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Abdominal infections are treated by resuscitation, abdominal drainage, control of the source of infection, and antimicrobial agents. Ideally, antimicrobial therapy is active against expected pathogens, safe and effective in clinical trials, inexpensive, and unlikely to promote drug resistance. Numerous single-agent and combination-drug regimens have been efficacious in clinical trials, based on coverage of Escherichia coli and Bacteroides species, the predominant pathogens isolated. Whether expanded antimicrobial coverage is required, especially in hospital-acquired infections, is controversial. Candida infections should be treated with antifungal therapy in patients with recurrent abdominal infections, immunosuppressed patients, and those with candidal abscesses. Most agents have few serious adverse effects; aminoglycosides are the least expensive agents but cause nephro- and ototoxicity. There is little information on the promotion of drug resistance in this condition. Recent developments include the introduction of ticarcillin/clavulanic acid, ampicillin/ sulbactam, piperacillin/tazobactam, meropenem, aztreonam/clindamycin, and ciprofloxacin/metronidazole; success with once-daily aminoglycosides; evidence that antibiotics limit infectious complications of pancreatitis; controversy over the value of diagnostic cultures; the use of oral therapy; evidence in favor of shorter courses of treatment; and the introduction of pharmacoeconomic studies. Clinical investigators are challenged to improve drug trials by stratifying and controlling for the adequacy of surgical intervention.

The distributions of radiolabelled free cefoxitin (FC) and liposome-encapsulated cefoxitin (LC) were compared in an animal model of intra-abdominal sepsis. Intraperitoneally administered LC was initially retained in the peritoneal cavity with subsequent preferential drug targeting to the liver (14% injected LC) and spleen (6% injected LC) by 3 h post-injection. Differing patterns of liposomal drug and lipid retention indicated that drug release from the liposome complex occurred within the peritoneum, liver and spleen. Intraperitoneal FC was rapidly taken up into the systemic circulation, with peak recovery in the blood (9% injected FC) and liver (5% injected FC) at 1 h post-injection. FC was also rapidly eliminated; 7% of the injected drug was recovered in the kidney 1 h post-injection. A negligible amount of FC was recovered in the spleen and very little FC or LC was found in the lungs of treated animals. Unlike FC, LC was found to provide a sustained bactericidal drug level (> 40 micrograms mL-1) in the peritoneal fluid for up to 5 h post-injection. LC also achieved significantly higher drug levels, compared with FC, within the liver at 3 and 5 h post-injection. Since severe intra-abdominal sepsis is often characterized by the presence of intraphagocytic bacteria in hepatic and splenic reticuloendothelial systems, the enhanced delivery of liposome-encapsulated anti-microbial agents, such as cefoxitin, to the liver and spleen may provide a more effective treatment for the septic condition.

Operation for intra-abdominal infection aims to prevent further contamination of the abdominal cavity, treat the underlying source of infection, and prevent residual or recurrent sepsis by cleaning the peritoneal cavity. Aggressive attempts at early diagnosis are warranted, even if laparotomy is occasionally required for diagnostic as well as therapeutic purposes. Conversely, the degree to which more aggressive methods of peritoneal debridement are helpful is the subject of great controversy that can be resolved only by prospective, randomized multicenter trials. Current standard treatment consists of closure, drainage, or excision of the source of contamination; intra-operative saline or antibiotic lavage of the peritoneal cavity; fascial closure; and secondary or delayed primary closure of the wound.

When used appropriately, antimicrobial prophylaxis is highly beneficial and cost effective. Antibiotics are not indicated for "clean procedures" such as hernia and breast surgery. A single preoperative dose will suffice, followed by an intraoperative dose if the operation takes more than 3 hours. For vascular (prosthesis or groin wound), head and neck (pharynx entered), thoracic (gastrointestinal or respiratory entrance) and high-risk gastroduodenal and biliary procedures, cefazolin, 1 g intravenously, is indicated. For procedures involving small intestine, appendix or penetrating abdominal trauma, cefoxitin or cefotetan, 2 g intravenously, is indicated. For colorectal procedures, either oral neomycin plus erythromycin or intravenous aminoglycoside plus clindamycin (or metronidazole) are effective. If valvular heart disease is present, endocarditis prophylaxis should be administered.

