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Perit Dial Int. 2022 Mar;42(2):110-153
https://doi.org/10.1177%2F08968608221080586
ISPD peritonitis guideline recommendations: 2022 update on prevention and treatment
PMID: 35264029
Introduction
In 1950, the first review on peritoneal dialysis included 101 patients over 25 years and reported the most common causes of death: pulmonary edema (40%), uremia (33%), and peritonitis (15%) (Odel et al, Am J Med 1950). Due to technical progress, nowadays nephrologists and patients with ESKD face fewer complications, and according to a recent meta-analysis the peritonitis rate has decreased from 0.6 episodes/patient/year in 1992 to 0.3 in 2019 (Marshall, PDI 2022). However, PD peritonitis is the main cause of technique failure. Early peritonitis (first 6 months) was associated with a higher risk of transfer to hemodialysis (Lobbedez et al, CJASN, 2012).
What is the ISPD and why are guidelines needed?
The International Society for Peritoneal Dialysis (ISPD) is a global organization whose purpose is to advance knowledge of peritoneal dialysis and to promote advancement of such knowledge through international scientific meetings and scientific publications. The society regularly publishes PD related guidelines in its flagship journal Peritoneal Dialysis International and all current PD related guidelines are available on their website. Previous guidelines for PD-related peritonitis were published in 1983, 1993, 1996, 2000, 2005, 2010, and 2016.
ISPD Peritonitis Guideline follows the Grades of Recommendation Assessment, Development and Evaluation system.
Peritonitis is one of the most serious complications faced by patients utilizing PD for kidney replacement therapy. Peritonitis is the most common PD-related infection and contributes to approximately increased acute care utilization, technique failure, transfer to hemodialysis, and sometimes even death. Not surprising, the Standardized Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD) initiative identified it as a core outcome for future trials in PD based on the shared priorities of all stakeholders (Manera et al, AJKD 2020).
Figure from Manera et al, AJKD 2020 - SONG-PD Core Outcome Domains
For a better understanding of this guideline, we will focus on the updates, and we will keep to a few key areas in the new recommendations:
Definitions and measurement of peritonitis;
Prevention of peritonitis;
Treatment of peritonitis: initial and subsequent;
Monitoring response to peritonitis treatment including indications for catheter removal
1. Definitions and measurement of peritonitis
Every nephrologist may ask why so many definitions are needed for a seemingly easy-to-understand pathology. But let’s try to remember the state of chronic kidney disease identification before KDOQI’s 2002 classification system: every clinician could regard the same patient differently through the prism of their own medical experience. In a 2020 meta-analysis that included 77 RCTs reporting PD peritonitis as a primary outcome, 29% hadn’t defined peritonitis and 42% used varying diagnostic criteria (Sahlawi et al, PDI 2022). There is a clear need for standardized definitions of PD-related peritonitis. This will help nephrology care teams monitor their practices and improve the quality of care as well as facilitate the development and comparability of future RCTs. This newest ISPD Peritonitis Guideline, like the one from 2016, reaffirms peritonitis as defined when at least 2 of 3 following criteria are met.
Guideline recommendations:
We recommend that peritonitis should be diagnosed when at least two of the following are present (1C):
clinical features consistent with peritonitis: abdominal pain and/or cloudy dialysis effluent;
dialysis effluent white blood cell (WBC) count > 100/µL or > 0.1x109/L (after a dwell time of at least 2 h), with > 50% polymorphonuclear leukocytes (PMN);
positive dialysis effluent culture
PD peritonitis is further classified according to causative organism (1C), concomitant event (e.g. association with exit-site/tunnel infections or intra-abdominal pathology), timing concerning previous episodes, and outcomes.
Pre-PD peritonitis is a peritonitis episode occurring after PD catheter insertion and prior initiation of PD (first day of PD training or PD treatment). The main motivation to define pre-PD peritonitis is the fact it is an under-recognized problem, and peritonitis incidence would be underestimated by 0.03 per patient-year at risk if peritonitis episodes occurring before completion of PD training were not counted (Balzer MS, PDI 2019).
PD catheter insertion-related peritonitis is defined as an episode of peritonitis that occurs within 30 days of PD catheter insertion and should be <5% of PD catheter insertion
ISPD peritonitis guideline recommends every PD program should monitor the incidence and outcomes of PD peritonitis at least annually (1C). Recommended monitoring parameters also include organism-specific peritonitis rates, antimicrobial susceptibilities, and culture-negative peritonitis.
Peritonitis rate should be calculated as the number of episodes per patient per year at risk (years counted from PD initiation). The guideline recommends an achievable goal of <0.4 episodes/patient-year, a lower target than 2016 guideline (<0.5 episodes/patient-year). The proportion of culture-negative peritonitis should be less than 15% of all peritonitis episodes (1C).
With a lower level of evidence (2C), the guideline recommends reporting monthly other peritonitis parameters: mean time to first peritonitis episode, percentage of peritonitis-free patients (targeting >80% peritonitis-free patients per year), and pre-PD peritonitis.
