Prevention Of Peritoneal Dialysis–Related Infections

Prevention Of Peritoneal Dialysis–Related Infections Sharon J. Nessim, MD, MSc Summary: Despite substantial advances in peritoneal dialysis (PD) as a renal replacement modality, PD-related infection remains an important cause of morbidity, technique failure, and mortality. This review describes the microbiology and outcomes of PD peritonitis and catheter infection, followed by a discussion of several strategies that may reduce the risk of PD-related infections. Strategies that are reviewed include use of antibiotics at the time of PD catheter insertion, selection of PD catheter design and insertion technique, patient training, PD connectology, exit site prophylaxis, periprocedural prophylaxis, fungal prophylaxis, and choice of PD solutions. Semin Nephrol 31:199-212 © 2011 Elsevier Inc. All rights reserved. Keywords: Peritoneal dialysis, peritonitis, catheter infection, prevention, prophylaxis

eritoneal dialysis (PD) is a renal replacement therapy modality that has evolved significantly since its inception more than 30 years ago. Despite substantial improvements, technique failure remains a common outcome. Although mechanical complications, dialysis adequacy, ultrafiltration failure, and psychosocial issues contribute to this, the most common cause of technique failure in many centers remains PD-related infection.1,2 The most frequent type of PD-related infection is peritonitis. Less commonly, PD patients can develop catheter infections, including exit site infection and/or tunnel infection. In this review, the microbiology and outcomes of PDrelated infections are discussed, followed by some evidence-based strategies to reduce the risk of infection.

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SOURCES OF PD-RELATED INFECTION Entry of organisms into the peritoneal cavity can occur via several mechanisms. The two most common mechanisms involve the PD catheter as a portal of entry, and comprise intraluminal and Department of Medicine, Division of Nephrology, Jewish General Hospital, Montreal, Quebec, Canada; and McGill University, Montreal, Quebec, Canada. Address reprint requests to Dr. Sharon J. Nessim, Jewish General Hospital, 3755 Cote-Sainte-Catherine Rd, Room G-225.1, Montreal, Quebec, Canada H3T 1E2. E-mail: [email protected] 0270-9295/ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2011.01.008

periluminal entry. Intraluminal infection refers to the introduction of organisms into the lumen of the catheter, usually by touch contamination at the time of catheter connection. This type of infection is very dependent on patient technique and PD connectology strategies. Periluminal infection refers to entry from the exit site along the outside wall of the catheter through the subcutaneous tunnel and into the peritoneal cavity. Consequently, peritonitis that occurs by this mechanism frequently is associated with exit site and/or tunnel infection. The most important risk factor for exit site colonization and subsequent periluminal entry of organisms is nasal colonization with Staphylococcus aureus.3 Peritonitis episodes can also result from transmigration of organisms across the intestinal wall. Some proposed risk factors for this route of infection include colonoscopy,4-8 hypokalemia,9 diverticulosis,10,11 constipation,12 and possibly use of H2-antagonists.13,14 Other more rare mechanisms of organism entry into the peritoneum that lead to peritonitis include bacteremia with secondary seeding of the peritoneal cavity, and migration of organisms from the genitourinary tract into the peritoneal cavity.15-17 MICROBIOLOGY OF PD-RELATED INFECTION Although the microbiology of peritonitis and catheter infection has varied to some extent

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over time and across different PD centers and countries, several findings are relatively consistent. For peritonitis, gram-positive organisms are at least twice as common as gram-negative infections, accounting for about 50% to 70% of episodes.1,2,18 The most common gram-positive organism is coagulase-negative Staphylococcus (CNS), followed by S aureus and Streptococcus species. Less common gram-positive organisms include Enterococcus and Corynebacterium. Gram-negative organisms currently account for approximately 20% to 25% of peritonitis episodes, with the proportion having increased over time with the evolution of better strategies to prevent gram-positive infections.19 The most common gram-negative organism is Escherichia coli, seen in approximately 6% of patients, followed by Klebsiella, Pseudomonas, and, more rarely, other enteric gram-negative bacteria.1 Although most gram-negative organisms enter the peritoneal cavity by transmigration across the intestinal wall, Pseudomonas is the exception in that it typically causes peritonitis by periluminal migration of organisms from the exit site along the catheter tunnel. Fungal peritonitis accounts for about 3% of infections, and mycobacterial infections are even less common. The remainder of peritonitis episodes show no growth of organisms, with the proportion of culturenegative episodes depending on each center’s specimen processing and culture technique. In most centers with proper culture methodology, negative peritoneal cultures are seen in fewer than 20%, in keeping with International Society for Peritoneal Dialysis (ISPD) recommendations.20,21 Similar to peritonitis, catheter infections most often are caused by gram-positive organisms, accounting for two thirds to three quarters of episodes.1 Although S aureus historically has been the most common exit site organism, use of prophylactic measures has led to a significant reduction in the frequency of this organism as a culprit in catheter infections.22 The most frequent cause of catheter infection among gram-negative organisms by far is Pseudomonas, accounting for 13% to 18% of exit site infections in North America.1

