Summary to Emerging Fungal Infections In Solid Organ Transplant Recipients

Publication Date: April 1, 2019
Last Updated: March 14, 2022

Recommendations

Treatment

1. Therapy with an agent that has proven activity against the fungus should be administered as early as possible.

(Low, Strong)
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2. Immunosuppression should be reduced when clinically feasible. To date, immune reconstitution inflammatory syndrome has not been described with emerging or rare fungal pathogens.

(Low, Strong)
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3. Surgical debridement of the affected areas should be performed whenever feasible and repeated as needed.

(Low, Strong)
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4. Antifungal therapy should be adjusted based on susceptibility testing at a reference laboratory. Although clinically validated antifungal susceptibility breakpoints are lacking, it is reasonable for therapy to be guided by general antifungal susceptibility patterns.

(Low, Weak)
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5. Clinicians should closely monitor for renal toxicity with AmB products. If using such agents, treatment should generally be with a lipid formulation of AmB (LF‐AmB; ie, liposomal or lipid complex formulations) as these have less toxicity.

(Low, Strong)
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6. Clinicians should closely monitor for Q‐T interval prolongation, drug interactions, hepatotoxicity, and neuropsychiatric side effects with azoles.

(, )
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7. Therapeutic drug monitoring of voriconazole should be considered to guide dose adjustments, especially in patients receiving higher doses or corticosteroids, although data for emerging fungal infections are lacking. Target voriconazole trough levels between 1.5‐4.5 mcg/mL are associated with the optimal balance of maximizing efficacy and minimizing toxicity. Based on very limited data in the prophylactic, setting the target posaconazole trough levels should be at least 0.7 mcg/mL. Routine monitoring of posaconazole levels may be unnecessary. We recommend checking serum trough levels when using the liquid formulation, in special populations (eg, patients with very high BMI, questionable drug absorption and those with cystic fibrosis) and when clinical response is suboptimal. It is unclear whether therapeutic drug levels are useful for isavuconazole.

(, )
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8. Adjuvant therapy with interferon‐gamma and/or granulocyte-macrophage colony stimulating factor may be considered with caution in cases refractory to standard antifungal therapy.

(Very Low, Weak)
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Mucormycetes

Posaconazole may be considered for maintenance therapy once clinical stability has been achieved.

(Low, Weak)
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Isavuconazole is a reasonable second‐line option for mucormycosis.

(Moderate, Weak)
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TABLE 2: Recommended treatment of emerging and rare fungal infections in solid organ transplant recipients

Having trouble viewing table?

Fungal pathogen
Initial therapy
Alternative therapy
Mucormycetes Surgical excision/debridement is recommended for all infections outside of lungs
Induction therapy:
  • LF‐AmB is the treatment of choice (Strong, Moderate)
  • Combination of an echinocandin + LF‐AmB may be considered based on animal studies and retrospective reports (Weak, Very Low)
  • AmB deoxycholate was historically the drug of choice but is associated with substantial nephrotoxicity and generally avoided in the current era (Strong, Moderate)
Maintenance therapy:
  • Posaconazole or isavuconazoniuma sulfate (Weak, Moderate)
 Induction therapy:
  • Posaconazole or isavuconazonium sulfatea for patients intolerant to or failing LF‐AmB (Weak, moderate)
  • Combination of posaconazole + LF‐AmB may be considered in refractory infections, but data are conflicting (Weak, Very Low)
Maintenance therapy:
  • LF‐AmB in patients who are clinically unstable or unable to tolerate oral intake
Fusarium Surgical excision or debridement is recommended whenever feasible
  • Voriconazole (Weak, Low)
  • Combination therapy (LF‐AmB + voriconazoleb) may be considered pending final identification and susceptibility data. Goal is to provide coverage for organisms resistant to one or the other of these agents. (Weak, Low)
  • Posaconazole (Weak, Low)
  • Fusarium solani and Fusarium verticilloides may be resistant to voriconazole and require LF‐AmB (Weak, Low)
Scedosporium Surgical excision or debridement is recommended whenever feasible
  • Voriconazoleb (Weak, Low)
  • Combination of an echinocandin and voriconazole may be considered (Weak, Very Low)
Lomentospora prolificans Surgical debridement should be considered primary therapy (resistant to virtually all of the available antifungal agents)
  • Echinocandin + LF‐AmBc or voriconazole (Weak, Low)
  • Voriconazole + terbinafined (Weak, Low)
Purpureocillium Surgical excision or debridement is recommended whenever feasible and may be sufficient for isolated cutaneous disease
  • Voriconazole or posaconazole for more extensive disease (Weak, Low)
Trichoderma Surgical excision or debridement is recommended whenever feasible
  • Antifungal susceptibility is necessary to guide therapy
  • Combination therapy LF‐AmB + voriconazole or posaconazole may be considered pending susceptibility data (Weak, Low)
Scopulariopsis and
Microascus		 Surgical excision or debridement is recommended whenever feasible
  • Antifungal susceptibility is necessary to guide therapy
  • Combination therapeutic options based on in vitro synergy data (Weak, Low)
o Terbinafine + voriconazole or posaconazole
o Caspofungin + voriconazole or posaconazole
Acremonium Surgical excision or debridement is recommended
Phaeohyphomycosis
Exophiala		 Surgical excision or debridement is recommended whenever feasible and may be sufficient for isolated cutaneous disease
  • Antifungal susceptibility is necessary to guide therapy
  • Voriconazole, posaconazole, or itraconazole are first‐line agents (Weak, Low)
  • Echinocandins may be considered based on in vitro data
  • Potential combination therapeutic options based on in vitro synergy data
  • LF‐AmB + flucytosine (Weak, Very Low)
  • Itraconazole + flucytosine (Weak, Very Low)
Chromoblastomycosis
  • Surgical excision or debridement is recommended whenever feasible and may be sufficient for isolated cutaneous disease
  • Antifungal susceptibility is necessary to guide therapy
  • Voriconazole, posaconazole or itraconazole are first-line agents (Weak, Low)
  • Echinocandins may be considered based on in vitro data (Weak, Very Low)
Trichosporon
  • Identification in urine of kidney transplant recipients
  • generally does not require treatment
  • Antifungal susceptibility is necessary to guide therapy
  • Azoles are recommended first‐line agents (Strong, Low)
  • LF‐AmB may be considered if susceptibility is confirmed (Weak, Low)
Malassezia
  • Topical preparation of clotrimazole 1% and selenium sulfide lotion or oral fluconazole for superficial infections
  • Identification to species level and antifungal susceptibility is necessary to guide therapy
  • Catheter removal and LF‐AmB for disseminated infection (Weak, Low)
  • Itraconazole, posaconazole, voriconazole (Weak, Low)
Rhodotorula
  • LF‐AmB or posaconazole are treatments of choice based on available susceptibility data (Weak, Low)
Penicillium
  • Terbinafine and the echinocandins show the best in vitro activity (Weak, Low)
Talaromyces marneffei
(formerly Penicillium
marneffei)
  • Induction treatment with LF‐AmB followed by maintenance treatment with itraconazole is recommended (Strong, Moderate)
  • Itraconazole (Weak, Low)
  • Voriconazole (Weak, Low)
Paracoccidioides
  • Induction treatment with LF‐AmB for severe disease followed by maintenance treatment with itraconazole or voriconazole is recommended (Weak, Low)
  • Itraconazole may be considered for less severe disease (Weak, Low)
  • May be prevented with trimethoprim-sulfamethoxazole
  • Voriconazole may be considered for less severe disease (Weak, Low)
  • Trimethoprim-sulfamethoxazole (Weak, Low)
Sporothrix
  • Induction treatment with LF‐AmB for severe disease followed by maintenance treatment with itraconazole (Weak, Low)c
  • Itraconazole or voriconazole may be considered for less severe disease (Weak, Low)