2. Prevention of peritonitis
Primary Prevention
Catheter Placement - Prophylactic Antibiotic
In the guideline, there is only one 1A recommendation, which can be found both in the 2016 and 2022 ISPD guidelines: that systemic prophylactic antibiotics be administered prior to catheter placement. Four randomized trials support this recommendation, including cefuroxime (Wikdahl et al, NDT 1997), gentamicin, vancomycin, and cefazolin versus no treatment (Lye et al, Scand J Urol Nephrol 1992; Gadallah et al, AJKD 2000). Even though use of systemic antibiotic prophylaxis is successful for catheter-related peritonitis prevention, it is unclear if they prevent exit site infections. The antibiotic choice should be determined according to the local antibiotic resistance spectrum.
Contamination of PD System
Guideline recommendations:
We suggest prophylactic antibiotics after wet contamination of the PD system to prevent peritonitis (2D).
We suggest advice be sought immediately from the treatment team if contamination during PD exchange is noted (Not Graded).
A grade 2D recommendation is prophylactic antibiotics after wet contamination of the PD system, to prevent peritonitis. Treatment is guided by the type of contamination: “dry” versus “wet”. According to a retrospective study including over 500 contamination episodes, the risk of peritonitis was higher after wet contamination, and higher if no antibiotic prophylaxis. Though the peritonitis rate was not as high one might expect (3.1%), peritonitis was observed only in the wet contamination group (Yap DY, et al. Perit Dial Int. 2012). There is no standard antibiotic recommended. Though not graded the guideline does reference the importance of quick communication with the nephrology care team when contamination is suspected.
Invasive gastrointestinal and gynecological procedures
Guideline recommendations:
We suggest antibiotic prophylaxis prior to colonoscopy (2C) and invasive gynecological procedure (2D).
We suggest drainage of PD fluid to keep the abdomen empty before endoscopic gastrointestinal and invasive or instrumental gynecological procedures (2D).
GI procedures, i.e. colonoscopy, without antibiotic prophylaxis has a peritonitis incidence of 3.4 to 8.5% (Gweon et al, BMC Gastroenterol 2019; Al-Hwiesh et al, Int J Artif Organs 2017). More than half of the peritonitis episodes occurring after colonoscopy are caused by E. coli (Gweon et al, BMC Gastroenterol 2019; Kim et al, Clin Transl Gastroenterol 2021). There is only one RTC of 93 patients utilizing automated PD (APD) examining prevention with antibiotic prophylaxis (1g IP ceftazidime 1h before the procedure) showing no difference in peritonitis rate with (6.5%) or without (8.5%) prophylaxis (p 0.27) (Al-Hwiesh et al, Int J Artif Organs 2017).
The guideline did not specify what counts as an invasive gynecological procedure. The reported peritonitis complication rate after endoscopic or instrumental gynecological procedures ranges from 26.9% (Fan et al, Perit Dial Int. 2019) to 38.5% (Wu et al, HH, PLoS One. 2013). These retrospective studies reviewed peritonitis rates after diagnostic hysteroscopy, endometrial biopsy, endometrial polypectomy, hysterosalpingogram, cervical biopsy, and intrauterine device insertion/removal. Both showed much less peritonitis when antibiotic prophylaxis was used. However, it is worth noting that the absolute numbers of events in these studies was very small considering international guidelines are being made based on them (7 peritonitis episodes over 26 procedures in Fan et al, and 5 peritonitis episodes in 13 procedures in Wu et al - indeed fewer peritonitis episodes than authors listed on the paper!). There are 2 retrospective studies (previously mentioned), showing lower peritonitis with antibiotic prophylaxis. Because of inadequate evidence, a specific antibiotic recommendation couldn’t be made, but Gram-negative and Gram-positive coverage is likely needed.
Draining the PD fluid before the procedure is standard practice for most programs, but can occasionally be missed. The rationale for draining the PD fluid prior to the procedure is related to the theory of suppressed macrophage phagocytic function and polymorphonuclear cell function.
Training Programs and Monitoring
Guideline recommendations:
We suggest that the characteristics of an optimal PD training programme (how, how long, where, when and by whom) remain uncertain (2C).
We recommend that PD exchange technique and knowledge be regularly reassessed and updated, with an emphasis on direct inspection of practice of PD technique (1C).
The guideline formulated some specific situations for retraining (table 3) because not all studies succeeded to demonstrate its efficacy. An open-label randomized controlled trial, including 661 patients from 57 European centers, showed that retraining at 1, 3, 6, 12, 18, 24, 30, and 36 months after PD start didn’t make any difference in peritonitis rates (Ljungman et al, PDI 2020). On the other hand, it has been proposed that a practical assessment of the PD technique is more important. A controlled trial randomizing incident PD patients to retraining via technique inspection, oral education, or usual care. The oral education group (retraining every 2 months using a checklist and focusing on knowledge) did not reduce the risk of peritonitis, whereas the technique inspection group (retraining every 2 months and focusing on behavior by nurses’ inspection of PD technique) demonstrated a lower risk of first non-enteric peritonitis (Xu et al, NDT 2020).
