Evaluation of antimicrobial therapy management of 120 consecutive patients with secondary peritonitis

Transcription

1 Journal of Antimicrobial Chemotherapy (2002) 50, DOI: /jac/dkf167 Evaluation of antimicrobial therapy management of 120 consecutive patients with secondary peritonitis Albert Sotto 1 *, Jean Yves Lefrant 2, Pascale Fabbro-Peray 3, Laurent Muller 2, Jérôme Tafuri 1, Francis Navarro 4, Michel Prudhomme 5 and Jean Emmanuel de La Coussaye 2 Departments of 1 Internal Medicine B, 2 Critical Care and Emergency, 3 Medical Biostatistics, 4 Surgery A and 5 Surgery B, University-Hospital of Nîmes, Nîmes, France Received 12 November 2001; returned 2 March 2002; revised 13 June 2002; accepted 8 July 2002 Objectives: To evaluate antimicrobial therapy management of secondary peritonitis in a University Hospital. Patients and methods: All patients admitted to the intensive care unit of the University Hospital of Nîmes from 1 January 1997 to 31 July 1999 with a diagnosis of secondary peritonitis were retrospectively included. Patients medical records were collected from the data recordings of the Department of Critical Care and Emergency and the Departments of Surgery. Acute Physiology and Chronic Health Evaluation II (APACHE II) was calculated for each patient at the time of admission. Antimicrobial treatment management before and after the diagnosis of peritonitis was studied. Results: One hundred and twenty patients were included. Results concerning mortality, aetiology of peritonitis and microbiological data were in accordance with previous studies. APACHE II score (P = 0.005), age (P = 0.002), presence of Enterococcus in the peri-operative samples (P = 0.02) and period between diagnosis and surgery (P = 0.04) were predictive of death within 30 days after diagnosis of peritonitis. No significant difference was shown in the mortality rate in patients whose post-operative antibiotic treatment was changed following results of intra-operative peritoneal cultures versus patients having inappropriate treatment (P = 0.96). The same observations were noted for anti-enterococcal treatment. Conclusion: This study emphasizes the importance of prompt surgical treatment and shows the modest impact of adapting antibiotic treatment. The morbidity and mortality associated with the presence of Enterococcus, which was not influenced by antibiotic treatment, would seem to suggest the pro-inflammatory role of Enterococcus. However, prospective randomized studies are needed to evaluate the real contribution of enterococcal antibiotic coverage in this context. Introduction Secondary peritonitis remains a major cause of morbidity, with a mortality of 30%. 1 3 The Acute Physiology and Chronic Health Evaluation II (APACHE II) 4 10 is the most studied severity index in peritonitis and has been shown to be equal or superior to specific peritonitis scores such as the Mannheim Peritonitis Index (MPI) and the Peritonitis Index of Altona II (PIA II). 5 The APACHE II score does not include microbiological data 4 and according to some authors the results of microbiological cultures do not seem to influence peritonitis prognosis. 11,12 However, Enterococcus was shown to increase post-operative morbidity both in animal models and in humans. 16 In the same way, when surgical procedure is effective, the role of suitable empirical antimicrobial therapy remains controversial, 11,12 particularly the necessity to systematically treat Enterococcus at an early stage. 11,16 The impact of potential post-operative antimicrobial alteration in... *Correspondence address. Département de Médecine Interne, Hopital Carémeau, rue du Professeur Debré, Nîmes Cedex 04, France. Tel: ; Fax: ; albert.sotto@chu-nimes.fr The British Society for Antimicrobial Chemotherapy

2 A. Sotto et al. accordance with microbiological samples is still poorly documented. We therefore analysed patients with secondary peritonitis, predicting factors of mortality, including microorganisms, and then evaluating antimicrobial management, particularly specific anti-enterococcal therapy, to study its impact on the patients outcomes. Patients and methods Patients All patients admitted to the intensive care unit (ICU) of a tertiary care University Hospital from 1 January 1997 to 31 July 1999 with a diagnosis of secondary peritonitis were retrospectively included. Patients medical records were collected from the data recordings of the Department of Critical Care and Emergency and the Departments of Surgery. Secondary peritonitis was defined as the result of the loss of integrity of the gastrointestinal or genito-urinary tract leading to contamination of the peritoneal space. 