Primary Cutaneous Cryptococcosis Treated with Debridement and Fluconazole Monotherapy in an Immunosuppressed Patient: A Case Report and Review of the Literature

Abstract

Cryptococcus neoformans is an opportunistic yeast present in the environment. Practitioners are familiar with the presentation and management of the most common manifestation of cryptococcal infection, meningoencephalitis, in patients with AIDS or other conditions of immunocompromise. There is less awareness, however, of uncommon presentations where experience rather than evidence guides therapy. We report a case of primary cutaneous cryptococcosis (PCC) in a patient who had been immunosuppressed by chronic high-dose corticosteroid for the treatment of severe asthma. This case highlights the importance of early recognition of aggressive cellulitis that fails standard empiric antibiotic treatment in an immunocompromised patient. It also demonstrates successful treatment of PCC with a multispecialty approach including local debridement and fluconazole monotherapy.

Jennifer Wang 1 and Luther Bartelt 2 and Deborah Yu 3 and Anjali Joshi 4 and Bradley Weinbaum 4 and Tiffany Pierson 4 and Michael Patrizio 4 and Cirle A. Warren 2 and Molly A. Hughes 2 and Gerald Donowitz 2

Academic Editor:Ban H. Tan

1, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
2, Division of Infectious Diseases, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22903, USA
3, Department of Plastic and Maxillofacial Surgery, University of Virginia, Charlottesville, VA 22903, USA
4, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22903, USA

Received 22 October 2014; Accepted 15 January 2015; 2 February 2015

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Cryptococcus is an encapsulated yeast, classified into four serotypes based on immunologic reactivity of the capsular polysaccharides [1]. C. neoformans var. neoformans belongs to serotype D and is the most prevalent serotype in the USA [2]. It is present in the environment and has been isolated from pigeon droppings, decaying wood, fruits, and vegetables [3]. Patients with impaired cell-mediated immunity, such as those infected with HIV, solid-organ transplant recipients, and those on chronic corticosteroid therapy, are most vulnerable to cryptococcal infections [4]. Cryptococcus can present with a variety of skin and soft tissue manifestations including acneiform lesions, purpura, vesicles, nodules, abscesses, ulcers, granulomas, pustules, draining sinuses, and cellulitis. Most skin and soft tissue manifestations occur in the setting of disseminated disease, which is apparent in 10-15% of patients with systemic cryptococcosis [5]. Primary cutaneous infection as a result of direct local inoculation, however, is rare.

2. Case

A 56-year-old male carpenter with a past medical history of hypertension, uncontrolled diabetes mellitus, and severe asthma had been treated with prolonged courses of oral prednisone up to 100 milligrams (mg) daily for several months and at least 50 mg daily for the past 7 consecutive months. He presented to the emergency department (ED) with a rapidly enlarging plaque on his right forearm. Five days prior to admission, the patient was moving firewood in his backyard when he noticed a pustule on his volar right forearm. The pustule became erythematous and indurated throughout the next day, and the patient presented to a walk-in clinic where clindamycin was prescribed. Despite this therapy, the erythema continued to expand, and the forearm became painful. The patient represented to his primary care doctor who added linezolid to his antibiotic regimen. Of note, the patient was intolerant to penicillin, sulfa drugs, erythromycin, ciprofloxacin, doxycycline, and metronidazole. Despite the change in antibiotic therapy, the erythema continued to expand prompting a visit to the ED (Figure 1(a)). He denied fever, night sweats, malaise, or other systemic symptoms. A pustule was noted on exam with minimal fluid expressed. A bedside ultrasound was performed that did not reveal a subcutaneous abscess. The patient was sent home with the instruction to continue clindamycin and linezolid. The patient noticed worsening of his rash with purulent drainage and returned to the ED the next day. He was found to be afebrile with a pulse of 110 beats per minute, a respiratory rate of 20 breaths per minute, and blood pressure of 141/85 mmHg. Physical examination revealed a single 7 cm painful bulla with surrounding erythema that extended proximal to the elbow (Figure 1(b)). Lymphadenopathy was absent. Laboratory testing was significant for a leukocytosis of 17,500 cells/μ L (83.6% neutrophils, 1.8% band, and 1.8% atypical lymphocyte) and a hemoglobin A1c of 8.8%.