Table 3 from ISPD 2022 Peritonitis Guideline
Domestic Pets and Zoonotic Infections
Guideline recommendations:
We recommend PD patients take extra precautions to prevent peritonitis if domestic pets are kept (1C).
We suggest pets not be allowed in the room where PD exchange takes place, and where dialysis tubing, equipment and machine are stored (2A).
There is a paucity of data here, mostly case reports of peritonitis with pet-related infectious organisms (e.g. Pasteurella multocida peritonitis). It is uncontroversial that ISPD recommends patients stop their cats chewing the tubing and take extra precautions to prevent peritonitis if domestic pets are kept. It is reasonable to keep pets clear of the treatment area and to follow strict hand-washing and aseptic technique procedures.
Dietary and Medication Effects
Guideline recommendations:
We suggest that avoidance and treatment of hypokalemia may reduce the risk of peritonitis (2C).
We suggest that avoiding or limiting the use of histamine-2 receptor antagonists may prevent enteric peritonitis (2C).
It is suggested that preventing hypokalemia may reduce the risk of peritonitis. International data from PDOPPS showed that hypokalemia persistent for 4 months was associated with 80% higher subsequent peritonitis rates (Davies et al, Kidney Int Rep 2021). However, it seems more likely that this is associated with malnutrition rather than causation, and there are no studies showing that correcting the numbers for serum potassium alone reduces the risk of peritonitis, (however, the ISPD guideline recommends dietary measures).
Histamine-2 receptor antagonists are included by the guideline as a modifiable risk factor for enteric peritonitis in patients on PD (2C). A meta-analysis revealed that histamine-2 receptor antagonist use was associated with an increased odds of enteric peritonitis (OR 1.4, 95% CI 1.01–1.93) (Zhong et al, J Clin Pharm Ther 2019), but (again) causality is questionable. The intriguing thing is the higher peritonitis rate was not higher for proton pump inhibitors (contrary to data from hepatic cirrhosis, where both medication classes possibly determine a higher risk of enteric peritonitis).
Secondary Prevention
Guideline recommendations:
To prevent fungal peritonitis, we recommend that anti-fungal prophylaxis be co-prescribed whenever PD patients receive an antibiotic course, regardless of the indication for that antibiotic course (1B).
Even though this anti-fungal prophylaxis recommendation is unchanged from the 2016 ISPD guidelines, not all nephrologists apply this routinely. Data to support this comes from a Cochrane meta-analysis including 2 randomized controlled studies on anti-fungal prophylaxis with oral nystatin or fluconazole showed a risk ratio of 0.28 (95% CI 0.12–0.63) for fungal peritonitis occurring after an antibiotic course (Lo et al, AJKD 1996; Restrepo et al, PDI 2010; Campbell et al, Cochrane Database Syst Rev 2017). However the evidence is based on just these 2 studies with relatively low GRADE due to high risk of bias in the old 1996 study and very few events in the other.
3. Treatment of peritonitis: initial and subsequent
Figure 1 from ISPD 2022 Peritonitis Guideline
The algorithm of initial management for PD patients presenting with a clinical diagnosis is summarized in Figure 1. If peritonitis is suspected, the guideline recommends that PD effluent be tested for cell count, differential gram stain, and culture (1B). PD patients presenting with cloudy effluent should be presumed to have peritonitis and treated as such until the diagnosis can be confirmed or excluded (1C).
Special consideration is needed for patients utilizing automated peritoneal dialysis (APD) as the WBC count in the effluent depends on the length of the dwell. For patients on APD with rapid cycle treatment, the percentage of PMN should be used the rather than the absolute WBC count to diagnose peritonitis, and a proportion above 50% PMN is strong evidence of peritonitis (even if the absolute WBC count < 100/µL). When APD patients without a daytime exchange present with abdominal pain during the daytime may have no effluent. To obtain a specimen for cell count and culture, 1 liter of dialysis solution should be infused, allowed to dwell for 2 h, and then drained for inspection and laboratory testing.
Identification of causative organisms
It is recommended that the blood culture bottle(s) be the preferred technique for the bacterial culture of PD effluent (1C). If the cultures remain negative after 3–5 days the guideline proposes repeat cell count, differential count, fungal and mycobacterial culture, furthermore subculture on media with aerobic, anaerobic, and microaerophilic incubation conditions for an another 3–4 days may identify slow-growing fastidious bacteria and yeasts- undetectable in automated culture systems. The culture of the PD catheter can improve the diagnostic yield, fungi, and enterococci. If more than 15% of peritonitis episodes of culture negative, a review of microbiological methods and standards is recommended
Empiric antibiotic selection
Guideline recommendations:
We recommend that empirical antibiotic therapy be initiated as soon as possible, using either IP or systemic IV route, after appropriate microbiological specimens have been obtained (1B).
We recommend that empirical antibiotic regimens be center-specific and cover both gram-positive and gram-negative organisms (1C).
