MISCELLANEOUS INFECTIONS

S629

Aztreonam plus Clindamycin Versus Tobramycin plus Clindamycin in the Treatment of Intraabdominal Infections R. Rex Williams and Don Hotchkin

From the Clinical Research and Clinical Information Departments, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey

Disruption of the integrity of the gastrointestinal tract by trauma, surgery, or intrinsic disease, with subsequent contaminationof the peritoneal cavityby the residentbowelflora, is the most common sequence of events leading to intraabdominalinfections. Suchinfections are usually polymicrobial, with both aerobic and anaerobic organisms isolated in the majority of cases. Effective therapydepends on early diagnosis, surgicaldrainageand debridement, and prompt administration of antibiotics to prevent infection of normal tissue by the invading bacteria and to decrease the incidence of septicemia and metastatic abscess formation [1]. Aminoglycosides, in combination with antibiotics active against anaerobes, are commonly employedin the treatment of intraabdominal sepsis. Use of these agents is complicated by the need to monitor serum aminoglycoside levels to assure efficacy and to preclude development of ototoxicity and nephrotoxicity. Furthermore, aminoglycosides are inactivated at acid pH and under anaerobic conditions [2]. These considerations havepromptedthe search for saferand more-effective alternative antibiotics. Aztreonam, the first commerciallyavailable monobactam, is highly active against the aerobic gram-negative bacteria likely to be encountered in intraabdominal infections. More Informedconsent was obtained from the patients or their guardians, and studieswereconductedin accordancewith guidelines for human experimentation of the institutions involved. Dr. Williamsand Mr. Hotchkin are employees of Bristol-Myers Squibb, the commercial vendor of aztreonam. The investigators whoparticipatedin this studywereDrs. MichaelBergeron, Quebec, Quebec, Canada;DarioBirolini, SaoPaulo, Brazil;Carl DeMatteo, Erie, PA, USA; Willard Johnson, Boston, MA, USA; Thomas Louie, Wmnipeg, Manitoba, Canada;MarcosMoraes,RiodeJaneiro, Brazil;Richard Simmons, Minneapolis, MN, USA; and Philip Wels, Buffalo, NY, USA. Reprints and correspondence: Dr. R. RexWilliams, Bristol-MyersSquibb Pharmaceutical ResearchInstitute, P.O. Box 4000, Princeton, New Jersey 08543-4000. Reviews of Infectious Diseases 1991;13(Suppl7):S629-33

© 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1303-0051$02.00

than 97 % of isolates of Escherichia coli, Klebsiella pneumoniae, Proteus species, Morganella morganii, Providencia species, and Serratia marcescens are inhibited by aztreonam at concentrations of ~8.0 #Lg/mL [3]. The minimum concentration required to inhibit 90 % of strains (MIC90) for Klebsiella ranges from 2 to 32 mg/L; for Enterobacter species, from 4 to 50 mg/L; and for Pseudomonas aeruginosa, from 8 to 32 mg/L [4]. Aztreonam is alsoactiveagainstaminoglycosideresistant strains of Enterobacteriaceae and P. aeruginosa [4, 5]. Aztreonamhas no significant activityagainstgram-positive or anaerobic organisms. Accordingly, in patients with polymicrobial infection or in seriously ill patientsreceiving empiric therapy pending identification of the causative organism(s), aztreonam shouldbe givenconcurrently with antibiotics possessing a complementary spectrum of activity. The activity of clindamycin againstanaerobesis not altered by the additionof aztreonam[6]. In one in vitro studyin which agar dilution techniques were used, high concentrations of clindamycin (10-14 #Lg/mL) combined with aztreonam were synergisticagainst 50 % of the 18 isolates of K. pneumoniae tested, 35 % of the 26 isolates of Enterobacter speciestested, and 14% of the 25 isolates of E. coli tested [7]. Similar in vitro studies of clindamycin and aminoglycosides (gentamicin, amikacin, and tobramycin) against Klebsiella speciesrevealed only antagonistic or indifferent interaction [7]. Studies in healthy volunteershave revealed no evidenceof significantpharmacokinetic interactions between aztreonam and clindamycin, metronidazole, nafcillin, or cephradine[8]. Other studies have established that aztreonam is well distributedinto bodyfluids andtissues, including peritonealfluid, after parenteral administration [9, 10]. Winslade et al. [11] foundthat under steady-stateconditions the penetration ratio (ratio of drug concentration in peritoneal fluid to that in serum) was higher for aztreonam (0.95:1) than for tobramycin (0.46:1) in patients treated for intraabdominal sepsis. This report summarizes data from a singlemulticenter clin-