Primary cutaneous cryptococcosis of the right forearm. Progressive skin changes documented at the initial visit to the emergency department on the third day of symptoms (a), during hospitalization (b-c), and at postdischarge clinic follow-up (d). White arrows denote the outlines of the region of erythema marked on each respective day prior to presentation (i.e., Days 1-3). Fluconazole was initiated along with two interrupted doses of amphotericin on Day 3. Broad-spectrum antibacterial therapy with vancomycin and piperacillin-tazobactam (Day 5-Day 7), ampicillin-sulbactam (Day 8-Day 10), and amoxicillin-clavulanate (Day 11-Day 17) was also administered. (e) Wound improvement seen on one-week follow-up in clinic. The gram stain (f) from fluid expressed on Day 5 demonstrated abundant variably sized encapsulated spherical yeast forms ( [figure omitted; refer to PDF] ) that were identified as C. neoformans on blood agar.

(a) [figure omitted; refer to PDF]

(b) [figure omitted; refer to PDF]

(c) [figure omitted; refer to PDF]

(d) [figure omitted; refer to PDF]

(e) [figure omitted; refer to PDF]

(f) [figure omitted; refer to PDF]

The antibiotics were changed to vancomycin and piperacillin/tazobactam, and the patient was admitted to the general medicine service. Plastic surgery was consulted. The epidermis of the bulla was carefully removed, draining a copious amount of purulent material with an unusual watery consistency. The expressed fluid gram stain revealed yeast forms and no bacteria (Figure 1(f)). Culture of the purulent material grew only Cryptococcus neoformans . Serological investigation for HIV was negative, and the patient's risk factor for immunosuppression was identified to be the chronic prednisone use. The patient was subsequently initiated on intravenous liposomal amphotericin B at 3 mg/kg/day for potential disseminated cryptococcal infection. However, he developed severe chest pain during liposomal amphotericin B administration that resolved after termination of the infusion. A second trial of liposomal amphotericin B was also terminated early due to recurrence of chest pain. In total, he received less than 300 mg (one dose) of liposomal amphotericin B. A decision was made to initiate oral fluconazole (12 mg/kg/day), which he tolerated well.

Workup for disseminated disease and meningeal involvement including serum cryptococcal antigen, blood culture, urine culture, computed tomography scan of the head, chest, abdomen, and pelvis, and cerebral spinal fluid (CSF) analysis for cryptococcal antigen all returned negative. The fluconazole dose was decreased to 8 mg/kg/day. Serial liver function test and QTc were monitored. In addition to systemic therapy for Cryptococcus , daily dressing changes with a Pluronic antimicrobial cream manufactured at our institution (Kolliphor P 188 50%, polymyxin 10,000 units/gram, nystatin 4,000 units/gram, and nitrofurantoin 0.3% within a Pluronic F68 carrier) were performed for topical preemptive antibacterial and antifungal coverage during wound healing. The patient continued to feel well with improvement in his arm tenderness. However, the surrounding erythema persisted with worsening leukocytosis that peaked at 22,000 cells/μ L, raising concern for a deeper infection that was not apparent on exam. An MRI of the arm was consistent with the clinical exam of superficial cellulitis with no evidence of abscess or necrotizing fasciitis. Although initial gram stain and cultures were negative, in the context of potential environmental wound contamination while carrying wood and possible inhibition of bacterial culture growth due to concurrent antibacterial therapy, the worsening leukocytosis raised concern for a superimposed bacterial cellulitis in this immunocompromised host, and antibacterial therapy was continued with ampicillin/sulbactam that was later changed to amoxicillin/clavulanate upon discharge.