We recommend that gram-positive organisms be covered by a first-generation cephalosporin or vancomycin and gram-negative organisms by a third-generation cephalosporin or an aminoglycoside (1B).
We suggest that cefepime monotherapy may be an acceptable alternative for empirical antibiotic regimens (2B).
PD-related peritonitis is a feared complication that should mount an emergent intervention with proper empirical antibiotic coverage (systemic or intraperitoneal), after collecting proper microbiological specimens. These recommendations advocate for timely antibiotic administration as delay has been shown to increase the risk of PD failure or death (Muthucumarana et al, Kidney Int Rep. 2016; Oki et al,, Sci Rep. 2021). Antibiotic administration should not be delayed in attempt to start with IP regimen, timely initiation of systemic/IV antibiotics is appropriate. However, there is insufficient evidence to recommend a standard antibiotic regimen for all and these empiric treatments should be guided by local antibiograms and in consultation with local infectious diseases teams. An updated Cochrane review (Ballinger et al, Cochrane Database Syst Rev 2014) identified 42 RCTs and quasi-RCTs assessing the treatment of peritonitis in PD patients. Many of these studies were out-dated, of poor quality, and did not show superiority of either a specific antibiotic regimen or administration route.
In terms of the dual antibiotic empiric coverage, this recommendation is supported by a large retrospective study from an Australian registry (Htay et al, Am J Kidney Dis 2018) that showed higher odds of cure with this approach. The use of Cefepime as a monotherapy empirically has been described since 2000 (Li et al, PDI 2000) with a more recent multicenter, open-label, RCT from Thailand (Kitrungphaiboon et al, AJKD 2019).
Dosage of antibiotics
Guideline recommendations:
We recommend that IP antibiotics be the preferred route of administration as long as the compatibility and stability of the IP antibiotics allow, unless the patient has features of systemic sepsis (1B).
We suggest that IP aminoglycoside be administered as daily intermittent dosing (2B).
We recommend that prolonged courses of IP aminoglycoside be avoided (1C).
We suggest that adjunctive oral N-acetylcysteine therapy may help to prevent aminoglycoside ototoxicity (2B).
There is insufficient evidence to make a recommendation as to whether patients on APD should be temporarily switched to CAPD during treatment of peritonitis (Not Graded).
Recommending IP as the route of choice is practical and more feasible for allowing ambulatory care for patients with PD peritonitis. The recommended dosage of antibiotics for the treatment of PD peritonitis is summarized in Table 5 (IP antibiotic dosing) below. These are mostly based on published clinical experience rather than formal pharmacokinetic studies, with IP dosage being studied in patients using CAPD as opposed to APD. However, these recommendations do not account for the presence of residual kidney function, which has been shown to be associated with treatment failure, possibly due to lower antibiotic concentration (Whitty et al, CJASN 2017). A proposed 25% increase in the dose of cephalosporins (cefepime, cefazolin, and ceftazidime) in patients with >100mL per day of urine output was advocated in a recent RCT (Kitrungphaiboon et al, AJKD 2019).
Vancomycin is commonly used, but there is no consensus for the optimal time to measure vancomycin levels. There is a poor correlation between trough levels and cure rates of peritonitis reported in observational studies (Stevenson et al, PDI 2015). Recent evidence supports a peak concentration level (30 min after IP dose) being more associated with higher cure rates (Falbo Dos Reis et al, Front Pharmacol 2021), but this has not yet been incorporated into treatment algorithms.
As for aminoglycosides, they feature a concentration-dependent activity and continue to suppress bacterial growth even below minimum inhibitory concentrations (Lortholary et al, Med Clin North Am 1995). Along with their broad-spectrum gram-negative coverage, this makes them an ideal choice for empiric treatment. Nonetheless, a major concern is ototoxicity that could occur with therapeutic antibiotic levels, resulting in either vestibular or cochlear damage regardless of the route of administration (Johnson DW, Semin Dial 2011; Warady et al, Pediatr Nephrol 1993). The protective use of oral N-acetylcysteine has been evaluated in patients receiving amikacin in three RCTs. NAC showed significantly better protection versus placebo in pure tone audiometry assessment of high-frequency hearing function in the largest of the three RCTs, with a pooled relative risk for otoprotection at 4–6 weeks of 0.14 (95% CI 0.05-0.45) . Of note, there was no formal assessment of vestibular function in any of the studies.(Kranzer et al, Thorax 2015). Another common concern in using aminoglycosides is the risk of loss of residual kidney function. However, 1 RCT and several observational studies do not support this (Lui et al, KI 2005).
Fluoroquinolones can be used via IP or oral route, with both ciprofloxacin and moxifloxacin achieving adequate IP concentration (Skalioti et al, PDI 2009; Lee et al, PDI 2018). Clear instruction to avoid concomitant use of aluminum-containing antacids and oral phosphate binders (including calcium carbonate, lanthanum, and sevelamer) to avoid poor oral absorption should be provided.
Table 5 from ISPD 2022 Peritonitis Guideline
Antibiotic delivery and stability
Guideline recommendations:
An important factor when using IP antibiotics is their stability and compatibility with different PD solutions. Antibiotic stability is summarized in Table 7.
