Narrative Review

Peritoneal DialysisRelated Peritonitis: Towards ImprovingEvidence, 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 itsimportance as a patient safety issue, peritonitis practices and outcomes vary markedly and unacceptablyamong 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 foraugmenting the existing limited evidence base and reducing the gap between evidence-based best practiceand actual practice also are discussed.Am J Kidney Dis. -(-):---. Crown Copyright 2014 Published by Elsevier Inc. on behalf of the NationalKidney Foundation, Inc. All rights reserved.

INDEX WORDS: Antibiotics; bacteria; fungi; microbiology; outcomes; peritoneal dialysis; peritonitis; practicevariation; prevention; quality improvement; risk factors.

David W. Johnson, PhD, was an International DistinguishedMedal recipient at the 2014 National Kidney FoundationSpring Clinical Meetings. The International DistinguishedMedals are awarded to honor the achievement of individualswho have made significant contributions to the field of kidneydisease and extended the goals of the National KidneyFoundation.

P eritoneal dialysis (PD) is used to treat end-stagekidney disease in more than 200,000 patientsacross 130 countries worldwide and accounts forw11% of the global dialysis population.1,2 Its out-comes are comparable to those of hemodialysis andmay even be superior in the rst few years.3,4

One of the most serious complications of PD isperitonitis, which results in considerable morbidity andmortality. PD peritonitis directly contributes tow20%of PD technique failures5 and 2%-6% of deaths.6,7

Severe and/or persistent peritonitis also may lead toperitoneal membrane failure and possibly to encapsu-lating peritoneal sclerosis.8-10 This article reviews theepidemiology, risk factors, diagnosis, treatment, andprevention of PD peritonitis, particularly focusing oncontroversial or unresolved areas or promising ave-nues warranting further research. Potential strategies toreduce the observed high variability in practices andoutcomes among different PD units also are discussed.

EPIDEMIOLOGY

There is wide variation in rates of PD peritonitisacross different centers and countries. Reported ratesrange from 0.06-1.66 episodes/patient-year.11 Thesereports tend to be dominated by single-center studies,which may reect publication bias because overallperitonitis rates tend to be higher in unselected

multicenter studies.12,13 Even within the same country,peritonitis rates vary substantially among PD units. In aprevious analysis of data from the Australian and NewZealand Dialysis and Transplant Registry (ANZ-DATA) in 2003-2008, our group demonstrated a 10-fold variation in PD peritonitis rates among centersthat was not related to center size.12 Three years later,the magnitude of this variation still is considerable andis not explained bydifferences in center size or case-mix(Fig 1). Similarly, Kavanagh et al14 demonstratedalmost 5-fold variation in peritonitis rates (0.78-3.8episodes/patient-year) in a study of 10 adult renalunits in Scotland between 1999 and 2002. Interunitdifferences in peritonitis rates were not explainedby center size, number of PD patients per nurse, oraverage PD training time, although peritonitis rates(particularly due to Staphylococcus aureus) werelower in units using nasal mupirocin.14 Compara-ble results (7-fold variation) also were reported ina study of 12 PD units in the Thames area of theUnited Kingdom.13

Although some of these observed differences maybe related to different approaches to patient selection

From the 1Centre for Kidney Disease Research, TranslationalResearch Institute at University of Queensland; and 2Departmentof 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 AlexandraHospital, Ipswich Road, Woolloongabba, Brisbane Qld 4102,Australia. E-mail: david.johnson2@health.qld.gov.auCrown Copyright ! 2014 Published by Elsevier Inc. on behalf

of the National Kidney Foundation, Inc. All rights reserved.0272-6386/$36.00http://dx.doi.org/10.1053/j.ajkd.2014.02.025