17 A distinction was made between community-acquired peritonitis and post-operative or nosocomial peritonitis. Baseline data collection For each patient, the age, gender, weight and height were recorded. Pre-existing comorbid disorders were collected according to the following criteria: current smoking was defined as a cigarette consumption >10 per day; alcoholism was defined as a current consumption exceeding 20 g per day for women and 60 g per day for men; the body mass index; and allergy was defined as a clinical history of anaphylactic reaction (urticaria, Quinck s oedema, shock). Comorbid conditions were collected with the following criteria: dyslipidaemia, patient receiving a specific treatment (e.g. statin, fibrates); diabetes mellitus, the patient was on insulin or oral antidiabetic therapy; cardiovascular disease, the patient was having treatment for congestive heart failure and/or coronary artery disease; chronic pulmonary disease, a clinical history of chronic obstructive, restrictive or vascular pulmonary disease giving rise to moderate to severe reduction of exercise tolerance, or the patient was on bronchodilatator treatment or long-term oxygen; immunodeficiency conditions (chemotherapy, radiotherapy, high doses of corticosteroids); or malignant progressive diseases. Previous abdominal surgery was also recorded. The patient s history was recorded: the date of the onset of symptoms, the date and reason for the patient s admission, date of peritonitis diagnosis and aetiology of peritonitis. APACHE II scores were calculated for each patient upon admission. The date and the type of surgical treatment of peritonitis were recorded. Microorganisms isolated from intra-operative peritoneal samples were also analysed. Antimicrobial treatment management Pre-hospitalization antimicrobial treatment was defined as that given before the patient s admission, pre-operative antimicrobial treatment as that given at the time of admission, and peri-operative empirical antimicrobial treatment as that given on the day of surgery and before the availability of microbiological data. Post-operative antimicrobial management was reported, focusing on its eventual modification according to the results of microbiological samples. Treatment for enterococcal infection was analysed specifically. Assessment of patient s outcome The duration of mechanical ventilation, lengths of stay in the ICU and in hospital and post-operative extra-abdominal nosocomial infections were recorded. The number of deaths within 30 days following the diagnosis of peritonitis was specified. For patients who had left before 30 days, these were considered as being still alive after 30 days if they had not been readmitted to our departments. Statistical analysis Quantitative parameters were expressed as mean ± S.D. or as median (5th and 95th percentiles) according to their distribution. The χ 2 test or Fisher s exact test was used for comparing distributions of the qualitative parameters. Prognostic factors at the day of peritonitis diagnosis were determined considering demographic data, patient s history, severity of the illness, surgical management, microbiological data and patient s outcome (death at 30 days after diagnosis of peritonitis). Univariate analysis of prognostic factors was performed using Student s t-test or the Kruskal Wallis test for comparing quantitative parameters or the Mantel Haenzel χ 2 test for comparing qualitative parameters. A multivariate analysis using an unconditional stepwise logistic regression was performed, with variables significant at a P value of 0.10 as assessed by univariate analysis, to control all the confounding factors. One analysis was thus made for each group of coherent variables. Adjusted odds ratios and their 95% confidence intervals were provided. The limit for entering or removing variables in the logistic regression models was a P value of <0.10. Statistical analyses were performed using SAS software, version 6.08 (SAS Institute Inc., Cary, NC, USA). Results One hundred and twenty patients (48 females, 40%) were included. Peritonitis was post-operative in 38 cases. Median age was 61 years (5% to 95% percentiles, 25 87). Underlying diseases are reported in Table 1. Causes of admission were 570

