Peritoneal Dialysis–Related Peritonitis: Towards Improving Evidence, Practices, and Outcomes

Narrative Review Peritoneal Dialysis–Related Peritonitis: Towards Improving Evidence, Practices, and Outcomes Yeoungjee Cho, MD,1,2 and David W. Johnson, PhD1,2 Peritonitis is a common serious complication of peritoneal dialysis that results in considerable morbidity, mortality, and health care costs. It also significantly 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, treatment, and prevention, particularly focusing on potential drivers of variable practices and outcomes, controversial 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 ª 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 significant contributions to the field of kidney disease and extended the goals of the National Kidney Foundation.

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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 outcomes are comparable to those of hemodialysis and may even be superior in the first 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 failures5 and 2%-6% of deaths.6,7 Severe and/or persistent peritonitis also may lead to peritoneal membrane failure and possibly to encapsulating 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 avenues 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 reflect publication bias because overall peritonitis rates tend to be higher in unselected Am J Kidney Dis. 2014;-(-):---

multicenter studies.12,13 Even within the same country, peritonitis rates vary substantially among PD units. In a previous analysis of data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) in 2003-2008, our group demonstrated a 10fold 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 explained by differences in center size or case-mix (Fig 1). Similarly, Kavanagh et al14 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 Comparable 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 1Centre for Kidney Disease Research, Translational Research Institute at University of Queensland; and 2Department 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, Department of Nephrology, Level 2, ARTS Building, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane Qld 4102, Australia. E-mail: [email protected] 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 1

Cho and Johnson Box 1. Reported Risk Factors for PD Peritonitis Non-modifiable          

Older age24,30 Female sex30-32 Indigenous racial origina,12,24-26,33 Black ethnicity34 Lower socioeconomic status115,116 Diabetes mellitus12,24 Coronary artery disease24,26 Chronic lung disease24 Hypertension25 Poor residual kidney function117

Modifiable Figure 1. Peritoneal dialysis (PD) peritonitis rates by treating center in Australia and New Zealand in 2011. Confidence intervals are not shown when upper limit is .3. Units with fewer than 5 person-years of PD over 2011 are not shown. Reproduced with permission from the ANZDATA 2012 Annual Report.5

     

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 prophylaxis strategies and PD-associated infection rates varied widely by center.15 Importantly, the authors identified lower mean infection rates in units performing prophylactic mupirocin therapy in S aureus carriers, although they did not formally statistically analyze the data.15 Overall, peritonitis rates generally have been reported to be decreasing over time. A retrospective observational cohort study of a single PD center in Korea16 reported significant improvement in peritonitis rates from 0.57 episodes/patient-year in 1993 to 0.29 episodes/patient-year in 2005. However, the improvement occurred primarily in Gram-positive peritonitis, whereas Gram-negative peritonitis rates were constant. The change in peritonitis pattern was attributed to improvements in PD equipment, leading to a reduction in contamination with skin organisms during connection procedures. Similar findings were reported by singlecenter studies in Brazil,17 Portugal,18 and Taiwan.19 Although the introduction of twin-bag connection systems was a major contributor to reductions in peritonitis rates,7,20 other factors include better identification of peritonitis risk factors,7 introduction of mupirocin prophylaxis for S aureus carriers,21 application of gentamicin cream to exit sites,22 and fluconazole or nystatin prophylaxis for fungal peritonitis.23

RISK FACTORS Reported risk factors for PD peritonitis are listed in Box 1. The majority of these associations originate from outcomes based on observational studies and may relate to factors that increase the risk of infection generally (eg, diabetes mellitus,12,24 frailty, and comorbid disease burden24-26) or of peritonitis specifically (eg, positive nasal S aureus carrier status27 and history of exit-site 2

        

Obesity12,24,25 Smoking24 Living distantly from PD unit 26,118 Depression119,120 Hypoalbuminemia34,121 Hypokalemia122 Medical procedures (eg, colonoscopy)123 Absence of vitamin D supplementation124 Biocompatible fluidsb,41 Nasal Staphylococcus aureus carrier status27 Previous exit-site infection28,29 PD against patient’s choice51,125 Prior hemodialysis126 Pets127 Patient training104,106,128

