OUTCOME FOLLOWING CAPD-ASSOCIATED GRAM-NEGATIVE PERITONITIS

66 OUTCOME FOLLOWING CAPD-ASSOCIATED GRAM-NEGATIVE PERITONITIS CHIA-SHENG CHEN, SHYI-YU CHUNG, WEN-LIANG YU*, MING-TZUNG KAO Peritonitis remains the leading cause of patient dropout from peritoneal dialysis therapy. Gram-positive [G (+)] bacteria predominate among the pathogens causing continuous ambulatory peritoneal dialysis (CAPD)-associated peritonitis. Gram-negative [G (-)] peritonitis has a poor outcome. Few studies have compared the outcomes for different kinds of G (-) peritonitis in patients undergoing CAPD. This study compared morbidity, mortality and outcomes for peritonitis caused by common G (-) bacilli, including Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa), and Enterobacter spp. A retrospective review study was designed for a single regional dialysis unit in a medical center. Between January 1, 1998 and December 31, 2000, a total of 220 episodes of CAPDassociated peritonitis were recorded in 120 patients, with 45 of these episodes caused by G (-) organisms. Survival analysis was performed for time to (1) death, (2) removal of the peritoneal dialysis catheter and (3) changing to hemodialysis. Demographic data, hospital admission, laboratory values, infection type and route of antibiotic administration were also recorded and analyzed. There were no differences in age, sex, diabetes mellitus (DM), hospital admission, positive blood cultures, infection type or the antibiotic administration route among the four etiologic groups. Of note, serum albumin was higher in the E. coli group than in the other groups (p < 0.05). No differences in time to death, removal of the peritoneal dialysis catheter, or change to hemodialysis were demonstrated among the four groups (p = 0.48). Results indicate that the outcomes for peritonitis caused by E. coli, K. pneumoniae, P. aeruginosa and Enterobacter spp do not differ significantly. Further observations and an increased sample size may confirm this finding. (Acta Nephrologica 2001; 15: 66-70) Key words: continuous ambulatory peritoneal dialysis, Gram-negative peritonitis, outcome INTRODUCTION Peritonitis remains the leading cause of patient dropout from peritoneal dialysis therapy. 1 Gram-positive [G (+)] bacteria predominate among the pathogens causing continuous ambulatory peritoneal dialysis (CAPD)- associated peritonitis. 2 Various studies have compared the outcomes of Gram-positive and Gram-negative [G ( )] peritonitis, 3 with some studies highlighting the serious nature of Staphylococcus aureus peritonitis and the need for effective preventive measures directed against this pathogen. 4 In contrast, few studies have compared outcomes among patients undergoing CAPD who develop various kinds of G ( ) peritonitis, even though G ( ) peritonitis is recognized as having a poorer outcome. The number of G ( ) peritonitis cases increased in recent years in the authors hospital. Some authors also report that the relative incidence of G ( ) peritonitis has increased. 5 In our experience, some cases caused by some G ( ) bacilli such as Klebsiella pneumonia other than Pseudomonas aeruginosa showed more virulent. In response, this study was designed to determine what, if any, differences existed in terms of morbidity, mortality and outcomes in patients with peritonitis caused by the more common G ( ) bacilli, including Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa) and Enterobacter spp. MATERIALS AND METHODS Divisions of Nephrology and *Infections Disease, Department of Internal Medicine, China Medical College Hospital, Taichung, Taiwan, ROC Received: February, 2002 Revised: May, 2002 Accepted: July, 2002 Address reprint requests to: Dr. Shyi-Yu Chung, Division of Nephrology, Department of Internal Medicine, China Medical College Hospital, No 2, Yuh-Der Road, Taichung 404, Taiwan, R.O.C. Tel: (04) 22052121 ext. 2012 E-mail: chiaseng@pagic.net

