Catheter-related fungemia caused by Candida intermedia

Introduction 

In recent decades, invasive candidiasis has emerged as an important nosocomial infection.1 Among the more than 200 Candida species, only a few can cause human diseases.2 Candida intermedia is rarely reported as a human pathogen. We report two patients, hospitalized in the same ward, who had catheter-related C. intermedia fungemia within a 20-day interval.

Case reports 

A 99-year-old man (patient A) with gastric adenocarcinoma had received a total gastrectomy with Billroth's II anastomosis in January 2007. He was admitted to the hospital in early 2008 because of post-operative adhesion ileus. A broad-spectrum cephalosporin was given for fever and a suspected intra-abdominal infection early in his hospital stay. Due to prolonged poor oral intake, a Port-A-Cath (Smiths Industries Medical Systems (SIMS), Deltec, Inc., St. Paul, MN, USA) was inserted for parenteral nutrition. After the administration of parenteral nutrition for two weeks, an episode of fever and leukocytosis with left-shift developed. He had no respiratory or urethral symptoms. A chest radiograph showed no pneumonia patch, and urinalysis was normal. Blood cultures from the Port-A-Cath (isolate 1) and peripheral vein (isolate 2) were both positive for yeasts. The species was identified as C. intermedia. The Port-A-Cath was removed and culture of the removed catheter tip was also positive for C. intermedia. Intravenous fluconazole (400mg every day) was administered. His fever subsided, his white blood cell (WBC) count decreased to the normal range, and C. intermedia fungemia was eradicated after fluconazole treatment for two weeks.

A 37-year-old man (patient B) had a history of megacolon and had received surgical intervention at birth. Short bowel syndrome developed after surgery and thereafter he received long-term parenteral nutrition via an implantable central venous catheter. Over the past decades, he had undergone replacement of the central venous catheter several times due to catheter-related infections. One month before this event, he had experienced an episode of catheter-related infection with Escherichia coli bacteremia, which was successfully treated with an advanced-generation cephem. In late March 2008, he had a high fever with chills. No other specific symptoms or physical signs were noted. His WBC count was within the normal range, but marked left-shift was noted. A chest radiograph was normal. Blood cultures from a peripheral vein (isolate 3) and a central venous catheter (isolate 4) both yielded yeasts. Catheter-related candidemia was highly suspected. The central venous catheter was replaced, but culture of the removed catheter tip was not performed. Intravenous fluconazole (200mg every day) was administered. The two isolates in blood cultures were identified as C. intermedia. His fever subsided and follow-up blood cultures were negative.

Microbiology 

The times to positivity of peripheral venous and central venous blood cultures for the two patients were 10h and 12h, respectively, compatible with a diagnosis of catheter-related fungemia. The four isolates grew well on CHROMOAgar (BBL Microbiology Systems, Cockeysville, MD, USA) with purple colonies at 37°C for 48hours of incubation. On cornmeal-Tween 80 agar (BBL Microbiology Systems), blastoconidia, singly or in small clusters, with pseudohyphae were seen at 37°C for 48h. These isolates were identified as C. intermedia (bionumber 4156155675343371; probability, 97%; confidence, excellent identification) by Vitek 2 Yeast cards (bioMerieux Vitek, St. Louis, MO, USA). The isolates were further identified by an oligonucleotide array assay as previously described3 and partial sequencing of rRNA genes.4 The positive oligonucleotide array result and high percentage of identity in the rRNA loci 5.8S–28S (98–100%), 18S–28S (100%), and 28S (100%) confirmed the identification of C. intermedia. Antifungal susceptibility testing of the isolates was performed using the broth microdilution method, and the results were interpreted according to the guidelines of the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards).5 Two reference strains, Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258, were used for quality control. The minimum inhibitory concentrations (MICs) of the two isolates were the same, with 1μg/ml for fluconazole, 4μg/ml for 5-fluorocytosine, 0.06μg/ml for voriconazole, 0.125μg/ml for itraconazole, and 0.5μg/ml for amphotericin B.

