Randomized Prospective Study Comparing Moxalactam and Cefoxitin with or without Tobramycin for the Treatment of Serious Surgical Infections

Transcription

1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1986, p /86/ $02.00/0 Copyright C 1986, American Society for Microbiology Vol. 29, No. 2 Randomized Prospective Study Comparing Moxalactam and Cefoxitin with or without Tobramycin for the Treatment of Serious Surgical Infections FRANCIS P. TALLY,'* JOHN M. KELLUM,2 JOHN L. HO,' THOMAS F. O'DONNELL,2 MICHAEL BARZA,1 AND SHERWOOD L. GORBACH' Infectious Diseases Division, Department of Medicinel and Department of Surgery,2 Tufts University School of Medicine, and New England Medical Center Hospitals, Boston, Massachusetts Received 8 April 1985/Accepted 12 November 1985 The efficacy and toxicity of moxalactam were compared with the efficacy and toxicity of cefoxitin given with or without tobramycin to 109 patients with surgical infections. A total of 66 patients could be assessed for efficacy (33 patients in each group); 13 of the cefoxitin-treated patients also received tobramycin for at least 72 h. Most patients had intraabdominal infections; 17 had peritonitis, 14 had intraabdominal abscess, and 7 had perforation of a gangrenous appendix. There were 15 patients with necrotizing soft-tissue infections. The predominant pathogens were members of the Enterobacteriaceae and fragiis. The cure rates were 79% (26 of 33 patients) for moxalactam and 88% (29 of 33 patients) for cefoxitin; the difference in cure rates was not statistically significant. In several patients, cultures of purulent intraabdominal exudates were negative, although bacteria were observed after Gram staining; this presumably reflected the potent activity of the antibiotic therapy which had been started before surgical drainage could be carried out. Adverse effects were observed in 18 of 44 assessable patients (41 %) in the cefoxitin group and in 12 of 36 patients (33%) in the moxalactam group; the difference in the rates of adverse effects was not statistically significant. Our results suggest that moxalactam is similar in efficacy and toxicity to cefoxitin given with or without tobramycin for the treatment of serious surgical sepsis caused by a mixture of anaerobic and aerobic pathogens. Treatment of serious infections of the abdomen, the pelvis, and the soft tissues of the lower extremities requires judicious surgical intervention together with the administration of appropriate antimicrobial agents. Studies over the past decade have called attention to the frequent occurrence of synergistic mixtures of aerobic and anaerobic bacteria in these infections (5, 6). The most common anaerobic organisms are fragilis strains, followed by clostridia and anaerobic streptococci. The most common facultatively aerobic bacteria are Klebsiella, streptococci, Proteus species, and Pseudomonas aeruginosa. Traditional treatment of these mixed infections usually involves the use of two drugs, one an aminoglycoside aimed at the common aerobic bacteria and the other an agent that is active against B. fragilis (9). The introduction of new beta-lactam antibiotics that are active against both the aerobic and anaerobic components of these infections provides an alternative to combinations of drugs. Cefoxitin has been shown to be effective in prospective, randomized studies (4, 10); however, in about one-third of the patients treated with cefoxitin, an aminoglycoside was believed to be required to obtain an adequate antibacterial spectrum. The activity of moxalactam in vitro is similar to the activity of cefoxitin against B. fragilis and broader than the activity of cefoxitin against aerobic pathogens (2). Therefore, moxalactam has the spectrum which is required for a single agent for treatment of mixed aerobic-anaerobic bacterial infections. The purpose of this study was to compare moxalactam with cefoxitin, the latter given alone or in combination with tobramycin, for treatment of serious surgical infections. * Corresponding author. MATERIALS AND METHODS Patients who were more than 12 years old on the surgical and medical services of Tufts-New England Medical Center were eligible for the study. The criterion for entry was clinical diagnosis of a mixed anaerobic-aerobic bacterial infection that was severe enough to require therapy with parenteral antimicrobial agents. The infections included intraabdominal, pelvic, biliary tract, and necrotizing soft-tissue infections suspected of containing B. fragilis. The reasons for exclusion were as follows: (i) known allergy to penicillins or aminoglycosides; (ii) pregnancy; (iii) antibiotic therapy which was given within the preceding 3 days and was likely to be effective against the infecting organisms; and (iv) infections known to harbor resistant organisms. Most patients were entered into the study before