Efficacy of Crushed Delayed-Release Posaconazole Tablets in Rhino-Orbito-Cerebral Mucormycosis

ABSTRACT

A significant proportion of patients with Rhino-orbito-cerebral mucormycosis (ROCM) develop oroantral fistulas. Due to the unclear efficacy of crushed delayed-release posaconazole tablets (DRPT) via nasogastric tube in this group of patients, clinicians often use inferior alternatives like posaconazole suspension. In this prospective study, we report good plasma concentrations (median, 2,639 ng/mL; interquartile range [IQR], 1,690 to 3,575 ng/mL; and range, 1,004 to 4,835ng/mL) and complete cure and survival at 3 and 6 months in 19 such patients.

INTRODUCTION

The delayed-release posaconazole tablet (DRPT) is commonly used in the management of invasive aspergillosis and mucormycosis (1, 2). It has replaced the suspension form in most clinical situations in view of its simplified administration schedules and improved bioavailability (3). A pH-sensitive polymer in DRPT protects posaconazole amid the low gastric pH and preferentially releases the molecule in the intestine (4). This results in steady and improved serum plasma concentrations and sustained drug exposure (4, 5). However, significant uncertainty exists regarding the efficacy of DRPT when it is crushed and administered via nasogastric tubes. The potential consequences are 2-fold. DRPT is designed to protect posaconazole from the acidic stomach environment and preferentially releases the drug in the intestine. Crushing DRPT will destroy this protective coating, reducing its bioavailability. The second concern is the possibility of acute side effects due to rapid absorption from the upper gastrointestinal tract due to crushing (6).

Both invasive mucormycosis and aspergillosis often involve the paranasal sinuses with erosion of the hard palate. Hence, patients are dependent on nasogastric tubes for extended periods of time due to the resultant oroantral fistula. In view of lack of data, most clinicians prefer to use the posaconazole suspension or intravenous preparation in this situation. Posaconazole suspension given via nasogastric tube is associated with low plasma levels among both healthy volunteers and critically ill patients (7, 8). Emerging data shows that DRPT may be a reasonable option in these patients (9), but no prospective data exists. We evaluated the clinical and therapeutic efficacy of 300 mg of crushed DRPT and effect on plasma concentrations in our prospective cohort of patients with biopsy-confirmed rhino-orbito-cerebral mucormycosis (ROCM) and oroantral fistula requiring a nasogastric tube.

From 1 July 2020 to 31 September 2021, we included patients with ROCM who received DRPT via nasogastric tubes in a prospective (POISE Mucor) study cohort conducted at our hospital in South India. The Institutional Review Board and Ethics Committee (no. 12930/24.06.2020) approved the study. A written informed consent was obtained from all of the patients.

Adult (≥18 years) patients with clinical and radiological features suggestive of ROCM with histopathological evidence of broad aseptate fungal hyphae with tissue invasion with or without fungal culture confirming mucorales who received oral posaconazole in crushed form via nasogastric tubes were included. All patients underwent surgery and received intravenous amphotericin (liposomal amphotericin-B [5 mg/kg of body weight/day], lipid emulsion amphotericin-B [5 mg/kg/day], and amphotericin-B deoxycholate [1 mg/kg/day]) followed by DRPT 300 mg per day as a single dose as step down therapy. All patients had oroantral fistulas due to maxillary osteomyelitis and/or surgical debridement.

A uniform process was adopted for crushing DRPT for all of the study patients. The DRPT was crushed into a fine powder using a pill crusher (mortar and pestle). The crushed tablet was then diluted in 30 mL purified water and administered to the patient without any delay. Care was taken that DRPT was not added or mixed with any feeding formula and was administered separately. The nasogastric tube was flushed with an additional 10 mL of purified water to ensure complete administration of the medicine.

Patients had plasma posaconazole trough concentrations measured using high-performance liquid chromatography at the end of 2 weeks of receiving the crushed posaconazole via nasogastric tubes. The chromatographic analysis was performed using the Shim-pack GIST C₁₈ column, 5 μm (4.6 by 250 mm), with the UV detection set at 262 nm. The calibration curve was linear from 200 to 6,000 ng/mL. The accuracy and precision of the assay reported earlier were within acceptable limits (10). Supported by previous literature, we set the cutoff trough value for efficacy as 1,000 ng/mL (11).

