Fungal peritonitis (FP) is a catastrophic complication that can occur in patients on peritoneal dialysis (PD). It is associated with a high rate of treatment failure and mortality, and current guidelines recommend immediate catheter removal upon identification of fungi.1 Most cases of FP are preceded by antibiotic exposure,2 which is frequently used in patients on PD for empirical treatment of PD-related episodes of peritonitis, posing a significant risk factor for FP.3

Nowadays, PD-related peritonitis remains one of the most serious complications for PD. Indeed, it is the leading cause of PD technique failure and carries a significant risk of death in this patient population.4 FP represents only about 1–12% of overall cases of peritonitis in patients on dialysis.5–7 However, it is associated with devastating impacts in clinical practice, including catheter removal, migration to hemodialysis, and high mortality rates, ranging from 10 to 36% in the literature,8,9 nearly ten-fold higher as compared with bacterial peritonitis.10

Antifungal prophylaxis for FP has been studied previously using various antimycotic agents, including fluconazole, ketoconazole, and nystatin.11 However, there are conflicting findings in the literature about the efficacy of these therapies in the prevention of FP.12–17 Fluconazole, a member of the triazole class of antifungal medications, inhibits the synthesis of ergosterol, a crucial component of fungal cell membranes.18 It has a broad-spectrum activity against various fungal species, including Candida albicans, the most common cause of FP in PD patients.3 It is well tolerated, with a favorable safety profile, making it a suitable option for prophylaxis in patients on PD.

The 2022 updates from the International Society for Peritoneal Dialysis (ISPD) and the Sociedad Española de Nefrología guideline recommend the use of antifungal prophylaxis to prevent peritonitis in patients on PD who have been exposed to antibiotics. This recommendation is supported by a 1B level of evidence (LOE).1,19 This is based on data from a previous Cochrane meta-analysis that included various strategies for peritonitis prevention. However, the prior meta-analysis included a limited number of studies and pooled different antifungal agents under the same comparison.2 Therefore, we performed a meta-analysis evaluating the efficacy of fluconazole compared with no antifungal prophylaxis during episodes of peritonitis for the reduction of FP.

The initial search yielded 593 results, as shown in Fig. 1. After removing duplicate records and ineligible studies, we thoroughly reviewed 24 studies. Six studies were ultimately included, comprising 4515 episodes of peritonitis from one RCT23 and five cohort studies.24–28 Among these episodes, 1124 (24.8%) were administered fluconazole prophylaxis, while 3390 (75.1%) did not receive any antifungal prophylaxis. Study characteristics are detailed in Table 1. One study also had an arm with nystatin prophylaxis; however, episodes of peritonitis treated with nystatin were not included in this meta-analysis, as per inclusion/exclusion criteria.26 There was some variability in the duration of prophylaxis, doses, and duration of follow-up, as reported in Table 1.

Fig. 1.

PRISMA flow diagram of study screening and selection.

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Patients receiving fluconazole had a significantly lower incidence of FP (1.0%) as compared with those who did not receive prophylaxis (3.0%) during an episode of peritonitis with antibiotic exposure (OR 0.22; 95% CI 0.12–0.41; p<0.001; I2=0%; Fig. 2). In a subgroup analysis of studies using daily dose of fluconazole, there was also a significant reduction in the incidence of FP in those who received fluconazole (OR 0.31; 95% CI 0.14–0.69; p=0.004; I2=0%; Fig. 3). In a subanalysis restricted to observational studies, the incidence of FP was also significantly lower in fluconazole-treated individuals (OR 0.23; 95% CI 0.12–0.46; p<0.01; I2=0%; Fig. 4). Leave-one-out sensitivity analyses confirmed the consistency of results after removing each study sequentially and recalculating results. The OR remained statistically significant, ranging from 0.15 to 0.25, when each study was systematically withdrawn from the analysis.

Fig. 2.

The incidence of fungal peritonitis was a significantly lower in patients who received fluconazole prophylaxis.

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Fig. 3.

In a subgroup analysis of studies with daily dosing of fluconazole, the incidence of fungal peritonitis was significantly lower in the fluconazole group.

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Fig. 4.

In a subgroup analysis of observational studies, the incidence of fungal peritonitis was a significantly lower in the fluconazole group.

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The RCT was appraised using the Cochrane Collaboration's tool RoB-2, and it was considered to have a low risk of bias in all the domains accessed (Table S1). In this study, patients and investigators were unblinded. All five nonrandomized publications achieved ≥7 points in the NOS. A funnel plot analysis of the primary outcome showed a symmetric distribution of studies with similar weights and point estimates that converged toward the pooled treatment effect as weight increased, indicating no evidence of publication bias (Fig. 5).