identification of the infecting bacteria. After written informed consent was obtained from a patient or guardian, the patient was assigned to receive either moxalactam or cefoxitin; the latter was given with or without tobramycin. The decision to use tobramycin in addition to cefoxitin was made by the attending physicians in consultation with the Infectious Disease Service. The patients were assigned to the regimens by a pharmacist, who was not part of the study group and who opened the next sealed envelope in a randomized series. The dosage of moxalactam was 1 to 3 g (usually 2 g) administered intravenously over 30 to 60 min every 8 h; the lower dose was used in mild infections, and only 8 of 54 patients received a dose of less than 4 g/day. The dosage of cefoxitin used was 1 to 2 g (usually 2 g) administered intravenously over 30 to 60 min every 6 h; the lower dose was used for patients with mild infections. The dose of tobramycin used was 3 to 5 mg/kg per 244

2 VOL. 29, 1986 TREATMENT OF SURGICAL INFECTIONS 245 Age (yr) TABLE 1. Antibiotic(s) ~No. of No. of Clinical characteristics of patients assessable for efficacy No. of patients with the following types of infection Intraabdominal Soft tissue Antibiotic(s) Median Range females males Pen- Perforated or Diverti- Chole- Perirectal Necrotizing Pelvic Other tonitis Abscess gangrenous ~appendix culitis cystitis abscess cellulitis Moxalactam Cefoxitin with or without tobramycin a Includes both assessable and nonassessable patients. day given in divided doses every 8 h. This dosage was modified according to the renal function of the patient in order to achieve a peak serum concentration of tobramycin of 5 to 8,ug/ml. Tobramycin was given when the presence of a cefoxitin-resistant organism, such as Enterobacter, Acinetobacter, or Pseudomonas aeruginosa, was suspected. This consideration arose mainly in patients who had received antibiotics recently or had acquired their infections in the hospital. Tobramycin treatment was discontinued after 48 to 72 h if resistant bacteria were not isolated from the infection. The decision to institute antibiotic therapy and the decision to use 1 or 2 g of the P-lactam drug were made by the attending physician or surgeon in conjunction with an infectious disease consultant. Patients had to receive therapy for at least 24 h to be assessable for efficacy. Cure was defined as resolution of local and systemic signs of infection, accompanied by eradication of the microbial pathogen. Because antibiotic therapy was instituted before surgery, patients with negative cultures from the surgical specimens but with clear-cut signs of purulent infection during the operation were considered to be clinically cured if all signs of the underlying infection resolved. Therapeutic failure was defined as the persistence or recurrence of clinical signs or symptoms of infection related to the original pathogen. Superinfection was defined as the occurrence of a new infection during treatment for the first infection. Determinations of clinical outcome were made by the consensus of two investigators (one internist and one surgeon) who were unaware of which regimen the patient had received. Bacteriological responses were based on Gram-stained smears and cultures of body fluids and exudates. All specimens except blood cultures were studied in the Tufts Anaerobic Laboratory in the Infectious Disease Section; blood cultures were sent to the Clinical Microbiology Laboratory. Specimens were obtained before, during, and (when available) after therapy. Bacteriological responses were defined as follows: elimination of the pathogen, persistence of the infecting organism(s), or superinfection (finding a new infecting organism during treatment). Susceptibility testing of aerobic isolates was initially done by using standard agar diffusion methods (3, 7). The MIC was subsequently determined for each isolate by broth dilution microtiter methods. Anaerobic organisms were tested by broth dilution methods. (3, 7). Patients were considered assessable for toxicity if they had received the drug for at least 72 h. The following routine tests were done at the beginning of therapy, during therapy, and after therapy: hemoglobin, hematocrit, leukocyte count and differential, platelet count, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, bilirubin, electrolytes, creatinine, blood urea nitrogen, and microscopic urinalysis. In most patients these tests were repeated every 3 days during therapy. Nephrotoxicity was defined as an increase in the serum creatinine level of at least 0.5 mg/dl over the base line. Antibiotic-associated diarrhea was evaluated by examining the stools for blood and mucus and the presence of Clostridium difficile toxin. Because hypoprothrombinemia was not a recognized risk of moxalactam treatment at the start of this study and through