Abstract
Objective
To evaluate the efficacy and safety of short-course intravenous amphotericin B followed by sustained release posaconazole tablets for diabetes or COVID-19 associated rhino-orbito-cerebral mucormycosis (ROCM).
Methods
This prospective, pragmatic study included adults with diabetes or COVID-19 associated ROCM. Patients received short (7–14 days) or long (15–28 days) or intravenous antifungal therapy (SHIFT, or LIFT respectively) depending on the presence or absence of brain involvement. All patients received step-down posaconazole tablets, debridement, and glycemic control. The primary outcome was the treatment success at week 14, which was determined by assessing survival and the absence of disease progression through clinical evaluation and nasal endoscopy. Log-binomial regression analysis (RR and 95% CI) was performed to assess factors associated with the primary outcome.
Results
Intravenous therapy was administered to 251 participants: SHIFT, 205 (median duration, 13 days); LIFT, 46 (median duration, 22 days). Treatment success at 3 months was 88% (217/248; 95% CI, 83%–91%): SHIFT group, 93% (189/203; 89%–96%); LIFT group, 62% (28/45; 47%–76%). All-cause mortality was 12% (30/251): SHIFT group, 6% (13/205); LIFT group, 37% (17/46). Age (aRR [95% CI]: 1.02 [1.00–1.05]; p=0.027), DKA at presentation (2.32 [1.20–4.46]; p=0·012), HbA1c (1.19 [1.03–1.39]; p=0.019), stroke (3.93 [1.94–7.95]; p=0·0001), and brain involvement (5.67 [3.05–10.54]; p<0.0001) were independently associated with unsuccessful outcomes.
Conclusion
Short intravenous amphotericin B with step-down posaconazole tablets should be further studied as primary treatment option for diabetes or COVID-19 associated mucormycosis in randomized controlled trials.
Introduction
A surge of mucormycosis cases involving the paranasal sinuses with or without brain extension was noted during the COVID-19 pandemic, which was fueled by the rampant use of steroids and loss of control of DM [1].
As trials evaluating antifungal therapy are lacking, current treatment of diabetes or COVID-19 associated ROCM is based on expert opinions and studies involving patients with hematological conditions and profound neutropenia or severe immunocompromise [2,3]. Expensive intravenous agents such as liposomal amphotericin B are often recommended for lengthy periods (4-6 weeks), extending hospital stay and increasing toxicity and risk of central line-associated bloodstream infections (CLABSI) [[2], [3], [4]]. This is not a feasible option for the majority in resource-limited settings where treatment interruptions are common. We hypothesized that a short intravenous treatment, stratified according to the level of involvement, followed by a step-down treatment using effective oral antifungals, could simplify the management of diabetes or COVID-19 associated ROCM and improve outcome. This hypothesis was evaluated in a large prospective cohort study.
Methodology
Patients and study design
Posaconazole for invasive sinusitis – evidence for mucormycosis (POISE-Mucor) trial was a prospective pragmatic study conducted at a 3000-bedded teaching hospital in India from July 2020 – September 2021. We included adult patients (≥18 years) with diabetes or COVID-19 associated ROCM. All patients provided written informed consent. The study was approved by the Institutional Review Board and Ethics Committee (No. 12930/24.06.2020).
Mucormycosis was confirmed by histopathology showing broad aseptate fungal hyphae with tissue invasion and/or culture growing Mucorales with supporting clinical and imaging features. The species identification was done by MALDI-TOF and when the exact species was not identified, the term Rhizopus spp was used. Patients with neutropenia, hematological malignancies, solid organ or stem cell transplant, lung involvement, isolated mandibular involvement, or disseminated disease were excluded. Diabetic Ketoacidosis was defined as urine ketone positivity with serum blood glucose more than 200mg/dL and venous pH <7.3. Patients with disease limited to sinus, bone, eye and meninges with no brain involvement were classified as SHIFT group and received short (7–14 days) intravenous antifungal therapy. LIFT group included patients with brain parenchymal involvement or internal carotid artery invasion. LIFT group patients received long (15-28) days intravenous antifungal therapy. All patients received step-down sustained release posaconazole tablets, underwent surgical debridement, and had optimal management of diabetes mellitus.
