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

Albert Sotto1,*, Jean Yves Lefrant2, Pascale Fabbro-Peray3, Laurent Muller2, Jérôme Tafuri1, Francis Navarro4, Michel Prudhomme5 and Jean Emmanuel de La Coussaye2

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Secondary peritonitis remains a major cause of morbidity, with a mortality of ~30%.13 The Acute Physiology and Chronic Health Evaluation II (APACHE II)410 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 data4 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 models1315 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 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
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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 {chi}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 {chi}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
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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 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 (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).


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Table 1.  Pre-existing comorbid disorders at the time of admission for 120 peritonitis patients
 
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 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).


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Table 2.  Microorganisms isolated from peri-operative intraperitoneal samples
 
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).


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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
 

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Table 4.  Multivariate analysis of factors present at the time of admission associated with death within 30 days
 
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 ß-lactam with an anti-anaerobic agent and seven consisted of a ß-lactam associated with an aminoglycoside. There were 76 three-agent regimens mainly consisting of a third-generation 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).


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Table 5.  Modification of the peri-operative antimicrobial treatment in the post-operative period for 120 patients with secondary peritonitis
 
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
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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 ß-lactam or combination with an aminoglycoside be used? What is the optimal duration of this treatment?1820 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 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 broad-spectrum antimicrobial treatment appears to be effective. In the peri-operative period, most of the patients received a combination of a ß-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 microbiological 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. These data could suggest that Enteroccocus has a pro-inflammatory 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 microorganisms30,31 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.


    Footnotes
 
* Correspondence address. Département de Médecine Interne, Hopital Carémeau, rue du Professeur Debré, 30029 Nîmes Cedex 04, France. Tel: +33-4-66-68-32-31; Fax: +33-4-66-68-38-24; E-mail: albert.sotto{at}chu-nimes.fr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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