 (10)

* Numbers in parentheses are deaths.' During operations on two patients to drain peripancreatic abscesses,

dehisced Roux-en-Y pancreaticojejunostomies were left in place; duringoperation to drain an intra-abdominal abscess and resect necrotic fascia,

an unrecognized gastric injury occurred that fistulized. A patient wasexplored for peritonitis and appendectomy performed, but developedsevere adult respiratory distress syndrome and at re-exploration a missedduodenal ulcer was found.

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SOLOMKIN AND OTHERS

TABLE 2. Demographics ofEvaluable Patients

Tobramycin/ Imipenem/Demographic Clindamycin Cilastatin

Sex (M:F) 49:32 51:30Age (years)<50 23 3350-59 10 1660-69 24 1 370-79 1 7 1 3>79 7 6

Malignancy 14 15Alcoholism 13 13Malnutrition 9 12Diabetes 3 2Cirrhosis 2 6

Definitions used for associated diseases are from reference 23.

ation to treat a perforated colonic diverticulum with peri-tonitis.

Four patients were considered to have had inadequateoperations for infection. In each case the operative pro-cedure failed to close communications between the gas-trointestinal tract and the peritoneal cavity. These casesare detailed further in Table 1.The operative therapy for four otherwise evaluable pa-

tients at one institution included insertion ofa zipper anddaily intensive care unit abdominal cavity irrigations withsaline.33 Three were randomized to imipenem/cilastatin(two successes) and one to tobramycin/clindamycin(failed). All had undergone previous operation for intra-abdominal infection and were entered in this study afterre-exploration for peritonitis or multiple abscesses. Theimipenem/cilastatin failure developed recurrent sepsiswith persisting Proteus mirabilis, P. aeruginosa, and en-terococci. The tobramycin/clindamycin failure died onthe eighth study day with continuing sepsis. While thereis considerable controversy regarding this procedure,34'35these four patients were considered evaluable.

The demographic characteristics of the 162 evaluablepatients, 81 randomized to tobramycin/clindamycin and81 to imipenem/cilastatin, are presented in Table 2. Therewere no significant differences between the treatment armsby X2. There were 48 tobramycin/clindamycin patientsaged 60 years or older compared to 32 imipenem/cilastatinpatients in this age range (p < 0.05). To examine the effectofthis population age difference, age and acute physiologypoint scores for each arm were summed. For the tobra-mycin/clindamycin group, 252 points were awarded forage compared to 221 points for the imipenem/cilastatingroup. Six hundred thirty-three points were awarded thetobramycin/clindamycin group for acute physiology score

compared to 704 points for the imipenem/cilastatin group.

Therefore the age discrepancy was counterbalanced byincreased severity scoring. This was confirmed by analysisof cumulative rates of enrollment by APACHE II score,

which showed no differences.

Diagnoses Treated

The organ sites responsible for intra-abdominal infec-tion are presented in Table 3, along with APACHE II

scoring and overall outcome data. The exclusion fromstudy entry of patients with uncomplicated acute chole-cystitis or acutely perforated gastroduodenal ulcers is re-

flected in the severity of illness of patients remaining inthese categories and, particularly in the gastric and duo-denal ulcer group, the mortality rate of 38%. Ninety-oneinfections arose from the distal small bowel or beyond,where a mixed aerobic and anaerobic flora would be an-

ticipated, and 32 patients were enrolled for postoperativeinfections. The highest failure rates occurred in patientswith infections arising from previous operation (38%, 12of 32 patients), stomach or duodenum (33%, 6 of 18 pa-

tients), small bowel (33%, 4 of 12 patients), and colon(28%, 11 of 40 patients).