Am J Kidney Dis. 2014;-(-):--- 1

or assessing peritonitis episodes, it is likely thatpractice variation was a major driver of outcomedifferences. For example, a nationwide survey of 23Austrian PD centers demonstrated that infection pro-phylaxis strategies and PD-associated infection ratesvaried widely by center.15 Importantly, the authorsidentied lower mean infection rates in units per-forming prophylactic mupirocin therapy in S aureuscarriers, although they did not formally statisticallyanalyze the data.15

Overall, peritonitis rates generally have been re-ported to be decreasing over time. A retrospectiveobservational cohort study of a single PD center inKorea16 reported signicant improvement in peritonitisrates from 0.57 episodes/patient-year in 1993 to 0.29episodes/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 incontamination with skin organisms during connectionprocedures. Similar ndings were reported by single-center studies in Brazil,17 Portugal,18 and Taiwan.19

Although the introduction of twin-bag connectionsystems was a major contributor to reductions in peri-tonitis rates,7,20 other factors include better identica-tion of peritonitis risk factors,7 introduction ofmupirocin 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 inBox1. Themajority of these associations originate fromoutcomes based on observational studies andmay relateto factors that increase the risk of infection generally(eg, diabetesmellitus,12,24 frailty, and comorbid diseaseburden24-26) or of peritonitis specically (eg, positivenasal S aureus carrier status27 and history of exit-site

infection28,29). Furthermore, there are several de-mographic factors that have been associated inconsis-tentlywith increased risk of peritonitis, such as age,24,30

sex,30-32 and ethnicity.5,11,12,24-26,33,34 Todate, there areconicting reports regarding the impact of biocompat-ible uids35-49 and automated PD (APD)19,30,50,51 onperitonitis rates, such that currently, no conclusions canbe drawn about these interventions.In addition to these variables, some risk factors

may be associated with organism-specic peritonitisepisodes only rather than overall peritonitis risk. Forexample, peaks in the incidence of peritonitis due tocoagulase-negative staphylococci and Gram-negativeorganisms in warmer seasons and Corynebacteriumspecies in winter demonstrate seasonal variations inorganism-specic peritonitis rates.52 These variationshave been attributed to both climate-related changesin human behavior and immunity, as well as variableorganism virulence.52 Similarly, recent antibiotictherapy and recent peritonitis also have been identi-ed as risk factors for fungal peritonitis.53

Although a number of the reported risk factors forPD peritonitis listed in Box 1 are modiable, therecurrently is no high-level evidence that modifying

Figure 1. Peritoneal dialysis (PD) peritonitis rates by treatingcenter in Australia and New Zealand in 2011. Confidence inter-vals are not shown when upper limit is .3. Units with fewerthan 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-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

! 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 patients choice51,125

! Prior hemodialysis126

! Pets127

! Patient training104,106,128

Abbreviation: PD, peritoneal dialysis.aIndigenous racial origin includes Aboriginal and Torres Strait

Islander, Maori and Pacific Islander, and First Nation Canadianracial origin.

bReduced peritonitis risk with the use of biocompatible fluids isnot consistently supported.107,129

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2 Am J Kidney Dis. 2014;-(-):---

these risk factors will lead to reduced peritonitis rates,apart from topical exit-site antimicrobial prophylaxisand nasal eradication of S aureus. Similarly, for pa-tients with nonmodiable peritonitis risk factors, therealso is no high-level clinical evidence that specicallytargeting these individuals for closer monitoring,augmented home support, regular refresher training,or more intensive infection prophylaxis strategiessignicantly mitigates their risk. More collaborativeresearch work is required in this area.