most of the period of this study, prothrombin times were measured in fewer than one-half of the patients in each group, and vitamin K was not administered prophylactically. Statistical analyses were performed by using the two-tailed Fisher exact test. RESULTS Between October 1980 and December 1982, 109 patients were enrolled in the study. A total of 54 patients received moxalactam, and 55 received cefoxitin with or without tobramycin. Twenty-one patients given moxalactam and 22 patients given cefoxitin could not be assessed for clinical efficacy. The reasons that these patients could not be evaluated were as follows: lack of proof of infection (29 patients); protocol violation (3 patients); death within 24 h of noninfectious causes (4 patients); and requirement for another antibiotic to treat gram-positive coccal or listerial infections (6 patients). The patients without documented infections had nonperforated appendicitis (14 patients), noninfectious tuboovarian disease, intestinal obstruction, hemoperitoneum, inflammatory bowel disease, or tumor. Protocol violations occurred because an additional antibiotic was added to the regimen or because a potentially effective drug had been administered within 3 days of the beginning of treatment with the study drug. Patients in these exclusionary categories were equally distributed between the moxalactam and cefoxitin regimens. Overall, 33 patients given moxalactam and 33 patients given cefoxitin could be evaluated for clinical efficacy of the drugs. In the cefoxitin group, 18 patients were initially given tobramycin, and 13 of these patients required the drug for the entire course. The recipients of the two regimens were similar in age, sex, and type of infection (Table 1). The majority had intraabdominal or necrotizing soft-tissue infections. The intraabdominal infections were most often due to colonic perforation. The soft-tissue infections included perirectal abscesses (six patients) and cellulitis of the lower extremities (nine patients). Most of the patients with necrotizing soft-tissue infections of the lower extremities had diabetes and peripheral neuropathy. The types of infection were evenly distributed between the two regimens, except that all five patients with diverticulitis fell into the moxalactam group. The outcomes were similar for the two treatment groups (Table 2). Of the 33 patients in the moxalactam group, 26

3 246 TALLY ET AL. ANTIMICROB. AGENTS CHEMOTHER. Clinical results TABLE 2. Therapeutic outcomes in assessable patients No. of patients who required the following surgical procedures: Antibiotic(s) No. No. of Intraabdominal Wound Bowel repair cured failures abscess abscess or colostomy Cholecystectomy Debridement Amputation Othera drainage drainage or both Moxalactam 26 (79)b 7 (21) Cefoxitin with 29 (88) 4 (12) or without tobramycin a Including chest tube and salpingo-oophorectomy. bthe numbers in parentheses are percentages. were cured, and 29 of the 33 patients who received cefoxitin with or without tobramycin were cured. A statistical analysis by using the x2 test showed that there was no significant difference in either cure rate or the failure rate between the regimens (P = 0.25). A surgical procedure was needed as part of the initial treatment in 30 patients in each group (Table 2). Bacteriological cultures were positive in 23 patients who received moxalactam and 30 patients who received cefoxitin (Table 3). Anaerobic bacteria were isolated from specimens from 18 of 33 patients (55%) in the moxalactam group and from 20 of 33 patients (61%) in the cefoxitin group. The most common anaerobic organisms were members of the B. fragilis group; 21 B. fragilis strains were isolated from 16 patients in the moxalactam group, and 24 B. fragilis strains were isolated from 17 patients in the cefoxitin group. Escherichia coli was the predominant aerobic organism. Pseudomonas aeruginosa was present in five patients in the moxalactam group and in seven patients in the cefoxitin group. Enterococci were recovered from nine patients in the moxalactam group and seven patients in the cefoxitin group. No fungi were isolated in the primary cultures. Two patients in the moxalactam group and six patients in the cefoxitin group had bacteremia. Bacteremia was caused by species in four patients, by members of the Enterobacteriaceae in two patients (one one Proteus vulgaris), by an alpha-streptococcus in one patient, and by a mixture of facultative aerobes in one patient. Microbiological cultures were not obtained from six patients who received moxalactam. Five of these patients had radiographically proven diverticulitis and responded to medical therapy alone; therefore, specimens could not be obtained for microbiological cultures. The sixth patient had a pericolonic abscess which was demonstrated by using a barium enema and responded to medical