3 Antimicrobial management of secondary peritonitis Table 1. Pre-existing comorbid disorders at the time of admission for 120 peritonitis patients Patients Comorbid conditions n % Current smoking Alcoholism Obesity Allergy Metabolic diseases dyslipidaemia diabetes mellitus Cardiovascular diseases congestive heart failure coronary artery disease Chronic pulmonary disease Immunocompromised patients corticotherapy HIV infection Malignant disease solid tumour haemopathy Previous abdominal surgery abdominal pain in 64 patients (54%), mechanical ileus in 17 (14%), deterioration of health in 11 (9.3%) and miscellaneous in 28 (22.7%). Upon admission to the ICU, the median APACHE II score was 10 (range 2 26). The median period between the onset of symptoms and diagnosis was 3 days Table 2. Microorganisms isolated from peri-operative intraperitoneal samples Organisms community acquired (n = 59) (range 0 70 days). The median period between diagnosis and surgery was 0 days (range 0 5 days). Aetiologies of peritonitis were: perforation of the large bowel (n = 48), perforation of the stomach (n = 23), appendicitis (n = 14), pancreatitis (n = 13), cholecystitis (n = 10), perforation of the small bowel (n = 9) and miscellaneous (n = 3). In all patients, surgical treatment was completed by evacuation of pus and peritoneal lavage. The type of surgery carried out was as follows: appendicectomy (n = 14), gastric or duodenal suture (n = 18), gastric resection (n = 5), cholecystectomy (n = 14), pancreatic necrosectomy (n = 13), small bowel suture (n = 4), small bowel resection with anastomosis (n = 5), small bowel anastomosis resection without anastomosis (n = 5), Hartman s operation (n = 23), colonic resection (n = 25) and miscellaneous (n = 3). Mortality was not significantly different in patients needing re-operation (23.5% versus 25.2%, P = 0.87). Patients were mechanically ventilated post-operatively for 1 day (range 0 32 days). The median lengths of stay at the ICU and in hospital were 4 (range 0 36) and 18 (range 4 70) days, respectively. Post-operative extra-abdominal nosocomial infection occurred in 22 patients (18.3%); it was most frequent in patients with peri-operative peritoneal sample isolates [10 (34.5%) versus 12 (13.2%), P = 0.01]. Thirty patients died within 30 days of admission (25%). Peri-operative intra-abdominal samples were taken in 90 patients and were positive in 68 patients. The median number of bacterial species per patient was 1 (range 0 4). The microorganisms isolated are shown in Table 2. Escherichia coli, Enterococcus, Staphylococcus aureus and fungi were Patients with samples available from cultures post-operative or nosocomial (n = 31) total (n = 90) Aerobic Gram-negative aerobic and facultative E. coli Klebsiella spp Pseudomonas aeruginosa others Gram-positive aerobic and facultative Enterococcus spp Streptococcus spp S. aureus Anaerobic Fungi Candida albicans Candida tropicalis 2 2 Candida parapsilosis 1 1 Total no. of microorganisms

4 A. Sotto et al. isolated in 39, 29, 12 and nine patients, respectively. Among the cases of E. coli, 43.6% were resistant to amoxicillin, 25.6% to a combination of amoxicillin and clavulanic acid and 5.1% to fluoroquinolones. Among the isolates of Enterococcus (n = 29), none was resistant to glycopeptides. Among Enterococcus faecalis (n = 26), none was resistant to gentamicin and one (3.8%) was resistant to amoxicillin. Among Enterococcus faecium (n = 3), one (33.3%) was resistant to gentamicin and two (66.6%) were resistant to amoxicillin. Among S. aureus, 25% were resistant to oxacillin. Fungi were isolated from peritonitis following upper gastrointestinal tract perforation in four patients and following necrotic pancreatitis in three patients. Enterococcus was associated with at least one other microorganism in 24 patients. In 25 out of 32 patients receiving pre-operative antimicrobial treatment, intraperitoneal samples were positive. They were positive in 43 of 58 patients not receiving pre-operative antimicrobial treatment (P = 0.67). Prognostic factors Using univariate and multivariate analyses, the APACHE II score (P = 0.005), age (P = 0.002), presence of Enterococcus in the peri-operative samples (P = 0.02) and period between diagnosis and surgery (P = 0.04) were predictive of death within 30 days after diagnosis of peritonitis. There was a trend to significance for post-operative or nosocomial peritonitis as predictors of death (P = 0.06) (Tables 3 and 4). Antimicrobial treatment In 21 patients (17.5%), pre-hospitalization antimicrobial treatment had been prescribed. Pre-operative antimicrobial treatment had been given in 42 patients (35%). The median duration for pre-operative antibiotic treatment was 1.5 days (range 0 24 days). Peri-operative empirical antimicrobial treatment was initiated in all patients, using 52 different antimicrobial regimens. The number of antimicrobial agents per patient was three (range one to four). These antimicrobial regimens