DIAGNOSIS

Another potentially signicant source of variabilityin peritonitis rates among different units relates tocoding bias according to the peritonitis denitions.The International Society of PD (ISPD) has attemptedto minimize such variability by publishing specicdiagnostic criteria for PD peritonitis to calculateperitonitis rates for the purpose of benchmarkingacross units.54 When a diagnosis of peritonitis ismade, empiric antimicrobial therapy covering bothGram-positive and Gram-negative organisms isadministered pending results of microbiological cul-tures, which generally take several days. Ideally, amore rapid microbiological diagnosis needs to bedeveloped in the hope that it might improve perito-nitis management and outcomes by facilitating timelyinstitution of appropriate therapy. A novel develop-ment in this regard was described recently by Linet al55 in their proof-of-concept study to use immunengerprints characteristic of individual organisms inPD uids to allow more rapid and accurate infectionidentication. The authors were able to identifydistinct patterns of humoral and cellular responsesusing multicolor ow cytometry and multipleenzyme-linked immunosorbent assay to distinguishbetween Gram-positive and Gram-negative in-fections.55 This research suggests the possibility ofdeveloping point-of-care tests, which might permit amore timely and targeted approach to peritonitismanagement than currently is available.After a diagnosis of peritonitis is conrmed, it is

important to determine whether the episode representsa relapsing, recurrent, or repeat infection because suchepisodes correspond to distinct clinical entities withdiffering clinical outcomes.54 Relapsing peritonitis isdened as an episode that occurs within 4 weeks ofcompleting therapy for the same organism or oneculture-negative episode, whereas recurrent peritonitisrefers to an infection within 4 weeks of completingtherapy for a different organism.54 Relapsing andrecurrent peritonitis complicate 14% and 5% ofperitonitis episodes, respectively,56 and both areassociated with a greater risk of catheter removal andpermanent transfer to hemodialysis therapy.56,57 Incontrast, repeat peritonitis, dened as an episode more

than 4 weeks after completing therapy for a priorepisode with the same organism,54 has been reportedto complicatew10% of peritonitis episodes,58,59 withthe highest rate in the second month after completingantibiotic treatment58,59 (Fig 2). For the purpose ofrecording peritonitis rates, recurrent or repeat perito-nitis counts as a second episode, whereas relapsingperitonitis does not.11 The other important consider-ation is that peritonitis episodes (particularly Gram-positive ones) continue to inuence the risk andoutcomes of a subsequent episode for up to 6 monthsand should be taken into account when approachingthe empiric management of a subsequent episodeoccurring within this time frame.56

Ideally, one should be able to predict a futureoccurrence of relapsing or repeat peritonitis prior toits occurrence. Szeto et al60 have measured bacteria-derived DNA fragments in PD efuent in patientswith peritonitis and were able to demonstrate signif-icantly higher bacterial DNA fragment levels (repre-sented by the number of polymerase chain reactioncycles at which bacterial DNA could be detected) inthose who developed relapsing or repeat peritonitis(32.3 6 2.6 cycles) compared with those who werecured by antibiotics (34.1 6 1.7 cycles; P , 0.001).Although previous studies have explored the utility ofbacteria-derived DNA fragments as a marker of sys-temic inammation in PD patients61 and as a predictorof spontaneous bacterial peritonitis in patients withcirrhosis-related ascites,62 this is the rst study toreport its use in predicting a future risk of peritonitisin PD patients. If results of this single-center studywith a relatively small number of participant(n 5 143) are conrmed by other investigators, thesemethods may enhance the approach to the diagnosisof peritonitis.

TREATMENT

Timely management of peritonitis is associatedwith improved patient outcomes, including decreasedrisk of catheter removal.63 However, there remainsconsiderable uncertainty about the optimal treatment

01020304050607080

1 2 3 4 5 6 7 to 12 13 to24

>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 peritonitisepisode.56,59

PD Peritonitis

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strategy for peritonitis. The most recent update of theISPD Peritonitis Treatment Guidelines recommendsempiric antibiotics to cover both Gram-positive andGram-negative organisms guided by local antimicro-bial sensitivities.54 Although this is the best advicethat can be offered in an evidence-sparse area, thereare many unanswered important questions that needto be addressed by high-quality, multicenter, ran-domized, controlled trials.A systematic review examining antibiotic treatment

of PD peritonitis was unable to identify a superiorantibiotic agent or regimen.64,65 In particular,glycopeptide-based (eg, vancomycin) and rst-generation cephalosporin-based regimens resulted incomparable primary response and relapse rates,although glycopeptide-based regimens achieved asignicantly higher complete cure rate (3 studies, 370episodes; relative risk [RR], 1.66; 95% condenceinterval [CI], 1.01-2.72).64,65 Based on one study,intravenous antibiotic administration resulted in ahigher treatment failure rate than intraperitonealadministration (RR, 3.52; 95% CI, 1.26-9.81).64-66