Abbreviation: PD, peritoneal dialysis. a Indigenous racial origin includes Aboriginal and Torres Strait Islander, Maori and Pacific Islander, and First Nation Canadian racial origin. b Reduced peritonitis risk with the use of biocompatible fluids is not consistently supported.107,129

infection28,29). Furthermore, there are several demographic factors that have been associated inconsistently with increased risk of peritonitis, such as age,24,30 sex,30-32 and ethnicity.5,11,12,24-26,33,34 To date, there are conflicting reports regarding the impact of biocompatible fluids35-49 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-specific 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-specific 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 identified as risk factors for fungal peritonitis.53 Although a number of the reported risk factors for PD peritonitis listed in Box 1 are modifiable, there currently is no high-level evidence that modifying Am J Kidney Dis. 2014;-(-):---

PD Peritonitis

these risk factors will lead to reduced peritonitis rates, apart from topical exit-site antimicrobial prophylaxis and nasal eradication of S aureus. Similarly, for patients with nonmodifiable peritonitis risk factors, there also is no high-level clinical evidence that specifically targeting these individuals for closer monitoring, augmented home support, regular refresher training, or more intensive infection prophylaxis strategies significantly mitigates their risk. More collaborative research work is required in this area.

DIAGNOSIS Another potentially significant source of variability in peritonitis rates among different units relates to coding bias according to the peritonitis definitions. The International Society of PD (ISPD) has attempted to minimize such variability by publishing specific 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 cultures, which generally take several days. Ideally, a more rapid microbiological diagnosis needs to be developed in the hope that it might improve peritonitis management and outcomes by facilitating timely institution of appropriate therapy. A novel development in this regard was described recently by Lin et al55 in their proof-of-concept study to use “immune fingerprints” characteristic of individual organisms in PD fluids to allow more rapid and accurate infection identification. The authors were able to identify distinct patterns of humoral and cellular responses using multicolor flow cytometry and multiple enzyme-linked immunosorbent assay to distinguish between Gram-positive and Gram-negative infections.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 confirmed, 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 defined 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, defined as an episode more Am J Kidney Dis. 2014;-(-):---

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 treatment58,59 (Fig 2). For the purpose of recording peritonitis rates, recurrent or repeat peritonitis counts as a second episode, whereas relapsing peritonitis does not.11 The other important consideration is that peritonitis episodes (particularly Grampositive ones) continue to influence 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 al60 have measured bacteriaderived DNA fragments in PD effluent in patients with peritonitis and were able to demonstrate significantly higher bacterial DNA fragment levels (represented 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 systemic inflammation in PD patients61 and as a predictor of spontaneous bacterial peritonitis in patients with cirrhosis-related ascites,62 this is the first 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 5 143) are confirmed 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 80 70 60 Proportion of patients with subsequent peritonitis due to same organism (%)

50 40 30 20 10 0 1

2

3

4

5

6

7 to 12 13 to 24

>24

Months following first peritonitis episode

Figure 2. Proportion of peritonitis caused by the same microbial organism according to time from the prior peritonitis episode.56,59 3

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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 antimicrobial 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, randomized, 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 firstgeneration cephalosporin-based regimens resulted in comparable primary response and relapse rates, although glycopeptide-based regimens achieved a significantly higher complete cure rate (3 studies, 370 episodes; relative risk [RR], 1.66; 95% confidence 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 significantly between 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, simultaneous 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 significantly influence treatment failure rate (RR, 2.50; 95% CI, 0.56-11.25). No significant harms were identified 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 definitions. Another important question is whether APD patients 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 absorption and increased clearance of antibiotics, which 4

in turn may lead to dialysate concentrations falling below minimal inhibitory concentrations, particularly with intermittent administration. Although the aforementioned systematic review identified comparable outcomes between continuous and intermittent intraperitoneal antibiotic dosing,64,65 this evidence is far from compelling (particularly in the case of cephalosporin-based regimens) and may not generalize to APD patients. A retrospective observational cohort study of 508 episodes of PD-associated peritonitis in 508 patients reported longer median duration of elevated dialysate effluent 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 findings may have been limited by indication bias secondary to nonrandom selection of PD modality, leading to differences in peritonitis risk profiles 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 highlight that further research in the area is needed and recommend that if intermittent dosing is to be instituted, 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 drugrelated toxicity. Our group recently attempted to address this question by measuring systemic levels of vancomycin71 and gentamicin72 during peritonitis treatment, which did not demonstrate an association between antibiotic levels and antibiotic-related harm or efficacy when drugs were dosed according to ISPD recommendations.54 Similar findings were reported in a single-center study from the United Kingdom.73 Nevertheless, given the single-center design, relatively small sample size, and short duration of antibiotic level measurements, no definitive 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 S aureus, Gram-negative, and enterococcal peritonitis.54 Based on the reported outcomes of organism-specific Am J Kidney Dis. 2014;-(-):---