TABLE 3. Disease Processes Encountered at the Initial Operation for Infection in Evaluable Patients

Tobraymycin/Clindamycin Patients Imipenem/Cilastatin Patients

APACHE Score APACHE ScoreOrigin of Infection No. Median Failed Dead No. Median Failed Dead

Stomach/Duodenum 10 21 4 5 8 16 2 2Biliary 12 12 3 1 5 16 0 2Small Bowel Abscess 0 0 0 0 1 17 1 0

Peritonitis 7 7 2 1 4 12 1 1Appendix Abscess 10 4 0 0 15 5 0 0

Peritonitis 6 12 1 0 8 7 0 0Colon Abscess 6 15 0 0 5 8 0 0

Peritonitis 14 13 6 4 15 15 5 3Postoperative Abscess 10 14 5 2 12 13 3 2

Peritonitis 5 11 2 0 5 21 2 1Other Abscess 1 16 1 1 2 9 0 0

Peritonitis 0 0 0 0 1 17 0 0

Total 81 24 14 81 14 11

584 Ann. Surg * November 1990

IMIPENEM FOR INTRA-ABDOMINAL INFECTIONS

Bacteriology and Activity of Study Agents

The organisms cultured from intra-abdominal foci are

presented in Table 4 and are consistent with previous re-

ports of bacteriology in intra-abdominal infection. Thepatterns of infection are detailed in Table 5. There were

an average of 3.0 isolates per patient in the tobramycin/clindamycin arm and 3.8 in the imipenem/cilastatin arm.

Fourteen patients in the tobramycin/clindamycin arm andpatients in the imipenem/cilastatin arm had monomi-

crobial infections, and 7 of which, respectively, were

due to gram-negative organisms. Gram-negative organ-isms were involved in 63 of the infections in patients re-

ceiving tobramycin/clindamycin (77%) and in 67 of theinfections in patients treated with imipenem/cilastatin(83%). Anaerobes were involved in 52% ofthe infections.The in vitro susceptibility of these organisms to the

study agents is presented in Table 6. Minimum inhibitoryconcentrations were determined for approximately one

TABLE 4. Organisms Encountered in Intra-abdominal Foci

Tobramycin/ Imipenem/Clindamycin Cilastatin

Organism (n = 81) (n = 81)

Gram-negative aerobic andfacultative

E. coli 49 (5) 43 (4)Enterobacter spp. 13 (1) 9 (1)Klebsiella spp. 10 (2) 15 (1)Pseudomonas a. 8 16 (1)Proteus spp. 5 5Serratia m. 2Citrobacter spp. 2 (1) 3Morganella m. 1 IOthers 1* 5t

Gram-positive aerobic andfacultative

Alpha streptococci 23 18Enterococci 18 (4) 20 (1)B. streptococci 8 (1) 9Staph aureus 4 3Staph epidermidis 3 (2) 7 (2)Fungi Candida species 6 9

Anaerobic OrganismsB. fragilis 18 (3) 19 (0)Other Bacteroides 11 (2) 23 (3)Clostridia spp. 10 (2) 19Peptococci/strep. 6 6Fusobacterium spp. 2 8Lactobacillus 4 5Eubacterium spp. 4 3 (1)Others 5 (2) 15C. albicans 6 9

Parentheses indicate bacteremias.* Hafnia alveoli.t Hemophilus parainfluenza X 3, Bacillus sp, and unidentifiable Lac

+ GNR. Blood cultures were obtained at the investigators' discretion.From this incomplete survey, 17 tobramycin/clindamycin-treated patientswere bacteremic within 72 hours of study entry and 6 of these werepolymicrobic. Eleven imipenem/cilastatin-treated patients were bacter-emic; three were polymicrobic.

585

TABLE 5. Microbiologic Patterns ofEncountered Infections

Tobramycin/ Imipenem/Clindamycin Cilastatin

Pattern (n = 81) (n = 81)

Gram-negative facultative rods only 21 14Gram-negative rods + anaerobes 10 12Gram-negative rods + gram-positive

cocci 16 17Gram-negative rods + anaerobes+ gram-positive cocci 16 24

Total gram-negative rods 63 67

Gram-positive cocci only 9 7Anaerobes only 2 3Gram-positive cocci + anaerobes 7 4

half of the encountered organisms and disk susceptibilitydata were available for the remaining organisms. The re-sistance ofEscherichia coli to tobramycin was seen at onecenter. Of the four patients harboring resistant E. coli,three were randomized to imipenem/cilastatin and thefourth was changed to amikacin when sensitivities becameavailable. This patient was considered a treatment failure.The surprisingly high level of resistance of Bacteroides

fragilis and other Bacteroides species to clindamycin was

attributed to organisms from Cincinnati and Seattle. Anadditional 15 B. fragilis organisms underwent disk testing,of which 13 were sensitive and 2 were resistant to clin-damycin. Thus of 37 B. fragilis encountered in the study,9 (24%) were resistant to clindamycin. In addition to the15 Bacteroides species tested by minimum inhibitoryconcentration, 12 were sensitive by disk and 7 were re-sistant. Persistence of B. fragilis was seen in one treatmentfailure, a patient randomized to imipenem/cilastatin.