Treatment failure did not differ signicantly bet-ween those treated with oral versus intraperitonealantibiotic regimens (7 trials, 452 patients; RR, 1.14;95% CI, 0.84-1.55). However, trials included in thisanalysis generally had a small number of participants(largest study, n 5 110)67 and only 2 studiesdemonstrated adequate allocation concealment.68,69

Furthermore, all studies evaluated a quinolone as anoral agent of choice, which introduced the risk ofdeveloping a class-related resistance. Results from thereview also yielded comparable outcomes with regardto 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 continuousand intermittent intraperitoneal antibiotic dosing.64 Inthe case of relapsing or persistent peritonitis, simul-taneous catheter removal/replacement resulted infewer treatment failures than urokinase (1 trial, 37patients; RR, 2.35; 95% CI, 1.13-4.91). Similarly, onthe basis of one trial involving 36 patients, a 24-hourperiod of peritoneal lavage did not signicantly in-uence treatment failure rate (RR, 2.50; 95% CI,0.56-11.25). No signicant harms were identiedfrom any of the interventions examined. However, thestrength of conclusions from this systematic reviewwas severely restricted by the generally suboptimalquality of the trials included, which had inconsistentoutcome denitions.Another important question is whether APD pa-

tients who experience peritonitis should be convertedto continuous ambulatory PD (CAPD) or have thecycler reset to permit longer dwell times. The shortdwells in APD therapy may result in reduced ab-sorption and increased clearance of antibiotics, which

in turn may lead to dialysate concentrations fallingbelow minimal inhibitory concentrations, particularlywith intermittent administration. Although the afore-mentioned systematic review identied comparableoutcomes between continuous and intermittent intra-peritoneal antibiotic dosing,64,65 this evidence is farfrom compelling (particularly in the case ofcephalosporin-based regimens) and may not gener-alize to APD patients. A retrospective observationalcohort study of 508 episodes of PD-associated peri-tonitis in 508 patients reported longer median dura-tion of elevated dialysate efuent leukocyte counts (5vs 4 days; P , 0.05) and longer median antibioticcourse duration (16 vs 15 days; P , 0.05) in APDpatients treated for peritonitis (n 5 239) comparedwith CAPD patients treated for peritonitis (n 5 269),but found no differences in patient-level outcomes ofrelapse rates, catheter removal rates, or death.70

However, these ndings may have been limited byindication bias secondary to nonrandom selection ofPD modality, leading to differences in peritonitis riskproles between the APD and CAPD cohorts (eg,APD patients were on average younger and had beenon PD therapy for a longer time than their CAPDcounterparts). The ISPD Peritonitis Guidelines high-light that further research in the area is needed andrecommend that if intermittent dosing is to be insti-tuted, the antibiotic-containing dialysis solution mustbe allowed to dwell for at least 6 hours to permitadequate absorption of the antibiotic into the systemiccirculation.54

An alternative approach to ensuring adequate drugdelivery might be through monitoring antibiotic levelto improve clinical outcomes while minimizing drug-related toxicity. Our group recently attempted toaddress this question by measuring systemic levels ofvancomycin71 and gentamicin72 during peritonitistreatment, which did not demonstrate an associationbetween antibiotic levels and antibiotic-related harmor efcacy when drugs were dosed according to ISPDrecommendations.54 Similar ndings were reported ina 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 conclusionscan be drawn at this stage about the role of serumgentamicin and vancomycin level measurementsduring peritonitis treatment.The duration of antibiotic treatment required to safely

and effectively treat peritonitis episodes also has notbeen studied rigorously. The expert opinion expressedin the ISPD Peritonitis Guidelines is that treatmentshould continue for at least 2 weeks and be extendedto 3 weeks for more severe infections, such asSaureus, Gram-negative, and enterococcal peritonitis.54

