Clinical Comparison of Cefotaxime with Gentamicin plus Clindamycin in the Treatment of Peritonitis and Other Soft-Tissue Infections

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1 REVIEWS OF INFECTIOUS DISEASES. VOL. 4, SUPPLEMENT. SEPTEMBER-OCTOBER by The University of Chicago. All rights reserved /82/ $02.00 Clinical Comparison of with Gentamicin plus Clindamycin in the Treatment of Peritonitis and Other Soft-Tissue Infections H. Harlan Stone, Evelyn S. Morris, Carol E. Geheber, Laura D. Kolb, and William E. Dunlop From the Department of Surgery, Emory University School of Medicine, A tlanta, Georgia The efficacy and safety of cefotaxime were compared with the efficacy and safety of gentamicin plus clindamycin in the treatment of peritonitis and soft-tissue infection in 2 patients. Patients received 20 mg of intravenous cefotaxime/kg of body weight every 6 hr or mg of gentamicin/kg every 8 hr plus 5 mg of cindamycin/kg every 6 hr (both intravenously). Therapy was continued for five to 0 days. The overall clinical cure rate was 82070, with no significant difference between cure rates in the two groups. Both antibiotic regimens were effective against aerobic and anaerobic isolates, although Pseudomonas aeruginosa, an occasional isolate of Enterobacter, and some anaerobes were resistant to cefotaxime. All clinical failures involved patients who had septicemia or who had received inadequate surgical treatment. Six (070) of the' patients who received combination therapy developed impaired renal function, as indicated by a rise in serum creatinine of No reduction in renal function was noted in patients given cefotaxime. The clinical efficacy of cefotaxime was equal to that of gentamicin plus cindamycin, and less nephrotoxicity was encountered with cefotaxime. The majority of surgical infections are due to aerobic gram-negative bacilli acting either alone or in symbiosis with various anaerobic species. Appropriate operative treatment is critical, and antibiotics are important for the control of associated bacteremia and the reduction of recurrent sepsis. For the treatment of infection due to aerobic gram-negative bacilli, aminoglycosides were superior to all other antibiotics until the introduction of' f3-lactamase-resistant cephalosporins []. Recent studies suggest that certain cephalosporins may be as effective as the combination of an aminoglycoside and a lincinoid compound in the treatment of abdominal infections [2, 3]. In addition, use of the cephalosporins involves a lower risk of renal toxicity than does treatment with the aminoglycosides and poses no risk of eighth-nerve toxicity [3-6]. Thus, we compared cefotaxime with gentamicin plus clindamycin in a randomized trial. Study Design Surgical patients admitted to the Trauma Service of This research was supported in part by a grant from Hoechst Roussel Pharmaceuticals, Inc., Somerville, New Jersey. Please address requests for reprints to Dr. H. Harlan Stone, Department of Surgery, Imory University School of Medicine, Atlanta, Georgia Grady Memorial Hospital (Atlanta, GA) with a clinical diagnosis of established peritonitis or with extensive soft-tissue sepsis believed to be due to gram-negative bacilli in synergy with anaerobes automatically became candidates for study. Other prerequisites were that the focus of infection be cultured within 24 hr of the initiation of antibiotic therapy and that the patient have no associated infectious problem needing additional antibiotic treatment. Informed, written consent for participation in the study was obtained from each patient or from a parent or guardian if the patient was a minor or legally incompetent. Antibiotic therapy was determined by the last digit in a patient's randomly assigned hospital number. An odd final digit dictated the use of iv cefotaxime at a dose of 20 mg/kg every 6 hr. If the final digit was even, gentamicin ( mg/kg every 8 hr) and clindamycin (5 mg/kg every 6 hr) were given iv. An initial double dose of each antibiotic was given in order to load the extracellular fluid compartment as quickly as possible. Unless failure of response warranted otherwise, therapy was continued five to 0 days. Appropriate records were kept of each patient's vital statistics, primary focus of infection, associated disease states, operative procedures, other treatments, clinical response, and adverse reactions. Laboratory tests for the detection of toxicity to organs included analyses of renal function S439