Outcome Results

The incidence oftreatment failure or death from intra-abdominal infection for this prospective study sample ispresented in Figure 1 using the combined data from bothtreatment arms. There was an increasing incidence ofbothfailure to control the intra-abdominal infection and deathfrom all causes with increasing APACHE II scores.We performed logistic regression using as outcome pa-

rameters either failure or death. APACHE II score was a

significant predictor of failure (X2 = 10. 1, p = 0.0015).Treatment regimen was also a significant predictor forfailure with X2 = 4.10, p = 0.043 favoring imipenem/cilastatin therapy. The model X2 was 14.46, p = 0.0007.These results were transformed into cumulative failuresversus APACHE II for display purposes and are presentedin Figure 2. Using survival as the predicted variable, onlyAPACHE II was a significant contributor to the predictivemodel (X2 = 19.02, p < 0.0001). The model X2 = 26.07,p <0.0001.

Vol. 212.No. 5

SOLOMKIN AND OTHERS Ann. Surg. * November 1990

TABLE 6. Activity ofStudy Agents Against Facultative Gram-negative Bacteria

Tobramycin ImipenemMIC MIC

Bacteria 90 50 Resistant 90 50 Resistant

E. coli (44) 4.0 1.0 5 0.25 0.25 0Enterobacter (17) 1.0 1.0 0 1.0 0.25 0Klebsiella (22) 1.0 0.57 0 1.0 0.25 0Proteus (8) 1.0 0.5 0 4.0 2.0 1Pseudomonas a. (10) 4.0 2.0 1 2.0 1.0 0Citrobacter sp. (5) 16.0 4.0 2 0.5 0.25 0Other gram negative (4) 2.0 1.0 0 4.0 4.0 0

Breakpoints ... tobramycin, 4 imipenem, 4

Activity of Study Agents Against Common Anaerobic BacteriaClindamycin Imipenem

MIC MIC

Bacteria 90 50 Resistant 90 50 Resistant

B. fragilis (22) 16.0 1.0 7 0.50 0.12 0Bacteroides sp. (15) 16.0 1.0 7 0.50 0.25 0Clostridia sp. (9) 4.0 2.0 4 2.0 0.12 0Enterococci (22) 4.0 1.0 0

Breakpoints ... clindamycin, 2 imipenem, 4

MIC, minimum inhibitory concentration.

The bases for failure are presented in Table 7. Thirty-three of the thirty-eight failures were due to persistent or

recurrent infection; 13 tobramycin/clindamycin and 8imipenem/cilastatin patients underwent reoperation and5 and 3 patients, respectively, died with clinically obviousongoing intra-abdominal sepsis before reintervention was

60%

50%

40%

30%

*20%

10%

0% -

% Fabd/Doad

0-4 5-9 10-14 15-19 20-24APACHE I Ronge

* enrold 24 39 36 36 18

% Fabd % Dead * Predoctd% Deaths

FIG. 1. Depicted are the numbers of patients in each APACHE II rangeusing the combined data from both treatment arms (left axis). APACHEII score was a significant predictor of failure (X2 = 10.1 1, p = 0.0015).APACHE II score was a more significant predictor ofdeath (X2 = 19.02,p < 0.0001). Data for predicted deaths were obtained from reference 28.

performed. The notable difference between the treatmentarms occurred in the incidence of fasciitis requiring op-

erative debridement and, in all but one, insertion of a

prosthetic fascial substitute (7 in the tobramycin/clinda-mycin arm versus 1 in the imipenem/cilastatin arm). Thisdifference was significant (X2 = 5.123, p < 0.05).