therapy. Four patients in the moxalactam group and three patients in the cefoxitin group had sterile cultures of intraabdominal exudates obtained at the time of surgery, although Gram staining of the material showed the presence of polymorphonuclear leukocytes and microorganisms. Each of these patients had received at least one dose (usually several doses) of an antibiotic before surgery. These patients were considered assessable for efficacy, and the negative cultures were attributed to the preoperative antibiotic treatments. There were seven failures in the moxalactam group (Table 4). Four patients were found to have postoperative intraabdominal abscesses following bowel perforation. Susceptibility studies of the original isolates obtained from patient 22 revealed the presence of a Streptococcus species and a distasonis strain resistant to moxalactam (MIC, -256 and 32,ug/ml, respectively). This patient subsequently responded to treatment with chloramphenicol and tobramycin without surgery. In patient 39, one initial isolate, a gram-positive anaerobic rod-shaped bacterium, was resistant to moxalactam (MIC, 64,ug/ml). This patient showed continued signs of infection despite 5 days of treatment with moxalactam. Clindamycin and tobramycin were substituted for moxalactam, and the patient underwent a second operation for drainage of an intraabdominal abscess. Cultures of the pus yielded a Pseudomonas aeruginosa strain which had intermediate susceptibility (MIC, 32,ugIml), an enterococcus which was resistant, and a Clostridium sp. strain which was resistant to moxalactam. Patient 98 had peritonitis because of a perforated duodenal ulcer. Despite initial defervescence with surgical repair of the perforation and treatment with moxalactam, the patient developed an intraabdominal abscess. This was drained and was found to contain anaerobic cocci and Pseudomonas aeruginosa. Patient 58 had a biliary tract infection with peritonitis and Escherichia coli bacteremia; she initially responded to treatment with moxalactam but then was found to have a subhepatic abscess containing TABLE 3. Bacteria isolated in initial cultures from 66 assessable patients No. of isolates from the: Bacteria Moxalactam Cefoxitin group group Anaerobic bacteria B. fragilis group B. fragilis 10 8 Others species and Fusobacterium Clostridium perfringens 1 2 Clostridium species 5 7 Gram-negative cocci 4 7 Gram-positive cocci 4 6 Gram-positive bacilli 10 9 Aerobic bacteria Escherichia coli Klebsiella 4 6 Proteus mirabilis 3 5 Pseudomonas aeruginosa 5 7 Other gram-negative bacillia 6 7 Staphylococcus aureus and 5 6 Staphylococcus epidermidis Enterococci 9 7 Micrococcus, streptococci, and a-hemolytic streptococci Diphtheroids and other gram-positive 4 8 bacillib "The other gram-negative bacilli included members of the following genera: Morganella, Citrobacter, Serratia, Acidaminococcus, Eikenella, and Haemophilus. b Lactobacilli.

4 VOL. 29, 1986 TREATMENT OF SURGICAL INFECTIONS 247 TABLE 4. Treatment failures Patient Underlying Initial bacteriology Ptet Therapy Infection UneligComments no. disease Aerobic organistns Anaerobic organisms 8 Moxalactam Appendicitis None Enterococcus, Proteus mirabilis, Enterobacter aerogenes Paracolonic Diverti- Enterococcus, abscess culitis Pseudomonas aeruginosa, Proteus mirabilis, a-streptococci, Streptococcus sp. Perforated Cancer of K. pneumoniae, colon colon Streptococcus sp., Citrobacter Perforated Diverti- K. pneumoniae, colon culitis Escherichia coli Pericolonic Diverti- abscess culitis K. pneumoniae, Enterobacter cloacae Peritonitis, Peritoneal Escherichia coli biliary dialysis (blood), tract infection Peritonitis Subphrenic abscess Peritonitis, LUQ abscess Peritonitis Ruptured urinary bladder Diverti- culitis Perforated colon Perforated duodenal ulcer Perforation of colon due to Crohn's disease Ischemic bowel 7 Cefoxitin with or without tobramycin enterococcus a-streptococci enterococcus, Morganella morganiia K. pneumoniae, Escherichia coli K. pneumorliae, Pseudomonas aeruginosa thetaiotaomicron, Clostridium sp., Fusobacterium sp. Enterobacter limmosum, ruminicola, Propionibacterium acnes, B. fragilis, thetaiotaomicron Clostridium sp., Fusobacterium sp., melaninogenicus, B. fragilis, B. distasonis ovatus, gram-positive coccus ovatus, B. fragilis, thetaiotaomicron None None thetaiotaomicron, ovatus, Clostridiuth perfringens No growth, patient receiving treatment None Clostridium perfringens, Clostridium ramosum, B. fragilis, B. distosonis, vulgatus, thetaiotaomicron, Eubacteriumb a The enterococcus strain was resistant to the drugs administered. b The B. fragilis, B. distosonis, B. vulgatus, and B. thetaiotaomicron strains were resistant to the drugs administered. Superinfection (enterococcal urinary tract infection) Wound dehiscence caused by a wound abscess containing a Pseudomonas aeruginosa