Treatment of candidal cholangitis with caspofungin therapy in a patient with a liver transplant: documentation of biliary excretion of caspofungin.

Sir—Cholangitis due to candidiasis is a rare infection in patients without predisposing factors, but it has become an increasingly recognized complication in patients who have received a liver transplant [1]. After liver transplantation is performed, strictures may develop in the extrahepatic biliary tract and lead to secondary sludge formation, which can predispose a patient to recurrent cholangitis. Cases of biliary candidiasis in patients with liver transplants are further complicated by the potential for infection with azole-resistant isolates [2] and the potential for pharmacologic interactions between immunosuppressants and other drugs [3]. Here, we present a case of recurrent polymicrobial cholangitis due to infection with Candida albicans in a patient with a liver transplant whose case was conservatively managed with percutaneous drainage and systemic antimicrobial therapy. A 54-year-old man who had received a liver transplant 4 years earlier presented with fever and chills. The patient had been diagnosed 6 months earlier with recurrent cholangitis after imaging studies demonstrated markedly dilated hepatic ducts with numerous filling defects. Alkaline phosphatase levels were 5–10 times the normal level, and cultures of bile samples obtained from the patient were positive for Enterococcus species, Streptococci milleri, anaerobes, and C. albicans. Prior to admission, the patient had undergone multiple failed endoscopic procedures to relieve the biliary obstruction, and his case had been managed with external biliary drainage and chronic suppressive antimicrobial therapy with levofloxacin, metronidazole, and intrabiliary infusions of amphotericin and fluconazole. Microbiological testing of bile samples obtained from the patient at admission again yielded multiple organisms, including yeasts. Management of the patient’s case was further complicated by elevated tacrolimus levels (which were 5 times greater than the target concentration) and chronic renal insufficiency. The principal pathogen involved in the patient’s infection was considered to be Candida species on the basis of a chronic candidal cast along the biliary tree. The patient was administered parenteral caspofungin therapy. The patient’s condition improved, and cultures of additional bile samples again showed the presence of fluconazole-susceptible C. albicans. Tacrolimus levels were adjusted, and the patient was discharged from the hospital and given a regimen of fluconazole in addition to combination amoxicillin-clavulanate for chronic suppressive antimicrobial therapy of polymicrobial cholangitis. Cultures of bile samples obtained from the patient 3 months after hospital discharge showed no growth of C. albicans. After allowing all antifungal agents to washout, biliary excretion of caspofungin was measured by determining caspofungin levels in both serum and bile samples. Serum and bile samples were obtained 1 h after a 70-mg infusion of caspofungin, and additional bile samples were obtained at 2 h and 3 h after the infusion. An agar well diffusion bioassay with C. albicans ATCC 24933 as the assay organism was used to quantify levels of caspofungin in bile and serum samples. Levels of caspofungin in bile samples were as follows: 0.8 mg/mL at 1 h, 1.0 mg/mL at 2 h, and 0.6 mg/mL at 3 h after the infusion. In the serum sample, obtained 1 h after the infusion, the caspofungin level was 3.1 mg/ mL. Bioassays have been successfully used to quantify antifungal agents and are comparable with high-performance liquid chromatography [4, 5]. The decision to use caspofungin therapy in treating our patient was influenced by several factors, including initial concerns over the recent emergence of azole resistance and possible drug interactions with fluconazole and tacrolimus. Finally, the presence of chronic renal insufficiency made treatment with systemic amphotericin a less attractive alternative. To our knowledge, this is the first report to document biliary caspofungin levels in samples obtained from a patient with a liver transplant. The level of caspofungin in the bile sample obtained 2 h after the infusion was ∼30% of the level of caspofungin in the serum sample. This is greater than the in vitro MIC50 of caspofungin for C. albicans (0.12 mg/mL) [6]. Whether this is clinically significant remains to be validated in clinical studies. However, caspofungin therapy may be considered for use in treating candidal biliary infection.