Because the principal purpose of aminoglycoside ther-apy is for treatment of facultative gram-negative bacteria,we compared outcome for patients with gram-negativebacteria randomized either to imipenem/cilastatin or totobramycin plus clindamycin. With this data set,APACHE II score was a significant predictor of failure(X2 = 8.95, p = 0.0028). Treatment was also a significantpredictor of outcome with an increased success rate fol-lowing therapy with imipenem/cilastatin (X2 = 5.65, p

= 0.0175). The model X2 was 14.26, p = 0.0008. Thesedata are presented in Figure 3. All ofthe statistical powerin this study came from differences in outcome of patientswith gram-negative infections. There were no differencesin outcome for patients infected with gram-positive and/or anaerobic organisms only.

This difference was primarily due to a higher incidenceof treatment failure associated with persisting, initiallysensitive gram-negative rods in the tobramycin-treatedpatients (1 3 of63 patients) as compared to the imipenem/cilastatin-treated patients (5 of 67 patients; X2=5.65, p<0.05). The failing initially sensitive gram-negative or-

ganisms in the tobramycin/clindamycin patients were E.coli (7), Enterobacter species (5), Citrobacterfreundii (1),Hafnia alveoli (1), and Morganella morganii (1). The ini-tially sensitive gram-negative organisms that failed in the

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Vol. 212-No. 5 IMIPENEM FOR INTRA-ABDOMINAL INFECTIONS

FIG. 2. This figure depictsfailure as a function ofAPACHE II score and anti-biotic regimen for all evalu-able patients. APACHE IIscore was a significant pre-dictor of failure (X2 = 10.1 1,p = 0.0015). Treatment reg-imen was also a significantpredictor for failure. Therewas a residual benefit of im-ipenem/cilastatin therapy forthe entire study populationwith X2 = 4.10, p = 0.0429.The model X2 was 14.46, p= 0.0007.

APACHE 11 Score

imipenem/cilastatin-treated patients were E. coli (3), En-terobacter species (3), Kiebsiella species (1), P. mirabilis(1), and P. aeruginosa (1).We examined the adequacy ofaminoglycoside therapy

by determining the maximum peak level at any time dur-ing therapy for the 63 patients harboring gram-negativeorganisms. Patients who failed had a maximum peak of

TABLE 7. Anatomic and Other Bases for Failure

Tobramycin/ Imipenem/Clindamycin Cilastatin

Basis for Failure (n = 24) (n = 14)

Wound infection 2 3Recurrent abscess 7t 6Fasciitis 7 1*

Requiring prosthetic fascialsubstitute 6 0

Persisting peritonitis 2tInitially resistant gram-negative

organisms 1Expired with ongoing sepsis 5 3Adverse reaction 3 1§

* X2 = 5.123; p < 0.05.t One tobramycin/clindamycin patient failed with both abscess and

fasciitis.t One imipenem/cilastatin patient failed with both peritonitis and fas-

ciitis.§ One imipenem/cilastatin patient failed with both diarrhea and ab-

scess.

6.38 ± 1.93 ,ug/mL, and ti.e time from initiation oftherapyto the maximum peak was 4.58 ± 5.19 days. For successes(n = 49) the maximum peak was 6.14 ± 1.72 ,ug/mL,occurring 3.84 ± 2.6 days into therapy. The differencesin interval from initiation of therapy to maximum peakwere not significant (t = 1.5509).

Nosocomial Infections

Infections at other sites were common with both treat-ment regimens. Of the 81 patients treated with tobra-mycin/clindamycin, 13 developed nosocomial infectionsoutside ofthe abdomen. Only three patients had APACHEII scores less than 10 and seven were microbiologic failuresat the intra-abdominal site of infection. Four patients de-veloped urinary tract infections, three with Candida al-bicans and one with enterococcus. Eight patients devel-oped pneumonias, seven of which were due to gram-neg-ative organisms (Acinetobacter, Citrobacter, Serratia, E.coli, P. aeruginosa, and Xanthomonas maltophilia). Twopatients, including one with a gram-negative pneumonia,developed bacteremias (S. aureus and S. epidermidis).The pattern ofnosocomial infections was similar in the

81 imipenem/cilastatin-treated patients. Eighteen suchpatients developed extra-abdominal infections, and onlyfour had an APACHE scores less than 10. Five were treat-ment failures for their abdominal infections. Eight patients

25

20

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SOLOMKIN AND OTHERS

25

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05 10

I~~~~~~~~~~~~~~~I.

