International Urology and Nephrology (2024) 56:583–595

https://doi.org/10.1007/s11255-023-03731-w

NEPHROLOGY - REVIEW

Persistent peritonitis in peritoneal dialysis: a comphrenesive review

of recurrent, relapsing, refractory, and repeat peritonitis
Aaron H. Wang1 · Kelsey Sawyer2 · Ankur D. Shah1,3

Received: 16 May 2023 / Accepted: 29 July 2023 / Published online: 10 August 2023
© The Author(s), under exclusive licence to Springer Nature B.V. 2023

Abstract
Peritonitis is a major cause of morbidity and technique failure in patients receiving peritoneal dialysis. Complicated perito-
nitis that manifests as multiple or unresolving episodes is classified as refractory, recurrent, relapsing, or repeat peritonitis,
and often possesses higher risk of technique failure and mortality as well as lower complete cure rates than primary or
uncomplicated episodes. While these peritonitis subtypes affect a considerable portion of PD patients, details regarding
their epidemiology, pathogenesis, diagnosis, clinical sequelae, and management have not yet been fully elucidated. Improved
clinical awareness and understanding of complicated peritonitis subtypes is crucial to ensure optimal management for these
patients; thus, we consolidate and report the pertinent findings of recent literature on these four entities.

Keywords Peritoneal dialysis · Peritonitis · Refractory · Relapsing · Recurrent · Repeat

Introduction complications, diagnosis, prophylaxis, and treatment of the

Peritonitis is a leading complication of peritoneal dialysis
(PD), often resulting in hemodialysis (HD) transfer, mor-
bidity, and mortality [1]. Peritonitis has been implicated
in 20% of deaths in patients receiving PD [2]. To improve
care outcomes associated with PD, understanding the clini-
cal considerations of PD-associated peritonitis has been of
major interest in recent literature [3]. In particular, efforts
have been made to elucidate the causes and consequences of
persistent or multiple episodes of peritonitis, which are clas-
sified as refractory, recurrent, relapsing, or repeat peritoni-
tis. However, no review that comprehensively discusses and
focuses specifically on the clinical considerations for each
of these four peritonitis subtypes has been created to our
knowledge. In this review, we summarize recent literature
pertinent to the epidemiology, risk factors, microbiology,
* Ankur D. Shah
AShah8@lifespan.org
1
Warren Alpert Medical School, Brown University,
Providence, RI, USA
2
Health and Biomedical Library Services, Brown University,
Providence, RI, USA
3
Division of Kidney Disease and Hypertension, Rhode
Island Hospital, Warren Alpert Medical School at Brown
University, 593 Eddy St, Providence, RI 02903, USA
aforementioned complicated, multiple-episode or unresolv-
ing forms of peritonitis to provide a guide for clinicians
encountering these pathologies.
Definitions
Peritonitis is diagnosed in the presence of two or greater
of the following: clinical features (most frequently abdomi-
nal pain and/or cloudy dialysis effluent), dialysis effluent
white blood cell (WBC) count > 100/µL with a neutrophil
predominance, or positive dialysis effluent culture [4, 5].
Culture-negative peritonitis is diagnosed with the same cri-
teria but differentiated by a lack of positive effluent culture.
Notably a dialysis effluent WBC > 100/µL without a positive
culture or neutrophil predominance is not consistent with
infectious peritonitis.
PD-associated peritonitis that is persistent or manifests
across multiple episodes is broadly characterized based
on duration of symptoms and causal organism. Guidelines
issued by the International Society for Peritoneal Dialysis
(ISPD) define the conditions for refractory, recurrent, relaps-
ing, and repeat peritonitis (Table 1) [4]. An episode with
persistently elevated WBC count despite 5 days of appro-
priate antibiotic regimen is classified as refractory. An epi-
sode that occurs within 4 weeks of completing therapy for