Acta Nephrologica CAPD-associated peritonitis 67 Design and patients The study was performed in the peritoneal dialysis (PD) unit of the China Medical College Hospital between January 1, 1998 and December 31, 2000. The PD center services about 250 patients. All patients had double-cuff silastic Tenckhoff catheters that had been inserted using standard surgical techniques. 6 The Baxter Solo (Baxter Healthcare, IL, U.S.A) disconnected system; Ultrabag and PD2-PD solution were used in this study and a nephrologist prescribed all PD orders. Peritonitis was defined as the presence of a cloudy dialysis effluent with greater than 100 white blood cells/ µl and a white blood cell differential count showing greater than 50% polymorphonuclear cells. 6 Peritoneal effluents were cultured using standard microbiological methods. 7 Patients were retrospectively identified by positive peritoneal dialysate culture after January 1, 1998 and were enrolled in the study if they fulfilled the following criteria: (1) dialysate culture positive for either E. coli, K. pneumoniae, Enterobacter spp or P. aeruginosa, in association with peritonitis. Patients with mixed infections were excluded. An episode of peritonitis was defined as either the first episode of infection, recurrence or re-infection. Recurrence was defined as another episode of peritonitis that was caused by the same genus/species that had caused the immediately preceding episode occurring within four weeks of completion of the antibiotic course. Re-infection was defined as a new episode of peritonitis more than four weeks later with the same organism. 8 The antibiotics prescribed and removal of the peritoneal catheter were in accordance with standard clinical practice guidelines. 9 Data analysis Demographic data, including age and sex, the presence or absence of diabetes mellitus (DM), hospital admission, causal organism, serum albumin concentration, infection type (new episode, recurrence or re-infection) and the antibiotic administration route [intravenous (IV) or intra-peritoneal (IP)] were recorded. Survival analysis was performed for time to (1) death within two weeks, (2) death within six months, (3) removal of the peritoneal dialysis catheter, and (4) change to hemodialysis. Nominal variables were compared using Fisher s exact test. Continuous variables were compared between groups using the Mann-Whitney U test. Survival analysis was done using the Kaplan-Meier method and survival groups were compared using the Peto-Peto-Wilcoxon test. Patients were censored at the time at which they were lost to follow-up, and censored for death when variables other than time to death were analyzed. RESULTS The study spanned the period between January 1, 1998 and December 31, 2000. There was a total of 220 CAPD-associated peritonitis episodes among 120 patients. Of these, 175 episodes were caused by G (+) organisms and 45 episodes were caused by G ( ) organisms. There were 35 episodes of G ( ) peritonitis enrolled into the study: nine episodes due to E. coli, 10 episodes due to P. aeruginosa, 4 episodes due to K. pneumoniae and 12 episodes due to Enterobacter spp peritonitis. There was no difference in age or sex among the four patient groups (Table 1). Patients developing E. coli peritonitis were less likely to have DM, require hospitalization or require IV antibiotics, but the differences were not statistically significant. The likelihood of a positive blood culture exhibited no differences among the four groups (Table 1). The infection types did not differ among the four groups either (Table 2). The only significantly different finding was that serum albumin was higher in the E. coli group than in the other groups (p < 0.05). (Fig. 1 and 2) show the Kaplan-Meyer cumulative survival plots for time to removal of the PD catheter and change to hemodialysis, comparing patients with E. coli, P. aeruginosa, K. pneumoniae or Enterobacter spp peritonitis. There was no difference among the four groups in time to removal of the peritoneal dialysis catheter, or change to hemodialysis (p = 0.48) The two-week and six-month outcomes of patients who developed peritonitis caused by each of the four organisms were analyzed. On casual inspection of the data, there seemed to be a better outcome for Enterobacter spp. associated peritonitis, but the difference was not statistically significant (p = 0.50) (Table 3). DISCUSSION The study aimed to analyze outcomes following CAPD-associated G ( ) peritonitis in order to establish how, if at all, infections caused by E. coli, P. aeruginosa, K. pneumoniae and Enterobacter spp differed. Troidle et al reported that G ( ) peritonitis was more severe in terms of morbidity and mortality than G (+) peritonitis in CAPD patients, 3 and an increased rate of hospitalization for CAPD patients was observed not only for patients with peritonitis caused by Pseudomonas organisms, but also for patients with peritonitis caused by other G ( ) organisms. The opsonic activity of spent dialysate against G ( ) bacteria is substantially lower than that seen against G (+) bacteria. 10 This may account, at least in part, for the greater severity of G ( ) infections in CAPD patients.

