Peritoneal Dialysis International, Vol. 25, pp. 142145 Printed in Canada. All rights reserved.

0896-8608/05 $3.00 + .00 Copyright 2005 International Society for Peritoneal Dialysis

PERITONITIS AND AUTOMATED PERITONEAL DIALYSIS: A THERAPEUTIC CONUNDRUM?

eritonitis remains the most significant cause of morbidity for patients maintained on chronic peritoneal dialysis (CPD) therapy (1,2). Thus, developing a practical and rational approach to treating peritonitis associated with CPD therapy is critically important. The revisions of the International Society for Peritoneal Dialysis (ISPD) treatment guidelines for CPD-associated peritonitis, presented in this issue of Peritoneal Dialysis International (PDI), including suggestions based on both evidence and opinion, are a welcome addition to the ISPDs management guidelines. Several recent reports have emphasized that CPD therapy is used for a declining percent of incident and prevalent patients with end-stage renal disease (ESRD) in many countries. For example, the most recent United States Renal Data System (USRDS) report noted that CPD use in the United States decreased to <9% of the prevalent ESRD patients in 2002 (3). Ontario, Canada, has noticed a decline in CPD use, with the percent of ESRD patients on CPD decreasing from 27.3% in 1997 to 22.6% in 2002 (4). In Germany, there has also been a decrease in CPD use, from 10% in the 1990s to 5% in 2004 (5). These declines have occurred despite the fact that nephrologists in Europe, Canada, and the United States all agree that approximately 35% of prevalent ESRD patients should be maintained on CPD therapy (610). A major reason for this decline in CPD involves, in addition to problems with education about chronic kidney disease, poor physician training in CPD, and various institutional barriers, nephrologists concerns with technique failure and long-term viability of CPD therapy (10). Infections are the leading cause of technique failure in CPD patients (3). This remains so despite the dramatic advances in both CPD therapy and the treatment of peritonitis many of which are discussed in the ISPDs peritonitis committees recommendations in this issue. Thus, many nephrologists feel that the development of effective and improved treatment strategies is critically important for programs managing CPD patients, not only to improve technique success, but also to reduce morbidity and mortality. The association between peritonitis and mortality has been well documented in several studies (2,11,12). The mechanisms responsible for CPD peritonitis-associated mortality are not clear. It is worth
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noting, however, that USRDS data have consistently observed that infections are the second leading cause of death in patients with ESRD, and that infection-associated mortality is higher in CPD than hemodialysis patients (3). Thus, the development of detailed guidelines for the management of peritonitis, including the appropriate selection of antibiotics, suggestions for when to remove the catheter, and clarification of the definitions and significance of refractory and recurrent peritonitis are indeed welcome. However, the guidelines are not so helpful in providing standards of care for patients maintained on cycler therapy. This, unfortunately, reflects the limited information available in the literature concerning the therapy of peritonitis for these patients and defines a critically important area that needs additional research. The problem with the treatment of peritonitis for cycler patients is becoming more of an issue as the percent of CPD patients maintained on cycler therapy has increased. Currently, the majority of CPD patients in the United States are maintained on cycler therapy (3). The increased use of cycler therapy has occurred for several reasons. Of particular importance are the concerns expressed about the dose of dialysis delivered to CPD patients with standard ambulatory CPD (CAPD) therapy and the observation that both urea and creatinine clearances can be increased with cycler therapy (13). Furthermore, the development of new, more efficient cyclers has facilitated CPD therapy and improved patients perception of the therapy by eliminating or minimizing the need for daytime exchanges. The problem with peritonitis in cycler patients is not that cycler patients have higher rates of peritonitis, but that the optimal therapy is unclear. In fact, most studies show a similar rate of peritonitis for patients maintained on cycler and manual CAPD therapy (1417). For example, the European Automated Peritoneal Dialysis Outcomes Study (EAPOS) noted that cycling CPD patients had a peritonitis rate of 1 episode per 29.1 patientmonths, compared to a rate of 1 episode per 22.5 patient-months in patients on manual CAPD therapy (17). And there appears to be no difference in the spectrum of organisms responsible for peritonitis between cycler