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Table 1  Definitions for refractory, recurrent, relapsing, and repeat peritonitis
Refractory Peritonitis episode with persistently cloudy bags or persistent dialysis effluent leukocyte count > 100 × ­109/L after 5 days
of appropriate antibiotic therapy
Recurrent Peritonitis episode that occurs within 4 weeks of completion of therapy of a prior episode but with a different organism
Relapsing Peritonitis episode that occurs within 4 weeks of completion of therapy of a prior episode with the same organism or
one sterile (culture negative) episode
Repeat Peritonitis episode that occurs more than 4 weeks after completion of therapy of a prior episode with the same organism
a previous episode, but with a different causal organism, is
recurrent. Relapsing episodes are those which occur within
4 weeks of completion of therapy for a prior episode with
the same organism, or a sterile episode. Finally, repeat peri-
tonitis is defined as an episode that occurs with the same
organism more than 4 weeks after completion of therapy.
A new episode after 4 weeks of therapy completion with a
different organism would be classified as a reinfection [6].
While repeat peritonitis was previously considered a delayed
form of relapsing peritonitis, it has since been clarified to be
a distinct clinical entity [6, 7].
Epidemiology
The incidence of peritonitis has previously been reported by
various authors. Abu-Aisha et al. found the rate in a cohort
of 60 PD patients to be 1 episode per 21.5 patient-months
in a multi-center study, and Tang et al. reported an overall
peritonitis rate of 0.184 episodes per patient-year in a sin-
gle-center study [1, 2]. A retrospective single-center cohort
study of 218 peritonitis episodes by Hu et al. recorded a rate
of 0.27 episodes per patient-year [8]. A systematic review
encompassing registries from 33 countries detected a grad-
ual decline in peritonitis rate from 0.60 to 0.30 episodes per
patient-year from 1992 to 2019, but noted that discrepancies
of up to 20-fold exist between countries [4]. Peritonitis has
been reported to be more common in younger patients [1].
While a retrospective analysis of peritonitis patients from
1996 to 2005 found a correlation between peritonitis and
older age, this existed only in PD patients prior to 2001, indi-
cating that this observation was likely due to era effect [9]. In
comparison to younger patients, those aged ≥ 65 years expe-
rienced lower odds of fever, cloudy dialysate, and Tenckhoff
catheter removal, although they present with similar odds of
relapse, mortality, and transfer to HD [10]. An observational
cohort study found that 65% of peritonitis episodes result
in complete cure wherein death, catheter removal, transfer
to HD, recurrence, or relapse do not occur; cure rate was
reported to be roughly similar across the 7 countries where
studied sites were located, ranging from 54%-68% [11]. A
retrospective analysis of 126 episodes of peritonitis revealed
that 38 episodes (30%) constituted multiple or unresolving
peritonitis [12], whereas Hu et al. determined that 82.4%
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International Urology and Nephrology (2024) 56:583–595
of 136 primary peritonitis episodes at a single Chinese PD
center resulted in complete cure [8]. The ISPD recommends
no more than 0.40 peritonitis episodes per patient-year at
risk and a target percentage of patients free of peritonitis per
unit time of 80% per year [4].
Refractory
In a single-center prospective, observational, cross-sectional
study conducted by Pindi et al. of 100 peritonitis episodes in
Indian patients, 4% were found to be refractory cases [13].
In a 10-year retrospective single-center study in Taiwan-
ese patients, the refractory rate was reported to be as high
as 14.2% (27/190 peritonitis episodes), despite an overall
peritonitis incidence of 0.25 episodes per patient-year, well
within the 0.40 episode per patient-year ISPD recommenda-
tion [14]. A single-center study of 90 patients with refractory
peritonitis determined that most episodes occurred within 1
to 5 years on PD treatment and carried a 40% mortality rate,
possibly owing to the predominance of fungal and culture-
negative cases [15]. Even among patients permanently tran-
sitioned to HD, mortality within the first 3 months was as
high as 33% [15].
Recurrent
Recurrent episodes comprised 4% of 100 peritonitis epi-
sodes in the prospective cohort study by Pindi et al. [13]
and accounted for 5.1% of 136 primary peritonitis episode
outcomes according to Hu et al. [8]. Prevalence of recurrent
peritonitis in Australian adult PD patients in the Austral-
ian and New Zealand Dialysis and Transplant (ANZDATA)
registry was relatively low, with only 230 episodes of
recurrence (5% of all peritonitis episodes) across the 4-year
period [16]. In comparison to uncomplicated peritonitis,
recurrent episodes present with significantly higher rates of
catheter removal (22% vs. 37%) and permanent transfer to
HD (20% vs. 32%), but comparable rates of hospitalization
(73% vs. 70%) and mortality (2.8% vs. 1.2%) [16].
Relapsing
Rate of relapsing peritonitis following primary episodes
ranges from 5 to 20% in various adult and pediatric series
International Urology and Nephrology (2024) 56:583–595
[17, 18]. Pindi et al. reported that 9% of 100 clinically-sus-
pected peritonitis episodes were relapsing in nature [13]. Hu
et al. determined that among 136 primary peritonitis epi-
sodes, the rate for relapse was 1.5% [8]. Among adult Aus-
tralian PD patients in the ANZDATA registry, 669 episodes
of relapsing peritonitis (14% of 4,864 peritonitis episodes)
were documented across 6,024 PD patients from October,
2003 to December, 2007 [16]. Compared with uncompli-
cated or primary peritonitis, relapsing episodes are associ-
ated with higher rates of catheter removal (22% vs. 30%)
and permanent HD transfer (20% vs. 25%), but similar rates
of hospitalization (73% vs. 70%) and mortality (2.8% vs.
2.0%) [16].
Repeat
Pindi et al. reported that 2% of 100 peritonitis episodes con-
stituted repeat episodes [13], and Hu et al. reported that 2.9%
of 136 primary episodes progressed to repeat peritonitis [8].
In Australian patients from ANZDATA multicenter registry,
repeat episodes represented 485 of 4,864 peritonitis episodes
(10%) from 2004 to 2007, while the Canadian multicenter
Peritonitis, Organism, Exit sites, Tunnel infections (POET)
registry reported that repeat episodes accounted for 181 of
1,605 peritonitis episodes (11%) from 1996 to 2005 [6].
Szeto et al. compared repeat to relapsing peritonitis, reveal-
ing that repeat peritonitis carries a lower complete cure rate
than relapsing peritonitis (54.9% vs. 70.7%), but similar
rates of catheter removal, primary response, and mortality
[7].
Risk factors
Prior studies have investigated specific risk factors that
predispose to higher odds of unresolving peritonitis. For
instance, factors including Caucasian race, low residual
GFR, simultaneous exit site or catheter tunnel infection,
persistently elevated WBC count, serum CRP, fibrinogen,
PD duration, concurrent intestinal obstruction, and diabetes
mellitus have all been associated with poor peritonitis out-
comes [19, 20]. In addition, nonadherence to best practices
guidelines, such as mistiming antibiotic therapy and catheter
removal, lack of antifungal prophylaxis, and failure to con-
sider non-PD peritonitis, increases risk for significant mor-
bidity and mortality in peritonitis outcomes [21]. Adequate
patient training in PD procedure, theory, and self-care has
been shown to decrease peritonitis rates in the PD popula-
tion, although specific timing of commencement and dura-
tion of training may vary; accumulating evidence also sug-
gests that periodic retraining may also mitigate peritonitis
risk [4]. Several other risk factors have been documented