2 5440 Stone et 0. (urinalysis, blood urea nitrogen, serum creatinine, and-when indicated-creatinine clearance); liver function (standard Sequential Multiple Analyzer-2, Technicon, Tarrytown, NY); bone marrow (white blood cell count, including platelet survey); clotting mechanism (prothrombin time and Coombs' test); and eighth-nerve function (gross hearing ability and selective audiometry). The clinical course of each patient was monitored carefully for any evidence of drug allergy, enteritis, rash, phlebitis, pain at the site of iv infusion, or other adverse reaction. Specimens for culture were taken from the foci of infection before, during, and after treatment whenever possible. The antibiotic sensitivity of the isolated aerobic pathogens was determined by both disk [7] and tube dilution [8] methods. Anaerobic pathogens were tested for susceptibility to cefotaxime and clindamycin by agar diffusion [9]. Responses to each of the antibiotic regimens were evaluated according to both bacteriologic and clinical data. Since the operative procedure is critical in the treatment of surgical infection, the role of drainage, excision, and/or debridement was also documented. Clinical cure was defined as the complete eradication of the primary focus of infection without the need for subsequent therapy, either antibiotic or surgical. Recurrence was defined as a reactivation of infection at the primary focus after antibiotic therapy had been discontinued. Failure was defined as a lack of alteration of infection at the primary focus by antibiotic therapy, with or without a concomitant surgical procedure. The safety and efficacy of the two treatment regimens were compared as well. Results After six months of study, hospital courses and charts had been completed for 2 of the 66 patients enrolled. The remaining 54 patients either were still undergoing therapy or were involved in follow-up evaluations of isolated bacterial pathogens or of organ system function that is delayed in onset. Fifty-six patients received cefotaxime, and 56 received gentamicin plus clindamycin. No significant differences were noted between groups in terms of age or race. However, the male-to-female ratio in the group receiving cefotaxime was 0.7 (23 males vs. 33 females), while it was 2.7 (4 males Table. Associated disease states in patients given cefotaxime or gentamicin plus clindamycin for peritonitis and other soft-tissue infections. Associated disease or condition Diabetes mellitus Liver disease Cancer Reticuloendothelial disease Malnutrition Obesity Hypertension Drug abuse Miscellaneous diseases None No. of patients with disease in indicated treatment group 8 I 2 I and 5 females) in the group receiving gentamicin plus clindamycin. The cefotaxime group included 46 blacks and 0 whites; the gentamicin-clindamycin group, 45 blacks and whites. The mean age of the patients given cefotaxime was 46 years (range, 7-9 years), compared with 47 years (range, 7-83 years) for those given gentamicin plus clindamycin. The incidence of an associated disease or condition that might have impaired host resistance was similar in the two groups (table ); only of all patients were free of another pathologic process. Clinical results. The overall clinical response to therapy did not differ statistically according to sex of treatment group (table 2). However, three of the seven patients in whom cefotaxime therapy failed clinically were among the six patients in that group who had septicemia. By contrast, cefotaxime therapy failed in the only patient in the gentamicin-clindarnycin group who had septicemia. This difference thus appeared to be a result ofcase distribution, not of antibiotic efficacy. Another discrepancy in clinical results was found in patients with deep soft-tissue infections (table 2). The three clinical failures were in patients who received cefotaxime. On closer analysis, it was discovered that the sites of infection in these three patients had been merely drained or debrided. Radical excision, when possible, consistently resulted in a clinical cure or at least made the recurrence of sepsis easily controllable. An analysis of results according to the type of operative procedure used supported the conten- Gentamicinclindamycin

3 Comparison with Clindamycin-Gentamicin S44 Table 2. Clinical response of 2 patients to therapy with cefotaxime or gentamicin plus clindamycin, by diagnosis. No. of No. of No. with No. of No. of No. of No. with No. of Diagnosis patients cures recurrence failures patients cures recurrence failures Peritonitis Intraabdominal abscess Appendicitis Gangrenous obstruction (*) Perforated ulcer Biliary tract Diverticulitis Pelvic inflammation Miscellaneous diagnoses Other Deep soft-tissue sepsis Perirectal abscess Septicemia Miscellaneous diagnoses Total *) * Indeterminate. tion that many clinical failures were due to inadequate surgery, not to an inferior antibiotic program (table 3). Although recurrence of sepsis frequently followed excisional therapy, failure to control or eradicate infection resulted when the operative procedure was less than thorough or (more commonly) when the true source of life-threatening septicemia could not be identified. Since essentially all of the infections were polymicrobial, it was difficult to analyze the response of any given pathogen. No significant difference in response to the two regimens was found when patients were grouped according to type of infecting pathogen: aerobic gram-negative bacilli, anaerobes, or a combination of the two (table 4). No statistically significant difference in response could be found among the patients with bacteremia. There were six deaths; four were unrelated to infection. Two patients in each group died of uncontrolled sepsis, and two patients in the gentamicinclindamycin group died of a superinfection and one died of an aortic thrombosis. With respect to adverse reactions, results were similar in the two groups except that six patients (070) who received gentamicin plus clindamycin developed a definite, albeit transient, decrease in renal function. A definite loss of renal function was defined as a serum creatinine elevation of Table 3. Clinical responses of 2 patients to therapy with cefotaxime or gentamicin plus clindamycin, by operative procedure. No. of No. of No. with No. of No. of No. of No. with No. of Diagnosis patients cures recurrence failures patients cures recurrence failures Drainage Excision *) Debridement Combination Intestinal vent only Repair Negative laparotomy None Total (*) * Indeterminate.