Procedure
All patients received intravenous therapy with liposomal amphotericin-B (AmBisome) (5 mg/kg/day), lipid emulsion amphotericin-B (Ambilon, Amphocin, Amphomul) (5 mg/kg/day), amphotericin-B deoxycholate (1 mg/kg/day), or posaconazole (300 mg/day). Once the intravenous course was completed, posaconazole tablets (300 mg) were administered daily.
Adverse drug events and disease status were noted daily while on intravenous therapy and during follow-up visits at 2, 4, 14, and 24 weeks. Investigators also recorded findings from physical examination, laboratory tests, nasal endoscopy, and imaging. Plasma posaconazole trough concentrations were measured two weeks after initiating the drug using high-performance liquid chromatography. The chromatographic analysis was performed using the Shim-pack GISTC18 column, 5μm (4.6 x 250 mm) with the ultraviolet detection set at 262 nm. The calibration curve was linear from 200–6000 ng/ml. The accuracy and precision of the assay reported earlier were within acceptable limits [5]. The therapeutic target was posaconazole trough concentrations of more than 1000 ng/ml.
Outcomes
The primary endpoint was treatment success at week 14 (3 months) measured as a composite of survival and the lack of progressive disease on clinical evaluation and rigid nasal endoscopy. Treatment success was defined as clinical resolution without evidence of active disease on endoscopy or biopsy, and disease regression or no progression on repeat imaging, while treatment failure included clinical worsening, residual disease on endoscopy with evidence of active disease on biopsy, or radiological progression on repeat imaging. A team of three infectious diseases physicians resolved any differences during analyses of treatment outcomes.
Secondary endpoints included persistent disease requiring continued therapy beyond 24 weeks, side effects of antifungal therapy, CLABSI, other nosocomial infections or complications, and all-cause mortality at 14 and 24 weeks.
Statistical Analysis
Baseline demographics and clinical characteristics are presented as frequencies with percentages for categorical data and mean (standard deviation [SD])/median (interquartile range [IQR]) for continuous data. The statistical analysis was performed using multivariable log-binomial regression. Risk ratios (RRs) and 95% confidence intervals (CI) to assess factors associated with the primary outcome were obtained. Factors significant on univariate analysis were adjusted to control for the confounding effects. Sex and age were considered natural confounders and were adjusted. Safety data were summarized by study groups and compared using Fisher's exact test. A likelihood ratio test was used to evaluate model performance. A significant likelihood ratio test meant that the resulting model had a better fit than the null (a model with outcome only) model. Data were analyzed using the statistical package SPSS version 21.0 and Stata version 17.0. Statistical significance was declared at p<0·05.
Results
Between July 2020 and September 2021, we screened 279 patients with mucormycosis and enrolled 251 patients. Twenty-eight patients were excluded. Ten patients were lost to follow-up (Figure 1 ).
Figure.1.
Table 1 summarizes the baseline characteristics. The mean age was 50 years (SD, 12 years), and 189/251 (75%) were male. The dominant predisposing factor was DM (239/251 [95%]), and 87% (217/249) of patients had uncontrolled DM (HbA1c of >7%) with mean HbA1c of 10·2%±2·4% at baseline. Diabetic ketoacidosis (DKA) was found in 4% (9/251) at presentation. Most patients (188/251 [75%]) had COVID-19 within 3 months before enrolment. Steroid use was common (109/219 [50%]), and 70/219 (32%) received high-dose steroids (>40 mg prednisolone or equivalent). Prior oxygen treatment for COVID-19 was more common in the SHIFT group (71/205[34·6%]) than in the LIFT group (8/46[17·4%]).