in the context of specific types of complicated peritonitis.
585
Refractory
Baseline hyponatremia (< 130 mmol/L) has been indepen-
dently associated with refractory peritonitis [14]. Hypona-
tremia has previously been linked to increased risk of various
bacterial infections and presents in nearly 27% of PD-associ-
ated peritonitis patients; however, the underlying etiology for
this association is unknown [22].
Recurrent and relapsing
Among patients with peritonitis caused by Gram-positive
or culture-negative infection, those with creatinine clear-
ance > 5 mL/min, indicating residual kidney function, have
been shown to be significantly more likely to experience
recurrence and relapse than anuric patients [23]. Addition-
ally, higher peritoneal glucose exposure (> 140 g/day) during
PD has been linked lower cure rate and higher incidence of
relapsing and recurrent peritonitis, as well as subsequent cath-
eter removal [24]. Malnutrition has also been shown to pre-
dispose to peritonitis relapses and recurrences in PD patients
and is a predictor of mortality in these patients [25]. Invasive
gastrointestinal and gynecological procedures are believed to
heighten risk of peritonitis, often requiring antibiotic prophy-
laxis [4]. Ma et al. reported a patient who underwent cervical
conization and endocervical curettage and later experienced
recurrent peritonitis, with the first episode appearing 2 weeks
postoperatively [26]. Additionally, the International Pediatric
Peritonitis Registry (IPPR) identified young age, single-cuff
catheter, downward-pointing exit site, and chronic antibiotic
prophylaxis as independent risk factors for relapsing peritonitis
[27].
Repeat
Timing of peritonitis course may contribute to risk of repeat
episodes; data from the ANZDATA registry indicate that the
probability of repeat peritonitis is highest at 2 months after
completion of therapy for a primary episode, decreasing sub-
stantially and plateauing beyond 6 months post-treatment [6].
It has also been reported that primary peritonitis episodes
occurring within the first 12 months of PD initiation are more
likely to evolve into repeat peritonitis than primary episodes
occurring after 24 months of treatment [28].
Microbiology
Common microorganisms
Specific microorganisms which most commonly cause
multiple or persistent peritonitis have been investigated.
A cohort study determined that culture-positive peritonitis
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comprised only 27% of peritonitis cases, whereas touch
contamination likely accounted for 46.7% of total perito-
nitis cases, of which 3 were refractory and 1 was relapsing
[1]. In a study of pre-training peritonitis patients, 53.7%
presented with a culture-negative cause [29]. Culture-
negative peritonitis demonstrated superior outcomes to
culture-positive cases in a retrospective multicenter reg-
ister study, having higher cure rate and lower mortality
than Staphylococcus aureus, Pseudomonas spp., and fun-
gal peritonitis; however, odds of relapsing and recurrence
were similar between culture-negative and culture-positive
patients [30]. Another single-center retrospective found no
significant differences in outcomes or mortality in refrac-
tory culture-negative and culture-positive cases [15].
A prospective study by Pindi et al. determined that
Gram-negative organisms accounted for more cases
of peritonitis than Gram-positive, at 62.3% and 31.1%,
respectively [13]. Novljan et al. reported that Gram-pos-
itive organisms were isolated in 53%, namely Staphylo-
coccus aureus and Staphylococcus epidermidis, whereas
Gram-negative organisms were present in 32.4%, namely
Escherichia coli and Pseudomonas spp., of 23 pediatric
peritonitis cases [31]. A single-center retrospective study
by Wang et al. reported that Gram-positive organisms
were the leading cause of peritonitis [14]. Liu et al. further
clarified that Staphylococcus epidermidis, Enterococcus
faecalis, and Staphylococcus haemolyticus constituted the
most common Gram-positive pathogens, while Escheri-
chia coli and Klebsiella pneumoniae were the most com-
mon Gram-negative organisms responsible for peritonitis
[12]. Gram-negative organisms have been correlated with
poorer peritonitis outcomes [19]. Tang et al. found that
Gram-positive and Gram-negative bacteria each accounted
for approximately one-third of peritonitis cases, noting
that coagulase-negative Staphylococcus (CoNS) were the
most commonly isolated Gram-positive species, and that
Gram-negative cases possessed a higher risk of catheter
loss [2].
The incidence of fungal peritonitis has been reported
to range from 2.6% to 6.4% [2, 13, 31]. Fungal peritonitis
has been shown to correlate with poor outcomes [19, 30].
Candida albicans is the major fungal pathogen associated
with peritonitis, with other possible organisms including
Aspergillus flavus and Mucor spp. [12, 13].
Refractory
A single-center retrospective study determined that 31%
of refractory peritonitis cases were culture-negative [15].
Regarding culture-positive cases, fungi have been identi-
fied as the most common cause of refractory peritonitis
[15]. Wang et al. also highlighted Staphylococcus spp. and
Escherichia coli as having significant associations with
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International Urology and Nephrology (2024) 56:583–595
refractory peritonitis [14]. Non-tuberculous mycobacteria
(NTM) have been identified as a difficult-to-diagnose cause
of refractory peritonitis, often returning negative cultures
and poorly responsive to standard antibiotic treatment [19,
32]. NTM-related peritonitis leads to catheter removal in
92.2% and PD withdrawal in 91.9% of patients [33]. Strep-
tococcus viridans has also been studied as a cause of peri-
tonitis, particularly refractory peritonitis. In a single-center
retrospective analysis, patients with Streptococcus viridans
peritonitis experienced significantly higher incidence of
refractory episodes compared to patients with other Strep-
tococcus spp. or Gram-positive cocci infections [34].
Recurrent
Recurrent peritonitis is more commonly associated with fun-
gal infections than either uncomplicated or relapsing peri-
tonitis, and rarely associated with either CoNS or Staphy-
lococcus aureus [16]. Compared with primary peritonitis
episodes, recurrent infections were more likely to involve
Gram-negative organisms (27.2% vs. 11%) [35]. Enterococ-
cus spp. are also more commonly implicated in recurrent
peritonitis than primary episodes (3.2% vs. 1.2%) [35].
Relapsing
A retrospective single-center cohort study by Szeto et al.
reported that organisms that cause relapsing peritonitis in
the adult population are more likely to be Gram-negative
(62%) [7]. In contrast, data from the IPPR identified the
causes of relapsing episodes in pediatric patients as 46%
Gram-positive, 21% Gram-negative, and 33% culture-nega-
tive [6]. Burke et al. reported that CoNS and Staphylococcus
aureus accounted for 48% of relapsing peritonitis, but were
less likely to be isolated as the cause of recurrent peritonitis
[16]. However, Szeto et al. determined that only 5.5% of
relapsing peritonitis cases were attributed to Staphylococ-
cus aureus [7]. Among cases of CoNS peritonitis, the rate of
relapse was found to be 12%, with relapsing episodes hav-
ing a significantly lower cure rate than initial episodes [36].
Pseudomonas spp. have been shown to cause a dispropor-
tionate number of relapsing peritonitis episodes compared
to primary peritonitis (16.6% vs. 9.4%) [35].
Repeat
Szeto et al. reported that the majority of repeat peritonitis is
caused by Gram-positive organisms (56%) [7]. Nessim et al.
determined that CoNS is the most common cause of repeat
peritonitis, constituting 65.7% of all cases, and is associated
with increased risk of a subsequent CoNS episode within
International Urology and Nephrology (2024) 56:583–595 587