15 20 25 30 35APACHE 11 Score

developed urinary tract infections, seven with Candidaand one with enterococcus. Nine patients developed gram-negative pneumonias. Four were associated with P. aeru-ginosa, and one each with Acinetobacter and Enterobac-ter. Three patients developed X. maltophilia pneumonia,with one death. One patient developed toxin-positiveClostridia difJicile diarrhea treated with metronidazole.

Causes of Death

There were 25 deaths among the 162 evaluable patients.The relationship between death and outcome at the ab-dominal site of infection is presented in Table 8. Sev-

FIG. 3. Depicted is failure asa function of APACHE IIscore and antibiotic regimenfor evaluable patients har-boring gram-negative organ-isms. APACHE II score wasagain a significant predictorof failure for this patientgroup with X2 = 8.95, p= 0.0028. Treatment wasalso a significant predictor ofoutcome with X2 = 5.65, p= 0.0 175. The model X2 was14.26, p = 0.0008.

enteen deaths were related to failure to control the initialinfection, including 10 tobramycin/cindamycin patientsand seven imipenem/cilastatin-treated patients. The clin-ical details for the eight patients who died following suc-cessful treatment of their abdominal infections are pre-sented in Table 8. The mortality rate for patients consid-ered to have received successful therapy for theirabdominal infection was 6% (8 of 124 patients), whereasthe mortality rate for patients failing therapy was 45% (17of 38 patients).

Regarding the adverse effects seen, we chose to consideras significant only events that resulted in a change in an-tibiotic therapy. We noted three patients with suspected

TABLE 8. Analysis ofDeaths

Tobramycin/Clindamycin Imipenem/Cilastatin

Average AverageAPACHE Survival Time APACHE Survival Time

No. Score (mean range) No. Score (mean range)

Death following successful therapyof intra-abdominal infection 4* 23 17 (11-29) 4t 17 50 (33-85)

Death within 7 days of study entry 5 18 5 (4-7) 1 14 3Death associated with failure at the

abdominal site (>7 days) 5 18 27 (10-42) 6 21 21 (11-40)Total deaths 14 11

* 1: unresectable pancreatic carcinoma with superior mesenteric arteryinvolvement; 1: cerebral vascular accident after operation with braindeath; 1: unresectable lung carcinoma causing terminal ventilatory failure;1: cerebral vascular accident and seizures with respiratory arrest andbrain death.

t 1: with 2 negative re-explorations, failed to recover and died on day

41; 1: diagnosed after operation with chronic myelogenous leukemia andpancreatic carcinoma; 1: admitted for exacerbation ofchronic obstructivepulmonary disease after operation required continuous ventilator supportand requested extubation; 1: with cirrhosis, liver failure, ascites developedprogressive liver failure with no residual abdominal infection.

588 Ann. Surg. * November 1990

Tobramycin/Clindamycinr.

x2w5 65, PwO. 0175

lmipenem/Cilastatin....e

. 0 . .. . :

I I r I I T

IMIPENEM FOR INTRA-ABDOMINAL INFECTIONS

aminoglycoside-induced renal failure who required dis-continuation of tobramycin; in each case cefotaxime wasadded. Two patients developed recurrent intra-abdominalinfection. One patient treated with imipenem/cilastatindeveloped a toxin-positive C. difficile diarrhea and wastreated with metronidazole. Two patients receiving imi-penem/cilastatin and one receiving tobramycin/clinda-mycin experienced seizures and all complications wereconsidered possibly drug related. One nonevaluable to-bramycin/clindamycin-treated patient was excluded fororthotopic liver transplantation and received additionalantimicrobial therapy. One evaluable patient with a com-puted tomogram-documented cerebral infarct was con-tinued on imipenem/cilastatin but failed with recurrentabscesses. The third patient experienced seizure on the12th day of therapy and antibiotic therapy was discon-tinued.