Participants received oral posaconazole and were followed up on an outpatient basis at 2, 14, and 24 weeks of posaconazole therapy. Compliance was assessed as a part of a standard proforma during each visit as a part of the POISE Mucor study. All of the patients had good compliance with oral posaconazole except 1 patient who received it for 2.5 months and stopped due to financial issues. He did not have any active disease on follow-up. Patients were on regular follow-up and monitored. Patients were instructed clearly not to take medication at the day of sample collection. A dose history was collected before trough blood specimens were processed in the laboratory to ensure its appropriateness. We documented disease status and side effects related to antifungal therapy at each visit. A successful outcome was defined as clinical resolution with no evidence of active disease on rigid nasal endoscopy and no radiological disease progression. Treatment failure was defined as clinical, endoscopic, or radiological progression with evidence of active disease on biopsy. All patients with suspicion of treatment failure underwent biopsy and histopathological examination with fungal cultures.

Of the 237 patients admitted in our hospital with acute invasive fungal sinusitis with mucormycosis treated with posaconazole during the study period, 19 patients required nasogastric tube insertion for feeding and received DRPT in crushed form. Most of them were male patients (n = 15; 79%), and the mean age was 51 years (range, 32 to 71 years). All except one patient had diabetes mellitus (DM) and (79%) had poorly controlled diabetes (hemoglobin A1C [HbA1c] > 7%) with the baseline mean HbA1c of 9.57%, and the majority had recent COVID-19 illness (n = 15; 79%). Hemi facial pain (n = 19), tooth pain or loosening (n = 16), restricted eye movements (n = 6), and unilateral visual loss (n = 4) were the common presenting symptoms (Table 1). While all patients had extensive osteomyelitis proven by biopsy, 42% had orbital and 10.5% had central nervous system extension. Seven of them grew Rhizopus arrhizus on fungal cultures (36.8%).

TABLE 1.

Clinical characteristics, posaconazole trough levels, and outcomes of the study participants

Study participant no.	Age/sex	DMa status	HbA1cb (%)	Extent of disease	Intravenous antifungal (type and duration)	Posaconazole dose and duration (in months)	Posaconazole levels after 2 wks on NG tube (ng/mL)	Outcome at 3 and 6 mo
1	61/Male	Yes	10.3	Paranasal sinus	Lipid emulsion amphotericin for 14 days	300 mg, (4)	1,446	Alive with no evidence of invasive fungal sinusitis
2	41/Male	No	5.2	Paranasal sinus and right maxillary osteomyelitis	Lipid emulsion amphotericin for 10 days	300 mg, (3)	1,910	Alive with no evidence of invasive fungal sinusitis
3	59/Male	Yes	7	Paranasal sinus and right maxillary osteomyelitis	Lipid emulsion amphotericin for 14 days	300 mg, (5)	3,649	Alive with no evidence of invasive fungal sinusitis
4	44/Male	Yes	8.8	Paranasal sinus and bilateral maxillary osteomyelitis	Amphotericin B for 14 days	300 mg, (4)	2,989	Alive with no evidence of invasive fungal sinusitis
5	48/Female	Yes	9.1	Paranasal sinus and right maxillary osteomyelitis	Liposomal amphotericin B for 14 days	300 mg, (5)	2,639	Alive with no evidence of invasive fungal sinusitis
6	45/Female	Yes	8.5	Paranasal sinus, right maxillary osteomyelitis, and orbital extraconal disease	Liposomal amphotericin B for 14 days	300 mg, (6)	4,527	Alive with no evidence of invasive fungal sinusitis
7	40/Male	Yes	7.7	Paranasal sinus and right maxillary osteomyelitis	Liposomal amphotericin B for 14 days	300 mg, (3)	2,204	Alive with no evidence of invasive fungal sinusitis
8	50/Male	Yes	10.7	Paranasal sinus, bilateral maxillary osteomyelitis, and left orbital extraconal disease	Lipid emulsion amphotericin for 14 days	300 mg, (3.5)	4,835	Alive with no evidence of invasive fungal sinusitis
9	57/Male	Yes	12.8	Paranasal sinus, left maxillary osteomyelitis, and orbital apex	Lipid emulsion amphotericin for 14 days	300 mg, (6)	2,741	Alive with no evidence of invasive fungal sinusitis
10	53/Female	Yes	12.4	Paranasal sinus, left maxillary osteomyelitis, and orbital abscess	Amphotericin B for 14 days	300 mg, (6)	4,102	Alive with no evidence of invasive fungal sinusitis
11	44/Male	Yes	13.5	Paranasal sinus and bilateral maxillary osteomyelitis	Amphotericin B for 10 days	300 mg, (2.5)	1,565	Alive with no evidence of invasive fungal sinusitis
12	32/Male	Yes	12.5	Paranasal sinus, bilateral maxillary osteomyelitis, right orbital extraconal disease, and ICAc thrombosis	Amphotericin B for 23 days	300 mg, (5)	1,004	Alive with no evidence of invasive fungal sinusitis
13	57/Male	Yes	12.6	Paranasal sinus, right maxillary osteomyelitis, orbital apex, and cavernous sinus	Liposomal amphotericin B for 14 days	300 mg, (9)	1,690	Alive with no evidence of invasive fungal sinusitis
14	54/Male	Yes	6.8	Paranasal sinus, bilateral maxillary osteomyelitis, left orbital extraconal disease, and dural disease	Lipid emulsion amphotericin for 24 days	300 mg, (4)	3,575	Alive with no evidence of invasive fungal sinusitis
15	51/Male	Yes	7.9	Paranasal sinus and bilateral maxillary osteomyelitis	Amphotericin B for 17 days	300 mg, (6)	2,815	Alive with no evidence of invasive fungal sinusitis
16	56/Female	Yes	5.9	Paranasal sinus and left maxillary osteomyelitis	Amphotericin B for 14 days	300 mg, (3.5)	2,090	Alive with no evidence of invasive fungal sinusitis
17	58/Male	Yes	10.7	Paranasal sinus and left maxillary osteomyelitis	Liposomal amphotericin B for 7 days	300 mg, (7)	2,574	Alive with no evidence of invasive fungal sinusitis
18	47/Male	Yes	7.8	Paranasal sinus and bilateral maxillary osteomyelitis	Amphotericin B for 7 days	300 mg, (6)	2,814	Alive with no evidence of invasive fungal sinusitis
19	71/Male	Yes	11.8	Paranasal sinus, bilateral maxillary osteomyelitis, right orbital apex, and right temporal lobe abscess	Amphotericin B for 23 days	300 mg, (3)	1,273	Alive with no evidence of invasive fungal sinusitis