one year of the initial episode [37]. A number of explana-
tions have been offered for the tendency of CoNS to precipi-
tate repeat episodes. CoNS infection is usually associated
with the introduction of organisms into the peritoneal cavity;
thus multiple episodes of CoNS peritonitis may be related
to multiple breaks in sterile technique [37]. Additionally,
many centers implement shortened antibiotic regimens and
longer times until catheter removal in treating CoNS peri-
tonitis cases [38]. Among cases of CoNS peritonitis, rate of
repeat episodes was found to be 16% [36]. Staphylococcus
aureus, which is coagulase-positive, has also been found to
account for up to 24% of repeat episodes [7].
while relatively uncommon, have also been documented
as a cause of PD-associated peritonitis [6]. Other rare
but previously reported pathogens resulting in unresolv-
ing peritonitis include Rhodococcus corynebacterioides,
Burkholderia cepacian, Corynebacterium amycolatum,
Pasteurella multocida, Enterococcus avium, Dokdonella
koreensis, Gordonia bronchialis, Serratia marcescens,
Achromobacter xylosoxidans, Sphingomonas paucimobi-
lis, Bacillus cereus, Caulobacter crescentus, Rhizobium
radiobacter, Micrococcus spp., Microbacterium resistens,
Brevibacterium casei, Zygomycetes, Kocuria varians, and
Rothia dentocariosa [39–56] (Table 2).

