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Peritonitis is a common serious complication of peritoneal dialysis. It results in considerable morbidity, mortality, and health care costs. It also significantly limits the use of this important dialysis modality.
Peritonitis is a common serious complication of peritoneal dialysis. It results in considerable morbidity, mortality, and health care costs. It also significantly limits the use of this important dialysis modality.
Peritonitis is a common serious complication of peritoneal dialysis. It results in considerable morbidity, mortality, and health care costs. It also significantly limits the use of this important dialysis modality.
Peritoneal DialysisRelated Peritonitis: Towards Improving
Evidence, Practices, and Outcomes Yeoungjee Cho, MD, 1,2 and David W. Johnson, PhD 1,2 Peritonitis is a common serious complication of peritoneal dialysis that results in considerable morbidity, mortality, and health care costs. It also signicantly limits the use of this important dialysis modality. Despite its importance as a patient safety issue, peritonitis practices and outcomes vary markedly and unacceptably among different centers, regions, and countries. This article reviews peritonitis risk factors, diagnosis, treat- ment, and prevention, particularly focusing on potential drivers of variable practices and outcomes, contro- versial or unresolved areas, and promising avenues warranting further research. Potential strategies for augmenting the existing limited evidence base and reducing the gap between evidence-based best practice and actual practice also are discussed. Am J Kidney Dis. -(-):---. Crown Copyright 2014 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. All rights reserved. INDEX WORDS: Antibiotics; bacteria; fungi; microbiology; outcomes; peritoneal dialysis; peritonitis; practice variation; prevention; quality improvement; risk factors. David W. Johnson, PhD, was an International Distinguished Medal recipient at the 2014 National Kidney Foundation Spring Clinical Meetings. The International Distinguished Medals are awarded to honor the achievement of individuals who have made signicant contributions to the eld of kidney disease and extended the goals of the National Kidney Foundation. P eritoneal dialysis (PD) is used to treat end-stage kidney disease in more than 200,000 patients across 130 countries worldwide and accounts for w11% of the global dialysis population. 1,2 Its out- comes are comparable to those of hemodialysis and may even be superior in the rst few years. 3,4 One of the most serious complications of PD is peritonitis, which results in considerable morbidity and mortality. PD peritonitis directly contributes to w20% of PD technique failures 5 and 2%-6% of deaths. 6,7 Severe and/or persistent peritonitis also may lead to peritoneal membrane failure and possibly to encapsu- lating peritoneal sclerosis. 8-10 This article reviews the epidemiology, risk factors, diagnosis, treatment, and prevention of PD peritonitis, particularly focusing on controversial or unresolved areas or promising ave- nues warranting further research. Potential strategies to reduce the observed high variability in practices and outcomes among different PD units also are discussed. EPIDEMIOLOGY There is wide variation in rates of PD peritonitis across different centers and countries. Reported rates range from 0.06-1.66 episodes/patient-year. 11 These reports tend to be dominated by single-center studies, which may reect publication bias because overall peritonitis rates tend to be higher in unselected multicenter studies. 12,13 Even within the same country, peritonitis rates vary substantially among PDunits. In a previous analysis of data from the Australian and New Zealand Dialysis and Transplant Registry (ANZ- DATA) in 2003-2008, our group demonstrated a 10- fold variation in PD peritonitis rates among centers that was not related to center size. 12 Three years later, the magnitude of this variation still is considerable and is not explainedbydifferences incenter size or case-mix (Fig 1). Similarly, Kavanagh et al 14 demonstrated almost 5-fold variation in peritonitis rates (0.78-3.8 episodes/patient-year) in a study of 10 adult renal units in Scotland between 1999 and 2002. Interunit differences in peritonitis rates were not explained by center size, number of PD patients per nurse, or average PD training time, although peritonitis rates (particularly due to Staphylococcus aureus) were lower in units using nasal mupirocin. 14 Compara- ble results (7-fold variation) also were reported in a study of 12 PD units in the Thames area of the United Kingdom. 13 Although some of these observed differences may be related to different approaches to patient selection From the 1 Centre for Kidney Disease Research, Translational Research Institute at University of Queensland; and 2 Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia. Received December 11, 2013. Accepted in revised form February 20, 2014. Address correspondence to David W. Johnson, PhD, Depart- ment of Nephrology, Level 2, ARTS Building, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane Qld 4102, Australia. E-mail: david.johnson2@health.qld.gov.au Crown Copyright 2014 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. All rights reserved. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.02.025 Am J Kidney Dis. 2014;-(-):--- 1 or assessing peritonitis episodes, it is likely that practice variation was a major driver of outcome differences. For example, a nationwide survey of 23 Austrian PD centers demonstrated that infection pro- phylaxis strategies and PD-associated infection rates varied widely by center. 15 Importantly, the authors identied lower mean infection rates in units per- forming prophylactic mupirocin therapy in S aureus carriers, although they did not formally statistically analyze the data. 15 Overall, peritonitis rates generally have been re- ported to be decreasing over time. A retrospective observational cohort study of a single PD center in Korea 16 reported signicant improvement in peritonitis rates from 0.57 episodes/patient-year in 1993 to 0.29 episodes/patient-year in 2005. However, the improve- ment occurred primarily in Gram-positive peritonitis, whereas Gram-negative peritonitis rates were constant. The change in peritonitis pattern was attributed to im- provements in PD equipment, leading to a reduction in contamination with skin organisms during connection procedures. Similar ndings were reported by single- center studies in Brazil, 17 Portugal, 18 and Taiwan. 19 Although the introduction of twin-bag connection systems was a major contributor to reductions in peri- tonitis rates, 7,20 other factors include better identica- tion of peritonitis risk factors, 7 introduction of mupirocin prophylaxis for S aureus carriers, 21 appli- cation of gentamicin cream to exit sites, 22 and ucon- azole or nystatin prophylaxis for fungal peritonitis. 23 RISK FACTORS Reported risk factors for PD peritonitis are listed in Box1. The majorityof these associations originate from outcomes basedon observational studies and may relate to factors that increase the risk of infection generally (eg, diabetes mellitus, 12,24 frailty, and comorbid disease burden 24-26 ) or of peritonitis specically (eg, positive nasal S aureus carrier status 27 and history of exit-site infection 28,29 ). Furthermore, there are several de- mographic factors that have been associated inconsis- tently with increased risk of peritonitis, such as age, 24,30 sex, 30-32 andethnicity. 5,11,12,24-26,33,34 Todate, there are conicting reports regarding the impact of biocompat- ible uids 35-49 and automated PD (APD) 19,30,50,51 on peritonitis rates, such that currently, no conclusions can be drawn about these interventions. In addition to these variables, some risk factors may be associated with organism-specic peritonitis episodes only rather than overall peritonitis risk. For example, peaks in the incidence of peritonitis due to coagulase-negative staphylococci and Gram-negative organisms in warmer seasons and Corynebacterium species in winter demonstrate seasonal variations in organism-specic peritonitis rates. 52 These variations have been attributed to both climate-related changes in human behavior and immunity, as well as variable organism virulence. 52 Similarly, recent antibiotic therapy and recent peritonitis also have been identi- ed as risk factors for fungal peritonitis. 53 Although a number of the reported risk factors for PD peritonitis listed in Box 1 are modiable, there currently is no high-level evidence that modifying Figure 1. Peritoneal dialysis (PD) peritonitis rates by treating center in Australia and New Zealand in 2011. Condence inter- vals are not shown when upper limit is .3. Units with fewer than 5 person-years of PD over 2011 are not shown. Repro- duced with permission from the ANZDATA 2012 Annual Report. 5 Box 1. Reported Risk Factors for PD Peritonitis Non-modiable Older age 24,30 Female sex 30-32 Indigenous racial origin a,12,24-26,33 Black ethnicity 34 Lower socioeconomic status 115,116 Diabetes mellitus 12,24 Coronary artery disease 24,26 Chronic lung disease 24 Hypertension 25 Poor residual kidney function 117 Modiable Obesity 12,24,25 Smoking 24 Living distantly from PD unit 26,118 Depression 119,120 Hypoalbuminemia 34,121 Hypokalemia 122 Medical procedures (eg, colonoscopy) 123 Absence of vitamin D supplementation 124 Biocompatible uids b,41 Nasal Staphylococcus aureus carrier status 27 Previous exit-site infection 28,29 PD against patients choice 51,125 Prior hemodialysis 126 Pets 127 Patient training 104,106,128 Abbreviation: PD, peritoneal dialysis. a Indigenous racial origin includes Aboriginal and Torres Strait Islander, Maori and Pacic Islander, and First Nation Canadian racial origin. b Reduced peritonitis risk with the use of biocompatible uids is not consistently supported. 