Downloaded from http://cid.oxfordjournals.org/ at Deakin University Library on August 12, 2015

In a multicenter, randomized clinical trial, aztreonam and tobramycin were compared for efficacy and safety in the treatment of intraabdominal infections. Patients were randomly assigned to one of the drug regimens, and all but two patients were treated concomitantly with clindamycin. Efficacy of treatment could not be evaluated for 107 of the 316 patients enrolled in the study. Among the 209 patients who could be evaluated (104treated with aztreonam and 105 with tobramycin), microbiologic cure was achieved in 93% and 86%, respectively, and a favorable clinical response was noted in 85% of the patients in both groups. The frequency of adverse drug reactions in the two groups was similar. In this study, the efficacy and safety profiles of aztreonam plus clindamycin were comparable to those of tobramycin plus clindamycin.

S630

Williams and Hotchkin

ical trial comparing aztreonam and tobramycin, each in combination with clindamycin, for safety and efficacy in the treatment of patients with intraabdominal infections.

Patients and Methods

clinically indicated. Blood was obtained for culture before treatment from patients with suspected bacteremia. Disk diffusion or tube dilution susceptibility testing was performed on all isolates. For aztreonam, resistant organisms were defined as those for which the diameter of the zone of inhibition was ~15 mm or the MIC was >16 p.g/mL. For tobramycin the breakpoints for disk diffusion and tube dilution susceptibility varied among laboratories. Patients whose isolates were resistant to the assigned study drug were excluded from the study and were not considered assessable for efficacy. Routine laboratory studies, including a complete blood cell count, serum chemistry determinations, and urinalysis, were obtained at enrollment, every 3-5 days during treatment, the last day of treatment, and at follow-up 7-14 days after completion of therapy. Clinical and microbiologic response. For each assessable patient, clinical and microbiologic responses were assigned according to predetermined criteria. Clinical cure was defined as complete resolution of signs and symptoms of intraabdominal infection, and clinical failure, as their persistence or progression. Microbiologic response was evaluated only for aerobic gram-negative organisms because clindamycin, the only antibiotic with activity against anaerobes, was employed in both regimens. Microbiologic cure was defined as the eradication of causative organisms from intraabdominal sites. If the site of infection was not accessible to follow-up sampling and culture and clinical cure was achieved, microbiologic cure was assumed to have occurred. Microbiologic failure was defined as failure to eradicate causative organisms from intraabdominal sites.

Results Eight investigators enrolled 316 patients in this multicenter study. Aztreonam/clindamycin or tobramycin/clindamycin was randomly assigned to 155 patients (49%) and 161 patients (51%), respectively. Of the 316 patients enrolled, 209 (66%) were assessable for microbiologic and clinical efficacy. The most common reason for exclusion was failure to obtain gram-negative pathogens from pretreatment cultures (table 1). Demographic characteristics and concomitant illnesses of the assessable patients are presented in table 2. All but two assessable patients underwent surgery. Several patients underwent more than one procedure during the same operation. The most common procedure in both treatment groups was appendectomy; small or large bowel resection, incision and drainage of an intraabdominal abscess, and cholecystectomy followed, in that order (table 3). Of the postoperative diagnoses (table 4), appendicitis and gallbladder disease were more common in the aztreonam/ clindamycin group and peptic ulcer disease with duodenal perforation was more common in the tobramycin/clindamycin group.

Downloaded from http://cid.oxfordjournals.org/ at Deakin University Library on August 12, 2015

Patient population. Patients >18 years of age with a confirmed or presumptive diagnosis of intraabdominal infection were eligible for enrollment. At least three of the following clinical criteria were necessary to establish a presumptive diagnosis: fever (~37.8°C orally or 1°C above the baseline value); leukocytosis (total leukocyte count ~10,000h(.L, representing a new finding, or ~15 % band forms with a total leukocyte count

Aztreonam plus clindamycin versus tobramycin plus clindamycin in the treatment of intraabdominal infections.

In a multicenter, randomized clinical trial, aztreonam and tobramycin were compared for efficacy and safety in the treatment of intraabdominal infecti...
515KB Sizes 0 Downloads 0 Views