Other organisms Other causes

Various other microbial causes of complicated peritonitis A range of other causes for complicated peritonitis has been
have been discussed. Mycobacterium tuberculosis has also suggested. Intestinal goblet cell carcinoid, which generally
been reported to comprise 5.3% of peritonitis, and pos- presents as acute appendicitis and a palpable abdominal
sess a higher risk of catheter loss [2]. Zoonotic infections, mass, has been described as a rare cause of recurrent sterile

Table 2  Causal organisms for complicated peritonitis episodes across several case reports between 2011 and 2022
PMID Year published Age Sex Organism Type of peritonitis Treatment Prognosis

35877040 2022 57 M Rhodococcus corynebacterioides Recurrent Vancomycin + catheter removal Survived

34587836 2022 60 F Sporothrix schenckii Relapsing Amphotericin B + Voriconazole nr
34889477 2022 62 M Burkholderia cepacia Refractory Piperacillin-Sulbactam + Catheter Survived
removal
36352270 2022 4 M Corynebacterium amycolatum Refractory, relapsing Cefepime + Ceftazidime + Vanco- Survived
mycin + Fluconazole
35929618 2022 57 M Pasteurella multocida Repeat Vancomycin + Levofloxacin Survived
31827990 2019 60 M Enterococcus avium Refractory Linezolid + Catheter removal Survived
30073100 2018 63 M Dokdonella koreensis Relapsing Amikacin + Catheter removal Survived
29198961 2018 32 M Gordonia bronchialis Relapsing Vancomycin + Catheter removal Survived
30588985 2018 40 F Serratia marcescens Relapsing Piperacillin-Tazobactam + Cath- Survived
eter removal
30155325 2018 27 F Achromobacter xylosoxidans Relapsing Imipenem + Ceftazidime + Cath- Survived
eter removal
27730806 2016 35 F Sphingomonas paucimobilis Relapsing Ciprofloxacin + Ceftriaxone Survived
27118739 2016 70 M Bacillus cereus Relapsing Vancomycin + Gentamycin + Cip- Survived
rofloxacin + Catheter removal
26703852 2015 63 F Caulobacter crescentus Relapsing Vancomycin + Cetazi- Survived
dime + Catheter removal
28663815 2014 54 M Rhizobium radiobacter Relapsing Cefazolin + Tobramycin + Cath- nr
eter removal
23054320 2014 63 M Micrococcus spp. Refractory Vancomycin + Catheter removal Survived
24637101 2014 71 M Microbacterium resistens Recurrent Ampicillin + Gentamycin + Cath- Survived
eter removal
24648477 2014 33 F Brevibacterium casei Relapsing Vancomycin + Catheter removal Survived
25097341 2014 46 M Zygomycetes Refractory Amphotericin B + Open lapa- Survived
rotomy
22806295 2012 70 M Kocuria varians Relapsing Vancomycin Survived
22506572 2011 58 M Rothia dentocariosa Repeat, relapsing Ciprofloxacin + Amikacin + Van- Survived
comycin