Compatible:
Gentamicin with cefazolin
Gentamicin with vancomycin
Ceftazidime with cefazolin
Ceftazidime with vancomycin
Incompatible:
Aminoglycosides with penicillins
Table 7 from ISPD 2022 Peritonitis Guideline
Special considerations for APD
A major consideration when treating PD peritonitis in patients using APD is the under-dosing of antibiotics. APD typically offers shorter dwell times than CAPD, and simply extrapolating CAPD dosing to APD is not recommended. The guidelines suggest exceeding the MIC for ≥50% of treatment time. This translates to a dwell time for Vancomycin of 4 hr (Fish et al, Perit Dial Int 2012), although aiming for 6 hr is advised (Falbo Dos Reis et al, Front Pharmacol 2021). Of note, cefazolin and ceftazidime use has been validated for short-dwell automated cycling exchanges (Triyawatanyu et al, PDI 2020, Peerapornratana et al, PDI 2017). Nonetheless, there appears to be insufficient evidence to support changing the dialysis modality but this should be a consideration for antibiotics requiring continuous dosing. Most of the antibiotics are compatible with Icodextrin and long dwells. Additionally, an easier option in patients with APD could be to use the long day dwell for once daily antibiotics treatment keeping the APD prescription unchanged. This needs to be adapted to each individual circumstance.
Adjunctive treatments
Guideline recommendations:
We suggest that augmented peritoneal lavage should not be performed for the purpose of improving peritonitis cure (2B).
We suggest that icodextrin be considered for volume overload which occurs during acute peritonitis (2C).
Other than commencing antibiotics, there is limited evidence to support adjunctive treatments in PD peritonitis. Many patients will experience abdominal pain, and common practice in some regions to relieve this is to perform one to two rapid exchanges on presentation, though with no data to support this and no effect on rates of cure or relapse (Ejlersen et al, PDI 1991; Wong et al, PDI 2019). Patients with cloudy effluent may benefit from adding heparin 500 units/L IP to prevent catheter occlusion via fibrin. RCTs have not shown benefit from using IP urokinase in limiting biofilm formation and reducing refractory peritonitis (Tong et al, J Nephrol 2005; Gadallah et al, Adv Perit Dial 2000; Innes et al, NDT 1994).
Patients with PD peritonitis can be at risk for volume overload due to changes in peritoneal membrane permeability during the acute phase. Basic interventions from fluid restriction, optimizing diuretics, and reinforcing low-salt diet can all be encouraged. The guidelines described the temporary addition of icodextrin as a reasonable therapeutic option. Glycemic control can also be challenging with increased glucose absorption and more protein loss. Thus, increased blood sugar monitoring in patients with diabetes is important, but no high-quality studies have studied the effect of nutritional supplements on outcomes.
Coagulase-negative Staphylococcus Peritonitis
Guideline recommendations:
We suggest that coagulase-negative staphylococci be treated with IP cephalosporin or vancomycin, according to susceptibility, for a period of 2 weeks (2C).
We suggest that retraining be considered for patients with coagulase-negative staphylococcal peritonitis (Not Graded).
Despite being less virulent than S. aureus, these organisms are more common and are becoming more challenging due to their sensitivity profile. An increasing prevalence of methicillin-resistant coagulase-negative staphylococci has been reported up to 50% in most centers (Chen et al, PDI 2018; Kitterer et al, PLoS One 2015; Wang et al, J Microbiol Immunol Infect 2019) and up to 70% in others (Zelenitsky et al, PDI 2017; Camargo et al, CJASN 2014). This has given vancomycin preferential use in these centers.
These organisms also appear to have a high risk for developing refractory and repeat peritonitis, reported risk of 12% in two large case series (Camargo et al, CJASN 2014; Szeto et al, CJASN 2008), often in the second month after completing treatment (Fahim et al, NDT 2010). This strongly suggests consideration needs to be given to simultaneous catheter removal and reinsertion.
Staphylococcus aureus Peritonitis
Guideline recommendations:
We suggest that S. aureus peritonitis be treated with effective antibiotics for 3 weeks (2C).
Figure 2 from ISPD 2022 Peritonitis Guideline
The treatment algorithm for S. aureus is summarized in Figure 2. The evidence for this recommendation stems from two retrospective observational studies with a total of >700 patients (Szeto et al, Clin J Am Soc Nephrol 2007, Govindarajulu et al, Perit Dial Int 2010 ). Both vancomycin and cefazolin have been shown to be equally effective as empirical treatment. In case the isolate was MRSA, adding rifampicin as adjuvant therapy for 5-7 days was shown to lower the relative risk of developing relapse or repeat S. aureus peritonitis (Szeto et al, Clin J Am Soc Nephrol 2007). If there was an unfavorable response to vancomycin, however, a case report showed improved response to IP daptomycin (Lin et al, Blood Purif 2011). PD catheter removal should be considered in cases with concurrent exit site or tunnel infection.