Based on the reported outcomes of organism-specic

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peritonitis from the Australian Peritonitis Registry(Table 1), extended durations of therapy also probablyshould 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 timelyPD catheter removal for individuals who present withrefractory peritonitis, relapsing peritonitis, and fungalperitonitis.54 At present, catheter removal is recom-mended if PD efuent fails to clear after 5 days ofappropriate antibiotic treatment,54 although the evi-dence underpinning this recommendation is limited.Our group previously demonstrated that delayingcatheter removal beyond the rst week was associatedwith signicantly higher rates of permanent transfer tohemodialysis therapy in peritonitis episodes causedby corynebacteria,74 enterococci,75 and multiple or-ganisms.76 Nevertheless, these processes often aredelayed in practice, especially if removal of a catheteris 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 toidentify those likely to experience treatment failure.An example of such a strategy is measuring thedialysate efuent leukocyte count on day 3 because aretrospective observational study by Chow et al77

reported that a peritoneal dialysate white blood cellcount $ 1,000/mL predicted treatment failure in anindependent validation cohort with sensitivity of 64%and specicity of 97%.When a specic microorganism is identied, the

ISPD Peritonitis Guidelines provide a series ofalgorithms for treating organism-specic peritonitisepisodes, although the evidence for these recom-mendations is limited primarily to case series andobservational cohort studies.74-76,78-86 Perhaps thebest available observational evidence to date appliesto fungal peritonitis, in which catheter removal com-bined with antifungal therapy produced the best

overall outcome, having the lowest rates of repeatfungal peritonitis episodes and death compared witheither therapeutic intervention alone.53 Similarly, inthe setting of Pseudomonas species peritonitis, cath-eter removal was associated with a lower risk of deaththan treatment with antibiotics alone.86

PREVENTION

There is systematic review and randomizedcontrolled trial evidence supporting the use ofdisconnect (twin-bag and Y-set) systems87,88 andpreoperative administration of intravenous antibiotic(typically cephalosporin) prior to PD catheter inser-tion89,90 to reduce the risk of peritonitis. However, todate, no benecial effect has been demonstratedconvincingly by randomized controlled trials for anyother catheter-related intervention, including catheterinsertion technique, catheter placement, immobiliza-tion device, catheter design, or cuff number.91 A sub-sequent analysis of the Canadian Baxter PeritonitisOrganism Exit-Sites Tunnel Infections (POET) data-base identied that double-cuff catheters were associ-ated with a signicant reduction in overall peritonitisrate (particularly S aureus peritonitis) in patientscommencing PD therapy between 1996 and 2000, butnot among those commencing PD therapy between2001 and 2005, which possibly is related to the obvi-ating effect of widespread adoption of prophylacticexit-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 nasalmupirocin prophylaxis,94-96 exit-site mupirocin pro-phylaxis,97,98 and exit-site gentamicin prophylaxis.22

Application of exit-site gentamicin cream has beenassociated with a lower overall peritonitis rate (RR,0.52; 95% CI, 0.29-0.93;P , 0.03), largely driven by adecrease in Gram-negative peritonitis episodes (0.02/yvs 0.15/y; P 5 0.003) compared to exit-site mupirocinprophylaxis.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 87% 3% 74% 10% 3% 9% 1.4%Coagulase-negative staphylococci81 77% 17% 61% 10% 2% 9% 1.0%Culture negative82 77% 14% 60% 12% 3% 10% 0.9%Corynebacteria74 67% 18% 70% 21% 7% 15% 2.4%S aureus (all)83 67% 20% 67% 23% 4% 18% 2.2%Non-Pseudomonas Gram-negative84 60% 11% 81% 31% 4% 26% 4.2%MRSA83 54% 19% 75% 31% 6% 25% 4.6%Polymicrobial76 52% 10% 83% 43% 5% 38% 3.9%Enterococci75 51% 15% 78% 37% 6% 32% 3.4%Pseudomonas86 50% 9% 79% 44% 11% 35% 3.1%Fungal53 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.

