Narrative Review

Peritoneal DialysisRelated Peritonitis: Towards Improving

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