Fungal peritonitis in peritoneal dialysis

INTRODUCTION — Infections of the peritoneal space are a common complication of peritoneal dialysis [1].

Among patients undergoing peritoneal dialysis, peritonitis is more commonly caused by bacteria than fungi. However, peritonitis caused by fungi carries a higher morbidity and mortality than bacterial infections. Reported complications include sclerosing peritonitis, adhesions with resulting bowel obstructions or stricture, invasion of the bowel wall, and abscess formation [2]. Extraperitoneal spread of infection is unusual, and mortality is usually related to underlying conditions.

An overview of fungal peritonitis in patients undergoing continuous peritoneal dialysis is presented in this topic review. A general overview of peritonitis in peritoneal dialysis is presented separately. (See "Microbiology and therapy of peritonitis in peritoneal dialysis".)

MICROBIOLOGY — Among peritoneal dialysis patients, infections of the peritoneal space are usually caused by staphylococcal species. (See "Microbiology and therapy of peritonitis in peritoneal dialysis", section on 'Microbiology'.)

By comparison, fungi are responsible for 2 to 13 percent of such cases. Most fungal peritoneal dialysis-associated infections are due to Candida species, especially C. albicans and C. parapsilosis. Assorted molds and yeasts, such as species of Aspergillus [3], Fusarium, Rhodotorula, Mucorales, and dematiaceous molds, are occasionally observed. Fungi, when found with bacteria as part of a polymicrobial peritonitis, are a predictor of a poor response to therapy [4].

CAUSES AND RISK FACTORS — Causes of fungal contamination of peritoneal fluid include breaks in sterile technique when connecting peritoneal catheters to bags of dialysate, infections at the cutaneous site of catheter entry, intestinal perforation, peritoneovaginal fistulae, and transmigration of fungi across the bowel wall into the peritoneum.

Recent history of bacterial peritonitis and exposure to antibacterial agents increase the risk for fungal peritonitis. Almost all published series have found an association with both recent antibacterial use and episodes of fungal peritonitis [1,5-10]. When these series are combined, 65 percent of patients had been exposed to antibiotics within 30 days of the onset of fungal peritonitis, and 48 percent had experienced an episode of bacterial peritonitis within the same time frame.

It is difficult to determine whether antibiotic exposure and peritoneal inflammation actually predispose to fungal infections or whether these factors merely identify a high-risk group of patients prone to peritonitis because of poor technique. Recent exposure to antibiotics may predispose to fungal peritonitis by shifting the balance of the patients' endogenous skin and bowel microbiota towards yeast species, thereby increasing the chances of contamination during catheter manipulation.

Other risk factors include the following:

●Use of emergency peritoneal dialysis – A trend towards infection with fungal organisms has been observed in association with acute or emergent peritoneal dialysis performed in the hospital; this may be due to the severity of illness of these patients, concurrent treatment with antibacterial agents, or the administration of dialysis by personnel unfamiliar with the techniques associated with peritoneal dialysis.

●Human immunodeficiency virus (HIV) infection – Patients with HIV infection who receive chronic peritoneal dialysis have a higher frequency of peritonitis with yeasts when compared with other chronic peritoneal dialysis patients. (See "Human immunodeficiency virus and dialysis".)

●Extraperitoneal fungal infection.

●Abdominal surgery.

●Environmental exposures – There are reports of outbreaks of Candida peritonitis associated with contamination of water baths used to warm dialysate solutions and even environmental contact with pigeon guano [11,12]. In addition, contact with soil during gardening or recreation may lead to peritonitis with certain molds.

SYMPTOMS AND SIGNS — The symptoms and signs of fungal peritonitis in peritoneal dialysis patients are the same as those for bacterial peritonitis. The most consistent findings are a cloudy dialysate and abdominal pain, which occur in approximately 90 and 75 percent of patients, respectively. Abdominal pain that is usually diffuse may be associated with nausea, vomiting, and diarrhea. The symptoms may also be subtle, consisting of only mild abdominal pain and low-grade fever. (See "Clinical manifestations and diagnosis of peritonitis in peritoneal dialysis".)

The majority of patients have an elevated temperature; examination of the abdomen typically displays signs of peritonitis, including diffuse tenderness with guarding, rebound tenderness, abdominal distention, and decreased bowel sounds. Poor return of the dialysate during episodes of fungal peritonitis occurs more frequently with infections by molds, which can potentially block catheter ports.