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OUTCOMES OF PD-RELATED INFECTION Although all PD-related infectious complications are worrisome, the infections of greatest concern are those that are associated with technique failure and mortality. The most severe infection in terms of morbidity and mortality is fungal peritonitis, with death occurring in up to 44% of patients.23-26 The poor outcomes of fungal peritonitis with conservative therapy have led to the recommendation that the PD catheter be removed immediately when fungal peritonitis is diagnosed.20,21 As a result of adoption of this strategy, rates of either temporary or permanent transfer to hemodialysis are high, but mortality has decreased significantly.27 With regard to bacterial infections, several organisms have been associated with high rates of technique failure. Among gram-positive organisms, S aureus peritonitis is a relatively common cause of PD catheter removal, particularly when the peritonitis episode occurs in association with a catheter infection with the same organism.28 Among gram-negative infections, the organism most commonly associated with catheter removal is Pseudomonas. As with S aureus, when Pseudomonas peritonitis occurs in association with a Pseudomonas catheter infection, the implication is that the whole catheter tract is infected, such that there is a very low probability (⬍10%) of successful eradication of the infection.28-31 Even when Pseudomonas catheter infection occurs in the absence of associated peritonitis, catheter loss is common.29 An additional concerning category is enteric peritonitis, since peritonitis episodes with gram negative organisms, Enterococcus or anaerobes may be associated with catheter loss in up to 40% of cases.1 Polymicrobial peritonitis, which typically is caused by translocation of multiple organisms from the gastrointestinal tract, is caused more often by intestinal microperforation rather than frank perforation. In a recent study from the Australia and New Zealand database, catheter loss as a result of polymicrobial peritonitis occurred in 43% of episodes.32 The importance of identifying infections with the highest rates of technique failure is that it is these infections that are most important to prevent. Some of the strategies dis-

Prevention of PD-related infections

cussed later aim to target a particular mechanism of entry of organisms, whereas others are intended to target specific organisms. STRATEGIES TO PREVENT INFECTION AT THE TIME OF CATHETER INSERTION Several strategies at the time of PD initiation have been studied to try to reduce the risk of developing early peritonitis or catheter infection. These include use of antibiotics at the time of catheter insertion, choice of PD catheter design, creation of a downward-directed tunnel, and enhanced patient training.

Antibiotics at the Time of Catheter Insertion The skin is colonized by many organisms, and typically this skin flora consists predominantly of gram-positive organisms such as CNS. Although the PD catheter is inserted under sterile conditions after appropriate cleansing of the skin, this procedure nevertheless may serve as an entry point for organisms into the peritoneal cavity, leading to peritonitis within the first few weeks after catheter insertion. The effectiveness of prophylactic antibiotics was first reported in a study comparing perioperative gentamicin with no prophylaxis.33 The favorable effect of prophylaxis in this study was subsequently confirmed in a large American observational study, in which use of antibiotics before catheter insertion was associated with a 29% reduction in peritonitis risk.18 Although a favorable effect of antibiotics was also seen in another study,34 not all observational studies have shown this association.35 There have been two randomized controlled trials (RCT) of antibiotic prophylaxis pre-PD catheter insertion.36,37 In the larger of the two studies, patients were randomized to one of three groups: (1) vancomycin 1 g intravenously 12 hours preprocedure, (2) cefazolin 1 g 3 hours preprocedure, or (3) placebo, with an end point of peritonitis in the subsequent 14 days.36 Among the 221 patients randomized, peritonitis occurred in 10 patients in the placebo group, 6 patients in the cefazolin group, and 1 patient in the vancomycin group. The benefit of antibiotics before catheter insertion was supported by