Streptococcal peritonitis
Guideline recommendations:
We suggest that streptococcal peritonitis be treated with appropriate antibiotics for 2 weeks (2C).
Figure 3 from ISPD 2022 Peritonitis Guideline
Streptococcal peritonitis management is summarized in Figure 3. It has a high cure rate (O’Shea et al, BMC Nephrol 2009, Santos et al, PLoS One 2020) but newer strains with lower susceptibility to ampicillin, penicillin and ceftriaxone have been observed (Zelenitsky et al, Perit Dial Int 2017, Liu et al, BMC Nephrol 2018). Along with higher risk of relapse in viridans streptococcal peritonitis (Chao et al, Perit Dial Int 2015).
Corynebacterium peritonitis
Guideline recommendations:
We suggest that Corynebacterium peritonitis be treated with effective antibiotics for 2 weeks (2D).
We suggest that peritonitis due to beta-lactam-resistant strains, such as Corynebacterium jeikeium, should be treated with vancomycin (2C).
The guidelines cited three outcome studies with differing conclusions on extending the antibiotic course beyond 2 weeks (Htay et al, Perit Dial Int 2017, Barraclough et al, Nephrol Dial Transplant 2009, Szeto et al, Nephrol Dial Transplant 2005). This could have been due to different Corynebacterium species (Corynebacterium jeikeium or Corynebacterium striatum) where vancomycin would be a more suitable treatment due to increasing resistance to beta-lactams (Chao et al, Perit Dial Int 2013, Schiffl et al, Perit Dial Int 2004, McMullen et al, Antimicrob Agents Chemother 2017). Some patients could also develop repeat peritonitis and using a 3-week course of IP vancomycin thereafter would be reasonable (Szeto et al, Nephrol Dial Transplant 2005).
Pseudomonas peritonitis
Guideline recommendations:
We suggest that Pseudomonas peritonitis be treated with 2 antibiotics with different mechanisms of action and to which the organism is sensitive for 3 weeks (2C).
We suggest that Pseudomonas peritonitis with concomitant exit-site and tunnel infection be treated with catheter removal (2D).
If there is no clinical response after 5 days of effective antibiotic treatment, we suggest that Pseudomonas peritonitis be treated with early catheter removal instead of using three antibiotics as an attempt to salvage (2D).
Figure 6 from ISPD 2022 Peritonitis Guideline
The management of Pseudomonas and other non-fermenting and environmental gram-negative bacteria is summarized in figure 6. Pseudomonas peritonitis is often a severe infection with <50% cure rate (Siva et al, Clin J Am Soc Nephrol 2009, Szeto et al, Kidney Int 2001). This is thought to be secondary to the biofilm production (Dos Santos et al, Sci Rep 2021), and early catheter removal should be considered to avoid treatment failure (Lu et al, PLoS One 2018, Siva et al, Clin J Am Soc Nephrol 2009). The benefits of using two antipseudomonal agents has been described in a retrospective case series of 191 cases, and therefore was included in this guideline (Siva et al, Clin J Am Soc Nephrol 2009).
Polymicrobial peritonitis
Polymicrobial culture results are highly suggestive of an intra-abdominal pathology as detailed in figure 8 algorithm. Worse outcomes are seen mostly with enteric bacteria, fungus and/or E. faecium (Ribera-Sanchez et al, Perit Dial Int 2018). Patients presenting with hypotension, sepsis, lactic acidosis, or elevated dialysis effluent amylase level are alarming for an abdominal catastrophe (Harwell et al, Perit Dial Int. 1997). A multi-antibiotic regimen is preferred with metronidazole plus vancomycin, in combination with ceftazidime or an aminoglycoside. In select patients, monotherapy with a carbapenem or piperacillin/tazobactam may also be considered. Urgent surgical assessment is warranted. Computed tomographic (CT) scan, especially in the presence of hemodynamic instability, is needed to manage these cases.
Figure 8 from ISPD 2022 Peritonitis Guideline
On the other hand, a mixed gram-positive growth has a more favorable prognosis. They tend to behave similarly to single organism peritonitis and could be simply due to touch contamination. Conservative management with targeted antibiotic therapy is often sufficient without the need for PD catheter removal (Szeto et al, Am J Med 2002).
Fungal peritonitis
Guideline recommendations:
We recommend immediate catheter removal when fungi are identified in PD effluent (1C).
We suggest that treatment with an appropriate antifungal agent be continued for at least 2 weeks after catheter removal (2C).
Treatment failure and mortality remain high in fungal peritonitis, even with prompt catheter removal (Nadeau-Fredette AC, et al. Perit Dial Int 2015, Chang TI, et al.Perit Dial Int 2011). Gram stain is the recommended method for more rapid fungal identification.