Treatment represents final antibiotics and procedures used

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588
peritonitis which resolves post-appendectomy [57]. Biofilm
formation within the lumens of PD catheters is also associ-
ated with recurrent, relapsing, and repeat peritonitis [58,
59]. Biofilms arise via a process involving adherence and
secretions of a bacterial microcolony on the catheter surface,
eventually producing a matrix of macromolecules [59]. This
complex can lead to entrapment of and inability to com-
pletely eradicate microbes, culminating in multiple infec-
tions with the same or several organisms as well as potential
antibiotic resistance [37, 60]. Biofilms on biotic surfaces
such as the patient’s tissue have similarly been implicated
in complicated cases of peritonitis [58].
Complications
Refractory, recurrent, relapsing, and repeat peritonitis have
been associated with various complications, causing patient
distress and morbidity as well as treatment disruption.
Refractory
High mortality in refractory peritonitis is largely attributed
to septic shock, and mortality rates remain as high as 33%
within 3 months even after permanent shift to HD [15].
Among patients who are reinitiated on PD following refrac-
tory peritonitis, ultrafiltration failure or technique failure are
common [15]. Furthermore, Lee et al. reported that patients
with refractory peritonitis may develop symptomatic ascites
requiring drainage post-catheter removal, often necessitating
a prolonged hospital stay [61]. Another complication linked
to refractory peritonitis is encapsulating peritoneal sclerosis
(EPS), an inflammatory event that leads to diffuse fibrosis
and ileus [62]. Removal of Tenckhoff catheter following
refractory peritonitis may in fact increase risk for EPS,
as persistence of sterile peritoneal inflammation in these
patients renders them high-risk for EPS and for 6-month
all-cause mortality [63].
Recurrent and relapsing
Recurrent peritonitis has been shown to cause intestinal fis-
tulas, sequelae of which include abdominal cavity inflamma-
tion, watery diarrhea, and a mortality rate approaching 57%
[64]. Recurrent and relapsing peritonitis are also risk factors
for development of peritoneal pseudocysts, a rare complica-
tion of PD [65]. Compared with uncomplicated peritonitis,
both recurrent and relapsing peritonitis have been correlated
with augmented rates of catheter removal and permanent
HD transfer [16]. Relapsing peritonitis has also been shown
to significantly curb the rate of recovery as well as create
ultrafiltration problems in pediatric PD patients [27]. Relaps-
ing peritonitis caused by P. aeruginosa has previously been
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International Urology and Nephrology (2024) 56:583–595
reported to contribute to formation of rinds, intra-abdominal
thick-walled fluid collections, which may progress to empy-
ema [66].
Repeat
Compared with a control group of peritonitis that was pre-
ceded by another episode greater than 4 weeks prior with
a different organism, the complete cure rate and mortality
rate in repeat episodes have been shown to be similar; how-
ever, repeat peritonitis possesses a higher risk of evolving
to relapsing peritonitis than this control group (14.3% vs.
2.2%) [7].
Diagnosis
Diagnosis of peritonitis is primarily centered on physical
examination findings as well as dialysis effluent WBC count
and microorganism culture [4]. Analysis of isolated micro-
organisms can help identify specific causes or concomitant
events preceding peritonitis; for instance, infection with
multiple Gram-positive and Gram-negative organisms is
indicative of an enteric cause, while Pasteurella multocida
and Capnocytophaga spp. are highly suggestive of animal
contact with PD equipment [4]. Differential diagnosis of
refractory, recurrent, relapsing, and repeat peritonitis is
based on timing of repeat clinical features, leukocyte count,
and positive cultures (Fig. 1). Methods have been developed
to enhance the effectiveness of these techniques. Centrifuga-
tion and saline washing of peritoneal dialysates have been
shown to produce concentrated, higher-yield samples, short-
ening average time for bacterial identification [67]. Direct
inoculation of dialysate fluid into automated blood culture
bottles has also been shown to improve sensitivity and facili-
tate early detection of peritonitis [13].
Clinical parameters for radiographic examination of peri-
tonitis patients have also been discussed. Trinh et al. deter-
mined that imaging abnormalities (on computed tomography
[CT] or ultrasound) could be detected in 47% of patients
with peritonitis, including bowel obstruction and biliary
abnormalities [68]. Likelihood of imaging requirement was
directly related to relapsing, recurrent, or refractory perito-
nitis, as well as admission to intensive care unit. The authors
concluded that abdominal imaging should be considered in
select patients with hemodynamic instability or complicated
cases of peritonitis.
Surgical exploration may also be indicated in certain
cases of peritonitis. Differentiation between refractory
catheter-related peritonitis and secondary peritonitis
stemming from visceral lesions is often difficult, requir-
ing early surgical exploration to assess the causative
mechanism in these cases [69]. In patients who meet the
International Urology and Nephrology (2024) 56:583–595
Fig. 1  Differentiation of refractory, recurrent, relapsing, and repeat peritonitis based on timing of clinical features, dialysate leukocytes, and
dialysate culture
definition of refractory peritonitis, prompt exploratory
laparotomy or laparoscopy should be considered [69].
The use of novel diagnostic tools has been reported,
including biomarker assays, mass spectrometry assays,
and bacterial 16S rRNA gene sequencing [4]. For
instance, Tanaka et al. reported the use of mass spectrom-
etry to rapidly identify Rhodococcus corynebacterioides
as the causative organism in a peritonitis patient, allowing
for timely treatment of the condition [39]. Analysis of
bacteria-derived DNA fragment in PD effluent fluid may
potentially be used to predict the probability of relaps-
ing or recurrent peritonitis, as relapsing and recurrent
cases have significantly higher levels of DNA fragments
in dialysate [70]. When bacterial DNA fragments were
detectable by a cutoff of 34 PCR cycles 5 days prior to