107,129 Cho and Johnson 2 Am J Kidney Dis. 2014;-(-):--- these risk factors will lead to reduced peritonitis rates, apart from topical exit-site antimicrobial prophylaxis and nasal eradication of S aureus. Similarly, for pa- tients with nonmodiable peritonitis risk factors, there also is no high-level clinical evidence that specically targeting these individuals for closer monitoring, augmented home support, regular refresher training, or more intensive infection prophylaxis strategies signicantly mitigates their risk. More collaborative research work is required in this area. DIAGNOSIS Another potentially signicant source of variability in peritonitis rates among different units relates to coding bias according to the peritonitis denitions. The International Society of PD (ISPD) has attempted to minimize such variability by publishing specic diagnostic criteria for PD peritonitis to calculate peritonitis rates for the purpose of benchmarking across units. 54 When a diagnosis of peritonitis is made, empiric antimicrobial therapy covering both Gram-positive and Gram-negative organisms is administered pending results of microbiological cul- tures, which generally take several days. Ideally, a more rapid microbiological diagnosis needs to be developed in the hope that it might improve perito- nitis management and outcomes by facilitating timely institution of appropriate therapy. A novel develop- ment in this regard was described recently by Lin et al 55 in their proof-of-concept study to use immune ngerprints characteristic of individual organisms in PD uids to allow more rapid and accurate infection identication. The authors were able to identify distinct patterns of humoral and cellular responses using multicolor ow cytometry and multiple enzyme-linked immunosorbent assay to distinguish between Gram-positive and Gram-negative in- fections. 55 This research suggests the possibility of developing point-of-care tests, which might permit a more timely and targeted approach to peritonitis management than currently is available. After a diagnosis of peritonitis is conrmed, it is important to determine whether the episode represents a relapsing, recurrent, or repeat infection because such episodes correspond to distinct clinical entities with differing clinical outcomes. 54 Relapsing peritonitis is dened as an episode that occurs within 4 weeks of completing therapy for the same organism or one culture-negative episode, whereas recurrent peritonitis refers to an infection within 4 weeks of completing therapy for a different organism. 54 Relapsing and recurrent peritonitis complicate 14% and 5% of peritonitis episodes, respectively, 56 and both are associated with a greater risk of catheter removal and permanent transfer to hemodialysis therapy. 56,57 In contrast, repeat peritonitis, dened as an episode more than 4 weeks after completing therapy for a prior episode with the same organism, 54 has been reported to complicate w10% of peritonitis episodes, 58,59 with the highest rate in the second month after completing antibiotic treatment 58,59 (Fig 2). For the purpose of recording peritonitis rates, recurrent or repeat perito- nitis counts as a second episode, whereas relapsing peritonitis does not. 11 The other important consider- ation is that peritonitis episodes (particularly Gram- positive ones) continue to inuence the risk and outcomes of a subsequent episode for up to 6 months and should be taken into account when approaching the empiric management of a subsequent episode occurring within this time frame. 56 Ideally, one should be able to predict a future occurrence of relapsing or repeat peritonitis prior to its occurrence. Szeto et al 60 have measured bacteria- derived DNA fragments in PD efuent in patients with peritonitis and were able to demonstrate signif- icantly higher bacterial DNA fragment levels (repre- sented by the number of polymerase chain reaction cycles at which bacterial DNA could be detected) in those who developed relapsing or repeat peritonitis (32.3 6 2.6 cycles) compared with those who were cured by antibiotics (34.1 6 1.7 cycles; P ,0.001). Although previous studies have explored the utility of bacteria-derived DNA fragments as a marker of sys- temic inammation in PD patients 61 and as a predictor of spontaneous bacterial peritonitis in patients with cirrhosis-related ascites, 62 this is the rst study to report its use in predicting a future risk of peritonitis in PD patients. If results of this single-center study with a relatively small number of participant (n 5143) are conrmed by other investigators, these methods may enhance the approach to the diagnosis of peritonitis. TREATMENT Timely management of peritonitis is associated with improved patient outcomes, including decreased risk of catheter removal. 63 However, there remains considerable uncertainty about the optimal treatment 0 10 20 30 40 50 60 70 80 1 2 3 4 5 6 7 to 12 13 to 24 >24 Months following first peritonitis episode Proportion of patients with subsequent peritonitis due to same organism (%) Figure 2. Proportion of peritonitis caused by the same micro- bial organism according to time from the prior peritonitis episode. 56,59 PD Peritonitis Am J Kidney Dis. 2014;-(-):--- 3 strategy for peritonitis. The most recent update of the ISPD Peritonitis Treatment Guidelines recommends empiric antibiotics to cover both Gram-positive and Gram-negative organisms guided by local antimicro- bial sensitivities. 