LABORATORY FINDINGS AND DIAGNOSIS — When examining the dialysate fluid for fungal infection, attention should be paid to the duration of the dwell and whether or not peritoneal lavage was performed prior to sample collection; these factors can influence cell counts and culture. As for all peritoneal dialysis-associated peritonitis, the criterion for infection is a cell count >100 cells/microL with >50 percent polymorphonuclear cells. However, among patients with fungal peritonitis, the peritoneal white blood count is almost always >200 cells/microL, with a polymorphonuclear cell predominance. (See "Clinical manifestations and diagnosis of peritonitis in peritoneal dialysis", section on 'Peritoneal fluid analysis'.)

Although local eosinophilia is a frequent transient finding during the first few weeks after initiating peritoneal dialysis, peritoneal eosinophilia has also been described with certain mold infections [13]. The finding of eosinophils in the peritoneal fluid of a patient on chronic peritoneal dialysis with suspected infection should raise the consideration of fungi as etiologic agents, although a predominance of eosinophils may also be observed in bacterial peritonitis. (See "Clinical manifestations and diagnosis of peritonitis in peritoneal dialysis", section on 'Cell count and differential'.)

Gram stain of the peritoneal fluid may reveal yeasts consistent with Candida. However, other stains, such as calcofluor white, are more sensitive for other fungi.

The diagnosis of fungal peritonitis is made by culturing the dialysate fluid. It is recommended that at least 10 mL (separated into multiple culture bottles) of peritoneal fluid be sent for fungal culture (see "Clinical manifestations and diagnosis of peritonitis in peritoneal dialysis", section on 'Evaluation'). Although Candida species usually grow quickly in culture, other fungi may require weeks to emerge. The diagnosis therefore requires a high level of suspicion, with some cases presenting as culture-negative peritonitis.

PREVENTION — Observational data and two randomized controlled trials suggest that antifungal prophylaxis during the course of antibiotic therapy may reduce the incidence of fungal peritonitis [14-18]. Either nystatin (500,000 units orally three to four times daily) or oral fluconazole (200 mg every other day or 100 mg once daily) can be given to peritoneal dialysis patients who receive prolonged antibiotics (defined as antibiotic duration beyond a single dose). The optimal duration of antifungal prophylaxis is unclear, but many clinicians (including the authors of this topic) would administer prophylactic therapy for the duration of antibiotic treatment. Some clinicians extend the duration of antifungal prophylaxis by an additional three days in patients receiving aminoglycosides or by an additional seven days in those receiving vancomycin since these antibiotics have prolonged half-lives in patients on peritoneal dialysis [18]. Routine prophylaxis for all peritoneal dialysis patients (ie, in the absence of prolonged antibiotic therapy) is not recommended.

TREATMENT

General approach — The goals of treatment are to eradicate infection and preserve the peritoneum for future use in peritoneal dialysis. Our approach is as follows:

●The peritoneum should be lavaged until the returning fluid is clear; this helps prevent adhesions and lowers the fungal burden.

●Systemic antifungals should be given if a calcofluor white or Gram stain reveals yeast or hyphae. Subsequent therapy is based upon culture results, susceptibility of the organism, and patient response. (See 'Antifungal agent and duration' below.)

●The catheter should be removed immediately after fungi are identified by microscopy or culture and the patient should be placed on hemodialysis [19,20].

Decisions regarding the specific antifungal agent and duration are discussed below. (See 'Antifungal agent and duration' below.)

Antifungal agent and duration — The choice of antifungal agent varies based upon the specific infecting organism:

●For empiric coverage of fungal peritonitis until cultures return, we use fluconazole (200 mg on day 1, followed by 100 to 200 mg/day). Since fluconazole is highly bioavailable, oral therapy is appropriate for most patients. Intravenous (IV) therapy (at the same dose) should be given to patients who are unable to take oral medications, who are not expected to have good gastrointestinal absorption, or who are severely ill. For patients who have had prior exposure to azole antifungals, we suggest IV amphotericin B deoxycholate (0.6 mg/kg per day) or an IV echinocandin (caspofungin [70 mg on day 1, with subsequent dosing of 50 mg/day]; micafungin [100 mg/day]; or anidulafungin [200 mg on day 1, with subsequent dosing of 100 mg/day]) [21-25]. After cultures return, further therapy can be tailored to the specific organism that has been isolated.

●If Candida species are found, susceptibility studies should be requested to help direct therapy. Generally, C. albicans, C. parapsilosis, and C. tropicalis are susceptible to fluconazole; C. krusei is resistant; and C. glabrata has variable susceptibilities but generally is resistant.

●If the fluid cultures yield C. albicans, C. tropicalis, or C. parapsilosis, we use fluconazole at 200 mg orally on day 1, with subsequent dosing of 100 to 200 mg/day [1,19,26-28]. The duration of therapy is generally two to four weeks.