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a smaller RCT involving 38 patients randomized to placebo or cefuroxime,37 although the proportion of patients in the placebo group who developed peritonitis was unusually high in this latter study. Despite the limited data and relatively small study size, it appears that use of prophylactic antibiotics before catheter insertion is beneficial. The optimal regimen is less clear because there is significant variability in antibiotic susceptibility across hospitals, cities, and countries. Antibiotic choice therefore should be guided by local susceptibility patterns. With regard to the optimal timing of antibiotic administration, there are few specific PD catheter insertion data, but extrapolation from the general literature on surgical wound infections would suggest that optimal timing of administration is in the 2 hours before the procedure.38 Vancomycin may be an exception to this recommendation, owing to its longer half-life in the setting of impaired renal clearance.

PD Catheter Design In addition to prophylactic antibiotics, several studies have looked at different PD catheter designs to determine whether any one catheter design is more protective against infection. Although modifications to the intraperitoneal and extraperitoneal segments of the catheter have not led to reduction in peritonitis,39-45 the data on use of single- versus double-cuff catheters are conflicting.46-49 In theory, the presence of a second, more superficial cuff could act as an additional microbial barrier. The only RCT to have tested whether double-cuff catheters are superior to single-cuff catheters for peritonitis prevention was a trial by Eklund et al.48 In this study, 60 patients were randomized to insertion of a single- or double-cuff catheter and followed for 2 years, with no difference in the peritonitis rate between the two groups. However, because peritonitis is a relatively rare event, and because the use of a double-cuff catheter would only be expected to reduce the rate of peritonitis episodes caused by periluminal entry of organisms, a large number of patient-years of follow-up evaluation might be required to detect such a difference, should one exist. More recently, using the multicenter Canadian peri-

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tonitis organism exit sites tunnel infections (POET) database, use of a double-cuff catheter relative to a single-cuff catheter was found to be independently associated with a reduced risk of peritonitis, although this effect was most pronounced before the year 2000.50 Interestingly, there was a 54% reduction in peritonitis caused by S aureus. Because this is the organism most likely to enter the peritoneal cavity via migration along the catheter tunnel, it supports the hypothesis that double-cuff catheters provide an added barrier to periluminal movement of organisms into the peritoneal cavity. However, it is unclear whether a double-cuff catheter provides additional protection against periluminal entry of organisms among patients already using ext site antibiotic prophylaxis. The 2005 ISPD guidelines, published before the latter study, suggest that no catheter type has been shown to be superior to the standard Tenckhoff catheter for peritonitis prevention.20

PD Catheter Insertion Technique The only PD catheter insertion technique that has been shown to be of benefit for prevention of infection is the creation of a downwarddirected catheter tunnel to prevent bacteria and skin debris from collecting in the exit site.18 This was described in the Network 9 study, in which 1,930 PD patients were followed up during 1991. After adjustment for other potentially important covariates, patients with downwarddirected tunnels were 33% less likely to experience peritonitis occurring in association with concomitant catheter infection. Other catheter insertion strategies such as buried PD catheters, which prevent exit site colonization with microorganisms during the healing process, have not been shown to reduce PD-related infections51,52 (see the article by Shahbazi et al on p. 138 in this issue of Seminars in Nephrology).

Patient Training In addition to specific perioperative considerations, the importance of proper patient training in the prevention of PD-related infections has also been studied. It is known that patient education about appropriate hand hygiene can dramatically reduce the risk of touch contami-

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nation.53 In addition, a multicenter survey of PD centers in Italy showed that predialysis training, home visits, and re-training were associated with a reduction in peritonitis rates.54 This finding was supported by another study comparing enhanced training using an adult learning theory– based curriculum with a nonstandardized conventional training program in 620 PD patients.55 Those who received the enhanced training had significantly fewer exit site infections and peritonitis episodes. The data are, however, somewhat inconsistent, with some studies showing no relationship between more intensive training and peritonitis.56,57 Although patient training is important, an additional factor may be the nurses who perform the training. Although greater nursing experience may seem advantageous, the opposite was shown in a study in which patients trained by nurses with 3 or more years of experience had a more than two-fold increased likelihood of subsequent gram-positive peritonitis,58 suggesting that maintenance of expertise among nurse trainers is critical. Overall, although the data are limited, improving the quality and quantity of PD patient education seems intuitively advantageous, particularly when it comes to reducing peritonitis caused by touch contamination. The bulk of this training should occur before PD initiation, but home visits and periodic retraining likely provide additional benefit, especially after an episode of CNS peritonitis. STRATEGIES TO PREVENT INFECTION WHILE ON PD Once the PD catheter is inserted and PD has been initiated, several modifications to PD practice have been studied to reduce peritonitis risk. The most-studied strategies include changes in PD connectology and use of prophylactic antibacterial ointments. Other strategies for which there are more limited data include prophylaxis before procedures such as colonoscopy, prophylaxis against fungal infection, and use of more biocompatible solutions.