54 Although this is the best advice that can be offered in an evidence-sparse area, there are many unanswered important questions that need to be addressed by high-quality, multicenter, ran- domized, controlled trials. A systematic review examining antibiotic treatment of PD peritonitis was unable to identify a superior antibiotic agent or regimen. 64,65 In particular, glycopeptide-based (eg, vancomycin) and rst- generation cephalosporin-based regimens resulted in comparable primary response and relapse rates, although glycopeptide-based regimens achieved a signicantly higher complete cure rate (3 studies, 370 episodes; relative risk [RR], 1.66; 95% condence interval [CI], 1.01-2.72). 64,65 Based on one study, intravenous antibiotic administration resulted in a higher treatment failure rate than intraperitoneal administration (RR, 3.52; 95% CI, 1.26-9.81). 64-66 Treatment failure did not differ signicantly bet- ween those treated with oral versus intraperitoneal antibiotic regimens (7 trials, 452 patients; RR, 1.14; 95% CI, 0.84-1.55). However, trials included in this analysis generally had a small number of participants (largest study, n 5 110) 67 and only 2 studies demonstrated adequate allocation concealment. 68,69 Furthermore, all studies evaluated a quinolone as an oral agent of choice, which introduced the risk of developing a class-related resistance. Results from the review also yielded comparable outcomes with regard to treatment failures (4 trials, 338 patients; RR, 0.92; 95% CI, 0.64-1.33) and relapse (4 trials, 338 patients; RR, 0.76; 95% CI, 0.45-1.28) between continuous and intermittent intraperitoneal antibiotic dosing. 64 In the case of relapsing or persistent peritonitis, simul- taneous catheter removal/replacement resulted in fewer treatment failures than urokinase (1 trial, 37 patients; RR, 2.35; 95% CI, 1.13-4.91). Similarly, on the basis of one trial involving 36 patients, a 24-hour period of peritoneal lavage did not signicantly in- uence treatment failure rate (RR, 2.50; 95% CI, 0.56-11.25). No signicant harms were identied from any of the interventions examined. However, the strength of conclusions from this systematic review was severely restricted by the generally suboptimal quality of the trials included, which had inconsistent outcome denitions. Another important question is whether APD pa- tients who experience peritonitis should be converted to continuous ambulatory PD (CAPD) or have the cycler reset to permit longer dwell times. The short dwells in APD therapy may result in reduced ab- sorption and increased clearance of antibiotics, which in turn may lead to dialysate concentrations falling below minimal inhibitory concentrations, particularly with intermittent administration. Although the afore- mentioned systematic review identied comparable outcomes between continuous and intermittent intra- peritoneal antibiotic dosing, 64,65 this evidence is far from compelling (particularly in the case of cephalosporin-based regimens) and may not gener- alize to APD patients. A retrospective observational cohort study of 508 episodes of PD-associated peri- tonitis in 508 patients reported longer median dura- tion of elevated dialysate efuent leukocyte counts (5 vs 4 days; P , 0.05) and longer median antibiotic course duration (16 vs 15 days; P ,0.05) in APD patients treated for peritonitis (n 5 239) compared with CAPD patients treated for peritonitis (n 5 269), but found no differences in patient-level outcomes of relapse rates, catheter removal rates, or death. 70 However, these ndings may have been limited by indication bias secondary to nonrandom selection of PD modality, leading to differences in peritonitis risk proles between the APD and CAPD cohorts (eg, APD patients were on average younger and had been on PD therapy for a longer time than their CAPD counterparts). The ISPD Peritonitis Guidelines high- light that further research in the area is needed and recommend that if intermittent dosing is to be insti- tuted, the antibiotic-containing dialysis solution must be allowed to dwell for at least 6 hours to permit adequate absorption of the antibiotic into the systemic circulation. 54 An alternative approach to ensuring adequate drug delivery might be through monitoring antibiotic level to improve clinical outcomes while minimizing drug- related toxicity. Our group recently attempted to address this question by measuring systemic levels of vancomycin 71 and gentamicin 72 during peritonitis treatment, which did not demonstrate an association between antibiotic levels and antibiotic-related harm or efcacy when drugs were dosed according to ISPD recommendations. 54 Similar ndings were reported in a single-center study from the United Kingdom. 73 Nevertheless, given the single-center design, rela- tively small sample size, and short duration of anti- biotic level measurements, no denitive conclusions can be drawn at this stage about the role of serum gentamicin and vancomycin level measurements during peritonitis treatment. The duration of antibiotic treatment required to safely and effectively treat peritonitis episodes also has not been studied rigorously. The expert opinion expressed in the ISPD Peritonitis Guidelines is that treatment should continue for at least 2 weeks and be extended to 3 weeks for more severe infections, such as Saureus, Gram-negative, andenterococcal peritonitis. 