strain susceptible to moxalactam Intraabdominal abscess treatment changed to treatment with chloramphenicol and tobramycin with good response Laparatomy revealed intraabdominal abscesses containing enterococcus, K. pneumoniae, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Clostridium species; treatment was changed on day 5 to clindamycin and tobramycin, and the abscesses were drained Superinfection (purulent wound infection containing enterococcus) Persistent infection of peritoneal fluid and gall bladder (day 6) with a subhepatic abscess Intraabdominal abscess yielded Micrococcus, Staphylococcus epidermidis, streptococci, and Pseudomonas aeruginosa Recurrent abscess yielded and clbstridial species; subsequently treated with clindamycin and tobramycin Fatal Pseudomonas bacteremia and probable pneumonia Died within 48 h because of continued infection Died within 48 h of overwhelming infection

5 248 TALLY ET AL. an enterococcus. This was considered to be a persisting infection rather than a superinfection. Three patients failed because of superinfections. Patients 13 and 49 had surgical wounds that were superinfected with Pseudomonas aeruginosa and enterococcus, respectively. Patient 8 had a urinary tract infection due to an enterococcus. The organisms in patients 8 and 49 were resistant to moxalactam. There were four clinical failures in the cefoxitin group. Three of these patients died of infections. Patient 79 had a ruptured urinary bladder and peritonitis. Cultures of the peritoneal fluid grew Klebsiella pneumoniae and Escherichia coli strains that were susceptible to both cefoxitin and tobramycin. Patient 110 had a perforated diverticulum; peritoneal cultures yielded a mixture of anaerobic and aerobic bacteria. Despite surgery, both of these patients died of overwhelming sepsis on the second day of treatment with cefoxitin and tobramycin. The third treatment failure occurred in patient 15, whose peritonitis initially responded to surgical resection of an ischemic bowel and therapy with cefoxitin and tobramycin. However, 4 days after cessation of antimicrobial therapy the patient developed signs of sepsis. Radiographic studies showed an intraabdominal abscess. Despite intensive antimicrobial chemotherapy she died on the next day; blood cultures yielded Pseudomonas aeruginosa and an enterococcus. Patient 7 had a recurrent intraabdominal abscess that yielded anaerobic bacteria which remained susceptible to cefoxitin. Adverse reactions to the drugs were evaluated in 36 patients in the moxalactam group and 44 patients in the cefoxitin group. There was a greater proportion of patients in the group treated with cefoxitin with or without tobramycin (18 of 44 patients [41%]) than in the moxalactam group (12 of 36 patients [33%]) who exhibited adverse reactions which could be attributed to the antibiotics; however, the differences were not statistically significant (P = 0.32). Increases in serum creatinine concentration occurred in two patients treated with moxalactam and in three patients treated with cefoxitin; all of the latter were also receiving tobramycin. Hepatic dysfunction, in the form of mild elevation of enzymes levels, was seen in eight patients in the cefoxitin group and five patients in the moxalactam group. Thrombocytopenia was noted in three patients, all in the cefoxitin group. The prothrombin time was monitored during therapy in 18 of 33 patients given moxalactam and in 19 of 33 patients given cefoxitin; 2 patients in the moxalactam group developed a prolongation of the prothrombin time. There were no episodes of bleeding. One patient had a disulfiramlike reaction 49 h after moxalactam therapy was stopped; all of the adverse reactions in both groups of patients were reversible. DISCUSSION Moxalactam has the spectrum required for a single agent for treatment of mixed aerobic-anaerobic bacterial infections suspected of containing B. fragilis. The activity of moxalactam against members of the Enterobacteriaceae is broader than that of cefoxitin, and the activity of moxalactam against B. fragilis is similar to that of cefoxitin (2). Studies in animal models of intraabdominal sepsis have shown that moxalactam is highly effective (1). Therefore, we compared treatment with moxalactam alone with treatment with cefoxitin with or without tobramycin for therapy of mixed aerobicanaerobic bacterial infections. The latter regimen has been shown to be equivalent in efficacy to treatment with clindamycin plus an aminoglycoside in this situation (4). ANTIMICROB. AGENTS CHEMOTHER. The results of this study show that treatment with moxalactam alone is similar in efficacy and toxicity to treatment with cefoxitin with or without tobramycin. These findings are in agreement with those of a previous report which described the utility of moxalactam therapy in the treatment of surgical infections (8). However, in the previous study there were a number of patients with perforations of the upper gastrointestinal tract and a miscellaneous group of patients which had no infection found during surgery. In addition, almost one-half of the patients in the moxalactam group had aerobic infections, and 43% in the clindamycin group had purely aerobic infections. Our study concentrated on patients who were suspected of having mixed infections, and patients were eliminated if they did not have any infection at the time of surgical exploration. We included patients with obvious signs of intraabdominal sepsis related to diverticular disease that did not require surgical therapy because these patients have been clearly demonstrated in other studies to have mixed anaerobic-aerobic bacterial infections. Several patients with clear signs of intraabdominal sepsis both clinically and during surgery were found to have sterile exudates despite the presence of bacteria as determined by Gram staining. This may have resulted from the excellent in vitro activity of both moxalactam and cefoxitin, which were given preoperatively to these patients. Similar observations were made for isolation of anaerobic bacteria when patients were treated with clindamycin (11). Enterococci played a role in the failure of moxalactam treatment in four of seven patients, and Pseudomonas aeruginosa was found in three superinfections (one with an enterococcus); together, these pathogens were important in six of the seven failures. Pseudomonas aeruginosa contributed to two failures of cefoxitin treatment. Although enterococci are not primary pathogens in intraabdominal sepsis, they are members of the normal flora and may emerge in patients who have a persisting anatomic defect or subsequent wound infections. Other pathogens that have been encountered previously in these instances are moxalactamresistant species and Candida species. When patients have failed moxalactam therapy, these pathogens should be sought and treated appropriately. The adverse effects encountered during this study were not serious and were of the kind to be expected in patients with major intraabdominal and soft-tissue infections treated with P-lactam antibiotics. Although vitamin K was not routinely administered, only two moxalactam recipients developed hypoprothrombinemia, and there were no bleeding episodes attributed to the drug. However, the prothrombin times were monitored in fewer than one-half of the patients. The results of our study show that moxalactam is a useful single agent for the treatment of mixed anaerobic-aerobic bacterial infections involving B. fragilis. Its place in the therapy of mixed infections should be based on the current antibiotic susceptibility patterns and the relative importance of the different types of adverse effects in particular patients. LITERATURE CITED 1. Bartlett, J. G., A. B. Onderdonk, T. Louie, D. L. Kasper, and S. L. Gorbach Lessons from an animal model of intraabdominal sepsis. Arch. Surg. 113: Barza, M., F. P. Tally, N. V. Jacobus, and S. L. Gorbach In vitro activity of ILY Antimicrob. Agents Chemother. 16: Cuchural, G. J., Jr., F. P. Tally, N. V. Jacobus, S. L. Gorbach,

6 VOL. 29, 1986 TREATMENT OF SURGICAL INFECTIONS 249 K. AIdridge, T. Cleary, S. M. Finegold, G. Hill, P. lannini, J. P. O'Keefe, and C. Pierson Antimicrobial susceptibility of 1,292 isolates of the fragilis group in the United States: comparison of 1981 with Antimicrob. Agents Chemother. 26: Drusano, G. L., J. W. Warren, A. J. Saah, E. S. Caplan, J. H. Tenney, S. Hansen, J. Granados, H. C. Standiford, and E. H. Miller, Jr A prospective randomized controlled trial of cefoxitin versus clindamycin-aminoglycoside in mixed anaerobic-aerobic infections. Surg. Gynecol. Obstet. 154: Finegold, S. M. (ed.) International symposium on anaerobic bacteria and their role in disease. Rev. Infect. Dis. 6:S1-S Gorbach, S. L., and J. G. Bartlett Medical progress: anaerobic infections. N. Engl. J. Med. 290: , , Jacobus, N. V., F. P. Tally, and M. Barza Antimicrobial spectrum of WIN Antimicrob. Agents Chemother. 26: Schentag, J. J., P. R. Wels, D. P. Reitberg, P. Walczak, J. H. Van Tyle, and R. J. Lascola A randomized clinical trial of moxalactam alone versus tobramycin plus clindamycin in abdominal sepsis. Ann. Surg. 198: Tally, F. P Mechanisms of resistance and resistance transfer in anaerobic bacteria: factors influencing antimicrobial therapy. Rev. Infect. Dis. 6(Suppl. 1):S260-S Tally, F. P., K. McGowani, J. L. Kellum, S. L. Gorbach, and T. F. O'Donnell A randomized comparison of cefoxitin with or without amikacin and clindamycin plus amikacin in surgical sepsis. Ann. Surg. 193: Thadepalli, H., S. L. Gorbach, P. W. Broido, J. Norsen, and L. Nyhus Abdominal trauma, anaerobes, and antibiotics. Surg. Gynecol. Obstet. 137: Downloaded from on September 25, 2018 by guest