Fungal Peritonitis + Voriconazole

Fungal peritonitis has been haunting us lately and the last few cases have involved Candida krusei, which is intrinsically resistant to fluconazole and has dose-dependent susceptibility with itraconazole.¹  Although I feel relatively comfortable with fluconazole and the echinocandins (kinda) for candidal peritonitis, I hadn’t had much experience with voriconazole in this setting.  (I was looking for an oral option for our patients, because the last thing we really needed was a catheter line associated blood stream infection.)  I looked at my trusty sources to see if there were any data about the penetration of voriconazole in peritoneal fluid (Lexicomp and Micromedex), but alas, there was no information available; however, given the wide distribution of the drug (4.6 L/kg), it suggests that there may be some distribution into peritoneal fluid.²

There is one pharmacokinetic study available that examined the distribution of voriconazole in peritoneal fluid.³  A total of five patients, who were undergoing peritoneal dialysis (PD), were in the study; a 200 mg single-dose of voriconazole was administered to each of the participants and serum and peritoneal dialysate concentrations of voriconazole were drawn.  It appears that voriconazole distributes into the peritoneal fluid, reaching maximum concentrations at the same time as the plasma.  Peritoneal clearance of voriconazole was minimal and the group suggested that dose adjustment was not needed for patients undergoing PD.

Pharmacokinetic Parameter	Study Group, Plasma	Study Group, Dialysate	Population (multiple 200 mg dose)
Cmax (mcg/mL)	0.55 ± 0.20	0.25 ± 0.09	2.08
Tmax­ ­(h)	2.4 ± 0.7	2.8 ± 0.5	1-2.8
AUC24h (mcg*h/mL)	5.8 ±1.3	--	19.86
t1/2 (h)	8.1 ± 1.3	--	6
Clearance/F (mL/min)	440 ± 77	3.7 ±0.6	--
Dialysate/Plasma concentration	--	0.66 ± 0.11	--

Although it appears that voriconazole distributes well into the peritoneal fluid (about 65% of the serum concentration), this was a single-dose study; multiple doses would be able to demonstrate if the distribution is consistent with time.  Also, only peak concentrations were obtained; although serum trough concentrations of voriconazole may be more predictive of efficacy, “trough” peritoneal concentrations may help determine if it is sufficient to treat fungal infections.  Lastly, this study was performed in uninfected patients undergoing peritoneal dialysis; it appears that general management of fungal peritonitis is to remove the PD catheter early and initiate hemodialysis in the patient in addition to antifungal therapy.⁴  The loss of volume in the peritoneal space as well as inflammation may increase the concentration of voriconazole in the fluid; however, further studies are needed to explore this avenue.   

Even though C. albicans is the primary culprit associated with fungal peritonitis, other Candida sp. and non-yeast species have been increasingly noted which has required the use of more broad-spectrum antifungals; although echinocandins have an FDA-labeled indication for disseminated candidiasis (including peritonitis), the role of other triazole antifungals have not been fully established for peritonitis.⁴  When searching the primary literature, there are a number of cases where voriconazole was used successfully to treat peritonitis associated with fungi, including Fusarium, non-albicans Candida, Aspergillus sp., C. bertholletiae (although it was found to be resistant to voriconazole), P. lilacinus (in combination with terbenifine), N. pseudofischeri, and O. gallopava.^4-11  While there are successes, it should be noted that mortality associated with severe fungal peritonitis is high (up to 50%), despite appropriate antifungal pharmacotherapy.^4,10

1.       Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503-35.  Available at: http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/Candidiasis.pdf

2.       VFEND® (voriconazole) Prescribing Information. Pfizer Inc. New York, NY. Updated November 2011.  Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=618

3.       Peng LW, Lien YH. Pharmacokinetics of single, oral-dose voriconazole in peritoneal dialysis patients. Am J Kidney Dis. 2005;45:162-6.

4.       Matuszkiewicz-Rowinska J. Update on fungal peritonitis and its treatment. Perit Dial Int. 2009;29:s161-5. PMID: 13270208

5.       Pimentel JD, Dreyer G, Lum GD. Peritonitis due to Cunninghamella bertholletiae in a patient undergoing continuous ambulatory peritoneal dialysis.  J Med Microbiol. 2006;55:115-8. PMID:16388039

6.       Chang BP, Sun PL, Huang FY, et al. Paecilomyces lilacinus peritonitis complicating peritoneal dialysis cured by oral voriconazole and terbinafine combination therapy. J Med Microbiol. 2008;57:1581-4. PMID: 19018033

7.       Ghebremedhin B, Bluemel A, Neumann KH, Koenig B, Koenig W. Peritonitis due to Neosartorya pseudofischeri in an elderly patient undergoing peritoneal dialysis successfully treated with voriconazole. J Med Microbiol. 2009;58:678-82. PMID: 19369533

8.       García-Martos P, Gil de Sola F, Marín P, García-Agudo L, García-Agudo R, Tejuca F, Calle L. Fungal peritonitis in ambulatory continuous peritoneal dialysis: description of 10 cases. Nefrologia. 2009;29:506-17. PMID: 19935994

9.       Wong JS, Schousboe MI, Metcalf SS, et al. Ochroconis gallopava peritonitis in a cardiac transplant patient on continuous ambulatory peritoneal dialysis. Transpl Infect Dis. 2010;12:455-8. PMID: 20534037

10.   Montravers P, Mira JP, Gangneux JP, Leroy O, Lortholary O. A multicentre study of antifungal strategies and outcome of Candida spp. peritonitis in intensive-care units. Clin Microbiol Infect. 2011;17:1061-7. PMID: 20825438

11.   Ulusoy S, Ozkan G, Tosun I, et al. Peritonitis due to Aspergillus nidulans and its effective treatment with voriconazole: the first case report. Perit Dial Int. 2011;31:212-3. PMID: 21427255