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the ISPD.11 However, there have been no direct head-to-head comparison studies of intranasal mupirocinwith either exit-site mupirocin or exit-site gentamicin.In addition, although these agents are effective inreducing exit-site infection22,94 and peritonitis rates,22

there have been some concerns that these antibioticsmay promote resistant organisms.99,100

Because antibacterial honey does not induceantimicrobial resistance and has been shown to beactive against a broad range of bacteria (includingmultiresistant 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 thesafety and efcacy of applying this agent to PD exitsites as an alternative infection control strategy.101

The HONEYPOT multicenter, open-label, random-ized, controlled trial involved 371 PD patients whowere randomly assigned to either daily topical exit-site application of antibacterial honey (n 5 186) orintranasal mupirocin prophylaxis in those who wereidentied as nasal S aureus carriers (n 5 185). Theuse of honey yielded PD-related infection-free sur-vival times (ie, exit-site infection, tunnel infection,or peritonitis) comparable to the standard mupirocingroup (16 vs 17.7 months; unadjusted hazard ratio[HR], 1.12; 95% CI, 0.83-1.51; P 5 0.47). In theprespecied subgroup of patients with diabetesmellitus, honey increased the risks of both thecomposite 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 whoreceived honey were more likely to withdraw fromthe study (29% vs 9%; P , 0.001). On the basis ofthese results, antibacterial honey was not recom-mended for routine clinical use in PD patients.Similar results were observed in the MP3 (Mupirocin

and Polysporin Triple ointment) study conducted byMcQuillan et al102 in 201 PD patients, in which the useof Polysporin Triple (Pzer) ointment was associatedwith comparable time to rst event (either exit-siteinfection or peritonitis) compared to exit-site mupir-ocin application (13.2 vs 14 months; P5 0.41).However, the safety of Polysporin Triple ointment wasof concern because its use was associated with signif-icantly higher rates of fungal exit-site infections (0.07vs 0.01; P5 0.02) and fungal peritonitis episodes(0.04 vs 0.00; P, 0.05).102 Consequently, PolysporinTriple ointment was not recommended for preventionof PD-related infections.Other PD-related infection prevention strategies

include practicing standard exit-site care, such asexcellent hand hygiene, and using noncytotoxicantiseptic cleaning agents to clean the exit site.11

However, there currently is no evidence that anyparticular cleansing agent is superior.

Training also has been a major focus of the ISPDguidelines for preventing PD peritonitis.11,103 Itgenerally is recommended that treating PD unitsshould ensure that appropriately trained staff deliverevidence-based training methods using the principlesof adult education. Patients also should be retrained 3months after initial training and routinely (at leastannually) thereafter, as well as after any hospitaliza-tion, episode of peritonitis or catheter infection, orchange in dexterity, vision, or mental acuity.11 It alsois emphasized that training the staff requires activecontinued learning and retraining to ensure optimaloutcomes.104 However, to date, there have been norandomized controlled trials comparing training pro-tocols and curricula for PD patients. There also isconicting observational evidence regarding whetherlonger 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 HongKong demonstrated extraordinary center variability inPD training practices and durations (9-96 hours perpatient).105

Finally, the BalANZ trial recently demonstratedthat the use of neutral-pH low-glucose-degradationproduct dialysis uids resulted in a signicantreduction 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 inshorter peritonitis-associated hospitalization duration,suggesting that biocompatible solutions decreasedboth the likelihood and severity of peritonitis.41,42

However, a subsequent systematic review of ran-domized controlled trials by our group did not nd asignicant effect of biocompatible uids on peritonitisrates, possibly because of heterogeneity in trial qual-ity.107 Consequently, the impact of neutral-pH low-glucose-degradation product uids on peritonitis riskremains uncertain.