54 Based on the reported outcomes of organism-specic Cho and Johnson 4 Am J Kidney Dis. 2014;-(-):--- peritonitis from the Australian Peritonitis Registry (Table 1), extended durations of therapy also probably should apply reasonably to polymicrobial, Pseudo- monas species, and fungal peritonitis episodes. In order to best preserve peritoneal membrane integrity to improve long-term PD technique survival, the ISPD Peritonitis Guidelines recommend timely PD catheter removal for individuals who present with refractory peritonitis, relapsing peritonitis, and fungal peritonitis. 54 At present, catheter removal is recom- mended if PD efuent fails to clear after 5 days of appropriate antibiotic treatment, 54 although the evi- dence underpinning this recommendation is limited. Our group previously demonstrated that delaying catheter removal beyond the rst week was associated with signicantly higher rates of permanent transfer to hemodialysis therapy in peritonitis episodes caused by corynebacteria, 74 enterococci, 75 and multiple or- ganisms. 76 Nevertheless, these processes often are delayed in practice, especially if removal of a catheter is dependent on another specialty (eg, surgical team). This process might be able to be improved by plan- ning catheter removal on day 5 if there were ways to identify those likely to experience treatment failure. An example of such a strategy is measuring the dialysate efuent leukocyte count on day 3 because a retrospective observational study by Chow et al 77 reported that a peritoneal dialysate white blood cell count $ 1,000/mL predicted treatment failure in an independent validation cohort with sensitivity of 64% and specicity of 97%. When a specic microorganism is identied, the ISPD Peritonitis Guidelines provide a series of algorithms for treating organism-specic peritonitis episodes, although the evidence for these recom- mendations is limited primarily to case series and observational cohort studies. 74-76,78-86 Perhaps the best available observational evidence to date applies to fungal peritonitis, in which catheter removal com- bined with antifungal therapy produced the best overall outcome, having the lowest rates of repeat fungal peritonitis episodes and death compared with either therapeutic intervention alone. 53 Similarly, in the setting of Pseudomonas species peritonitis, cath- eter removal was associated with a lower risk of death than treatment with antibiotics alone. 86 PREVENTION There is systematic review and randomized controlled trial evidence supporting the use of disconnect (twin-bag and Y-set) systems 87,88 and preoperative administration of intravenous antibiotic (typically cephalosporin) prior to PD catheter inser- tion 89,90 to reduce the risk of peritonitis. However, to date, no benecial effect has been demonstrated convincingly by randomized controlled trials for any other catheter-related intervention, including catheter insertion technique, catheter placement, immobiliza- tion device, catheter design, or cuff number. 91 A sub- sequent analysis of the Canadian Baxter Peritonitis Organism Exit-Sites Tunnel Infections (POET) data- base identied that double-cuff catheters were associ- ated with a signicant reduction in overall peritonitis rate (particularly S aureus peritonitis) in patients commencing PD therapy between 1996 and 2000, but not among those commencing PD therapy between 2001 and 2005, which possibly is related to the obvi- ating effect of widespread adoption of prophylactic exit-site and intranasal ointments in the latter era. 92 With respect to antimicrobial prophylaxis strategies, there is evidence supporting the use of antifungal pro- phylaxis (to prevent fungal peritonitis), 23,93 nasal mupirocin prophylaxis, 94-96 exit-site mupirocin pro- phylaxis, 97,98 and exit-site gentamicin prophylaxis. 22 Application of exit-site gentamicin cream has been associated with a lower overall peritonitis rate (RR, 0.52; 95% CI, 0.29-0.93; P , 0.03), largely driven bya decrease in Gram-negative peritonitis episodes (0.02/y vs 0.15/y; P 5 0.003) compared to exit-site mupirocin prophylaxis. 22 These practices have been endorsed by Table 1. Outcomes of Organism-Specic PD-Related Peritonitis in Australia Organism Cure Relapse Hospitalization Catheter Removal Interim HD Permanent HD Death Streptococci 85 87% 3% 74% 10% 3% 9% 1.4% Coagulase-negative staphylococci 81 77% 17% 61% 10% 2% 9% 1.0% Culture negative 82 77% 14% 60% 12% 3% 10% 0.9% Corynebacteria 74 67% 18% 70% 21% 7% 15% 2.4% S aureus (all) 83 67% 20% 67% 23% 4% 18% 2.2% Non-Pseudomonas Gram-negative 84 60% 11% 81% 31% 4% 26% 4.2% MRSA 83 54% 19% 75% 31% 6% 25% 4.6% Polymicrobial 76 52% 10% 83% 43% 5% 38% 3.9% Enterococci 75 51% 15% 78% 37% 6% 32% 3.4% Pseudomonas 86 50% 9% 79% 44% 11% 35% 3.1% Fungal 53 9% 9% 98% 88% 12% 74% 8.6% Overall 68% 14% 70% 22% 4% 18% 2.3% Abbreviations: HD, hemodialysis; PD, peritoneal dialysis, MRSA, methicillin-resistant Staphylococcus aureus. PD Peritonitis Am J Kidney Dis. 2014;-(-):--- 5 the ISPD. 11 However, there have been no direct head- to-head comparison studies of intranasal mupirocin with either exit-site mupirocin or exit-site gentamicin. In addition, although these agents are effective in reducing exit-site infection 22,94 and peritonitis rates, 22 there have been some concerns that these antibiotics may promote resistant organisms. 