completion of antibiotic therapy, the sensitivity and speci-
ficity of this metric were reported as 88.9% and 60.5%,
respectively [70].
589
Prophylaxis
Prophylaxis for peritonitis generally involves careful cath-
eter placement, exit-site care such as daily application of
topical antibiotic cream, and prophylactic antimicrobials,
particularly prior to PD catheter insertion or in cases of
contamination within the closed PD system [4]. Additional
considerations include prophylactic antibiotics prior to inva-
sive gynecologic, gastrointestinal, or dental procedures, and
antifungal prophylaxis such as oral nystatin or fluconazole to
prevent fungal peritonitis secondary to systemic antibiotic
use [4, 71]. Novel methods for prophylaxis have recently
been investigated. Fukuzaki et al. suggested the use of nega-
tive pressure wound therapy for postoperative PD catheter
exit sites, significantly reducing risk of exit-site infections
and consequent peritonitis [72]. Far-infrared therapy along-
side PD has also been proposed to mitigate side effects asso-
ciated with dialysate glucose and curb peritoneal inflamma-
tion and peritoneal cell fibrosis, thereby reducing risk of
recurrent peritonitis [73].
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Fig. 2  Algorithm for managing refractory, recurrent, relapsing, and
repeat peritonitis in regard to antibiotic use, immune globulin ther-
apy, catheter removal, biofilm eradication, and additional procedures.
Treatment (Fig. 2)
See Fig. 2 here.
Antibiotics
ISPD guidelines recommend empiric antibiotic therapy with
broad coverage against both Gram-positives and Gram-neg-
atives once culture report for peritonitis has been obtained,
with intraperitoneal (IP) being the preferred route of admin-
istration [71]. Initial empiric therapy often includes ceftazi-
dime along with a first-generation cephalosporin or glyco-
peptide such as vancomycin, which has been shown to avoid
increased risk of relapse as opposed to cephalosporin mono-
therapy [74]. The effects of vancomycin alone on primary
treatment response, relapse rate, and possibility of catheter
removal have been mixed when compared to first-generation
cephalosporins, but has been shown to have higher complete
cure rate [75]. In a retrospective study, 73% of 114 bacterial
isolates were shown to be susceptible to either cefazolin or
gentamicin [14]. Liu et al. reported that Gram-positive cocci
showed resistance to gentamicin, levofloxacin, vancomycin,
13
International Urology and Nephrology (2024) 56:583–595
Simultaneous catheter removal and replacement should be attempted
only when PD effluent is culture-negative and WBC count < 100/µL
and linezolid and Gram-negative bacilli to cephalosporins
and gentamycin; however, no strains resistant to imipenem,
amikacin, and piperacillin/tazobactam were found [12].
Extending antibiotic treatment duration beyond ISPD rec-
ommendations has not been shown to improve cure rate or
decrease risk of relapsing, recurrent, or repeat peritonitis,
and in fact may lead to higher risk of repeat peritonitis epi-
sodes [76].
Catheter removal
Refractory, recurrent, relapsing, and repeat peritonitis often
require catheter removal and temporary HD transfer [4, 71].
Simultaneous removal and reinsertion of the PD catheter,
which would allow for continuation of PD without transition
to HD, has been proposed to reduce the risk of relapsing,
recurrent, or repeat peritonitis [4]. This procedure should
be performed under perioperative antibiotic coverage, which
involves continuation of the appropriate regimen through
the intravenous route, and only when PD effluent is culture-
negative and WBC count falls below 100/µL to avoid the
possibility of residual planktonic bacteria [4].
International Urology and Nephrology (2024) 56:583–595
Biofilm eradication
Treatment of biofilms, and hence prevention of consequent
peritonitis episodes, usually involves antimicrobial lock
therapy. Taurolidine lock has been shown to significantly
decrease both bacterial load and biofilm presence on con-
taminated PD catheters in Pseudomonas aeruginosa peri-
tonitis patients [77]. Taurolidine treatment has also been
demonstrated to reduce the risk of relapsing and refrac-
tory episodes, as well as eliminate the need for catheter
removal and switch to HD [78]. In a series of four clinical
cases, administration of fibrinolytic agents such as uroki-
nase in PD catheters has also shown the ability to eradicate
infection and cure relapsing peritonitis in patients with
biofilm formation [79]. On the other hand, a prospective
study of 88 PD patients concluded that adjuvant uroki-
nase administration did not significantly improve rates of
primary response, catheter removal, or mortality in peri-
tonitis resistant to initial IP antibiotics [80]. Furthermore,
a randomized control trial has shown that simultaneous
catheter removal and replacement has greater efficacy in
reducing treatment failure than use of IP urokinase [75].
Refractory
Delivery of antibiotics intravenously, instead of intraperi-
toneally, along with adjunctive lavage has shown promise
in treating refractory peritonitis patients who are unable to
undergo catheter removal, as lavage may promote removal
of bacterial and inflammatory cells [81]. However, lav-
age also carries the risk of imposing damage to perito-
neal defenses. A study of 16 patients with refractory or
relapsing peritonitis unresponsive to standard antibiotic
therapy determined that adjuvant IP immunoglobulin over
the course of 7 days potentially enhances host defenses
and prevents the risk of further peritonitis attacks [82].
ISPD guidelines recommend catheter removal in refrac-
tory peritonitis with delayed reinsertion after 2 to 3 weeks
to allow for peritoneal rest [83]; however, cases in which
effluent WBC count is decreasing toward normal despite
not clearing completely by the fifth day after antibiotic
initiation do not require immediate catheter removal, but
rather continued observation of antibiotic effect [4]. Pelvic
drainage during catheter removal has been suggested to
minimize risk of intra-abdominal complications in refrac-
tory peritonitis patients, and thus decrease the need for
subsequent invasive interventions [84]. In cases of refrac-
tory peritonitis in which robust antibiotic therapy and
catheter removal are not adequate, exploratory laparotomy