Fig. 5.

Funnel plot analysis for the outcome of fungal peritonitis showed no evidence of publication bias.

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This systematic review and meta-analysis including 6 studies and 4515 episodes of peritonitis compared the efficacy of fluconazole prophylaxis with no prophylaxis in patients on PD upon antibiotic exposure for treatment of peritonitis. The main findings from the pooled analyses showed that fluconazole significantly reduced the risk of FP to one-third of that in the no prophylaxis group (1% vs. 3%, respectively). Moreover, this finding was robust and remained significant in leave-one-out sensitivity analyses and exploration of subgroups, including data restricted to daily fluconazole dosing and observational studies.

Most FP events are preceded by antibiotic exposure, either for PD-related infections, such as peritonitis, exit-site infection, or tunnel infection, or for other common clinical bacterial infections.29 A previous metanalysis of RCTs showed a significantly lower risk of fungal peritonitis when compared with placebo/no prophylaxis (RR 0.28; 95% CI 0.12–0.63).2 However, that prior meta-analysis included only two RCTs, with different antifungal regimens, specifically nystatin13 or fluconazole.23 Our meta-analysis builds on prior results by showing evidence of benefit from fluconazole specifically in this patient population.

Interestingly, observational studies were not included in the prior meta-analysis.24–28 This is notable because these studies had mixed and conflicting results for this intervention, creating uncertainty in the literature as to the benefit of fluconazole prophylaxis in the prevention of FP in patients with peritonitis. However, our results found a significant reduction in FP with fluconazole therapy even among the subgroup restricted to observational studies. The low heterogeneity (I2=0%) of this analysis indicates that the observational studies were consistent with each other, but likely underpowered to show a statistically significant benefit, which becomes evident in the pooled analysis of these studies (Fig. 4).

The ISPD 2022 expert consensus statement on peritonitis recommends anti-fungal prophylaxis whenever PD patients receive an antibiotic course, regardless of the indication for that antibiotic course (level 1B of evidence).1 This recommendation has no preference for either nystatin or fluconazole, with the latter being recommended at a dose of 200mg every 48h. The 2022 guideline from the Sociedad Española de Nefrología supports the use of fluconazole for prophylactic purposes in this scenario, but it does not provide information on the dosage for its use.19 The PDOPPS cohort conducted a prior study which revealed a noteworthy variance in antifungal prophylaxis utilization across various countries. Routine use of antifungal prophylaxis was observed in Australia and New Zealand, while Japan, Thailand, and the United Kingdom exhibited minimal usage.30 Although the doses and posology of fluconazole varied among the studies included in this meta-analysis, a subgroup of studies that used daily fluconazole also found a significant reduction in the incidence of FP in those who received prophylaxis with fluconazole.24,25,27 After conducting our study, we strongly suggest following the current guidelines and administering antifungal prophylaxis with fluconazole when a patient on peritoneal dialysis is being treated with antibiotics, with the dose of 200mg on alternate days being a well-established scheme for this purpose.

Our study has some limitations. First, most of the included studies were not randomized, which adds risk of bias related to confounding factors. However, the results of observational studies and the RCT were consistent with each other, with a low heterogeneity between studies (I2=0%). Also, sensitivity analyses confirmed consistency of study results after removing each individual study. Second, there was a variation in the dose of fluconazole prescribed by different studies. Third, the absence of patient-level data precluded evaluating additional outcomes, such as need to transition to hemodialysis, hospitalizations, and mortality. Whether fluconazole prophylaxis reduces these endpoints in PD-related peritonitis remains a gap in the literature. Finally, four studies used historical controls for the control group (no prophylaxis). Whether other concomitant interventions were distributed unevenly between patients treated with vs. without fluconazole prophylaxis is unclear.

In this meta-analysis including 4515 episodes of peritonitis in patients on PD, prophylaxis with fluconazole was associated with a significant reduction in the incidence of FP as compared with no antifungal prophylaxis. Given the potential implications of FP, the low cost of fluconazole, and its safety profile, this agent should be considered as standard-of-care in patients with PD-related peritonitis. Future research should evaluate the role of fluconazole prophylaxis in patients on PD who are treated with antibiotic therapy for other, non-peritonitis, bacterial infections.

The authors report no funding sources for this manuscript.

All authors report no relationships that could be construed as a conflict of interest. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.