PD Connectology The first major advance was the introduction of improved PD connectology. The initial catheter

Prevention of PD-related infections

connection method involved conventional spike connection systems. In the 1980s, it was hypothesized that disconnect systems using a Y-set would be superior to spike connection systems for the prevention of peritonitis. The flush before fill technique with a Y connection system was shown to result in important reductions in the rate of peritonitis in several studies.59-62 Subsequently, a more advanced form of disconnect system known as the double-bag (or twin-bag) system also was shown to be superior to standard spike connection systems.62 Although the double-bag system was hypothesized to further reduce peritonitis risk relative to standard Y-sets by having one fewer connection, studies comparing these two disconnect systems have not consistently shown a benefit of one over the other.62-65 Based on the available data, the 2005 ISPD guidelines have suggested to avoid spiking dialysis bags in continuous ambulatory PD patients, and to instead use a double-bag system with the flush-before-fill technique to reduce the risk of contamination.20 For automated PD patients, luer lock connectology for the cycler should be used.

Exit Site Prophylaxis The second major advance after improved PD connectology was the introduction of antibacterial ointments applied to the PD catheter exit site or nares to reduce bacterial colonization. The risk associated with bacterial colonization with S aureus was recognized in several early studies.3,66,67 For example, one study found that PD patients who were S aureus nasal carriers had exit site infection rates that were four-fold higher than noncarriers,3 suggesting that patients who have S aureus colonization in their nares are more likely to have S aureus at their PD catheter exit site. The corollary of this finding was that eradication of colonization might reduce exit site infection as well as peritonitis occurring via periluminal migration of organisms along the catheter tunnel. The data on exit site prophylaxis are robust relative to most other aspects of PD infection prevention (Table 1). One of the earliest studies compared cyclic use of rifampin for 5 days every 3 months with placebo.68 Although this strategy reduced exit site infection, the side-

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effect profile of rifampin, as well as the potential for drug interactions and development of resistance, led to a search for other more favorable options. Studies instead began to focus on topical mupirocin, an agent known to have excellent activity against gram-positive organisms, including methicillin-resistant S aureus. A randomized trial comparing cyclic rifampin with exit site mupirocin showed that both were equally effective after 1 year of therapy, with better drug tolerance in the mupirocin group.69 The majority of data on exit site care have compared mupirocin with placebo, highlighted by a multicenter RCT of intranasal mupirocin versus placebo ointment in 267 S aureus nasal carriers on PD.70 In this study, application of mupirocin to the nares for 5 days every month resulted in a significant reduction in the frequency of S aureus exit site infection, but not peritonitis. The favorable effect of mupirocin prophylaxis on catheter infection has been confirmed in several other studies,71-78 with many of these also showing a reduction in peritonitis.71-79 Although the use of topical mupirocin has been shown to reduce the frequency of exit site infection and peritonitis, the antibacterial spectrum of mupirocin has done little to address the issue of gram-negative exit site infection and peritonitis, particularly those caused by Pseudomonas. The hypothesis that gram-negative exit site coverage might provide added benefit in the prevention of catheter infection and peritonitis was tested by Bernardini et al22 in a RCT of exit site mupirocin versus gentamicin. Among the 133 PD patients randomized, both strategies resulted in low rates of S aureus exit site infections. However, patients in the gentamicin arm had significantly fewer gram-negative catheter infections and peritonitis episodes. Subsequent to this RCT, two recent observational studies have shown equivalent exit site infection and peritonitis rates with mupirocin and gentamicin.80,81 Two other RCTs of exit site prophylaxis currently are being conducted. In the first trial, which was recently completed, Canadian PD patients were randomized to exit site application of mupirocin or Polysporin triple antibiotic ointment (Pfizer Canada, Markham, Ontario).82

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Table 1. Studies of Exit Site Prophylaxis