^aDM, diabetes mellitus.

^bHbA1c, glycated hemoglobin A1C.

^cInternal carotid artery.

In addition to endoscopic sinus surgery, 17 patients required partial or total maxillectomy. All patients received intravenous amphotericin preparations for 14 days, followed by crushed DRPT. Posaconazole was given at a dose of 300 mg per day (3× 100 mg tablets) as a single dose for a mean duration of 4.8 months (range, 2.5 to 9 months). The median trough plasma concentration of posaconazole after 2 weeks of posaconazole via the nasogastric tube was 2,639 ng/mL (interquartile range [IQR], 1,690 to 3,575 ng/mL). The lowest posaconazole level documented was 1,004 ng/mL. The median duration of follow-up was 8.4 months (range, 6.0 to 12.5 months).

All patients had treatment success with no clinical, rigid nasal endoscopic, or radiological evidence of active disease at 3 and 6 months of follow-up. No patient had limiting side effects requiring drug discontinuation. Mild hypokalemia (potassium, 2.5 to 3.5 meq/L) was documented in 13 patients. New onset hypertension and diarrhea was reported in 4 patients each.

This prospective study shows that among patients with mucormycosis and oroantral fistula, gastric administration of crushed DRPT via nasogastric tube with plasma concentration monitoring is a reasonable strategy. Commonly, posaconazole suspension or intravenous preparation is used in this situation (2, 12). Administration of crushed DRPT can avoid the unpredictable pharmacokinetics of posaconazole suspension as well as their complications. Additionally, the study also confirms clinical success in all patients who received crushed DRPT for up to 6 months.

The literature in this area is sparse. A recent retrospective study evaluated the target therapeutic level achievement with crushed posaconazole tablets via enteral feeding among 14 patients who underwent solid organ transplantation. Four patients had subtherapeutic posaconazole levels at first assessment (after 7 days of posaconazole), requiring dose optimization. Though two patients developed invasive fungal infections (IFIs), the authors commented that they are less likely to be a failure of prophylaxis, as they occurred either too early or too late after prophylaxis (9). Another small study with four patients reported that half (n = 2) of their patients did not reach therapeutic levels after doses of 300 mg/day of crushed DRPT (12).

Another concern with crushed DRPT is the rapid absorption of the active drug into circulation and toxicity (13). In our study, we did not see any major threatening side effects with crushed DRPT. Toxicities noted were comparable to that in published literature (1, 14). This study has limitations. Although our study’s sample size is among the largest available in the literature, it is too small to make definitive recommendations using this data alone. Trough levels could have been done earlier at 1 week to identify patients with poor plasma levels early. The results may not be translatable to patients with other forms of enteral feeding, patients with impaired gut absorption, or critically ill patients.

In summary, crushed DRPT via nasogastric tube with close plasma concentration monitoring appears to be a reasonable option with good clinical efficacy and safety profile for patients with invasive mucormycosis and swallowing difficulty.