None of the above treatments are FDA‐approved except where noted.
Standard antifungal dosing is recommended: LF‐AmB 5 mg/kg daily; AmBd 1‐1.5 mg/kg daily; voriconazole 6 mg/kg intravenous q 12 h × 2 loading doses followed by 4 mg/kg intravenous or 200-300 mg orally twice daily; itraconazole 200 mg twice daily; posaconazole delayed release tablets 300 mg daily; caspofungin 70 mg loading dose followed by 50 mg daily; micafungin 100 mg daily; anidulafungin 200 mg loading dose followed by 100 mg daily; isavuconazonium sulfate 372 mg intravenous or oral q 8 h for six doses followed by 372 mg daily).
AmBd, amphotericin B deoxycholate; LF‐AmB, lipid formulation of amphotericin B.
a Isavuconazonium sulfate is FDA‐approved for Mucorales infections.
b Voriconazole is FDA‐approved for Scedosporium apiospermum and Fusarium infections when intolerant or refractory to other agents.
c Amphotericin B deoxycholate is FDA‐approved for Sporothrix infections.
d Terbinafine has some in vitro synergy but the agent is keratinophilic and does not penetrate well into other tissues hence limiting efficacy for invasive disease.

PREVENTION AND PROPHYLAXIS

The most common mechanism for colonization or infection is via environmental exposure. Patients should be instructed to avoid visiting construction sites and poultry farms, manipulating air‐conditioning filters, and contact with sewage or decaying material. To reduce the risk of invasive fungal infection due to transmission during the transplantation process, care should be taken in accepting organs from near drowning victims. Organ procurement agencies should report all fungal isolates from a donor to the recipient center. Not all patient with fungal colonization require prophylaxis. Certain colonizing fungi are very rarely pathogenic (eg, Cladosporium¸ Purpureocillium, and Penicillium species) and their presence generally does not require prophylaxis. By contrast, the mucormycetes and Scedosporium have been associated with disseminated infection in highly immunocompromised patients. Prophylaxis may be considered in such patients and in recipients of donor lungs that are colonized with these fungi.

(Very Low, Weak)
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Recommendation Grading

Overview

Title

Emerging Fungal Infections In Solid Organ Transplant Recipients

Authoring Organization

American Society of Transplantation

Publication Month/Year

April 1, 2019

Last Updated Month/Year

December 2, 2022

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Document Objectives

These updated AST‐IDCOP guidelines review the epidemiology, diagnosis, and management of emerging fungi after organ transplantation.

Target Patient Population

Solid organ transplant patients

Inclusion Criteria

Female, Male, Adolescent, Adult, Older adult

Health Care Settings

Ambulatory, Hospital, Operating and recovery room, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Diagnosis, Management, Treatment

Diseases/Conditions (MeSH)

D014180 - Transplantation, D019737 - Transplants, D000935 - Antifungal Agents, D016377 - Organ Transplantation, D000908 - Antibodies, Fungal, D000072742 - Invasive Fungal Infections

Keywords

prophylaxis, antimicrobial prophylaxis, antifungal, solid organ transplant

Source Citation

Shoham, S, Dominguez, EA; on behalf of the AST Infectious Diseases Community of Practice. Emerging fungal infections in solid organ transplant recipients: Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019; 33:e13525.