Study

Study Design

Years of Study

Zimmerman et al68

Randomized trial

1987-1989

Bernardini et al69

Randomized trial

1992-1994

Mupirocin Study Group70

Randomized trial

1996

Wong et al77

Randomized trial

2002

PerezFontan et al71

Observational

1990-1992

Thodis et al (study 1)72

Observational

1996 versus 1997

Thodis et al (study 2)72

Observational

1990-1995 versus 1996-1997

Casey et al73

Observational

1998

Mahajan et al74

Observational

2002-2003 versus 2003-2004

Uttley et al75

Observational

Pre-1999 versus 1999-2001

Zeybel et al76

Observational

1996-2002

Lim et al78

Observational

1998-1999 versus 2000-2004

Crabtree et al79

Observational

1992-1997 versus 1998-1999

Bernardini et al22

Randomized trial

Chu et al80

Observational

2001-2003

2005

Intervention Cyclic rifampin versus no prophylaxis Cyclic rifampin versus exit site mupirocin Intranasal mupirocin versus placebo ointment Exit site mupirocin versus no prophylaxis Intranasal mupirocin versus no prophylaxis Exit site mupirocin versus no prophylaxis Exit site mupirocin versus no prophylaxis Exit site mupirocin versus no prophylaxis Exit site mupirocin versus exit site povidoneiodine Exit site mupirocin versus no prophylaxis Exit site mupirocin versus no prophylaxis Exit site mupirocin versus no prophylaxis Intranasal mupirocin versus no prophylaxis Exit site gentamicin versus exit site mupirocin Exit site gentamicin versus exit site mupirocin

Patients per Group, n

Duration of Follow-Up Evaluation

Effect of Intervention on ESI

Effect of Intervention on Peritonitis

32 R/32 C

10-12 mo

Decreased

No effect

41 R/41 M

1y

Equivalent for SA

Equivalent for SA

134 M/133 C*

18 mo

Decreased SA ESI

No effect

73 M/81 C

5 mo

Decreased grampositive ESI

Decreased grampositive peritonitis

94 M/74 C

Decreased

Decreased

181 M/181 C

1,097 M patientmonths versus 1,043 C patient-months 1y

Decreased SA ESI

Decreased SA and overall peritonitis rate

70 M/118 C

1y

Decreased SA ESI

Decreased SA peritonitis

143 M/148 C

7 mo

Decreased

Decreased SA and overall peritonitis rate

40 M/40 C

1y

Decreased SA and overall

Decreased SA and overall

86 M/113 C

22 mo

Decreased SA and overall

Decreased SA peritonitis

18 M/18 C

20 mo

Decreased

Decreased

491 M/249 C

N/A

Decreased SA and overall

Decreased SA and overall

129 M/63 C

2y

No effect

Decreased

67 G/66 M

8 mo

Decreased gramnegative ESI with gentamicin

43 G/38 M

476 G patient months versus 539 M patientmonths

Equivalent

Decreased gramnegative peritonitis with gentamicin Equivalent

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Table 1. Continued

Study Mahaldar et al81

Study Design

Years of Study

Observational

2003-2007

Intervention Exit site gentamicin versus exit site mupirocin

Patients per Group, n 50 G/50 M

Duration of Follow-Up Evaluation 713 G patientmonths versus 590 M patientmonths

Effect of Intervention on ESI Equivalent

Effect of Intervention on Peritonitis Equivalent

Abbreviations: C, control; ESI, exit site infection; G, gentamicin; M, mupirocin; N/A, data not available; R, rifampin; SA, S aureus. *All patients in the study were S aureus nasal carriers.

Because Polysporin triple includes polymyxin, bacitracin, and gramicidin, it was hypothesized that this broader coverage would prove to be superior to mupirocin for prophylaxis against exit site infection and peritonitis. A second RCT is underway in Australia and New Zealand, in which PD patients are being randomized to nasal mupirocin in S aureus carriers only versus exit site antibacterial honey in all patients.83 Although honey has not been used previously for the prevention of PD-related infections, the idea behind its use comes from the wound management literature, as well as a recent RCT showing its equivalence to topical mupirocin for catheter exit site prophylaxis in hemodialysis patients.84 Based on the abundant mupirocin data and the randomized trial favoring gentamicin, the 2005 ISPD guidelines for PD-related infections suggested using one of the following regimens: (1) exit site mupirocin daily in all patients or only in S aureus nasal carriers, (2) intranasal mupirocin for 5 to 7 days each month in nasal carriers, or (3) exit site gentamicin cream daily in all patients.20 When deciding on exit site prophylaxis at a given center, the available literature should be interpreted in the context of local bacterial pathogens and resistance patterns. For example, mupirocin should be used in patients colonized with methicillin-resistant S aureus, whereas gentamicin may provide greater benefit in centers with high rates of gram-negative catheter infection and/or peritonitis. Despite the clear benefit of prophylactic ointments for the prevention of exit site infection and peritonitis, there is a concern about