to obliterate peritoneal abscesses along with simultaneous
adhesiolysis have been reported to dramatically improve
symptoms in this select group of patients [85].
591
Recurrent
Szeto et al. reported that vancomycin as empiric therapy in
recurrent peritonitis yielded significantly higher response
rate (87.9% vs. 72.7%) and significantly lower mortality
rate (6.8% vs. 20.0%) than cefazolin, particularly in cases
with Gram-positive causes [35]. Empiric treatment with
ceftazidime was associated with significantly higher pri-
mary response rate (82.3% vs. 62.5%) than aminoglyco-
sides (netilmicin or gentamicin) in refractory cases caused
by Gram-negative organisms [35]. Daptomycin, another
lipopeptide antibiotic, has been shown to rapidly reach
minimum inhibitory concentration (MIC) for Staphylo-
cocci spp. in a recurrent peritonitis case associated with
biofilm formation; however, use of daptomycin in peri-
tonitis is not a widespread practice [59]. While the ISPD
currently recommends simultaneous catheter removal and
reinsertion in recurrent peritonitis [4], treatment is fre-
quently carried out without need for catheter removal [86].
Relapsing
Aside from cases of culture-negative peritonitis, the causal
organism responsible for relapsing peritonitis is by defini-
tion the same as the primary episode. Thus, ISPD guide-
lines recommend reinitiating empiric antibiotic therapy
targeting previously identified organisms; post-empiric
antibiotic regimen should then be guided by results of
susceptibility testing [83]. In patients with a history of
methicillin-resistant Staphylococcus aureus, empiric
therapy should consist of IP glycopeptide along with an
antibiotic with broad Gram-negative coverage [83]. Simi-
lar to recurrent peritonitis, empiric treatment with van-
comycin and ceftazidime have shown superior efficacy in
relapsing episodes caused by Gram-positive and Gram-
negative organisms, respectively [35]. As with refractory
peritonitis, immunoglobulin co-therapy has been shown to
mitigate the risk of further peritonitis episodes in patients
with relapsing peritonitis unresponsive to antibiotic treat-
ment [82].
While the efficacy of IP urokinase in treating primary
episodes is unclear, use of high-dose intraluminal fibrino-
lytic agents targeting biofilms in relapsing peritonitis has
been shown to prevent secondary relapses [87]. Simulta-
neous catheter removal and replacement is also recom-
mended in relapsing episodes once adequately managed
by antibiotic therapy [83]. A retrospective single-center
study found that 63.6% of patients experiencing or at high
risk for relapsing peritonitis who underwent simultaneous
catheter removal and replacement successfully remained
on PD at 1-year post-procedure [88].
13
592
Repeat
As with relapsing peritonitis, repeat episodes are caused
by the same organism as the primary episode and warrant
empiric antibiotic therapy guided by susceptibility testing
[83]. Data from the ANZDATA registry revealed that IP
vancomycin or cefazolin combined with gentamicin con-
stituted the most common first-line antibiotic choices for
repeat peritonitis patients, with vancomycin regimens pre-
ferred over cephalosporin-based ones [6]. Eradication of
biofilms in repeat episodes may involve adjusting antibiotic
treatment to the minimal biofilm eradication concentration
as opposed to the MIC [89]. Furthermore, repeat episodes
are more likely to be managed with addition of urokinase in
the Tenckhoff catheter than primary episodes [6]. Szeto et al.
also recommend treatment of concomitant exit-site infec-
tions [7], and the ISPD recommends considering simulta-
neous catheter removal and replacement [4]. While repeat
peritonitis is only a relative indication for catheter removal
[83], failure to remove catheter after a repeat episode has
been linked to a nearly 60% probability of precipitating a
new repeat or relapsing episode [90].
Mycobacteria and fungi
Current ISPD recommendations for primary treatment of
Mycobacterium tuberculosis peritonitis is antituberculous
therapy (including rifampin, isoniazid, pyrazinamide, or
ethambutol) as opposed to catheter removal [4]. For NTM,
management should include ordering Ziehl–Neelsen acid-
fast stain when there is clinical suspicion of NTM peritoni-
tis, such as persistent culture-negative peritonitis, and sub-
sequent treatment with appropriate antibiotics and catheter
removal [4]. In fungal peritonitis cases, immediate catheter
removal along with appropriate anti-fungal regimen is rec-
ommended [4].
Conclusion
Refractory, relapsing, recurrent, and repeat peritonitis are
major causes of technique failure, morbidity, and mortal-
ity in a substantial subset of PD patients. However, reports
regarding their incidence and relative effects on patient
course have varied. Additional prospective, multicenter stud-
ies with large sample sizes should be conducted to clarify
the epidemiology of these four subtypes of complicated peri-
tonitis. Inclusion of diagnostic techniques such as CT and
ultrasound, exploratory laparotomy, and PD effluent bacterial
DNA analysis should be considered in select patients with
suspected complicated peritonitis to improve early detection.
Refractory, relapsing, recurrent, and repeat peritonitis pos-
sess different risk profiles and microbiological causes, thus
13
International Urology and Nephrology (2024) 56:583–595
warranting different management considerations. Antibiotic
selection and indications for catheter removal or fibrinolytic
administration require special attention and are specific to
peritonitis subtype. Future research, including retrospective
analyses of longitudinal registries and databases, should be
pursued to identify additional independent risk factors and
further solidify our understanding of the causal microor-
ganisms for complicated peritonitis. Moreover, randomized
controlled trials should be carried out to provide level one
evidence for efficacy of various antimicrobial strategies,
catheter removal, and biofilm-targeting therapies in treating
each complicated peritonitis subtype. Ultimately, instead of
relying on center-specific guidelines for treating peritonitis
in general, a comprehensive algorithm for diagnosing and
managing multiple-episode and unresolving peritonitis may
be developed to aid clinical decision-making in these cases.
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