PD Peritonitis

peritonitis from the Australian Peritonitis Registry (Table 1), extended durations of therapy also probably should apply reasonably to polymicrobial, Pseudomonas 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 recommended if PD effluent fails to clear after 5 days of appropriate antibiotic treatment,54 although the evidence underpinning this recommendation is limited. Our group previously demonstrated that delaying catheter removal beyond the first week was associated with significantly higher rates of permanent transfer to hemodialysis therapy in peritonitis episodes caused by corynebacteria,74 enterococci,75 and multiple organisms.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 planning 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 effluent leukocyte count on day 3 because a retrospective observational study by Chow et al77 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 specificity of 97%. When a specific microorganism is identified, the ISPD Peritonitis Guidelines provide a series of algorithms for treating organism-specific peritonitis episodes, although the evidence for these recommendations 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 combined 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, catheter 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) systems87,88 and preoperative administration of intravenous antibiotic (typically cephalosporin) prior to PD catheter insertion89,90 to reduce the risk of peritonitis. However, to date, no beneficial effect has been demonstrated convincingly by randomized controlled trials for any other catheter-related intervention, including catheter insertion technique, catheter placement, immobilization device, catheter design, or cuff number.91 A subsequent analysis of the Canadian Baxter Peritonitis Organism Exit-Sites Tunnel Infections (POET) database identified that double-cuff catheters were associated with a significant 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 obviating 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 prophylaxis (to prevent fungal peritonitis),23,93 nasal mupirocin prophylaxis,94-96 exit-site mupirocin prophylaxis,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 by a 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-Specific PD-Related Peritonitis in Australia Organism

Cure

Relapse

Hospitalization

Catheter Removal

Interim HD

Permanent HD

Death

Streptococci85 Coagulase-negative staphylococci81 Culture negative82 Corynebacteria74 S aureus (all)83 Non-Pseudomonas Gram-negative84 MRSA83 Polymicrobial76 Enterococci75 Pseudomonas86 Fungal53 Overall

87% 77% 77% 67% 67% 60% 54% 52% 51% 50% 9% 68%

3% 17% 14% 18% 20% 11% 19% 10% 15% 9% 9% 14%

74% 61% 60% 70% 67% 81% 75% 83% 78% 79% 98% 70%

10% 10% 12% 21% 23% 31% 31% 43% 37% 44% 88% 22%

3% 2% 3% 7% 4% 4% 6% 5% 6% 11% 12% 4%

9% 9% 10% 15% 18% 26% 25% 38% 32% 35% 74% 18%

1.4% 1.0% 0.9% 2.4% 2.2% 4.2% 4.6% 3.9% 3.4% 3.1% 8.6% 2.3%

Abbreviations: HD, hemodialysis; PD, peritoneal dialysis, MRSA, methicillin-resistant Staphylococcus aureus. Am J Kidney Dis. 2014;-(-):---

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the ISPD.11 However, there have been no direct headto-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 infection22,94 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 HONEYPOT (Honey Versus Nasal Eradication of Staphylococci for the Prevention of Tenckhoff Infections) study collaborative group recently looked at the safety and efficacy of applying this agent to PD exit sites as an alternative infection control strategy.101 The HONEYPOT multicenter, open-label, randomized, controlled trial involved 371 PD patients who were randomly assigned to either daily topical exitsite application of antibacterial honey (n 5 186) or intranasal mupirocin prophylaxis in those who were identified as nasal S aureus carriers (n 5 185). The use of honey yielded PD-related infection-free survival 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 prespecified 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 recommended for routine clinical use in PD patients. Similar results were observed in the MP3 (Mupirocin and Polysporin Triple ointment) study conducted by McQuillan et al102 in 201 PD patients, in which the use of Polysporin Triple (Pfizer) ointment was associated with comparable time to first event (either exit-site infection or peritonitis) compared to exit-site mupirocin application (13.2 vs 14 months; P 5 0.41). However, the safety of Polysporin Triple ointment was of concern because its use was associated with significantly higher rates of fungal exit-site infections (0.07 vs 0.01; P 5 0.02) 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. 6