the potential for the development of bacterial resistance over time. Although early data did not identify any mupirocin resistance after 1 year of exposure,85 there have since been several studies in which mupirocin resistance has been reported, with a prevalence ranging from 16% to 25%.86-88 To date, there have been no reported cases of gentamicin resistance among PD patients using daily exit site gentamicin, and it remains to be seen whether any resistance will emerge. One of the potential advantages of antibacterial honey, should it prove to be effective, is the absence of demonstrable resistance.

Preprocedural Antibiotics Several procedures have been associated with an increased risk of peritonitis. The best example of this is colonoscopy, with several case reports of peritonitis with enteric organisms occurring shortly after the procedure.5-8,20 In an observational study by Yip et al,4 among 79 patients who had colonoscopies without concurrent antibiotics, there were 5 peritonitis episodes occurring within 5 days of the procedure. In contrast, no peritonitis episodes were observed after the 18 colonoscopies for which patients were on antibiotics at the time of the procedure. Although the occurrence of peritonitis after colonoscopy is rare, the episodes that do occur tend to be caused by enteric organisms, which are known to be associated with significant rates of catheter loss. As such, in the absence of a larger literature to guide practice, antibiotic prophylaxis should be given at the time of colonoscopy.20 With respect to the optimal regimen, there are no data to support one regimen

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Table 2. Studies of Antifungal Prophylaxis

Study

Study Design

Number of Patients per Group: Control Versus Treated

Years of Study

Intervention Nystatin with each course of antibiotics versus no prophylaxis Fluconazole with each course of antibiotics versus no prophylaxis No prophylaxis versus nystatin No prophylaxis versus nystatin or ketoconazole No prophylaxis versus fluconazole No prophylaxis versus nystatin No prophylaxis versus nystatin No prophylaxis versus nystatin

Lo et al92

Randomized trial

1991-1993

Restrepo et al93

Randomized trial

2004-2007

Zaruba et al94

Observational

Robitaille et al95

Observational

Wadhwa et al96

Observational

Wong et al97

Observational

Thodis et al98

Observational

1991-1993 versus 1993-1995 1995-1999 versus 1999-2005 1996 versus 1997

Williams et al99

Observational

1997-1999

1979-1982 versus 1983-1989 1989-1991 versus 1991-1993

Follow-Up Time: Control Versus Treated, Patient-Months

Result of Intervention

199 versus 198

16.6 months versus 18 months

Benefit

608 PD-related infections requiring antibiotics

150 days after each antibiotic administration

Benefit

38 versus 93

415 versus 2,102

Benefit

25 children overall

361 (total)

Benefit

122 versus 112

1,832 versus 1,705

Benefit

320 versus 481

Benefit

240 versus 240

8,875 versus 13,725 2,400 versus 2,400

N/A

3,911 versus 2,124

No benefit

No benefit

Abbreviation: N/A, data not available.

over another, but one should choose antibiotics that will provide coverage against Enterococcus, enteric gram-negative organisms, and anaerobes. In addition, patients should empty their peritoneal cavity of dialysate before the procedure. Another procedure that may lead to peritonitis is PD catheter manipulation, either by introduction of organisms into the lumen of the catheter via the guidewire or by gut translocation of organisms if the bowel is aggressively shifted during the manipulation procedure. Despite the theoretical risk, there are no case reports or studies to date describing the development of peritonitis after catheter manipulation. Nevertheless, antibiotic prophylaxis should be considered. Similarly, given the potential for translocation of organisms across the genitourinary tract,17 antibiotics at the time of cystoscopy, colposcopy, and hysteroscopy are recommended.

