Successful Treatment of Refractory Cutaneous Protothecosis With MAT2203, an Oral Lipid Nanocrystal Formulation of Amphotericin B

Abstract

Prototheca wickerhamii is a rare cause of cutaneous and systemic infection that requires long treatment courses with potentially toxic medications. We describe a patient with cutaneous protothecosis refractory to triazole monotherapy who experienced clinical and radiographic improvement with the novel oral lipid nanocrystal formulation of amphotericin B without experiencing toxicity.

Described in 1894 as a fungus and subsequently reclassified, Prototheca are achlorophyllic saprophytic algae found ubiquitously in soil and water, especially when contaminated by organic waste as in sewage, tree slime flux, and ponds [1–3]. Prototheca spp.—chiefly Prototheca wickerhamii and Prototheca zopfii—have been known to be pathogenic in both animals and humans. Indeed, Prototheca can cause bovine mastitis and disseminated infection in dogs and other domesticated animals [1, 3, 4]. Human disease is largely restricted to olecranon bursitis in immunocompetent patients, although cutaneous infection—at times widespread—and systemic infection have been described in immunosuppressed patients [3–7]. Treatment can be challenging and often requires surgical debridement or prolonged courses of antifungal medications that have the potential for drug–drug interactions and toxicities. Prototheca contains ergosterols within its cell wall, allowing for treatment with amphotericin B (AmB) and triazoles, typically used for fungal infections, although clinical trials comparing therapeutic options are lacking [1–5].

AmB is a polyene antifungal with broad activity against a range of human fungal pathogens. Discovered in 1953, AmB interacts with ergosterol in the fungal cell membrane, disrupting the cell membrane and leading to fungal death [8]. AmB's use is limited by its poor oral availability—leading to its compounding with sodium deoxycholate (AmB deoxycholate) for intravenous use—and its toxicities owing to nonselective disruption of mammalian cell membranes. While lipid-associated intravenous (IV) formulations of AmB such as liposomal AmB and AmB lipid complex have been shown to improve the therapeutic index of AmB, substantial limiting toxicities still exist [8]. Infusion reactions, nephrotoxicity—including renal tubular acidosis (RTA) and azotemia—electrolyte disturbances, anemia associated with low erythropoietin levels, and the need for intravenous access [8–10] all pose challenges when treating with conventional formulations of AmB. Novel lipid nanocrystal (LNC) amphotericin B (MAT2203; Matinas Biopharma) is an investigational encochleated formulation given as a bioavailable oral suspension that aims to provide the broad antifungal coverage of conventional AmB with fewer toxicities. Oral LNC AmB recently showed promise for the treatment of chronic mucocutaneous candidiasis [11] and cryptococcal meningitis in people with HIV, in whom it exhibited similar efficacy and less toxicity compared with conventional IV AmB [12].

Herein, we describe a patient with cutaneous protothecosis who failed triazole therapy and for whom the toxicities of a prolonged course of IV AmB were prohibitive. He was treated with oral LNC AmB for 1 year with radiographic and clinical response without any apparent toxicity.

CLINICAL COURSE

The patient is a 71-year-old man with a history of coronary artery disease requiring coronary stenting and congestive heart failure with ICD placement living in Florida and Virginia who presented to care with painful nodules on his dorsal right second and third digits about 2 weeks after lacerating his right second digit on utensils in his dishwasher. He was started on antibiotics without improvement. He was subsequently treated with itraconazole given sporotrichoid spread of the nodules along his right arm. Cutaneous biopsies were performed, and cultures grew Prototheca wickerhamii, which was identified by matrix-assisted laser desorption/ionization. Susceptibility testing was not performed. Histological evaluation was consistent with cutaneous protothecosis. Itraconazole was discontinued, and voriconazole was started at 200 mg twice daily. The nodules initially regressed with treatment until he self-discontinued voriconazole after 2 months. He then noted recurrence of lesions on the dorsum of his right hand and his right elbow. Voriconazole was promptly restarted, but he noted progression over the following 2 months with continued spread and increasing erythema, tenderness, and pain, especially at night. He was then referred to the National Institutes of Health (NIH) and was enrolled onto our natural history protocol NCT01386437 as well as a protocol to obtain whole-genome sequencing (WGS) (NCT03206099). He was found to have persistently low voriconazole trough levels (ranging from 0.1 to 0.5 mcg/mL while receiving 300 mg twice daily) and was found to be a rapid metabolizer via CYP2C19 on pharmacogenomic testing. Voriconazole was stopped, and posaconazole was initiated. Punch biopsies obtained at the time of the NIH referral were consistent with cutaneous protothecosis with necrotizing granulomatous dermatitis and yeast-like organisms seen on periodic acid-Schiff and Grocott's methenamine silver stains (Figure 1A and B). Cultures taken from biopsy were negative at this time, and serum beta-D-glucan was negative. His posaconazole dose was adjusted based on trough levels (range, 600–4600 ng/mL) to 400 mg twice daily with slow improvement of lesions over the subsequent 10 months and lesion resolution proximal to the wrist. WGS did not identify deleterious CARD9 variants [6], which have been associated with susceptibility to protothecosis. It revealed somatic variants in ASXL1 and TET2, which confer risk of developing myelodysplastic syndrome (MDS). A bone marrow biopsy was performed and at that time showed trilineage hematopoiesis without MDS.

Figure 1.