Table 1.
Characteristics of patients
| Characteristics | SHIFTa group (N=205) | LIFTb group (N=46) | Total (N=251) |
|---|---|---|---|
| Age (y), mean±SD | 51±12 | 48±13 | 50±12 |
| Gender (male), n (%) | 154 (75) | 35 (76) | 189 (75) |
| Comorbidity | n (%) | n (%) | n (%) |
| Diabetes Mellitus (DM) | 194 (95) | 45 (98) | 239 (95) |
| Hypertension | 92 (45) | 17 (37) | 109 (43) |
| Others | 33 (16) | 5 (11) | 38 (15) |
| Newly detected diabetes mellitus | 60 (29) | 19 (41) | 79 (31) |
| HbA1cc (%), mean±SD | (N=205) 10·0±2·5 | (N=44) 11·2±2·2 | (N=249) 10·2±2·4 |
| Uncontrolled DM (HbA1c >7%) | 176/205 (86) | 41/44 (93) | 217/249 (87) |
| Recent or concurrent COVID-19dinfection within 3 months | 151 (74) | 37 (80) | 188 (75) |
| Steroid use for COVID-19, n/N (%) | 91/182 (50) | 18/37 (49) | 109/219 (50) |
| Duration of symptoms (days), median (IQR) | 14 (6–30) | 10 (5–18) | 13 (6–30) |
| Clinical presentation | n (%) | n (%) | n (%) |
| Acute (≤7 days) | 66 (32) | 17 (37) | 83 (33) |
| Sub-acute (≥8 days) | 139 (68) | 29 (63) | 168 (67) |
| Clinical Manifestation | |||
| Facial pain/swelling | 196 (96) | 46 (100) | 242 (96) |
| Tooth pain/loosening | 127 (62) | 21 (46) | 148 (59) |
| Restriction of eye movement | 54 (26) | 34 (74) | 88 (35) |
| Visual loss | 49 (24) | 35 (76) | 84 (34) |
| Organ Involvement | |||
| Orbital involvement | 119 (58) | 45 (98) | 164 (65) |
| Brain Parenchymal involvement | 1 (0.5) | 30 (65) | 31 (12) |
| Intracranial abscess | 0 (0) | 16 (35) | 16 (6) |
| Dural involvement | 24 (12) | 9 (20) | 33 (13) |
| Cavernous sinus involvement | 22 (11) | 38 (83) | 60 (24) |
| Internal carotid artery thrombosis | 0 (0) | 28 (61) | 28 (11) |
| Osteomyelitis/extra-sinus soft tissue involvement | 151 (74) | 40 (87) | 191 (76) |
| Extensivee | 126 (61·5) | 34 (74) | 160 (64) |
| Minimalf | 25 (12) | 6 (13) | 31 (12) |
| Laboratory parameters | |||
| Mycology | n/N (%) | n/N (%) | n/N (%) |
| Fungal Smear | 181/181 (100) | 41/41 (100) | 222/222 (100) |
| Histopathology showing broad aseptate fungal hyphae with invasion | 203/204 (100) | 46/46 (100) | 249/250 (100) |
| Fungal culture positive for Mucorales species | 103/204 (50·5) | 29/45 (64) | 132/249 (53) |
| R. arrhizusg | 82/204 (40) | 25/45 (56) | 107/249 (43) |
| Rhizopusspp | 13/204 (6) | 3/45 (7) | 16/249 (6) |
| Other | 9/204 (4) | 0/45 (0) | 10/249 (4) |
| Other tests | median (IQR) | median (IQR) | median (IQR) |
| Serum ferritin (ng/mL) | (N=173) 320 (188–511) | (N=37) 629 (331–1,240) | (N=210) 340 (199–617) |
| C-reactive protein (mg/L) | (N=189) 70 (27–118) | (N=41) 110 (47–161) | (N=230) 75 (30–122) |
| Total count (cells/cmm) | (N=203) 10,900 (8,500–14,700) | (N=246) 14,000 (10,200–18,200) | (N=249) 11,300 (8,600–15,200) |
| Surgery Details | n (%) | n (%) | n (%) |
| Sinus Surgery | 203 (99) | 46 (100) | 249 (99) |
| Maxillectomy | 72 (35) | 8 (17) | 80 (32) |
| Orbital exenteration | 9 (4) | 7 (15) | 16 (6) |