99,100 Because antibacterial honey does not induce antimicrobial resistance and has been shown to be active against a broad range of bacteria (including multiresistant organisms) and fungi, the HONEY- POT (Honey Versus Nasal Eradication of Staphy- lococci for the Prevention of Tenckhoff Infections) study collaborative group recently looked at the safety and efcacy of applying this agent to PD exit sites as an alternative infection control strategy. 101 The HONEYPOT multicenter, open-label, random- ized, controlled trial involved 371 PD patients who were randomly assigned to either daily topical exit- site application of antibacterial honey (n 5186) or intranasal mupirocin prophylaxis in those who were identied as nasal S aureus carriers (n 5 185). The use of honey yielded PD-related infection-free sur- vival times (ie, exit-site infection, tunnel infection, or peritonitis) comparable to the standard mupirocin group (16 vs 17.7 months; unadjusted hazard ratio [HR], 1.12; 95% CI, 0.83-1.51; P 5 0.47). In the prespecied subgroup of patients with diabetes mellitus, honey increased the risks of both the composite end point of PD-associated infection (HR, 1.85; 95% CI, 1.05-3.24) and peritonitis (HR, 2.25; 95% CI, 1.16-4.36). Moreover, patients who received honey were more likely to withdraw from the study (29% vs 9%; P ,0.001). On the basis of these results, antibacterial honey was not recom- mended for routine clinical use in PD patients. Similar results were observed in the MP 3 (Mupirocin and Polysporin Triple ointment) study conducted by McQuillan et al 102 in 201 PD patients, in which the use of Polysporin Triple (Pzer) ointment was associated with comparable time to rst event (either exit-site infection or peritonitis) compared to exit-site mupir- ocin application (13.2 vs 14 months; P 50.41). However, the safety of Polysporin Triple ointment was of concern because its use was associated with signif- icantly higher rates of fungal exit-site infections (0.07 vs 0.01; P 50.02) and fungal peritonitis episodes (0.04 vs 0.00; P , 0.05). 102 Consequently, Polysporin Triple ointment was not recommended for prevention of PD-related infections. Other PD-related infection prevention strategies include practicing standard exit-site care, such as excellent hand hygiene, and using noncytotoxic antiseptic cleaning agents to clean the exit site. 11 However, there currently is no evidence that any particular cleansing agent is superior. Training also has been a major focus of the ISPD guidelines for preventing PD peritonitis. 11,103 It generally is recommended that treating PD units should ensure that appropriately trained staff deliver evidence-based training methods using the principles of adult education. Patients also should be retrained 3 months after initial training and routinely (at least annually) thereafter, as well as after any hospitaliza- tion, episode of peritonitis or catheter infection, or change in dexterity, vision, or mental acuity. 11 It also is emphasized that training the staff requires active continued learning and retraining to ensure optimal outcomes. 104 However, to date, there have been no randomized controlled trials comparing training pro- tocols and curricula for PD patients. There also is conicting observational evidence regarding whether longer training times are associated with lower peri- tonitis rates. 105,106 Perhaps not surprisingly, an inter- national survey of PD nurses from the United States, Canada, South America, the Netherlands, and Hong Kong demonstrated extraordinary center variability in PD training practices and durations (9-96 hours per patient). 105 Finally, the BalANZ trial recently demonstrated that the use of neutral-pH low-glucose-degradation product dialysis uids resulted in a signicant reduction in peritonitis rates compared with conven- tional PD solutions (0.30 vs 0.49 episodes per year, P 5 0.01). 41 Moreover, using neutral-pH low- glucose-degradation product solutions resulted in shorter peritonitis-associated hospitalization duration, suggesting that biocompatible solutions decreased both the likelihood and severity of peritonitis. 41,42 However, a subsequent systematic review of ran- domized controlled trials by our group did not nd a signicant effect of biocompatible uids on peritonitis rates, possibly because of heterogeneity in trial qual- ity. 107 Consequently, the impact of neutral-pH low- glucose-degradation product uids on peritonitis risk remains uncertain. IMPROVING PD PERITONITIS OUTCOMES Despite the widespread availability and awareness of the ISPD guidelines for the prevention and treat- ment of PD peritonitis, there is substantial variation in PD peritonitis outcomes among different centers and countries. 