corresponded to seven types of monotherapy, three of which (42.8%) corresponded to a co-amoxiclav combination, 25 regimens with two agents, 10 of which corresponded to a β-lactam with an anti-anaerobic agent and seven consisted of a β-lactam associated with an aminoglycoside. There were 76 three-agent regimens mainly consisting of a thirdgeneration cephalosporin used in combination with aminoglycoside and an anti-anaerobic agent. Lastly, there were 12 four-agent regimens consisting of a third-generation cephalosporin, an aminoglycoside, an anti-anaerobic agent and a glycopeptide. Management of the post-operative treatment is shown in Table 5. In 71 patients (59%) the initial antimicrobial treatment was continued. The time taken to change the antimicrobial treatment according to the microorganism identified was 6 days (range 0 19 days). The mortality rate was 27.7% (15 deaths) among the 54 patients receiving appropriate post-operative treatment versus 28.5% (four deaths) among the 14 patients receiving inappropriate treatment (P = 0.96). The mortality rate was 29.4% (20 deaths) among the 68 patients with a positive culture of intraperitoneal sample versus 19.2% (10 deaths) in the 52 with negative cultures (P = 0.2). A potentially effective treatment against Enterococcus was given pre-operatively for 26 patients (16 antimicrobial regimens including amoxicillin, five including piperacillin and five a glycopeptide). When secondary peritonitis was diagnosed, a potentially efficient anti-enterococcus treatment was initiated for 53 patients (17 antimicrobial regimens including amoxicillin, 22 including piperacillin and 14 including a glycopeptide). The management of anti-enteroccocal treatment was only analysed in 28 of 29 patients in whom Enterococcus was identified peri-operatively, because one died prematurely. When peri-operative treatment is considered, the mortality rate was the same (six of 14) for patients with appropriate empirical treatment against Enterococcus and those treated inappropriately (P = 1). In the post-operative period, antimicrobial treatment was changed in 19 of 28 patients. Antimicrobial therapy was changed to treat Enterococcus in eight patients, to treat other pathogens in eight patients, Enterococcus having been treated already, and to treat another bacteria in three patients, without treatment against Enterococcus. In the 22 patients with adapted post-operative treatment (14 with empirical appropriate treatment: seven antimicrobial regimens including piperacillin and seven including a glycopeptide) and eight with a post-operative change to treat Enterococcus (one antimicrobial regimen including amoxicillin, one including piperacillin and six including a glycopeptide), the mortality rate was 40.9% (nine out of 22) versus 50% (three out of six) in the other patients (P = 1). Discussion The treatment of secondary peritonitis is a subject to debate, and several fundamental questions remain unanswered. Should the antibiotics chosen be effective against all the intraperitoneal microorganisms? Should a single broad-spectrum β-lactam or combination with an aminoglycoside be used? What is the optimal duration of this treatment? What abdominal lavage should be performed? 21 This study showed results that were comparable to previous studies, confirming that our population of patients was representative. The mortality rate was 25% compared with other studies that report it to be 30%, with a wide range (0 70%). 7,22 The predictive factors that we found were reported in other studies. APACHE II appears to be the most reliable prognosis index for peritonitis. 4 The sites of perforation causing peritonitis were comparable with those described 572

5 Antimicrobial management of secondary peritonitis Table 3. Univariate analysis of demography, history, clinical and paraclinical factors present at the time of admission that were associated with death within 30 days Univariate analysis deaths (n = 30) survivors (n = 90) Risk factors n % n % P Male sex Alcoholism Current smoking Diabetes mellitus Dyslipidaemia Allergy Prior abdominal surgery Corticotherapy Congestive heart failure Coronary artery disease Respiratory insufficiency Haemopathy Solid tumour HIV infection Post-operative or nosocomial peritonitis Enterococcus Fungus Post-operative extra-abdominal nosocomial infection median (5% to 95% pc) median (5% to 95% pc) Age (years) 78 (40 92) 53 (19 82) Body mass index 23 (16 30) 24 (17 32) 0.13 Maximal temperature ( C) 39 ( ) 38.5 ( ) APACHE II 18 (10 36) 9 (2 22) Period between onset of symptoms and 6 (0 95) 2 (0 47) 0.03 diagnosis (days) Period between diagnosis and surgery (days) 0 (0 15) 0 (0 3) 0.07 Maximal leucocytosis (cells/mm 3 ) ( ) ( ) 0.02 Number of sites infected 1 (0 3) 1 (0 2) 0.05 Number of microorganisms isolated per patient 2 (0 6) 1 (0 3) 0.02 pc, percentiles. in the literature. 