●If the fluid cultures yield C. krusei or C. glabrata, we suggest an IV echinocandin (caspofungin [70 mg on day 1, with subsequent dosing of 50 mg/day]; micafungin [100 mg/day]; or anidulafungin [200 mg on day 1, with subsequent dosing of 100 mg/day]) or IV amphotericin B at a dose of 0.6 to 1 mg/kg per day [21-25]. Patients should be treated for four weeks.

●If the fluid cultures yield a mold, we suggest IV amphotericin B deoxycholate at 0.6 to 1 mg/kg per day until the specific organism is identified and the most appropriate antifungal agent can be given. For Aspergillus species or Scedosporium apiospermum complex, oral voriconazole should be used [29]. Patients should be treated for at least four weeks and until all symptoms and signs have resolved.

●Infections due to dematiaceous molds should be treated with oral voriconazole (loading dose of 400 mg twice daily for the first day, followed by 200 mg twice a day), although some cases have responded to IV amphotericin B [30,31]. Patients should be treated for at least four weeks and until all symptoms and signs have resolved. Patients receiving voriconazole should have serum levels checked to avoid toxicity and ensure adequate absorption, as discussed separately. (See "Pharmacology of azoles", section on 'Voriconazole'.)

●There is limited experience using lipid formulations of amphotericin B [32,33], but they should be as effective as the deoxycholate formulation. Lipid formulations should be used among patients who have residual kidney function in order to limit nephrotoxicity. These agents may also be used in patients who experience severe infusion-related reactions to the deoxycholate formulation. The dose is 3 to 5 mg/kg/day.

The experience with echinocandins in continuous ambulatory peritoneal dialysis (CAPD)-associated fungal peritonitis is only anecdotal [21]. However, all three echinocandins have proven effective for the treatment of candidemia. In all of the randomized, controlled trials of echinocandins for candidemia and invasive candidiasis, a small number of patients had peritoneal infection and responded well to the echinocandin agent [22-25].

Instillation of amphotericin B into the peritoneal cavity has occasionally been used as the sole or adjunctive therapy in the rare patient in whom the peritoneal dialysis catheter has not been removed. However, we do not use this regimen, because it is not consistently successful in curing infections, it causes abdominal pain upon instillation, and it can contribute to adhesion formation with subsequent loss of the peritoneum as a dialyzing membrane. In addition, catheter removal as part of the initial management of fungal peritonitis eliminates the possibility of intraperitoneal administration of antifungal agents.

Timing of catheter replacement — The patient should be maintained with hemodialysis during treatment with systemic antifungal agents. After peritoneal dialysis catheter removal, the catheter may be reinserted after at least two weeks of antifungal therapy and complete resolution of peritoneal symptoms.

However, the timing of replacement is complex and depends on the response to therapy and the severity of the initial event. In a study of 36 episodes of fungal peritonitis, peritoneal dialysis was eventually resumed in 12 cases, and the median time to catheter reinsertion was 15 weeks [34].

MORTALITY — Compared with other causes of peritonitis, fungal peritonitis in peritoneal dialysis is associated with decreased survival [35]. Reported mortality rates have ranged from 15 to 45 percent [19,35,36].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis".)

SUMMARY AND RECOMMENDATIONS

●Microbiology – Patients undergoing maintenance peritoneal dialysis have a markedly increased incidence of fungal infection compared with the general population. Fungi are responsible for 2 to 13 percent of all cases of peritoneal dialysis-associated peritonitis. Most fungal infections are due to Candida species. (See 'Introduction' above and 'Microbiology' above.)

●Risk factors – The reasons for fungal peritonitis include breaks in sterile technique, infections at the cutaneous site of catheter entry, intestinal perforation, peritoneovaginal fistulae, and transmigration of fungi across the bowel wall into the peritoneum. Other risk factors include recent antibacterial use, episodes of bacterial peritonitis, emergent peritoneal dialysis, human immunodeficiency virus (HIV) infection, extraperitoneal fungal infection, abdominal surgery, and environmental exposures. (See 'Causes and risk factors' above.)

●Clinical manifestations – The symptoms and signs of fungal peritonitis in peritoneal dialysis patients are the same as those for bacterial peritonitis. The most consistent findings are a cloudy dialysate and diffuse abdominal pain. Abdominal pain may be associated with nausea, vomiting, and diarrhea. The symptoms may also be subtle, consisting of only mild abdominal pain and low-grade fever. (See 'Symptoms and signs' above and "Clinical manifestations and diagnosis of peritonitis in peritoneal dialysis".)