12-15 The available evidence suggests that center variation in PD practice contributes substan- tially to these disparate outcomes. For example, a previous survey of Australian PD units by our group reported relatively low adherence (,50%) to evidence-based policies such as administering pro- phylactic antibiotics at the time of catheter insertion or prescribing topical antimicrobial prophylaxis. 108 Moreover, a recent ANZDATA analysis observed low (7%) use of antifungal prophylaxis during Cho and Johnson 6 Am J Kidney Dis. 2014;-(-):--- antibiotic treatment of bacterial peritonitis in Australia. 53 Poorer outcomes also were observed in other ANZDATA analyses when practices deviated signicantly from evidence-based recommendations, such as using 1 antibiotic rather than 2 to treat Pseudomonas species peritonitis, failing to use a glycopeptide (eg, vancomycin) when treating methicillin-resistant S aureus peritonitis, and not treating fungal peritonitis with both catheter removal and antifungal therapy. 109 One of the barriers to bridging this treatment gap in PD units is the overall poor quantity and quality of evidence pertaining to PD peritonitis prevention and management. There are many PD interventions and practices that still require formal evaluation by clinical studies (Box 2). The creation of peritonitis registries such as those in Australia, 5 Brazil, 110 and Hong Kong 111 has been critically important for generating hypotheses for future studies and for audit and feedback. Multicenter, investigator- initiated, randomized, controlled trials remain the gold standard for testing PD interventions, but are limited because any such investigation would require 1,000 patients or more to be adequately powered for the outcome of peritonitis. Realistically, many PD practices therefore are not going to be informed by well-designed, well-run, adequately powered, multicenter randomized, controlled trials. Recently, the Peritoneal Dialysis Outcomes and Practice Pat- terns Study (PDOPPS) was established as a pro- spective multicenter international observational study aiming to identify measurable and modiable practices that are associated with improved PD out- comes in more than 100 PD units from at least 5 countries. The future outcomes of PDOPPS hope- fully will include identication of innovative prac- tices and service organization that deliver the best outcomes in a variety of clinical situations in the real-world setting, improved patient safety (eg, reduced peritonitis), better informed policy de- cisions, better evaluation of the effect of policy on patient care and outcomes, guidance of the rational development and optimal design of future clinical trials in PD peritonitis, development of consensus denitions and nomenclature to be used across all Box 2. Interventions That Require Further Clinical Study to Determine Their Impact on Peritonitis Rates and/or Outcomes in PD Patients Preoperative screening and eradication of nasal staphylococci Preoperative laxative administration Preoperative marking of PD catheter site on abdomen Catheter implantation method, including operator (sur- geon vs nephrologist) Duration of break-in period Training method used Refresher training (routine vs event-triggered vs none) Frequency of exit-site cleaning Type of exit-site cleansing agent used Type of hand-washing agent used Duration of hand washing Exit-site cleaning approach (gloves, mask) Nasal vs exit-site application of mupirocin Role of catheter immobilization Antibiotic prophylaxis prior to medical procedures (eg, colonoscopy, dental procedure) Vitamin D supplementation Correction of hypokalemia with potassium supplements Weight reduction in obese PD patients Neutral-pH low-glucose-degradation product uid vs conventional PD uid Presence of a continuous quality improvement program Peritonitis empiric antimicrobial regimen (type, route) Duration of antibiotic therapy for peritonitis Conversion to CAPD vs continued APD during treatment of peritonitis in APD patients Monitoring vancomycin/gentamicin levels during perito- nitis treatment Abbreviations: APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; PD, peritoneal dialysis. Box 3. Recommended Standard of Care for PD Patients 109 Catheter Insertion Eradication of Staphylococcus aureus 11,54 Catheter insertion by an appropriately trained experi- enced operator 130 Avoidance of constipation 54,130 Placement of catheter with a downward-facing exit site 54,130 Prophylactic antibiotic administration during catheter insertion 11,54 Infection Control Patient education on aseptic technique 11,54 Topical exit-site or nasal antibiotics 11,22,94 Coprescription of antifungal prophylaxis with any antibiotic treatments 11,54 Timely administration of antibiotics in the case of touch contamination 11,54 Regular assessment of exit site 11,54 Peritonitis Administration of appropriate antibiotic(s) for organism being treated 54 Adherence to ISPD-recommended route and duration of treatment 54 Administration of antifungal prophylaxis during antibiotic treatments 11,54 Timely removal of catheter in refractory peritonitis 11,54 Audit Recording of infection rates and outcomes for bench- marking against national and international data 11 Continuous quality improvement programs 113 Support Patient education and training (initial and mainte- nance) 103,128,131,132 Abbreviation: ISPD, International Society of Peritoneal Dial- ysis; PD, peritoneal dialysis. PD Peritonitis Am J Kidney Dis. 2014;-(-):--- 7 PD-related peritonitis research, and standardization of international registry data collection. Apart from improving the existing limited evidence base, the other great challenge for the PD community is improving outcomes not just in centers with a specic PD interest/focus, but in all centers in which PD is practiced. Typically, signicant improvements in PD outcomes, including peritonitis, have been re- ported by centers incorporating the principles of continuous quality improvement. 