Because the two C. intermedia fungemias developed in the same ward over a short interval (3 weeks), molecular typing was performed to rule out the possibility of nosocomial infection. Random amplified polymorphic DNA (RAPD) patterns of the three isolates (isolates 1–3) were generated by arbitrarily primed PCR (APPCR) as described previously.6 Four oligonucleotide primers were used: ERIC1 (5′-GTGAATCCCCAGGAGCTTACAT-3′), M13 (5′-TTATGTAAAACGACGGCCAGT-3′), OPA3 (5′-AGTCAGCCAC-3′), and OPH15 (5′-AATGGCGCAG-3′) were purchased from Operon Technologies, Inc. (Alameda, CA, USA). The RAPD patterns of the two isolates were different indicating that they belonged to different strains (Figure 1).

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Figure 1. Random amplified polymorphic DNA (RAPD) patterns of three Candida intermedia isolates generated by arbitrarily primed PCR with four primers: upper panels, OPA3 and OPH15; lower panels, ERIC1 and M13. M, 1-kb ladder marker (GIBCO BRL Products, Gaithersburg, MD, USA); lanes 1 and 2, two isolates from patient A; lane 3, one isolate from patient B; lanes 4–7, isolates of Candida albicans, Candida glabrata, Candida tropicalis, and Candida parapsilosis, respectively, from four patients with candidemia.

Discussion 

Candida species are an important cause of nosocomial bloodstream infections and are associated with high mortality.1, 7 Although more than 200 species of Candida have been identified, only a few cause diseases in humans.2 The great majority of Candida infection is caused by Candida albicans. However, there is some evidence that non-albicans infections may be increasing.8, 9 C. intermedia, a rare non-albicans Candida, is known to be part of the microflora on the surface of cheese and in the human oropharyngeal cavity,10, 11, 12 and has seldom been linked to human disease. This organism has been reported in a case series of fungemia, but no detailed clinical and microbiological information has been provided.13 To our knowledge, this is the first case report to describe clinical features and microbiological characteristics of C. intermedia fungemia in the English literature. The reasons why these two reported patients were susceptible to C. intermedia infection are not clear. The chronic malnutrition status and long-term use of parenteral nutrition or intravenous catheter might have contributed to their susceptibility to C. intermedia infection.

Many risk factors, including prior antibiotic therapy, use of a central venous catheter, abdominal surgery, parenteral nutrition, malignancy, and renal failure requiring hemodialysis, are considered to be associated with candidemia.1, 14 In the two reported cases, the C. intermedia fungemia was associated with central venous catheters and the use of parenteral nutrition. In addition, the two reported patients had also received broad-spectrum antibiotics within 30 days before the onset of fungemia. Some Candida species, such as C. parapsilosis, have been considered to have a strong association with catheter-related infections.15, 16 C. intermedia may be another Candida species that tends to cause catheter-related infections. However, more reports are needed to support this presumption.

The clinical presentation of the C. intermedia fungemia in the two cases, including fever, leukocytosis or left-shift differential count, was non-specific. The disease course was relatively benign and no shock or irreversible end-organ damage was noted. Even in an immunocompromised host, such as the elderly patient with advanced cancer in the first case (patient A), the C. intermedia fungemia was cured by catheter removal and two weeks of fluconazole therapy. Fluconazole resistance is one of the great concerns in treating patients with fungemia, especially where prompt susceptibility testing is not available. In this report, the C. intermedia isolates were susceptible to the five tested antifungal agents, and fluconazole had potent in vitro activity against the isolates. 5, 17, 18

In summary, this is the first case report of human bloodstream infections caused by C. intermedia. It raises the possibility that C. intermedia may be a causative pathogen of catheter-related fungemia in patients with long-term parenteral nutrition or intravenous catheters over a long period.

Conflict of interest: No conflict of interest to declare.