IMPROVING PD PERITONITIS OUTCOMESDespite the widespread availability and awareness

of the ISPD guidelines for the prevention and treat-ment of PD peritonitis, there is substantial variation inPD peritonitis outcomes among different centers andcountries.12-15 The available evidence suggests thatcenter variation in PD practice contributes substan-tially to these disparate outcomes. For example, aprevious survey of Australian PD units by our groupreported relatively low adherence (,50%) toevidence-based policies such as administering pro-phylactic antibiotics at the time of catheter insertionor prescribing topical antimicrobial prophylaxis.108

Moreover, a recent ANZDATA analysis observedlow (7%) use of antifungal prophylaxis during

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antibiotic treatment of bacterial peritonitis inAustralia.53 Poorer outcomes also were observed inother ANZDATA analyses when practices deviatedsignicantly from evidence-based recommendations,such as using 1 antibiotic rather than 2 to treatPseudomonas species peritonitis, failing to use aglycopeptide (eg, vancomycin) when treatingmethicillin-resistant S aureus peritonitis, and nottreating fungal peritonitis with both catheter removaland antifungal therapy.109

One of the barriers to bridging this treatment gapin PD units is the overall poor quantity and quality ofevidence pertaining to PD peritonitis prevention andmanagement. There are many PD interventions andpractices that still require formal evaluation byclinical studies (Box 2). The creation of peritonitisregistries such as those in Australia,5 Brazil,110 andHong Kong111 has been critically important forgenerating hypotheses for future studies and foraudit and feedback. Multicenter, investigator-initiated, randomized, controlled trials remain thegold standard for testing PD interventions, but arelimited because any such investigation would require

1,000 patients or more to be adequately powered forthe outcome of peritonitis. Realistically, many PDpractices therefore are not going to be informed bywell-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 observationalstudy aiming to identify measurable and modiablepractices that are associated with improved PD out-comes in more than 100 PD units from at least 5countries. The future outcomes of PDOPPS hope-fully will include identication of innovative prac-tices and service organization that deliver the bestoutcomes in a variety of clinical situations in thereal-world setting, improved patient safety (eg,reduced peritonitis), better informed policy de-cisions, better evaluation of the effect of policy onpatient care and outcomes, guidance of the rationaldevelopment and optimal design of future clinicaltrials in PD peritonitis, development of consensusdenitions and nomenclature to be used across all

Box 2. Interventions That Require Further Clinical Study toDetermine Their Impact on Peritonitis Rates and/or Outcomes in

PD Patients

! Preoperative screening and eradication of nasalstaphylococci

! 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 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 perito-

nitis treatment

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

Box 3. Recommended Standard of Care for PD Patients109

Catheter Insertion

! Eradication of Staphylococcus aureus11,54

! Catheter insertion by an appropriately trained experi-enced operator130

! Avoidance of constipation54,130

! Placement of catheter with a downward-facing exitsite54,130

! Prophylactic antibiotic administration during catheterinsertion11,54

Infection Control

! Patient education on aseptic technique11,54

! Topical exit-site or nasal antibiotics11,22,94

! Coprescription of antifungal prophylaxis with any antibiotictreatments11,54

! Timely administration of antibiotics in the case of touchcontamination11,54

! Regular assessment of exit site11,54

Peritonitis

! Administration of appropriate antibiotic(s) for organismbeing treated54

! Adherence to ISPD-recommended route and duration oftreatment54

! Administration of antifungal prophylaxis during antibiotictreatments11,54

! Timely removal of catheter in refractory peritonitis11,54

Audit

! Recording of infection rates and outcomes for bench-marking against national and international data11