68 C. S. CHEN, S. Y. CHUNG, W. L. YU, M. T. KAO Vol. 15, No. 2, 2001 Table 1. Demographic data E. coli Pseudomonas Klebsiella Enterobacter P value N= 9 N= 10 N= 4 N= 12 Age (y/o) 62.0±14.7 61.9±9.4 52.0±12.8 50.5±16.1 0.197 Sex (male) 44.4% 40% 25% 58.3% NS Patients with DM 22.2% 50% 50% 58.3% 0.423 Patients with Admission 55.6% 80% 100% 66.7% 0.425 Blood culture (+) 33.3% 30% 25% 8.3% 0.459 Serum albumin 3.42±0.78 2.43±0.60 2.45±0.79 2.69±0.40 0.0481* Antibiotics (ivd) 44.4% 50% 75% 50% 0.84 * P value < 0.05, NS = not significant Table 2. The infection types among the four groups E. coli Pseudomonas Klebsiella Enterobacter N= 9 N= 10 N= 4 N= 12 New infection 77.78% 100.00% 75.00% 75.00% Recurrence 22.22% 0.00 25.00% 8.33% Re-infection 0.00 0.00 0.00 16.67% Fisher s Exact Test (2-Tail) P value: 0.332 Table 3. Survival analysis E. coli P. aeruginosa K. pneumonia Enterobacter P value Time to HD (score) 19.28 15.5 18.75 18.88 0.791 Time to remove catheter (score) 19.28 15.5 18.75 18.88 0.7917 Death within 2 weeks 33.33% 20% 25% 8.33% 0.5 Death within 6 months 33.33% 30% 25% 8.33% 0.459 A: E. coli, B: P. aeruginosa, C: K. pneumoniae, D: Enterobacter spp. Fig. 1. Survival analysis (P = 0.791) showing the Kaplan-Meyer cumulative survival plots for time to change to hemodialysis, comparing patients with E. coli, P. aeruginosa, K. pneumoniae or Enterobacter spp peritonitis.

Acta Nephrologica CAPD-associated peritonitis 69 A: E. coli, B: P. aeruginosa, C: K. pneumoniae, D: Enterobacter spp. Fig. 2. Survival analysis (P=0.791) showing the Kaplan-Meyer cumulative survival plots for time to removal of the PD catheter, comparing patients with E. coli, P. aeruginosa, K. pneumoniae or Enterobacter spp peritonitis. There are five different possible routes of infection in CAPD: (1) intra- or transluminal, (2) periluminal, (3) transmural, (4) hematogenous and (5) ascending. The first three types occur most frequently, of which the first two directly involve the catheter. 2 The Enterobacteriaceae are a large, heterogeneous group of G ( ) rods whose natural habitat is the intestinal tract of humans and animals. The family includes many genera: Escherichia, Shigella, Salmonella, Enterobacter, Klebsiella, Serratia, Proteus, and others. 11 Transmural infection by the Enterobacteriaceae in CAPD patients may be via intact bowel wall or severely compromised bowel wall, following wall perforation or necrosis. The passage of bacteria through a viable bowel wall may be promoted by otherwise silent diverticulosis or bowel ischemia, and in susceptible individuals, may occur after chemical laxative treatment of constipation. 2 Pseudomonas organisms are widely found in the environment, in soil, water, plants and animals. Pseudomonas aeruginosa is frequently present in small numbers in the normal intestinal flora and on the skin of humans. It is the most frequently encountered pathogen of the Pseudomonas group. 11 Pseudomonas can sometimes infect CAPD patients periluminally. 2 Peritonitis caused by Pseudomonas spp is notoriously resistant to treatment, 12-14 because the bacteria are highly adherent to Tenckhoff catheter material, 15 and they have often caused tunnel infection. 16 Due to the biofilm produced by Pseudomonas aeruginosa, at least three to four weeks of antibiotic treatment are necessary to eradicate the infection, and early removal of the PD catheter is indicated if the patient s clinical condition deteriorates. 12 Most patients with CAPD associated peritonitis can be treated in the clinical setting and will not require hospital admission. Patients with (1) hypotension, (2) refractory nausea and vomiting, (3) severe abdominal pain or (4) toxic clinical appearance (sepsis signs) warrant inpatient observation and care. 2 Antibiotics were administrated intraperitoneally (IP) by adding the antibiotics into the PD solution bag. 17 If patients developed toxic signs, antibiotic administration was switched from IP to intravenous (IV). Our study failed to show any statistically significant difference in severity or toxicity between the different organisms. Although blood cultures are uniformly negative and unnecessary in uncomplicated cases of CAPD-associated peritonitis, bacteremia may occur if intra-abdominal or extra-abdominal septic foci are present. Blood cultures were obtained from the patients if the dialysate fluid cultures yielded G ( ) bacteria. The rate of positive blood cultures exhibited no correlation to the clinical severity of CAPD- associated peritonitis. A commonly held notion is that a poorer outcome generally follows CAPD- associated Pseudomonas aeruginosa peritonitis when compared to peritonitis caused by other Enterobacteriaceae. Our study failed to show