Clinical response of cutaneous protothecosis to MAT2203 without observed toxicity: A and B, Representative histological images from biopsy of one of the patient's lesions showing Prototheca yeast-like bodies with endospores on GMS (A) and PAS (B) staining. C–F, Photographs of his affected hand before initiation of MAT2203 (C and E) and after 6 months of therapy (D and F) showing marked improvement in the gross appearance of his lesions. G–H, PET/CT scans with inset displaying his affected hand before MAT2203 (G) and after 6 months of therapy (H) showing resolution of FDG avid lesion corresponding to the location of one of his cutaneous nodules. I, Temporal levels of serum potassium (normal range 3.5–5.1 mmol/L), magnesium (normal range 1.6–2.6 mg/dL), and creatinine (normal range 0.73–1.18 mg/dL) throughout the course of MAT2203 therapy. Abbreviations: Cr, creatinine; GMS, Grocott's methenamine silver; K, serum potassium; Mg, magnesium; PAS, periodic acid-Schiff; PET/CT, positron emission tomography/computed tomography.

After this period of improvement, he noted worsening of nodules with increased erythema and pain as well as return of additional nodules along his distal right arm to the elbow despite posaconazole trough levels of 3900 ng/mL (Figure 1C and E). Computed tomography (CT) scanning of his right upper extremity showed multifocal subcutaneous nodularities at the dorsal aspect of his right wrist and dorsal aspect of multiple digits corresponding to where his painful lesions were noted. Positron emission tomography (PET) demonstrated a focus of increased FDG uptake of the skin superficial to the right third metacarpophalangeal joint (SUVmax, 3.44) (Figure 1G). Given his age and comorbidities, intravenous AmB was considered to have unacceptably high risk of toxicity while surgical debridement of all affected tissue was impractical given the extent of disease. Compassionate use of MAT2203 was sought and granted under eIND 164203 with NIH institutional review board approval under protocol 001183-I. Before initiating MAT2203, laboratory analysis revealed chronic leukopenia (1.29–4.31 L/mcL) with mild to moderate neutropenia (0.79–2.99 K/mcL).

He began MAT2203 with a 2-week loading dose of 300 mg every 4 hours, which was initiated in an inpatient setting, followed by a maintenance dose of 300 mg every 6 hours as per the regimen used in patients with cryptococcal meningitis [12]. At day 2 post–MAT2203 initiation, posaconazole was reduced to 300 mg twice daily and co-administered with MAT2203. He had weekly laboratory analysis for the initial 4 weeks on the drug including complete blood count, liver function panel, and basic metabolic panel, followed by labs checked monthly thereafter. After a month on MAT2203, he had some improvement in pain around his lesions as well as mild improvement in the appearance of lesions on his right hand. His lesions progressively improved, and his pain entirely remitted. He returned to NIH for repeat PET/CT after 6 months on MAT2203 and at that time had no ulcerations over his hand or forearm and denied any further pain over the affected skin. PET/CT showed resolution of the FDG avid area in the skin of the right dorsal hand (Figure 1H). Given his clinical and radiographic improvement in addition to continued tolerance of MAT2203, posaconazole was then further reduced to 300 mg daily and, given no regression of symptoms with this change, was discontinued 2 weeks later without worsening of symptoms. The patient thus remained on MAT2203 monotherapy for the next 6 months. After 1 year on MAT2203, he was deemed to have achieved maximal clinical response, and the drug was discontinued (Figures 1D and F). Throughout the study period, he had no laboratory evidence of renal toxicity, hepatotoxicity, or electrolyte abnormalities (Figure 1I). His erythropoietin levels remained stable within the normal range (baseline level, 24.2 mIU/mL; level at completion of MAT2203 therapy, 30.0 mIU/mL). During the last month of therapy, he developed worsening neutropenia (nadir, 0.35 K/mcL) and new thrombocytopenia (nadir, 84 K/mcL) that persisted after cessation of MAT2203. This prompted repeat bone marrow biopsy, which was consistent with development of MDS, likely related to the ASXL1 and TET2 risk alleles. MAT2203 was stopped after 1 year of therapy; he remains in remission 6 months after discontinuation of MAT2203 and is receiving treatment for MDS.

DISCUSSION

Herein, we describe a patient with cutaneous protothecosis refractory to triazole therapy who was successfully treated with the addition of the novel orally delivered LNC AmB, MAT2203. Our patient's treatment was complicated by the lack of available options as he was refractory to triazoles and the first-line treatment choice—IV AmB—would have carried significant risk of toxicity. Additional challenges related to the treatment of protothecosis include lack of randomized clinical trials, lack of standardization of in vitro susceptibility testing, and unclear correlation between in vitro susceptibility testing results and clinical outcomes. This is the first use of LNC AmB for the treatment of protothecosis and establishes it as a promising option for the treatment of azole-refractory Prototheca, especially in patients who cannot tolerate conventional formulations of AmB. Our patient suffered no toxicity attributable to the medication. Although he had progressively worsening neutropenia and thrombocytopenia during the year of MAT2203 therapy, this was attributable to the somatic risk variants for MDS. As seen in previous studies [11, 12], we found no renal injury, hepatotoxicity, erythropoietin suppression, or electrolyte abnormalities, which are often seen with IV AmB formulations. This report adds to the existing literature that indicates MAT2203 to be a promising therapy for challenging infections with minimal attributable toxicity. Moreover, it supports its role in the treatment of protothecosis and potentially other cutaneous infections caused by fungi, algae, or Leishmania in which AmB is known to be active.