! Continuous quality improvement programs113

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 standardizationof international registry data collection.Apart from improving the existing limited evidence

base, the other great challenge for the PD communityis improving outcomes not just in centers with aspecic PD interest/focus, but in all centers in whichPD is practiced. Typically, signicant improvementsin PD outcomes, including peritonitis, have been re-ported by centers incorporating the principles ofcontinuous quality improvement.112,113 Ideally, aroot-cause analysis should be applied to each episodeof peritonitis in a PD unit to try to identify areas forimprovement.113

In an attempt to address the appreciable gap bet-ween evidence-based best practice and actual practiceacross many PD units in Australia, multipronged in-terventions have taken place over the past few years,

including augmentation of the existing evidence baseby conducting investigator-initiated trials in PD bythe Australasian Kidney Trials Network, as well ascontinued analysis of ANZDATA data, improvementof existing guidelines, implementation of a teamapproach for continuous quality improvement,development of key performance indicators to meetevidence-based practice (eg, 100% prophylacticantibiotic administration prior to catheter insertion,PD peritonitis rate , 0.36 episodes per patient peryear, and 100% antifungal agent prescription duringtreatment of peritonitis),114 reinforcement of PDtraining especially targeting young nephrologists atannual PD Academy meetings, and publication of aCall to Action guideline highlighting gaps inAustralian practice and promulgating locally appro-priate evidence-based recommendations to improvepatient outcomes and clinician awareness (Box 3).109

These approaches were associated with a dramaticreduction in peritonitis rate in 2011 to 0.43 episode/patient-year in Australia, which is the rst time theperitonitis rate was documented at ,0.50 episode/patient-year since the establishment of a peritonitisregistry in 2003 (Fig 3).5 Examination of organism-specic peritonitis rates demonstrated decreases inthe 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 asa 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 NewZealand, 2003-2011. Data are expressed as number of episodesper patient-year and patient-months per episode. Reproducedwith permission from the ANZDATA 2012 Annual Report.5

Figure 4. Organism-specific peritonitis rates in Australian and New Zealand PD patients 2003-2011. Abbreviations: Coag negStaph, coagulase-negative staphylococci; MRSA, methicillin-resistant Staphylococcus aureus; org, organism; pos, positive. Repro-duced with permission from the ANZDATA 2012 Annual Report.5

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8 Am J Kidney Dis. 2014;-(-):---

terms of morbidity, mortality, and health care costs.Despite the importance of peritonitis as a patientsafety issue, there is extraordinary and unacceptablevariation in PD peritonitis rates and outcomes amongdifferent centers, regions, and countries. The reasonsfor this variation have been poorly studied, but maybe related to a combination of patient selection withdifferent peritonitis risk-factor proles, variable ap-proaches to dening and calculating peritonitis rates,and, perhaps most importantly, different PD centerpractices with respect to treating and preventingperitonitis. Key strategies for addressing these issuesshould include continuous quality improvement pro-grams with routine auditing and benchmarking ofperitonitis rates and outcomes, together with imple-mentation of evidence-based best practice andimproved staff and patient training and retrainingprograms. Insights obtained from results of futurerandomized controlled trials and PDOPPS also shouldhelp identify innovative practices and service orga-nizations that deliver the best outcomes.

ACKNOWLEDGEMENTSSupport: None.Financial Disclosure: Dr Johnson is a consultant for Baxter

Healthcare Pty Ltd and has previously received research fundsfrom this company; has also received speakers honoraria andresearch grants from Fresenius Medical Care; and is a currentrecipient of a Queensland Government Health Research Fellow-ship. Dr Cho declares that she has no relevant nancial interests.

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Peritoneal DialysisRelated Peritonitis: Towards Improving Evidence, Practices, and OutcomesEpidemiologyRisk factorsDiagnosisTreatmentPreventionImproving PD peritonitis outcomesSummary and future directionsAcknowledgementsReferences