Figure 9 from ISPD 2022 Peritonitis Guideline
Prompt empirical treatment with antifungal therapy should be initiated even based on the Gram stain. The subsequent choice of antifungal regimen depends on the correct identification of the pathogens and their susceptibility profiles. Candida albicans is the most common pathogen (Auricchio S, et al. Clin Kidney J 2018). Choosing the right antifungal might be challenging, so ISPD proposed an algorithm for it (Figure 9)
Catheter removal remains the cornerstone of managing fungal peritonitis. Previous studies have reported a mortality of 50% to 91%among patients without catheter removal (Goldie SJ, et al. Am J Kidney Dis 1996, Wang AY, et al. Am J Kidney Dis 2000). The early catheter has been reported to be associated with lower mortality and a better chance of resuming PD (Goldie SJ, et al. Am J Kidney Dis 1996, Chang TI, et al. Perit Dial Int 2011).
About antifungal treatment duration, it’s recommended to be continued for at least 2 weeks after catheter removal, and sometimes up to 4 weeks (Wang AY, et al. Am J Kidney Dis 2000). However, irrespective of the treatment duration, catheter reinsertion and resumption of PD have been reported after a median period of 15 weeks in less than one-third of cases (Nadeau-Fredette AC, et al. Perit Dial Int 2015).
Culture-negative peritonitis
Risk factors for culture-negative peritonitis include recent antibiotic usage and improper culture technique.37,38,372 (Szeto CC, et al. Am J Kidney Dis 2003, Fahim et al, Am J Kidney Dis 2010; Bunke M, et al. Adv Perit Dial, 1994).
Treatment outcomes of culture-negative peritonitis is in general favorable. Many culture-negative peritonitis episodes were resolved with medical therapy; the cure rate by antibiotics alone ranged from 67.5% to 82.3% (Htay H, et al. Perit Dial Int 2020, Chen KH, et al. Ren Fail 2007). For culture-negative peritonitis responds very well to antibiotics, and they are most probably caused by gram-positive organisms, and initial antibiotherapy should be continued. Duration should be limited to 2 weeks.
On the other hand, for patients whose PD effluent culture is negative after 3 days, it is recommended WBC count, together with a special culture request to exclude unusual organisms such as mycobacteria, Nocardia, filamentous fungus, and other fastidious bacteria. For suboptimal initial responses, it is suggested to use a combination of ampicillin-sulbactam and amikacin, which demonstrated a response in 80% of 10 cases (Lam MF, et al. Perit Dial Int 2008). PD catheter removal was required in around 10% of cases of culture-negative peritonitis (Holley JL, et al. Perit Dial Int 1994, Htay H, et al. Perit Dial Int 2020).
Tuberculous peritonitis
Guideline recommendations:
We suggest antituberculous therapy, instead of PD catheter removal, as the primary treatment of peritonitis caused by Mycobacterium tuberculosis (2C).
Tuberculosis PD- peritonitis is challenging because in the majority of cases it has the same clinical features as any PD peritonitis: 89% abdominal pain and 81% fever (Akpolat T. Perit Dial Int 2009), and high PMN in the effluent. Therefore request for cultures for acid-fast bacilli (gold standard) is delayed, moreover, Mycobacterium is a slow-growing bacteria, and the mean time from presentation to initiation of treatment of tuberculous peritonitis is extended to 6.7 weeks (Al Sahlawi M et al. Kidney Med 2020). Another diagnosis modality could be (Lye WC. Adv Perit Dial 2002):
Adenosine deaminase in the peritoneal dialysate
low specificity
or PCR analysis to detect M. tuberculosis DNA
low sensitivity (could not exclude it)
The recommended dosages of drugs for treating tuberculous peritonitis in PD patients are depicted in Table 8. Initial drug treatment of pan-susceptible tuberculosis consists of four drugs for a total of 2 months followed by two drugs (isoniazid and rifampicin) given for at least a total of 12 months.
Table 8 from ISPD 2022 Peritonitis Guideline
Many patients respond to anti-tuberculous therapy without catheter removal, although attributable mortality of 15% has been reported (Al Sahlawi M et al. Kidney Med 2020). In a scoping review of 216 cases of Mycobacterium tuberculosis peritonitis in patients on PD, the catheter was removed in 52.4% of cases. Most of the cases requiring catheter removal were empirical, based on the rationale of failed treatment of usual bacterial peritonitis before the diagnosis of tuberculous peritonitis was recognized. PD catheter removal was not associated with an increased probability of survival (Thomson BKA, et al. Nephrology (Carlton), 2022)
Non-tuberculous mycobacterial peritonitis
Guideline recommendations:
We suggest that Ziehl–Neelsen staining for acid-fast bacilli be requested when there is a clinical suggestion of non-tuberculous mycobacterial (NTM) peritonitis, including persistent culture-negative peritonitis (2D).
We suggest that NTM peritonitis be treated with both effective antibiotics and catheter removal (2D).
The most frequent NTM are Mycobacterium fortuitum and chelonae. Diagnosis of NTM PD-peritonitis is difficult because the NMT often gets confused with diphtheroids and Corynebacterium, mostly delayed by a median of 6–30 days (Fung WW, et al. Perit Dial Int 2021, Jiang SH et al. Int Urol Nephrol 2013). Negative cultures with persistent symptoms of peritonitis, often with concomitant exit-site infection, should raise concern for the possibility of NTM infection.