4 5442 Stone et al. Table 4. Clinical response of 2 patients to therapy with cefotaxime or gentamicin plus clindamycin, by type of infecting organism. Types of infecting No. of No. of No. with No. of No. of No. of No. with No. of organism patients cures recurrence failures patients cures recurrence failures Aerobic gram-negative bacilli (± enterococci) Aerobic gram-negative bacilli plus anaerobes (± enterococci) Anaerobes alone o 0 ) Other bacterial sets No growth Culture unobtainable Total ) Indeterminate. >.5 mg/dl or a fall in creatinine clearance by ;?;30 ml/min during or after a course of therapy. No instance of reduced kidney function was noted in patients given cefotaxime. One patient taking cefotaxime and two patients taking gentamicin plus clindamycin developed phlebitis; three patients taking cefotaxime and two taking the combination developed diarrhea; and one patient on each regimen developed a superinfection. Antibiotic sensitivities. Some isolates of Enterobacter and Pseudomonas aeruginosa were resistant to cefotaxime but susceptible to gentamicin in vitro. The MICs of cefotaxime and gen- tamicin for these aerobic pathogens confirm that observation (table 5). Although the majority of anaerobic isolates were susceptible to both cefotaxime and clindamycin, the latter agent inhibited the growth of more isolates (table 6). Discussion Data in this report substantiate the nearly equal therapeutic efficacy of cefotaxime and gentamicin plus clindamycin for the treatment of infection due entirely, or in part, to aerobic gram-negative bacilli. Although the recurrence of infection ap- Table 5. In vitro susceptibility ofaerobic pathogens to Table 6. In vitro susceptibility of aerobic pathogens to cefotaxime and gentamicin. cefotaxime and clindamycin, as determined by the standard Mean MIC (s.tg/ml) disk method. No. of Percentage of isolates susceptible Infecting organism isolates Gentamicin No. of Clindamycin Escherichia coli Infecting organism isolates (30 mg) (5 mg) Klebsiella pneumoniae Bacteroides fragilis Proteus mirabilis Bacteroides species Proteus vulgaris Clostridium perfringens Proteus morganii Clostridium species Enterobacter aerogenes Eubacterium species Enterobacter cloacae Fusobacterium species Citrobacter diversus Propionibacterium species Serratia marcescens Lactobacillus species Pseudomonas aeruginosa Peptococcus species Enterococcus species Peptostreptococcus species Staphylococcus aureus Streptococcus species Streptococcus fj-hemolytic Veillonella species

5 Comparison with Clindamycin-Gentamicin S443 pears to be more common if there is synergy between aerobic and anaerobic pathogens, a failure of therapy is usually the result of late or inadequate surgery rather than of use of a less effective antimicrobial agent. Safety, however, is equally important. In the present study, nephrotoxicity was a significant complication of aminoglycoside use. No patient who received cefotaxime suffered an unequivocal decrease in renal function, while six of 56 patients (070) who received gentamicin plus clindamycin manifested some degree of renal impairment. Since the therapeutic results are equal, it appears that the use of cefotaxime would be preferable to the use of an antibiotic regimen that includes an aminoglycoside, such as gentamicin. References. Stone, H. H., Kolb, L. D., Geheber, C. E., Dawkins, E. J. Use of aminoglycosides in surgical infections. Ann. Surg. 83: , Stone, H. R, Guest, B. S., Geheber, C. E., Kolb, L. D. Cefamandole in treatment of peritonitis. J. Infect. Dis. 37(Suppl.):S03-S09, Stone, H. H., Fabian, T. C. Clinical comparison of antibiotic combinations in the treatment of peritonitis and related mixed aerobic-anaerobic surgical sepsis. World J. Surg. 4:45-42, Appel, G. B., Neu, H. C. The nephrotoxicity of antimicrobial agents. I. (First of three parts) N. Engl. J. Med. 296: , Appel, G. B., Neu, H. C. The nephrotoxicity of antimicrobial agents. II. (Second of three parts). N. Engl. J. Med. 2%: , Appel, G. B., Nell, H. C. The nephrotoxicity of antimicrobial agents. III. (Third of three parts). N. Engl. J. Med. 2%: , Bauer, A. W., Kirby, W. M. M., Sherris, J. C., Turck, M. Antibiotic susceptibility testing by a standardized single disk method. Am. J. Clin. Pathol. 45:493-4%, Gavan, T. L., Town, M. A. A microdilution method for antibiotic susceptibility testing; an evaluation. Am. J. Clin. Pathol. 53: , Martin, W. J., Gardner, M., Washington, J. A., III. In vitro antimicrobial susceptibility of anerobic bacteria isolated from clinical specimens. Antimicrob. Agents Chemother. :48-58, 972.