The patient's wound improved remarkably over the course of his hospital stay with near resolution of the surrounding erythema and edema (Figure 1(d)). He was sent home on oral fluconazole 8 mg/kg/day and a total of 14-day course amoxicillin/clavulanate. His prednisone was gradually weaned down to 10 mg/day; however, he had to increase the dosage to 30 mg/day due to asthma exacerbation after 2 months. At a one-week follow-up visit, his wound showed great improvement (Figure 1(e)). Within 3 months of fluconazole therapy, his wound showed complete healing. He tolerated fluconazole well and was continued on an 8 mg/kg/day regimen for an additional 3 months for a total duration of 6 months. He was last seen near completion of his fluconazole therapy (more than 6 months from symptom onset) without signs of relapse (Figure 2). Throughout this time he never experienced evidence of disseminated disease or meningeal involvement, and the serum cryptococcal antigen remained negative at the last clinic visit.

Figure 2: Healed right forearm lesion 6 months after symptom onset and at the conclusion of fluconazole therapy. The patient was seen in clinic 6 months after symptom onset and towards the end of the planned 6-month course of fluconazole therapy. Skin pigmentation changes remained, but the ulcer was entirely healed and there was no pain or evidence of subcutaneous involvement. Follow-up clinical evaluation was notable for the absence of systemic symptoms and serial serum cryptococcal antigen remained negative.

[figure omitted; refer to PDF]

3. Discussion

Primary cutaneous cryptococcosis (PCC) is defined as identification of Cryptococcus neoformans in a skin lesion without evidence of simultaneous disseminated disease [35]. Most cases of PCC have been reported from Europe, Japan, and South America [6, 7, 9-12, 16-21, 30, 31, 35]. A nationwide survey conducted by the French Cryptococcosis Study Group identified 28 cases of PCC of the 1,974 total cryptococcosis cases reported to the National Reference Center for Mycoses from 1985 to 2000. Of the 28 patients with PCC, 50% were immunocompetent and only 11% had HIV infection, suggesting that PCC can develop regardless of immune status. Five patients were receiving long-term corticosteroid therapy [35]. Neuville et al. also observed that the skin lesions of PCC usually presented as solitary lesions resembling cellulitis, ulceration, or whitlow and were located on unclothed areas. In contrast, lesions from disseminated disease usually presented as scattered umbilicated papules resembling molluscum contagiosum [35]. Although the distinction is nonspecific and should not be used as a diagnostic tool, it is interesting to note that our patient's presentation is similar to many other patients with PCC. In addition, the French Cryptococcosis Study Group also highlighted that the spectrum of skin manifestations due to either disseminated or primary cutaneous cryptococcosis overlaps with other skin infections, necessitating biopsy for histopathological and microbiological diagnosis [35].

The treatment of choice for C. neoformans infection is determined by anatomic site of involvement and the host's immune status. While recent randomized-control trials are helping to clarify the evidence-based treatment of cryptococcal meningitis in patients with HIV/AIDS [36], management for unusual manifestations of disease in non-HIV-infected populations remains primarily guided by expert opinion. The Infectious Disease Society of America (IDSA) recommendation for patients with noncentral nervous system (CNS), nondisseminated Cryptococcus is oral azole therapy for 6-12 months (B-III recommendation) [37]. Furthermore, it is recommended that non-HIV-infected, nontransplant recipients be treated in the same fashion as those with CNS disease which consists of induction therapy with amphotericin B (or high-dose fluconazole if intolerant to amphotericin) plus flucytosine followed by fluconazole maintenance therapy [37]. Consensus on the duration of induction therapy in this population, however, is lacking as most data come from cohort studies of HIV-infected or organ transplant recipients [38]. The absence of well-controlled randomized trials for PCC or patients on chronic corticosteroids is a limitation in specific treatment guidelines. In most cases, disease remains limited to the skin, but there are reports of secondary systemic dissemination [39], including the CNS, and persistent antigenemia [40]. The patient in our case followed the typical pattern of uncomplicated PCC, manifesting neither systemic symptoms nor a positive serum cryptococcal antigen test.