Most experts recommend two agents to which NMT is susceptible for a minimum of 6 weeks (Renaud CJ, et al. Nephrology (Carlton) 2011). The majority of NTM are sensitive to amikacin, but in vivo resistance to clarithromycin often occurs due to active inducible macrolide resistance genes (Imam O, et al. Open Forum Infect Dis, 2021, Fung WW, et al. Perit Dial Int 2021). PD-catheter removal is recommended, although previous studies showed that less than 20% of patients could be resumed on PD (Song Y, et al. Nephrol Dial Transplant 2012, Washida N et al. Contrib Nephrol 2018, Bnaya A, et al. Perit Dial Int 2021).
4. Monitoring response to peritonitis treatment including indications for catheter removal
Subsequent management of peritonitis
Guideline recommendations:
We recommend that antibiotic therapy be adjusted once results and sensitivities are known (1C).
There is clear need for clinical assessment, reviewing antibiotic sensitivity and duration, and measuring the dialysis effluent WBC count as per the organism algorithm. A higher dialysis effluent WBC count, >1090/µL or >1000/µL on day 3, have been described in two retrospective studies to correlate with the likelihood of treatment failure (Chow et al, Clin J Am Soc Nephrol 2006, Nochaiwong et al, Sci Rep 2018). Stepwise algorithms for specific organisms are outlined below.
Refractory peritonitis
Guideline recommendations:
We recommend that PD catheter be removed in refractory peritonitis episodes, defined as failure of the PD effluent to clear after 5 days of appropriate antibiotics (1D).
We suggest that observation for antibiotic effect longer than 5 days is appropriate if PD effluent white cell count is decreasing towards normal, instead of mandatory PD catheter removal if effluent does not clear up by day 5 (2C).
Refractory peritonitis that does not show improvement puts patients at significant risk of extended hospital stay, peritoneal membrane damage, fungal peritonitis, and excessive mortality (Choi et al, Am J Kidney Dis 2004, Lu et al, PLoS One 2018). However, after making the initial recommendation regarding catheter removal on day 5 sound mandatory, these guidelines then use downtrending of the PD effluent white cell count as a pivot point by which you might consider persisting with prolonged antibiotics for a little longer despite the bags not quite clearing up. A large observational study including 266 patients who did not reach a satisfactory effluent WCC by day 5 found that 122 of these still ultimately had cure without catheter removal and that trending the rate and magnitude of WCC decline would help predict this 'delayed success' over the treatment failure in the remaining 144 patients (Tantiyavarong et al, Int J Nephrol 2016).
Relapsing, recurrent, and repeat peritonitis
Guideline recommendations:
We recommend timely PD catheter removal be considered for relapsing, recurrent, or repeat peritonitis episodes (1C).
We suggest that simultaneous PD catheter removal and reinsertion be considered after the culture of the PD effluent has become negative and the PD effluent white cell count is below 100/µL, in the absence of concomitant exit site or tunnel infection (2C).
Retrospective studies suggest that relapsing, recurrent, and repeat peritonitis are likely to represent distinct clinical entities with worse outcomes (Szeto et al, Am J Kidney Dis 2009, Burke et al, Am J Kidney Dis 2011, Szeto et al, Clin J Am Soc Nephrol 2011, Thirugnanasambathan et al, Am J Kidney Dis 2012, Reis et al, Int J Nephrol 2021). A French retrospective monocentric study of 271 incident patients on PD over 10 years, had 11 patients undergoing a simultaneous removal and insertion of the PD catheter due to relapsing peritonitis (8) or high risk of relapse peritonitis (3). Eight patients remained on PD without transfer to HD and at 1 year, 7 patients were still on PD (Viron et al, Perit Dial Int 2019). The median technique survival was reported to be 5.1 years in a study that analyzed the clinical outcomes of 55 consecutive simultaneous catheter replacements, 28 cases related to relapsing peritonitis (Crabtree et al, Perit Dial Int 2016).
Bacterial DNA fragments in PD effluent from patients who develop relapsing or recurrent peritonitis have been reported to be significantly higher 5 days before and on the date of completion of antibiotics (Szeto et al, Clin J Am Soc Nephrol 2013). However, prolonged antibiotic courses have not been shown to be effective in decreasing DNA fragments levels (Szeto et al, Clin Kidney J 2021).
Points to Conclude:
Unifying the definitions and delineating outcomes aims to avoid confusion and standardize practice and research outcomes
Peritonitis prophylaxis remains a challenge, as the evidence supporting the guide's recommendations is low evidence, or comes from studies that identify an associative relationship rather than a causal one
Peritonitis remains a challenge to manage with increasing antibiotic resistance and the need for PD catheter removal
Nephrologists need new sophisticated tools to reach an early microbiological diagnosis and practice antibiotic stewardship. The use of pathogen-specific immune fingerprints with the utilization of machine learning in decision making and guiding treatment/intervention could be a promising new opportunity
Our patients need more robust trials and prospective data to guide their management and develop more rigorous future guidelines