Cefepime Plus Metronidazole for Complicated Intra-Abdominal Infections
ABSTRACT & COMMENTARY
Source: Barie PS, A randomized, double-blind, clinical trial comparing cefepime plus metronidazole with imipenem-cilastatin in the treatment of complicated intra-abdominal infections. Arch Surg 1997;132: 1294-1302.
Barie and colleagues at 17 medical centers enrolled patients with a preoperative diagnosis of complicated intra-abdominal infection (significant abdominal findings plus evidence of a systemic inflammatory response) or a postoperative diagnosis of peritonitis in a randomized trial of antibiotic therapy. Patients with severe renal failure, leukopenia, APACHE II score higher than 30 or limited survival prognosis, a history of seizures or of relevant antibiotic allergy were excluded. Patients who proved to have a gynecological infection, nonperforated appendicitis, traumatic perforation less than 12 hours old, or perforated gastroduodenal ulcer less than 24 hours old were also excluded. The study was designed to have a power of 80% to detect a 15% difference in clinical cure rates with an a = 0.05.
Patients were randomized to receive either cefepime 2 g q 12h plus metronidazole q6h or imipenem q6h beginning within six hours prior to or 12 hours after surgery. Placebos were administered at appropriate times to maintain blinding.
Three hundred twenty-three patients received study treatment and, thus, constituted the intent-to-treat population. However, only 217 patients were "protocol valid." One-half of the remaining 106 were "not protocol valid" as a consequence of failure to detect a pathogen in pretreatment cultures, with the rest having uncomplicated infection (17), more than five days of treatment (18), loss to follow-up (15), or inability to determine response (3). Approximately 85% of patients in each group received at least a single dose of antibiotic prior to study entry.
Patients in the two groups were similar except that only 9% in the cefepime-metronidazole protocol valid group had an APACHE II score higher than 15, compared to 17% (P = 0.04) in the imipenem group.
Of 237 pretreatment aerobic bacterial isolates tested against cefepime, 284 (84%) were susceptible while 309 (92%) of 337 tested against imipenem were susceptible to this carbapenem. The difference was largely due to the expected differing susceptibility of enterococci. Among aerobic gram-negative rods, 96% were susceptible to cefepime and 94% to imipenem. All anaerobes tested were susceptible to imipenem, while 97% were susceptible to metronidazole.
Patients received study antibiotics for a mean of 9.2 days. Twelve percent of patients, evenly distributed between treatment groups, were given an additional antibacterial agent (frequently vancomycin) which was allowed by protocol.
The intent-to-treat analysis found that 134 (82%) of 164 patients assigned cefepime-metronidazole and 121 (76%; P = 0.36) of 159 assigned imipenem experienced clinical cure. The mortality rate was 2% in the former and 7% (P = 0.03) in the latter group; the rates of mortality related to the original infection were, respectively, 1% and 3%. High APACHE II score and prolonged prestudy hospital stay were each associated with poor outcome on stepwise regression analysis; the presence of Enterococcus was not.
Among protocol valid patients, 88% of the cefepime-metronidazole group and 76% (P = 0.02) of the imipenem group were clinically cured, with the most common reason for failure being clinical worsening resulting in a change in antibiotic therapy. Two patients in the cefepime-metronidazole group and nine of the imipenem recipients required additional surgery.
Pretreatment pathogens were eradicated in 89% of those assigned cefepime-metronidazole and in only 76% (P = 0.01) of those assigned imipenem. E. coli persisted in three patients from the former and of the latter group. Anaerobes were eradicated equally well by the two regimens. Thirteen of 48 patients from whom enterococci had been recovered were given vancomycin. Enterococci persisted in two patients in the cefepime-metronidazole and five in the imipenem group; the likelihood of persistence did not appear to be affected by the administration of vancomycin.
COMMENT BY STAN DERESINSKI, MD, FACP
We can now add cefepime plus metronidazole to the list of antibiotic regimens that are effective in the treatment of intra-abdominal infections. This study by Barie and colleagues demonstrates that, in patients with complicated infections, more than two-thirds of which were caused by lower intestinal flora, this combination, in an intent-to-treat analysis, was as effective as imipenem with regard to clinical cure and was more effective in pathogen eradication. Furthermore, analysis of "protocol-valid" patients after adjustment for imbalance in randomization of patients with high APACHE II scores, found that treatment with cefepime-metronidazole was associated with a cure rate that approached (but didn't quite reach) being significantly better than treatment with imipenem.
Cefepime-metronidazole is not effective against enterococci, while imipenem inhibits most Enterococcus faecalis. Despite this, the presence of Enterococcus in pretreatment cultures was not associated, in multivariate analysis, with poor outcome in either treatment group. A number of patients were given vancomycin because of the presence of enterococci, but Barie et al could not detect evidence that administration of this glycopeptide was associated with improved outcome. Thus, the pathogenic role played by the Enterococcus in intra-abdominal infection remains confusing.
We previously discussed evidence concerning the role played by this organism in our review of a study comparing ciprofloxacin plus metronidazole to imipenem in the treatment of intra-abdominal infection (Infect Dis Alert 1996;16:26-27; Solomkin JS, Ann Surg 1996;223:303-325). Many widely used treatment regimens (e.g., clindamycin plus gentamicin) do not have activity against enterococci yet constitute effective antibiotic therapy for most patients with intra-abdominal infection. The Enterococcus appears to play an important pathogenic role when present in high numbers and in patients whose infection occurs after prolonged hospitalization or as a complication of a surgical procedure-especially after the receipt of broad spectrum cephalosporin therapy.
In patients with uncomplicated intra-abdominal infections, such as non-perforated acute appendicitis or traumatic bowel perforation of less than 12 hours duration, the broad antibacterial spectrum provided by regimens such as those evaluated in this study may not be necessary. In such cases, therapy with antibiotics such as ampicillin/sulbactam is often effective. However, in patients with serious, potentially life-threatening infection, particularly in a setting that raises concern about the presence of antimicrobial-resistant pathogens, the clinician can use cefepime plus metronidazole with confidence.
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