To facilitate management in this case, we performed a literature search in PubMed using the search terms "cutaneous, Cryptococcus , and primary." After excluding cases of documented or probable disseminated disease, we identified 43 reports in the English language from 1981 through 2014 (Table 1), 23 of which were reported over the last four years, although it is unclear if this is due to a true increase in PCC incidence or increased awareness among physicians, and thus reporting bias. Our search yielded a broad geographic distribution of reported cases among a wide age range in both immunocompetent and immunocompromised hosts. Compared with cases reported in immunocompromised hosts (44.1%), all of which were caused by C. neoformans , immunocompetent hosts had fewer reports of necrotic lesions and more commonly had infection with the emerging C. gattii species (23.3%). Interestingly, C. gattii was reported predominantly in Australia, Singapore, and Brazil, consistent with known restricted geographic distribution of C. gattii [41]. Other than three deaths, at least two of which were due to other causes, prognosis for PCC in these reports was overwhelmingly favorable as all patients were cured after as few as two weeks (in combination with surgical debridement) to up to ten months of antifungal therapy. In addition, fluconazole monotherapy has been increasingly reported in the recent medical literature, utilized in 17 out of 21 cases since 2011 and 5 out of 22 cases prior to 2011. For cases reported by the French Cryptococcosis Study Group, fluconazole was prescribed to 20 patients regardless of immune status for a median therapy duration of 32 days. Of these patients, 75% were definitively cured and 15% were attenuated [35].

Table 1: Clinical characteristics of cases reports of PCC in English language literature searched on PubMed.

Citation

Year

Age/gender

Region of origin

Immune status

Occupation/exposure

Site of lesion

Type of lesion

Species

Medical treatment

Duration of therapy

Topical care

Outcome

[6]

2014

68/male (M)

Southeast Brazil

Immunocompetent

Bus driver

Forearm

Nodule

Cryptococcus gattii

Fluconazole (200 mg/d)

40 days

None documented

Cured

[7]

2013

8/female (F)

Spain (child from Mongolia)

Immunocompetent

Not reported

Forearm

Macule

C. laurentii

Fluconazole (3 mg/kg/d)

2 weeks

None documented

Cured

[8]

2013

87/M

Rural area of Taiwan

Immunocompetent

Not reported

Arm

Indurated papules and plaques

C. neoformans

Fluconazole 400 mg/d for 2 weeks followed by 200 mg/d for 2 weeks

1 month

None documented

Cured

[9]

2012

66/M

Rural Central America

Immunocompetent

Not reported

Penis

Nodule

No fungal culture

Itraconazole (400 mg/d)

3 months

None documented

Cured

[10]

2012

89/M

Brazil

Immunocompetent

Collects firewood

Forearm

Ulceration

C. gattii

Itraconazole (400 mg/d)

3 months

None documented

Cured

[11]

2012

58/M

Greece

Immunocompetent

Poultry farmer

Hand

Ulceration

C. neoformans

Fluconazole (200 mg/d)

2 weeks

Surgical debridement

Cured

[12]

2012

Case series of 11 patients, mean age 71.2/9M2F

Brazil

5 immunocompetent, 6 on corticosteroid therapy

5 reported trauma or exposure to contaminated sources

Forearm

Circumscribed lesions ranged from an infiltrative plaque to a solid tumor mass

3 C. neoformans 4 C. gattii 4 C. spp.

Fluconazole (150 mg/d-400 mg/d)

1-6 months

None documented

9 cured,1 unrelated death,1 marked improvement

[13]

2012

55/M

Not reported

Renal transplant recipient

Not reported

Thigh

Umbilicated

C. laurentii

Amphotericin B + flucytosine

7 days (patient deceased)

None documented

Local lesion improving; however, patient deceased due to other causes

[14]

2011

67/M

Not reported

Immunocompetent

Poultry farmer

Forearm

Nodule

C. neoformans

Fluconazole (450 mg/d)

40 days

None documented

Cured

[15]

2011

37/M

Singapore

Immunocompetent

Forklift driver

Scalp

Nodule

C. gattii

Not reported

[16]

2011

75/M

Brazil

Immunocompetent

Handles Eucalyptus logs

Forearm

Nodule

C. gattii

Fluconazole

5 months

None documented

Cured

[17]

2010

60/M

Slovenia

Renal transplant recipient

Cat scratch

Hand

Necrosis

C. neoformans

Amphotericin B + fluconazole

3 weeks (amp. + fluc.) + 15 weeks (fluc.)