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 hospitalization, 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 protocols and curricula for PD patients. There also is conflicting observational evidence regarding whether longer training times are associated with lower peritonitis rates.105,106 Perhaps not surprisingly, an international 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 fluids resulted in a significant reduction in peritonitis rates compared with conventional PD solutions (0.30 vs 0.49 episodes per year, P 5 0.01).41 Moreover, using neutral-pH lowglucose-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 randomized controlled trials by our group did not find a significant effect of biocompatible fluids on peritonitis rates, possibly because of heterogeneity in trial quality.107 Consequently, the impact of neutral-pH lowglucose-degradation product fluids on peritonitis risk remains uncertain.

IMPROVING PD PERITONITIS OUTCOMES Despite the widespread availability and awareness of the ISPD guidelines for the prevention and treatment 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 substantially 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 prophylactic 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 Am J Kidney Dis. 2014;-(-):---

PD Peritonitis 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 (surgeon 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 fluid vs conventional PD fluid 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 peritonitis treatment

Abbreviations: APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; PD, peritoneal dialysis.

antibiotic treatment of bacterial peritonitis in Australia.53 Poorer outcomes also were observed in other ANZDATA analyses when practices deviated significantly 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 Kong111 has been critically important for generating hypotheses for future studies and for audit and feedback. Multicenter, investigatorinitiated, randomized, controlled trials remain the gold standard for testing PD interventions, but are limited because any such investigation would require Am J Kidney Dis. 2014;-(-):---

Box 3. Recommended Standard of Care for PD Patients109 Catheter Insertion     

Eradication of Staphylococcus aureus11,54 Catheter insertion by an appropriately trained experienced operator130 Avoidance of constipation54,130 Placement of catheter with a downward-facing exit site54,130 Prophylactic antibiotic administration during catheter insertion11,54

Infection Control     

Patient education on aseptic technique11,54 Topical exit-site or nasal antibiotics11,22,94 Coprescription of antifungal prophylaxis with any antibiotic treatments11,54 Timely administration of antibiotics in the case of touch contamination11,54 Regular assessment of exit site11,54

Peritonitis    

Administration of appropriate antibiotic(s) for organism being treated54 Adherence to ISPD-recommended route and duration of treatment54 Administration of antifungal prophylaxis during antibiotic treatments11,54 Timely removal of catheter in refractory peritonitis11,54

Audit  

Recording of infection rates and outcomes for benchmarking against national and international data11 Continuous quality improvement programs113

Support 

Patient education and training (initial and maintenance)103,128,131,132

Abbreviation: ISPD, International Society of Peritoneal Dialysis; PD, peritoneal dialysis.

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 Patterns Study (PDOPPS) was established as a prospective multicenter international observational study aiming to identify measurable and modifiable practices that are associated with improved PD outcomes in more than 100 PD units from at least 5 countries. The future outcomes of PDOPPS hopefully will include identification of innovative practices 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 decisions, 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 definitions and nomenclature to be used across all 7

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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

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 specific PD interest/focus, but in all centers in which PD is practiced. Typically, significant improvements in PD outcomes, including peritonitis, have been reported 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 between evidence-based best practice and actual practice across many PD units in Australia, multipronged interventions 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 appropriate 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 first 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 organismspecific peritonitis rates demonstrated decreases in the rates of both Gram-positive peritonitis (particularly 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 important dialysis modality and extracts a heavy toll in

Figure 4. Organism-specific 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. Reproduced with permission from the ANZDATA 2012 Annual Report.5 8

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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 profiles, variable approaches to defining 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 programs with routine auditing and benchmarking of peritonitis rates and outcomes, together with implementation 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 organizations 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 Fellowship. Dr Cho declares that she has no relevant financial interests.

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