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and CAPD therapy; at least two studies have confirmed that the rates of gram-positive, gram-negative, and fungal peritonitis were not statistically different between patients maintained on cycler and CAPD therapy (15,16). Pharmacokinetic studies for patients maintained on manual CAPD therapy have been performed with several antibiotics, demonstrating that adequate levels above target minimum inhibitory concentrations (MICs) for specific organisms are met using dosing strategies as outlined in the ISPD recommendations (1822). But, few studies have been performed examining the pharmacokinetics of antibiotic administration in patients maintained on cycler therapy who receive once-daily antibiotics. And, these studies have been carried out in patients who did not have peritonitis. Furthermore, the cycler prescription in these studies generally used fewer cycles than most clinicians prescribe. Manley et al. studied the effect of 2.5 g vancomycin administered intraperitoneally with a long dwell exchange and found that the dialysate concentration of vancomycin fell rapidly during three exchanges (23). Cefazolin and ceftazidime were also studied by that group (24,25). After a load of intraperitoneal 15 mg/kg ceftazidime or cefazolin, dialysate concentrations rapidly fell below target MIC with cycler therapy (24,25). Pooled dialysate concentrations of patients on automated peritoneal dialysis receiving cefazolin and ceftazidime were also well below the MIC for these antibiotics (25). More encouraging are the recent observations by Yeung et al. examining the pharmacokinetics of oral ciprofloxacin in cycler patients (26). That group noted that an oral dose of 750 mg, twice daily, provided dialysate concentrations that were above the MIC for Escherichia coli and Klebsiella sp, but were still below the MIC for Pseudomonas aeruginosa (26). Those pharmacokinetic studies raise important theoretical concerns regarding the maintenance of adequate antibiotic levels in the peritoneal dialysis fluid in patients being treated for peritonitis while still using cycler therapy. However, the few outcome studies that have been published examining outcomes of peritonitis therapy with once-daily antibiotics in patients maintained on cycler therapy with peritonitis have been encouraging. Those studies looked at once-daily gentamicin and cefazolin, once-daily gentamicin and oral ciprofloxacin, and vancomycin with once-daily ceftazidime, aztreonam, or gentamicin (11,16,27,28). Those four studies found that cure rates with continued cycler therapy occurred in 73% 88% of the episodes; catheter removal rates varied from 7.5% to 17.5% of episodes; and peritonitis-related deaths occurred in 2% 10% of episodes. These results are similar to what has been described for therapy for peritonitis in patients

maintained on CAPD therapy (1). The results of EAPOS are of interest: these authors noted a 15% recurrence rate of peritonitis in patients maintained on cycler therapy (17). Could the inadequate levels of antibiotics in the dialysate during cycler therapy result in poorer outcomes of therapy on long-term follow-up? One area of concern involves the issue of biofilm. Biofilm is a complex microbiotic community with sophisticated communication and defensive mechanisms, frequently encountered on indwelling catheters. Bacteria within the biofilm are less susceptible to leukocytes and macrophages and antibiotic penetration into biofilm is limited. Biofilm contains two dominant populations of bacteria: planktonic and sessile (29,30). Quorum-sensing molecules in the planktonic cells control biofilm development. The planktonic and the sessile populations have different genetic makeups that impact on their antibiotic susceptibility and limit the ability of antibiotics to kill the bacteria. Sepandj et al. have called attention to the importance of biofilm by noting that the minimum biofilm eradication concentration of a first-generation cephalosporin for coagulasenegative staphylococci and various gram-negative antibiotics directed at E. coli or Pseudomonas sp are substantially higher than MIC levels necessary to inhibit bacterial growth (31,32). Biofilm has been shown to be present on the peritoneal catheter (33). The organisms identified within the biofilm, after catheter removal, are the same as the organisms isolated from the patients during preceding episodes of peritonitis (34). The association of biofilm with peritonitis has been emphasized by Dasgupta (35). Of particular note in this regard is the recent study by Finkelstein et al.: these authors studied patients with more than one episode of peritonitis and observed that 80% of those repeat episodes involved the same organism that was present in prior peritonitis episodes (36). These authors raised the question of whether biofilm may play a significant role in the development of repeat or recurrent infections (36). The current ISPD peritonitis committees recommendations, in this issue of PDI, for the treatment of peritonitis in patients maintained on cycler therapy emphasize the paucity of data that has been published concerning both pharmacokinetic assessments and treatment outcome data in this critically important area. It is essential that further research be done so we can best understand the optimal therapy for peritonitis in cycler patients, particularly as the percent of CPD patients maintained on cycler therapy continues to increase (3). At present, it remains uncertain whether intermittent antibiotic therapy is as effective as continuous therapy,
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whether cycler patients should be converted back to manual CAPD therapy, or whether the rapidity of cycles needs to be decreased during intermittent antibiotic therapy. Appropriate pharmacokinetic studies need to be done and careful outcome studies need to be undertaken, looking at cure rates, recurrence and repeat infection rates, and biofilm formation on peritoneal dialysis catheters. Laura Troidle Fredric O. Finkelstein* New Haven CAPD Renal Research Institute Hospital of St. Raphael Yale University School of Medicine New Haven, Connecticut, USA *e-mail: fof@comcast.net REFERENCES
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