1,3,5,8 The need for further surgical intervention did not have any influence on prognosis. The types of microorganisms identified were those commonly observed. 2,9,23,24 A variety of antimicrobial regimens were initiated because the choice of antibiotic treatment was at the discretion of physicians. Numerous combinations of treatment are commonly used because a large number of antimicrobial agents are effective. It should be noted that in a study by Mosdell et al. 11 there were over 24 different combinations of antibiotics, and in another study by Christou et al., 1 there were 123. The difficulty of antimicrobial management lies in the diversity of the microbiological aetiology and the variation of quantity and quality of bacteria according to the position of perforation in the gastrointestinal tract. Empirical broadspectrum antimicrobial treatment appears to be effective. In the peri-operative period, most of the patients received a combination of a β-lactam with an aminoglycoside when the diagnosis of peritonitis was made. Antimicrobial treatment was changed in 49 patients. In the 36 patients with available cultures, the changes were in accordance with microbiological data. Among the 71 patients with no change in antimicrobial agents, 14 should have had changes according to the microbiological data and 13 others for reduction of the antimicrobial spectrum. Considering only the microbio- 573

6 A. Sotto et al. Table 4. Multivariate analysis of factors present at the time of admission associated with death within 30 days Risk factors Coefficients Odds ratio (95% CI) P Post-operative or nosocomial peritonitis ( ) 0.06 Enterococcus a ( ) b (0.2 5) c 0.96 Age (years) Maximal temperature ( C) APACHE II Period between diagnosis and surgery (days) a The reference level is considered as absence of Enterococcus. b Presence of Enterococcus. c Missing data. Table 5. Modification of the peri-operative antimicrobial treatment in the post-operative period for 120 patients with secondary peritonitis Patient category No. of patients (n = 120) Death (n = 30) Patients without modification of the peri-operative antimicrobial treatment in the post-operative period n = 71 n = 19 No culture data (on the peri-operative samples) available or premature death Cultures showed that a modification of the peri-operative antimicrobial 14 4 treatment was indicated in the post-operative period a Cultures showed that peri-operative antimicrobial treatment was appropriate 5 2 and no reduction of spectrum was possible in the post-operative period b Cultures showed that peri-operative antimicrobial treatment was appropriate but reduction of spectrum was possible in the post-operative period b 13 3 Patients with modification of the peri-operative antimicrobial treatment in the post-operative period n = 49 n = 11 No culture data available c 11 0 Cultures showed that a modification of the peri-operative antimicrobial 26 9 treatment was indicated in the post-operative period b Cultures showed that peri-operative antimicrobial treatment was appropriate 10 1 but modification was made in order to reduce the spectrum b Modification was made due to adverse effects 2 1 a Inappropriate treatment strategy. b Appropriate strategy. c Change was motivated by clinical failure because microbiological samples were not contributive or available. logical aspect, 14 of 68 patients (20.6%) with cultures available received inappropriate antimicrobial treatment, but the mortality rate was not affected. The exact role of Enterococcus remains controversial. 25 Authors have suggested that its presence increases the infectious post-operative complication rate, but does not seem to affect the overall mortality. 16,23 Experimental data have showed that Enterococcus has developed a synergic relationship with other bacteria, leading to increased morbidity and mortality. 26,27 Nevertheless, clinical success could be obtained with an empirical treatment that does not take Enterococcus into account. The treatment of other bacteria, such as E. coli or anaerobic bacteria, stops the development of Enterococcus. 27 In the patients from the present study in whom Enterococcus was peri-operatively isolated, the mortality rate was not influenced by appropriate antibiotic treatment. 574