●Diagnosis – The criterion for diagnosis of peritoneal dialysis-associated peritonitis is a peritoneal cell count >100 cells/microL with >50 percent polymorphonuclear cells; the cell count is usually >200 cells/microL among patients with fungal peritonitis. Gram stain of the peritoneal fluid may reveal yeasts consistent with Candida. The diagnosis is made by culturing the dialysate fluid. (See 'Laboratory findings and diagnosis' above and "Clinical manifestations and diagnosis of peritonitis in peritoneal dialysis", section on 'Cell count and differential'.)

●Management – The goals of treatment include both eradication of infection and preservation of the peritoneum for future use for dialysis. If the dialysate is grossly turbid, peritoneal lavage should be done until the returning fluid is clear. Systemic antifungals should be given, and the catheter should be removed as soon as possible. Prompt initiation of antifungal therapy is indicated if a calcofluor white or Gram stain reveals yeast or hyphae. (See 'Treatment' above.)

•Empiric antifungal therapy – The choice of antifungal agent varies based upon the specific infecting organism:

-Oral fluconazole (200 mg on day 1, followed by 100 to 200 mg/day) should be used for empiric coverage of fungal peritonitis when there is no suggestion of the identity of the fungus from inspection of the fluid and until cultures return.

-Intravenous (IV) amphotericin B deoxycholate (0.6 mg/kg per day) or an IV echinocandin (caspofungin [70 mg on day 1, with subsequent dosing of 50 mg/day], micafungin [100 mg/day], or anidulafungin [200 mg on day 1, with subsequent dosing of 100 mg/day]) may be used for empiric coverage for patients who have had prior exposure to azole antifungals.

•Tailoring therapy – After cultures return, further therapy can be tailored to the specific organism that has been isolated. If Candida species are found, susceptibility studies should be requested to help direct therapy. (See 'Treatment' above.)

-For C. albicans, C. tropicalis, or C. parapsilosis, we use fluconazole at 200 mg on day 1, with subsequent dosing of 100 to 200 mg/day. Since fluconazole is highly bioavailable, oral therapy is appropriate for most patients. IV therapy (at the same dose) should be given to patients who are unable to take oral medications, who are not expected to have good gastrointestinal absorption, or who are severely ill. The duration of therapy is generally two to four weeks.

-For C. krusei or C. glabrata, we use an IV echinocandin (caspofungin [70 mg on day 1, with subsequent dosing of 50 mg/day], micafungin [100 mg/day], or anidulafungin [200 mg on day 1, with subsequent dosing of 100 mg/day]) or IV amphotericin B deoxycholate at a dose of 0.6 to 1 mg/kg per day. Patients should be treated for four weeks.

-For a mold, we use IV amphotericin B deoxycholate at 0.6 to 1 mg/kg per day until the specific organism is identified and the most appropriate antifungal agent can be given.

-For Aspergillus species or Scedosporium apiospermum complex, oral voriconazole should be used. Patients should be treated for at least four weeks and until all symptoms and signs have resolved.

-Infections due to dematiaceous molds should be treated with oral voriconazole (loading dose of 400 mg twice daily for the first day, followed by 200 mg twice a day). Patients should be treated for at least four weeks and until all symptoms and signs have resolved.

-If amphotericin B is required for treatment, lipid formulations should be used in those who have residual kidney function to limit nephrotoxicity. These agents may also be used in patients who experience severe infusion-related reactions to the deoxycholate formulation. The dose is 3 to 5 mg/kg/day. Although there is limited experience using lipid formulations of amphotericin B for treatment of fungal peritonitis, they should be as effective as the deoxycholate formulation.

●Timing of catheter replacement – The patient should be maintained with hemodialysis during treatment with systemic antifungal agents. After peritoneal dialysis catheter removal, the catheter may be reinserted after at least two weeks of antifungal therapy and complete resolution of peritoneal symptoms. However, the timing of catheter replacement is complex and depends on the response to therapy and the severity of the initial event. (See 'Timing of catheter replacement' above.)

●Role of prophylaxis – Antifungal prophylaxis during the course of antibiotic therapy may reduce the incidence of fungal peritonitis. For peritoneal dialysis patients who receive prolonged antibiotics (defined as antibiotic duration beyond a single dose), we suggest the administration of antifungal prophylaxis with nystatin (500,000 units orally three to four times daily) or fluconazole (200 mg every other day or 100 mg once daily). We recommend not providing routine prophylaxis for all peritoneal dialysis patients (ie, in the absence of prolonged antibiotic therapy). (See 'Prevention' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Steve J Schwab, MD, who contributed to earlier versions of this topic review.