Discussion

The current study was intended to evaluate a recentlyproposed design for comparative trials of therapeutic in-terventions in intra-abdominal infections.'4"5 This designwas based on exclusion from study entry of patients withno organisms isolated from the site of infection and ex-clusion of patients with intra-abdominal contaminationor inflammation only (perforated gastroduodenal ulcersoperated on within 24 hours, traumatic bowel perforationoperated on within 12 hours, simple appendicitis, or cho-lecystitis). Furthermore either operative or percutaneousdrainage procedures were required. These criteria resultedin a study population with demographic characteristics,intra-abdominal diseases, and microbiologic findingsconsistent with perceptions and previously reported stud-ies of intra-abdominal infections.We used the APACHE II scoring system as a single

numerical descriptor of severity of illness with weightingfor age and chronic disease. In a previous study of intra-abdominal infections, we identified the highly significantrole of the Acute Physiology Score, the numerically prin-cipal element in the APACHE system, in mortality pre-diction by use of discriminant function analysis.2' Therewas a residual effect of age in predicting mortality, aneffect only half as powerful as APS. A prospective vali-dation of these results, subsuming age under the morerecent APACHE II score, has been reported.36 Additionalfindings ofthese studies were that the degree oflocalization(abscess versus peritonitis) and site of infection, other thanappendicitis, did not correlate with outcome independentof the APACHE II score. These observations were con-firmed in the present study.The mortality data from the current study fit well with

those previously reported using the APACHE II score (Fig.1). Comparison of mortality rates with that predicted by

589APACHE II appears useful in providing assurance thatthe control arm in the study sample was representativeof the class of patients being studied.The APACHE II system is emerging as a defacto stan-

dard for describing the severity of illness in studies ofintra-abdominal infections.37 We believe that acceptanceof the structure ofAPACHE II is warranted. This systemmay be refined as it is applied in settings other than itsoriginal use, epidemiologic research on outcome from in-tensive care. Large sample sizes are required to validatethe benefit of added or deleted factors and general use ofthis system would result in considerable research econ-omies.APACHE II scoring has been used to group patients

into regions of interest. Three scoring regions have beensuggested, encompassing low-risk (0 to 10), moderate risk(10 to 20), and high risk (more than 20) patients.36 Thisanalytic technique obscures the continuous relationshipbetween APACHE II and both failure and mortality and,by decreasing the sizes ofcomparative groups, reduces thepower of the statistical tests applied.APACHE II scores did not correlate as closely with

failure at the local site of infection. While there was ahighly significant correlation of APACHE II scores withfailure (X2 = 10.11, p = 0.0015), failure rates reached aplat,,au of approximately 30% over an APACHE scorerange of 10 to 19 and did not increase further until mor-tality rates increased to 50% (APACHE score range of 20to 25). At this level of severity early death with docu-mented or suspected on-going intra-abdominal sepsisemerged as a major cause of failure.We chose to use events at the abdominal site ofinfection

as the primary basis for comparing two antibiotic regimensfor intra-abdominal infection. We focused on this end-point because there is convincing evidence that other ac-companiments of infection (e.g., organ failure syndromes)are due to host inflammatory and immunologic responsesto lipopolysaccharides and to other products of facultativegram-negative organisms.38 This response is independentof the presence of live bacteria.

There is no basis for the beliefthat roughly comparableantibiotic regimens would alter the complex inflammatorypathways triggered early in the disease course by bacterialproducts. Furthermore we found that 32% of the deathsin this study occurred after cure ofthe local infection andwere due to rapidly progressing malignancy, preterminalchronic cardiac and lung disease, or cirrhosis. Inclusionof these patients as failures of antibiotic therapy wouldhave misstated the role of infection in their deaths.We compared two antimicrobial regimens with simi-

larly broad activity against facultative gram-negative or-

ganisms. The in vitro efficacy of both regimens was con-

firmed by susceptibility testing (Tables 4 and 5). The pri-mary differences between the regimens therefore are