7 Antimicrobial management of secondary peritonitis These data could suggest that Enteroccocus has a proinflammatory role and is therefore not susceptible to antibiotics. 27,28 The absence of correlation between the expected outcome and susceptibility of the isolated microorganisms is frequently reported in the literature. For Mosdell et al., 11,29 peri-operative samples may not be justified because the culture results were ignored by the physician in the post-operative period and an appropriate change did not seem to influence the outcome. There are several contributing factors. (i) The period between the onset of symptoms and diagnosis. In this study, it was greater in patients who died, 6 versus 2 days (P = 0.03 by univariate analysis). (ii) An early and efficient surgical treatment. In this study the period between diagnosis and surgery was a predicting factor of mortality by multivariate analysis (P = 0.04). (iii) The delay in finding suitable post-operative antimicrobial treatment according to the culture results. However, the time required to obtain culture results is at least 2 days (up to 4 days for anaerobic bacteria). (iv) The virulence of the microorganisms 30,31 and the large inoculum size, 32 which may explain failure of antimicrobial treatment even though the bacteria were susceptible. 19 In our study, a number of infected sites and the number of microorganisms isolated per patient were associated with mortality by univariate analysis. (v) The host defence responses. 33 Therefore, the outcome is probably determined in the first few hours of the history of peritonitis, and these factors must be taken into account in clinical trial procedures to investigate the efficiency of antimicrobial treatment. Although the study by Christou et al. 1 does not suggest it, there are several bibliographic arguments for thinking that there could be a linear relationship between the time from diagnosis to surgical intervention and the increase in mortality. 6,9 Only 90 peritoneal samples were taken from 120 patients, and they were positive in only 68 patients. This situation is frequently encountered in literature since, in the study by Mosdell et al., 11 only 68% of patients had had peri-operative samples taken compared with 70.2% in the Pacelli et al. 8 study. Pre-operative antimicrobial treatment did not influence the results of the microbiological samples, partly because of the difficulty in isolating anaerobic organisms, which were found in only 18 patients. The importance of isolated anaerobes varies according to authors. In some studies, specifically intended to explore microbial aetiology, optimal techniques were employed and their proportion could reach 80%. 33 In conclusion, this study confirms the ability of the APACHE II score to predict the severity of peritonitis at the time of admission and emphasizes the importance of prompt surgical treatment, in contrast to the modest impact of adapted antibiotic treatment on prognosis. The latter seems to be decisive in the first hours of the evolution. The morbidity and mortality associated with the presence of Enterococcus in peritoneal fluid, not influenced by the treatment of this microorganism, would seem to suggest a pro-inflammatory role of Enterococcus, as shown in animal models and evoked in humans. 16,27,28 Specific, prospective, randomized studies are needed to evaluate the real contribution of enterococcal antibiotic coverage in this context, where underlying diseases and surgical techniques are important. Acknowledgements We gratefully acknowledge the assistance of A. Dadban and O. Ghalembor in the preparation of this manuscript. References 1. Christou, N. V., Barie, P. S., Dellinger, E. P., Waymack, J. P. & Stone, H. H. (1993). Surgical Infection Society intra-abdominal infection study. Prospective evaluation of management techniques and outcome. Archives of Surgery 128, Wacha, H., Hau, T., Dittmer, R., Ohmann, C. & the Peritonitis Study Group. (1999). Risk factors associated with intraabdominal infections: a prospective multicenter study. Langenbecks Archiv für Chirurgie 384, Schoeffel, U., Jacobs, E., Ruf, G., Mierswa, F., Von Specht, B. U. & Farthmann, E. H. (1995). Intraperitoneal micro-organisms and the severity of peritonitis. European Journal of Surgery 161, Knaus, W. A., Draper, E. A., Wagner, D. P. & Zimmerman, J. E. (1985). APACHE II: a severity of disease classification system. Critical Care Medicine 13, Ohmann, C. & Hau, T. (1997). Prognostic indices in peritonitis. Hepatogastroenterology 44, Ohmann, C., Yang, Q., Hau, T., Wacha, H. & the Peritonitis Study Group of the Surgical Infection Society Europe. (1997). Prognostic modelling in peritonitis. European Journal of Surgery 163, Koperna, T. & Schulz, F. S. (1996). Prognosis