70 C. S. CHEN, S. Y. CHUNG, W. L. YU, M. T. KAO Vol. 15, No. 2, 2001 any difference in survival among the patient groups with peritonitis due to the four different bacteria studied. We suspect that although P. aeruginosa is more virulent, it invades the human body commonly through periluminal route. However, other Enterobacteriaceae invade the human body commonly through the transmural route, so it seems that a poorer underlying condition allows pathogens invade through the transmural route. Besides, there are some variant Enterobacteriaceae with more antibiotic resistance in recent years. Accordingly, the fundamental principle for treatment of CAPD-associated G ( ) peritonitis should administer antibiotics according to the dialysate culture and antibiotic sensitivity test. We should pay more attention not only to P. aeruginosa but also to other Enterobacteriaceae. Why is the serum albumin higher in the E. coli group than in the other groups (p < 0.05)? We cannot explain. It may be due to the limited case numbers. We hope that further prospective observations and an increased sample size may confirm this finding. REFERENCE 1.Burkart J, Schreiber M, Tabor T, et al: Prospective, multicenter evaluation of patient transfer from peritoneal dialysis to hemodialysis in 1995. Perit Dial Int 1996; 16: 66. 2.Antonios H, Tzamalouks, Lucy Fox: infections in patients on continuous ambulatory peritoneal dialysis. In: William L. Henrich. Principles and practices of dialysis, Baltimore; William & Wilkins, 1999: 556-77. 3.Troidle L, Gorban-Brennan N, Kliger A, et al: differing outcomes of Gram-positive and Gram-negative peritonitis. Am J Kidney Dis 1998; 32: 623-8. 4.Peacock SJ, Howe PA, Day NPJ, et al: Outcome following staphylococcal peritonitis. Perit Dial Int 2000; 20: 215-9. 5.Keane WF, Bailie GR, Boeschoten E, et al: Adult peritoneal dialysis-related peritonitis treatment recommendation 2000 updates. Perit Dial Int 2000; 20: 396-411. 6.Kazmi H, Raffone D, Kliger A, et al: Pseudomonas exit site infections in continuous ambulatory peritoneal dialysis patients. J Am Soc Nephrol 1988; 16: 128-40. 7.Troidle L, Kliger AS, Gorban-Brennan R, et al: Nine episodes of CPD associated peritonitis with vancomycin-resistant enterococci. Kidney Int 1996; 50: 1368-72. 8.Gokal R: Infectious complications and peritonitis and their management. In: Lameire N, Mehta RL. Complication of dialysis, New York; Marcel Dekker, 2000: 195-6. 9.Keane W, Alexander SR, Bailie GR, et al: Peritoneal dialysis-related peritonitis treatment recommendations: 1996 update. Perit Dial Int 1996; 16: 557-73. 10.Keane WF, Comty CM, Verbrugh HA, et al: Opsonic deficiencies of peritoneal dialysis effluent in CAPD. Kidney Int 1984; 25: 539-43. 11.Brooks GF, Butel JS, Morse SA: Medical microbiology. New York; McGraw-Hill, 2001; 229-34. 12.Bernardini J, Piraino B, Sorkin M: Analysis of continuous ambulatory peritoneal dialysis-related Pseudomonas aeruginosa infections. Am J Med 1987; 83: 829-32. 13.Chan MK, Chan PCK, and Cheng IPK, et al: Pseudomonas peritonitis in CAPD patients: characteristics and outcomes of treatment. Nephrol Dial Transplant 1989; 4: 814-7. 14.Bunke M, Brier ME, Golper TA: Pseudomonas peritonitis in peritoneal dialysis patients: the Network 9 peritonitis study. Am J Kidney Dis 1995; 25: 769-74. 15.Craddock CF, Edwards R, Finch RG: Pseudomonas peritonitis in continuous ambulatory peritoneal dialysis: laboratory prediction of treatment failure. J Hosp Infect 1987; 10: 179-86. 16.Krothapali R, Duffy WB, Lacke C, et al: Pseudomonas peritonitis and continuous ambulatory peritoneal dialysis. Arch Intern Med 1982; 142: 1862-3. 17. Keane WF, Alexander SE, Bailie GR, et al: Peritoneal dialysis related peritonitis treatment recommendation. Perit Dial Int 1996; 17: 561.