Fungal Prophylaxis It is known that antibiotics increase the risk of fungal peritonitis, presumably by altering the bowel flora and promoting fungal colonization

of the gastrointestinal tract.23,89-91 It is also known that fungal peritonitis is associated with a high mortality, technique failure, and peritoneal membrane injury that may limit future resumption of PD.24-26 Several studies have assessed the role of fungal prophylaxis, although most have been observational in nature (Table 2). There have been only two randomized trials to date.92,93 In the first of these trials, Lo et al92 randomized 397 PD patients to receive oral nystatin 500,000 U four times daily or no fungal prophylaxis with each course of antibiotics. After approximately 18 months of follow-up evaluation, there were 12 episodes of fungal peritonitis among the 198 patients who did not receive prophylaxis versus 4 episodes among 199 patients who received nystatin (P ⬍ .05). This included 6 antibiotic-related cases in the group without prophylaxis and 3 in the nystatin group. This was followed more recently by a second prospective randomized trial in which patients either received or did not receive oral fluconazole (200 mg every 48 hours) for the duration of time when antibiotics were being given for PD-related infection.93 Among the 210 patients

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receiving fluconazole, there were 3 episodes of fungal peritonitis, as compared with 15 episodes among the 210 patients who did not receive fungal prophylaxis. In addition to the clinical trial data, several observational studies have also reported on fungal prophylaxis. These studies, using various antifungal agents, compared occurrence of fungal peritonitis after initiation of fungal prophylaxis with a historical cohort of patients who were not given prophylaxis. The results of these studies have been variable, with some reporting benefit,94-97 and others unable to show a statistically significant reduction in fungal peritonitis.98,99 Of note, the baseline incidence of fungal peritonitis in the two negative studies was very low, limiting the power of these studies to discern any potential benefit of the intervention. Given the significant morbidity and mortality associated with fungal peritonitis, the potential for benefit based on the available evidence, and the low risk of the intervention, use of fungal prophylaxis with either nystatin or fluconazole at the time of antibiotic use is recommended to prevent antibiotic-related fungal peritonitis.

Biocompatible PD Solutions Local peritoneal immunity plays an important role in the prevention and clearance of PD peritonitis. Exposure to conventional dialysate, however, leads to abnormal leukocyte recruitment in response to inflammatory stimuli100 and impaired phagocytic function.101 Because the bioincompatibility of standard dialysis solutions may contribute to impaired peritoneal immunity, it is plausible that the neutral pH and low glucose degradation product content of the newer PD solutions might be associated with improved peritoneal immune function. Although there are some data to suggest improvement in markers of peritoneal immunity with biocompatible solutions,102,103 the more relevant question is whether use of these solutions leads to a reduction in peritonitis risk. The largest observational study to address this question was a retrospective study of 1,909 incident Korean patients on continuous ambulatory peritoneal dialysis between 2002 and 2005. In this study, after multivariable adjustment, there was no effect of solution type on

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peritonitis rate.104,105 In contrast, there have been three smaller observational studies that reported a lower peritonitis rate among patients using biocompatible solutions.106-108 The basis for the conflicting results of these observational studies could be related to residual confounding between the conventional and biocompatible PD solution groups. Because these were not randomized trials, it is possible that patients receiving biocompatible PD fluid differed from those receiving conventional solutions in their underlying comorbidities or other aspects of their PD therapy that were not adjusted for and could have influenced peritonitis risk. There are two RCTs to date of conventional versus biocompatible PD fluids that included data on infectious outcomes, although infection was not the primary outcome in either trial.109,110 In the first trial, Fan et al109 randomized 93 incident PD patients to standard or biocompatible dialysis solutions for 1 year. There were 19 peritonitis episodes among 49 patients in the conventional dialysate group and 27 episodes among 44 patients in the biocompatible group, with no significant difference in the peritonitis rates between the two groups. The second trial randomized 80 patients to conventional or biocompatible dialysate for 18 months, and again there was no observed difference in peritonitis risk between the groups. Although these studies were not powered to detect a difference in peritonitis rates, there was no suggestion of benefit of the newer solutions for this end point. Further RCTs with adequate power to study the occurrence of peritonitis with exposure to different PD solutions are necessary before inferring whether neutral pH, low glucose degradation product solutions might reduce peritonitis risk. CONCLUSIONS Given that PD peritonitis and catheter infection remain an important cause of technique failure, it is important to understand the microbiology and outcomes of these infections, as well as all available strategies to try to mitigate the risk of infection in this population. Some strategies, such as PD connectology and exit site care, are supported by strong evidence. Other strategies are less well studied. For these strategies, until

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