Surgical debridement, amputation of the arm

Healed

[18]

2010

58/M

Italy

Immunocompetent

Collects firewood

Hand

Nodule

C. neoformans

Itraconazole (200 mg/d)

4 months

None documented

Cured

[19]

2005

43/M

Saudi Arabia

Immunocompetent

Driver for a furniture company

Forehead

Nodule

C. neoformans

Not reported

[20]

2005

26/M

Japan

Long-term prednisolone therapy for minimal change nephrotic syndrome

Not reported

Leg

Nodule

C. neoformans

Intravenous fluconazole

3 months

None documented

Cured

[21]

2005

73/M

Spain

Liver transplant recipient

Insect bite in Costa Rica 2 days prior to presentation

Arm

Intense edema and suppuration

C. neoformans

Amphotericin B + fluconazole (100 mg/d)

15 days (amp. + fluc.) + 3 months (fluc.)

Surgical debridement and reconstruction

Cured

[22]

2004

57/M

Not reported

Lung transplant recipient

Gardener

Leg

Ulceration

C. neoformans

Fluconazole (200 mg/d)

2 months

None documented

Cured

[23]

2004

81/M

Not reported

Immunocompetent

Cattle farmer

Forearm

Pustules

C. neoformans

Fluconazole (400 mg/d)

2 months

None documented

Cured

[4]

2003

41/M

Southern Wisconsin

Immunocompetent

Puncture wound from hay bale wire in a barn

Hand

Erythematous nodule

C. neoformans

Fluconazole (400 mg/d)

8 weeks

Surgical excision

Cured

[24]

2002

46/M

Not reported

Immunocompetent

Not reported

Finger

Cellulitis

C. neoformans

Itraconazole (200 mg/d)

10 months

Surgical excision

Cured

[25]

2002

65/M

Brazil

Immunocompetent

Not reported

Forearm

Ulceration

C. gattii

Fluconazole (150 mg/d)

45 days

None documented

Cured

[26]

2000

36/F

Not reported

Liver transplant recipient for Budd-Chiari syndrome

Not reported

Leg

Ulceration

C. neoformans

Fluconazole (200 mg/d)

3 months

None documented

Cured

[27]

1997

75/M

Australia

Immunocompetent

Orchid grower

Forearm

Tender, erythema

C. gattii

Amphotericin B + 5-flucytosine Itraconazole (200 mg/d)

3 weeks3 months

Normal saline and miconazole cream applied once daily

Cured

[28]

1997

77/M

Not reported

Long-term steroid treatment

Chronic obstructive pulmonary disease

Hand

Ulceration

C. neoformans

Amphotericin B + fluconazole

12 days + 6 weeks

None documented

Cured

[29]

1996

62/F

Not reported

Long-term steroid treatment

Sarcoidosis

Forearm

Bullous

C. neoformans

Itraconazole (400 mg/d)

Not reported

None documented

Cured

[30]

1995

73/F

Japan

Immunocompetent

Not reported

Cheeks

Ulceration

C. neoformans

No antifungal therapy

Not reported

Cured

[5]

1992

52/M

Not reported

Renal transplant recipient

Undergoing surgery for below knee amputation

Leg stump

Necrosis

C. neoformans

Amphotericin B

Patient deceased

Surgical debridement

Patient died of multisystem organ failure

[5]

1992

55/M

Not reported

Renal transplant recipient

Polycystic kidney disease

Forearm

Nodule

C. neoformans

Amphotericin B + 5-fluorocytosine

Not reported

None documented

Cured

[5]

1992

27/F

Not reported

Severe lymphopenia

Hereditary lymphangiectasia

Legs, lower abdomen, and groin

Necrosis

C. neoformans

Amphotericin B + 5-fluorocytosine

Not reported

None documented

Cured

[31]

1990

63/F

Japan

Immunocompetent

Housewife

Earlobe

Erosion

C. neoformans

Itraconazole (100 mg/d)

13 weeks

Cured

[32]