112,113 Ideally, a root-cause analysis should be applied to each episode of peritonitis in a PD unit to try to identify areas for improvement. 113 In an attempt to address the appreciable gap bet- ween evidence-based best practice and actual practice across many PD units in Australia, multipronged in- terventions have taken place over the past few years, including augmentation of the existing evidence base by conducting investigator-initiated trials in PD by the Australasian Kidney Trials Network, as well as continued analysis of ANZDATA data, improvement of existing guidelines, implementation of a team approach for continuous quality improvement, development of key performance indicators to meet evidence-based practice (eg, 100% prophylactic antibiotic administration prior to catheter insertion, PD peritonitis rate , 0.36 episodes per patient per year, and 100% antifungal agent prescription during treatment of peritonitis), 114 reinforcement of PD training especially targeting young nephrologists at annual PD Academy meetings, and publication of a Call to Action guideline highlighting gaps in Australian practice and promulgating locally appro- priate evidence-based recommendations to improve patient outcomes and clinician awareness (Box 3). 109 These approaches were associated with a dramatic reduction in peritonitis rate in 2011 to 0.43 episode/ patient-year in Australia, which is the rst time the peritonitis rate was documented at ,0.50 episode/ patient-year since the establishment of a peritonitis registry in 2003 (Fig 3). 5 Examination of organism- specic peritonitis rates demonstrated decreases in the rates of both Gram-positive peritonitis (particu- larly S aureus and coagulase-negative staphylococci) and Gram-negative peritonitis for the last 3 years (2009-2011; Fig 4). SUMMARY AND FUTURE DIRECTIONS Peritonitis is a major complication of PD. It acts as a major disincentive to greater uptake of this impor- tant dialysis modality and extracts a heavy toll in Figure 3. Peritonitis rates over time in Australia and New Zealand, 2003-2011. Data are expressed as number of episodes per patient-year and patient-months per episode. Reproduced with permission from the ANZDATA 2012 Annual Report. 5 Figure 4. Organism-specic peritonitis rates in Australian and New Zealand PD patients 2003-2011. Abbreviations: Coag neg Staph, coagulase-negative staphylococci; MRSA, methicillin-resistant Staphylococcus aureus; org, organism; pos, positive. Repro- duced with permission from the ANZDATA 2012 Annual Report. 5 Cho and Johnson 8 Am J Kidney Dis. 2014;-(-):--- terms of morbidity, mortality, and health care costs. Despite the importance of peritonitis as a patient safety issue, there is extraordinary and unacceptable variation in PD peritonitis rates and outcomes among different centers, regions, and countries. The reasons for this variation have been poorly studied, but may be related to a combination of patient selection with different peritonitis risk-factor proles, variable ap- proaches to dening and calculating peritonitis rates, and, perhaps most importantly, different PD center practices with respect to treating and preventing peritonitis. Key strategies for addressing these issues should include continuous quality improvement pro- grams with routine auditing and benchmarking of peritonitis rates and outcomes, together with imple- mentation of evidence-based best practice and improved staff and patient training and retraining programs. Insights obtained from results of future randomized controlled trials and PDOPPS also should help identify innovative practices and service orga- nizations that deliver the best outcomes. ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Johnson is a consultant for Baxter Healthcare Pty Ltd and has previously received research funds from this company; has also received speakers honoraria and research grants from Fresenius Medical Care; and is a current recipient of a Queensland Government Health Research Fellow- ship. Dr Cho declares that she has no relevant nancial interests. REFERENCES 1. Jain AK, Blake P, Cordy P, Garg AX. Global trends in rates of peritoneal dialysis. J Am Soc Nephrol. 2012;23(3):533-544. 2. Fresenius Medical Care. ESRD patients in 2011a global perspective. 2012. http://www.vision-fmc.com/les/download/ESRD/ ESRD_Patients_in_2011.pdf. Accessed November 20, 2013. 3. Bargman JM. Advances in peritoneal dialysis: a review. Semin Dial. 2012;25(5):545-549. 4. 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