Vol. 212 * No. S

590 SOLOMKIN AND OTHERS Ann. Surg. November 1990

related to the pharmacokinetics of the agents and theirmechanisms of antimicrobial activity.The significant improvement in outcome associated

with imipenem/cilastatin therapy was due to fewer failuresin patients with gram-negative infections (Fig. 3). Ourdata showed, in turn, that this benefit was due to a de-creased incidence of recurrent local infection requiringreintervention and associated with initially infecting gram-negatives susceptible in vitro to study therapy. While otherforms of analysis have been used, we believe that efficacyof antibiotic therapy is best defined on the basis of theterminal bacteriology at the site of recurrent or persistinginfection. We consider the need for reintervention a cat-astrophic event and we noted a higher mortality rate anda higher incidence of extra-abdominal nosocomial infec-tion in patients requiring reoperation.Our finding that failures were significantly related to

persistence of facultative gram-negative organisms sug-gests a priority for therapy directed against these bacteria.Aminoglycosides have been considered the agents ofchoice for serious gram-negative infections. Effectivenessofaminoglycoside therapy has been related to several dif-ferent parameters derived from time-serum concentrationcurves. These include the maximum peak plasma levelobtained during therapy, the area under the time-concen-tration curve, and time/24 hours above the minimuminhibitory concentration.39'4 These variables are inter-connected because elevating the peak concentration whilemaintaining trough concentrations will increase both thearea under the time-concentration curve and the timeabove the MIC. More recently the ratio of the peak leveland minimum inhibitory concentration for organismstreated has been suggested as a pharmacokinetic end-point.4' We sought to optimize both the maximum peakconcentration and area under the curve by specifying tar-get peak levels of 6 or more and trough levels morethan 1.

For this report we analyzed outcome ofaminoglycoside-treated patients in relation to the maximum peak levelobtained. This was not rewarding in that successes andfailures achieved similar peak levels at similar intervalsinto therapy.The striking finding ofthis analysis was that the interval

from initiation of therapy to achievement of maximumpeak levels in patients harboring gram-negative organismsaveraged approximately 4 days for successes and failures.This delay is similar to that reported by others in clinicaltrials.4' Because efficacy is, in part, related to the timingof therapy, we believe the increased failure rate seen inthis study with aminoglycoside therapy was related to thisfactor. We would speculate that this delay in achievingtherapeutic levels accounted for the surprisingly high in-cidence of fasciitis in the aminoglycoside-treated patients.

Persisting gram-negative organisms were recovered fromall of these infections.The other notable microbiologic finding of this study

was the lack ofcorrelation between clindamycin resistanceand persistence ofB. fragilis and other Bacteroides speciesat the abdominal site of infection. The clindamycin re-sistance encountered reflected an increase in MICs to therange of 8 to 16 ,ug/mL. A previous study analyzing re-sponse of B. fragilis and other Bacteroides species in ap-pendicitis noted no failures with nonfragilis species, re-gardless of therapy and clinical success against B. fragilisfor cefoperazone where the organisms were not susceptiblein vitro by standard guidelines.42 These data suggest thatB. fragilis organisms are more easily killed in non-neu-tropenic hosts than are gram-negative organisms.

Based on our findings, we prefer imipenem/cilastatinas initial therapy for intra-abdominal infections unlessthe presence of organisms resistant to imipenem/cilastatinor other B-lactamlike agents is highly suspected (e.g.,postoperative intra-abdominal infections in which culturesare available before reintervention). Imipenem/cilastatinwas found to be significantly more effective against fac-ultative gram-negative organisms than tobramycin andthis finding would recommend its use for intra-abdominalinfections other than appendicitis. If aminoglycosides areused in any setting, considerable effort should be devotedto rapid achievement of peak plasma levels six or eighttimes the measured MIC for the gram-negative organismsbeing treated.4'

AcknowledgmentsThe authors thank Gary C. Calandra, M.D., Ph.D., Frederick M. Ka-

han, M.A., Laura Edwards, M.S., Nancy Ehlers, R.N., Margaret J. Wertz,R.N., M.S., Mary DeSantis, R.N., Patricia Levy, R.N., Barbara Nuesse,R.N., William K. Fant, Pharm. D., Sue A. Lewis, B.S., and Carol Liggettfor their assistance.

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