1986

7/M

Not reported

Nonspecific failure in cellular immunity

Not reported

Postauricular

Not reported

C. neoformans

No antifungal therapy

Spontaneous healing

[33]

1985

53/M

Not reported

Long-term corticosteroid therapy for asthma

Pigeon fancier

Wrist

Mass

C. neoformans

Ketoconazole

3 months

Cured

[34]

1981

81/M

Not reported

Immunocompetent

Not reported

Forearm

-

-

IV and oral miconazole

25 days

None documented

Cured

Our patient had a favorable response to fluconazole monotherapy, amoxicillin-clavulanate, and topical wound care after only a few days of treatment. Regarding the use and role of antibacterial therapy in this case, the initial presentation suggested a worsening cellulitis despite adequate coverage for typical gram-positive bacterial causes of cellulitis (Streptococcus pyogenes and Staphylococcus aureus ) initially with clindamycin and then with linezolid to treat possible methicillin-resistant S. aureus (MRSA). Failure to respond to these first-line empiric agents suggested either inadequate spectrum of antimicrobial activity due to an atypical or polymicrobial infection, presence or development of antimicrobial resistance in the pathogen, or need for drainage of an abscess not penetrated by the antimicrobial agent. Clinical worsening in this immunocompromised host with possible environmental inoculation while carrying wood thus prompted modifying coverage and bedside debridement to avert the rare, but potentially life-threatening circumstance of PCC with superimposed bacterial infection [42]. Piperacillin/tazobactam was initiated to cover gram-negative bacteria including Pseudomonas aeruginosa and anaerobes, and linezolid was changed to vancomycin for possible ongoing MRSA and other gram-positive activity. Either gram-negative organisms or a resistant S. aureus (including rare cases of linezolid-resistant S. aureus ) from the purulent drainage would have been isolated in culture or visualized on gram stain. Fastidious pathogens and anaerobes, though difficult to isolate in the laboratory, would typically occur in the context of polymicrobial infection, and even if not isolated, evidence of bacteria would be expected on gram stain. The complete absence of microbiologic data to support a bacterial process in this case suggests that the antibacterials did not play a role in the healing process.

As this case illustrates, however, the overlapping manifestations between PCC and complicated bacterial skin and soft tissue infections may necessitate an early multidisciplinary approach involving infectious diseases and surgery consultants. Indeed, as our patient's treatment was complicated by intolerance to liposomal amphotericin B and a potential superimposed bacterial infection, we cannot dismiss that early debridement facilitated more rapid clinical improvement. Although data supporting the role of surgical debridement in the management of PCC is lacking [43], the use of this strategy as an augmentation to systemic antifungal therapy may be a consideration for patients in whom early drug intolerance is noted, or concerns of potential hepatotoxicity, QTc prolongation, or drug-drug interactions resultant from long-term azole therapy are substantial. Similarly, topical Pluronic antimicrobial cream for postdebridement wound healing is commonly used in our facility [44, 45], but the literature guiding its specific use in PCC is lacking. While the nystatin contained in Pluronic could be active against Cryptococcus , it should be emphasized that treatment of any cryptococcal infection should include systemic therapy, and the role of post-debridement topical therapy in this case was to facilitate wound healing in a patient taking chronic corticosteroids rather than for any direct anti-cryptococcal effect.

In summary, our case illustrates that prompt microbiologic testing and thorough evaluations for opportunistic atypical infections such as PCC should be considered in diabetic and immunocompromised patients who present with cellulitis that fails to respond to empiric antibiotic therapy. This case also demonstrates successful treatment of PCC with extended fluconazole monotherapy and local wound care. Clinicians should remain alert to the possibility of fungal skin soft tissue infections or coexistence of both bacterial and fungal infections. Although it is rare, coinfection of C. neoformans with bacterial infection can be devastating, particularly in immunocompromised hosts, if the diagnosis is delayed [42]. Finally, this case serves as a reminder to educate immunosuppressed patients about occupational risks from environmental exposures including unprotected handling of pigeons, decaying wood, and soil.

Abbreviations

CSF:

Cerebrospinal fluid

PCC:

Primary cutaneous cryptococcosis.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

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