and treatment of peritonitis. Do we need new scoring systems? Archives of Surgery 131, Pacelli, F., Doglietto, G. B., Alfieri, S., Piccioni, E., Sgadari, A., Gui, D. et al. (1996). Prognosis in intra abdominal infections. Multivariate analysis of 604 patients. Archives of Surgery 131, Bohnen, J. M., Mustard, R. A., Oxholm, S. E. & Schouten, D. (1988). APACHE II score and abdominal sepsis. A prospective study. Archives of Surgery 123, Goffi, L., Saba, V., Ghiselli, R., Necozione, S., Mattei, A. & Carle, F. (1999). Preoperative APACHE II and ASA scores in patients having major general surgical operations: prognostic value and potential clinical applications. European Journal of Surgery 165, Mosdell, D. M., Morris, D. M., Voltura, A., Pitcher, D. E., Twiest, M. W., Milne, R. L. et al. (1991). Antibiotic treatment for surgical peritonitis. Annals of Surgery 214, Dougherty, S. H. (1997). Antimicrobial culture and susceptibility testing has little value for routine management of secondary bacterial peritonitis. Clinical Infectious Diseases 25, S

8 A. Sotto et al. 13. Onderdonk, A. B., Bartlett, J. G., Louie, T., Sullivan-Seigler, N. & Gorbach, S. L. (1976). Microbial synergy in experimental intraabdominal abscess. Infection and Immunity 13, Weinstein, W. M., Onderdonk, A. B., Bartlett, J. G. & Gorbach, S. L. (1974). Experimental intra-abdominal abscesses in rats: development of an experimental model. Infection and Immunity 10, Weinstein, W. M., Onderdonk, A. B., Bartlett, J. G., Louie, T. J. & Gorbach, S. L. (1975). Antimicrobial therapy of experimental intraabdominal sepsis. Journal of Infectious Diseases 132, Burnett, R. J., Haverstock, D. C., Dellinger, P., Reinhart, H. H., Bohnen, J. M., Rotstein, O. D. et al. (1995). Definition of the role of Enterococcus in intraabdominal infection: analysis of a prospective randomized trial. Surgery 118, Laroche, M. & Harding, G. (1998). Primary and secondary peritonitis: an update. European Journal of Clinical Microbiology and Infectious Diseases 17, Dupont, H., Carbon, C. & Carlet, J. (2000). Monotherapy with broad spectrum beta-lactam is as effective as its combination with an aminoglycoside in treatment of generalized peritonitis: a multicenter randomized controlled trial. Severe Generalized Peritonitis Study Group. Antimicrobial Agents and Chemotherapy 44, Cohen, J. (2000). Combination antibiotic therapy for severe peritonitis. Lancet 356, Crowley, B. (2001). Antibiotic therapy and peritonitis. Lancet 357, Scheuerlein, H., Kube, R., Gastinger, I. & Kockerling, F. (2000). Prospective multicenter comparative study of the management of peritonitis. Quality assurance in severe intraabdominal infection. Zentralblatt für Chirurgie 125, Suppl. 2, Bohnen, J., Boulanger, M., Meakins, J. L. & McLean, P. H. (1983). Prognosis in generalized peritonitis. Relation to cause and risk factors. Archives of Surgery 118, Hopkins, J. A., Lee, J. C. & Wilson, S. E. (1993). Susceptibility of intra abdominal isolates at operation: a predictor of postoperative infection. American Surgeon 59, Sawyer, R. G., Rosenlof, L. K., Adams, R. B., May, A. K., Spengler, M. D. & Pruett, T. L. (1992). Peritonitis into the 1990s: changing pathogens and changing strategies in the critically ill. American Surgeon 58, Nichols, R. L. & Muzik, A. C. (1992). Enterococcal infections in surgical patients: the mystery continues. Clinical Infectious Diseases 15, Matlow, A. G., Bohnen, J. M., Nohr, C., Christou, N. & Meakins, J. (1989). Pathogenicity of enterococci in a rat model of fecal peritonitis. Journal of Infectious Diseases 160, Montravers, P., Andremont, L., Massias, L. & Carbon, C. (1994). Investigation of the potential role of Enterococcus faecalis in the pathophysiology of experimental peritonitis. Journal of Infectious Diseases 169, Montravers, P., Mohler, J., Saint Julien, L. & Carbon, C. (1997). Evidence of the proinflammatory role of Enterococcus faecalis in polymicrobial peritonitis in rats. Infection and Immunity 65, Mosdell, D. M., Morris, D. M. & Fry, D. E. (1994). Peritoneal cultures and antibiotic therapy in pediatric perforated appendicitis. American Journal of Surgery 167, Murray, B. E. & Weinstock, G. M. (1999). Enterococci: new aspects of an old organism. Proceedings of the Association of American Physicians 111, Duerden, B. I. (1994). Virulence factors in anaerobes. Clinical Infectious Diseases 18, Suppl. 4, S Condon, R. E. (1999). Microbiology in intraabdominal infections: what is the message for clinical studies? Infection 27, Farthmann, E. H. & Schöffel, U. (1998). Epidemiology and pathophysiology of intraabdominal infection. Infection 26,