Nosocomial pneumonia (NP) is associated with a significant mortality, 66% in a previous retrospective study of NP complicating intra-abdominal sepsis (IAS). We prospectively compared the outcome of NP complicating IAS with that of recurrent IAS (R-IAS) in the absence of NP. Data were collected prospectively on 300 patients with IAS; 34 patients who presented with pneumonia were excluded from the analysis (44% mortality). One hundred seventy-one patients with no NP and no R-IAS (group 1) had a hospital mortality of 20% (34 patients); 36 without NP in whom R-IAS developed (group 2) had a 17% mortality (six patients); and 47 with NP but no R-IAS (group 3) had a 53% mortality (25 patients). Finally, 12 patients who had both NP and R-IAS suffered a 75% mortality (nine patients). We examined the relationships among the following putative risk factors and mortality: APACHE (acute physiology and chronic health evaluation) II score (at initial presentation with IAS), the need for mechanical ventilatory assistance following initial treatment for peritonitis, steroid requirement, generalized peritonitis vs abscess, and the need for surgical as opposed to percutaneous treatment. Using mortality as the dependent variable, group 2 vs 3 as the explanatory variable, and the risk factors as confounders, logistic regression analysis indicated that the group difference was significant after controlling for confounders. We conclude that NP complicating IAS is an independent risk factor associated with a significant mortality compared with R-IAS. These data challenge the notion that death in IAS is usually due to recurrent or persistent intra-abdominal infection.

Scheduled relaparotomy is attracting interest as a means of treating intra-abdominal sepsis. It is the subject of several studies to evaluate its role in the management of peritoneal infection. However, indications for this procedure are not clear and current knowledge does not allow for adequate scientific evaluation. Many trials lack control groups and historical control groups cannot be evaluated on criteria, such as illness severity, concomitant health problems or even surgical technique. Indicators of outcome are generally described in insufficient detail; only death or survival are reported and important morbidity and resource utilization data are not included. A randomized, prospective, multicenter clinical trial using standardized techniques is necessary to determine the usefulness of scheduled relaparotomy performed on different patients.

A rat model was developed to determine if delayed hypersensitivity skin tests during early peritonitis would predict outcome. Presensitized rats were simultaneously tested intradermally with keyhole-limpet hemocyanin and given four types of fecal bacteria and 10% barium sulfate intraperitoneally. Rats were divided into four groups according to inoculum dose. Skin tests were read at 24 hours in survivors and correlated with death and abscesses during the next 19 days. In the two groups with greatest mortality, 35% of anergic rats died, compared with 0% of reactive rats. In the three groups with most abscesses, anergic rats had more abscesses than those that reacted. Overall, 90% of anergic rats died or had abscesses v only 10% of reactors. We concluded that the outcome of untreated peritonitis is determined in the first 24 hours; anergy at that time predicts death or abscess formation.

We present preliminary data on the role of antibiotics in intraabdominal sepsis using a new, clinically relevant animal model. Peritoneal cavity infection was induced by ligation and perforation of the cecum in adult rats. Surviving rats were randomized to receive either saline or cefoxitin at the time of cecal excision and peritoneal lavage, 18 h after the onset of infection. This is different from previous models of abdominal sepsis (in which antibiotics are given within 4 h of peritoneal contamination) and mimics the clinical setting in which antibiotics are initiated much later, at the time of operation. Antibiotic-treated rats received 20 mg cefoxitin i.m. every 8 h for 7 days; controls received saline at similar times. Thirty-nine of 67 control rats died (58%) versus 20 of 64 (31%) that received cefoxitin (p less than 0.005). We conclude that even with delayed administration, antibiotics appear to improve the outcome of intraabdominal sepsis. With further characterization of this model we plan to use it as an in vivo assay to compare the efficacy of different antimicrobial agents in intraabdominal sepsis.

We studied 108 patients undergoing clean-contaminated and dirty surgical procedures to determine whether daily C-reactive protein (CRP) measurements for 14 days postoperatively could predict the occurrence of septic complications prior to clinical diagnosis. Diagnostic criteria for septic complications and positive CRP response were defined in advance of the study. The CRP assays were carried out using an automated laser nephelometer system after the patient's discharge from the hospital. Forty-six septic complications were diagnosed in 40 patients. These complications consisted of wound infection (23), urinary tract infection (11), pneumonia (six), upper respiratory tract infection (three), intra-abdominal abscess (one), and other (two). The CRP testing was found to have a positive predictive value of 69% and a negative predictive value of 78%. We conclude that serial CRP measurements may be a valuable adjunct to surgical care in patients at high risk of postoperative septic complications.

Therapeutic trials for intra-abdominal sepsis require pretreatment stratification; physiologic scoring has been recently proposed for this purpose. We have prospectively tested the validity of one such scoring system, namely, the Acute Physiology and Chronic Health Evaluation (APACHE II). As part of a larger database, we correlated APACHE II scores with mortality in 100 patients hospitalized for generalized peritonitis or abdominal abscess. Use of steroids was recorded because of our suspicion that steroids increase mortality but blunt the physiologic response to sepsis. Thirty-one patients died, including 12 of 19 patients receiving steroids. Stepwise discriminant analysis revealed that the APACHE II score and steroid use were each independently associated with the rate of mortality. We report a prospective validation of pretreatment APACHE II scoring in abdominal sepsis. Steroid use is an independent risk factor.