| Treatment received | |||
| Intravenous antifungal therapyh | |||
| Deoxycholate Amphotericin B | 107 (52) | 31 (67) | 138 (55) |
| Lipid Emulsion Amphotericin B | 69 (34) | 6 (13) | 75 (30) |
| Liposomal Amphotericin B | 28 (14) | 7 (15) | 35 (14) |
| Intravenous Posaconazole | 1 (0·5) | 2 (4) | 3 (1) |
| Duration of intravenous antifungal therapy (days), median (IQR) | 13 (7–14) | 22 (8–28) | 14 (7–14) |
| Oral antifungal therapy | |||
| Received step-down oral antifungal therapyi, n (%) | 201 (98) | 36 (78) | 237 (94) |
| Duration of oral antifungal therapy (months) | (N=201) | (N=36) | (N=237) |
| Median (IQR) | 4 (3–6) | 5 (3–6) | 4·5 (3–6) |
SHIFT, short intravenous antifungal treatment.
LIFT, long intravenous antifungal treatment.
HBA1c, glycated hemoglobin A1c.
COVID-19, coronavirus disease 2019 (mild, 121/188 (64%); moderate, 52/188 (28%); severe, 14/188 (7%).
Extensive osteomyelitis is defined as ≥2 facial bone involvement or skull base osteomyelitis.
Minimal osteomyelitis is defined as localized involvement (walls of the sinuses) or 1 bone involvement.
There was 1 patient with both R. arrhizus and R. Apophysomyceselegans.
Refers to the intravenous antibiotic administered for at least 50% of the duration of intravenous therapy.
The majority (167/237 [70%]) received oral therapy for over three months: 5% (13/237) had residual active disease, such as undrained cerebral or orbital abscess or extensive osteomyelitis. Twenty patients (8%) did not complete three months of oral treatment: twelve died, seven had financial constraints, and one was lost to follow-up.
Facial pain or swelling [242/251(96%)] was the most common symptom. 12/251 (5%) patients experienced stroke. All patients had paranasal sinus involvement: 11% (27/251) had disease limited to the sinus, 76% (191/251) had osteomyelitis or extra-sinus soft tissue involvement, 65% (164/251) had orbital involvement [orbital apex, 29% (73/251); orbital abscess, 7% (18/251); extensive and minimal soft-tissue involvement, 8% (20/251) and 26% (65/251)], 28% (70/251) had intracranial involvement. Isolated dural involvement was seen in 9% (4/251) and 12% (25/205) of patients in the LIFT and SHIFT groups, respectively.
The histopathology of 249/250 (99·6%) patients showed broad aseptate fungal hyphae with invasion. Cultures grew Mucorales in 132/249 (53%), with the majority growing R. arrhizus 107/249 (43%).
Treatment
Out of 251 patients, 249 (99%) underwent endoscopic sinus surgery sixteen (6%) had orbital exenteration and eighty (32%) had maxillectomy, of whom, 29/80 (36%) developed oro-antral fistula. SHIFT was administered to 205 patients, while 46 patients received LIFT. Intravenous amphotericin B deoxycholate (138/251 [55%]) was used most, followed by lipid emulsion amphotericin B (75/251 [30%]), liposomal amphotericin B (35/251 [14%]), and intravenous posaconazole (3/251 [1%]).
Although the median duration of intravenous therapy was 13 days (IQR, 7–14 days) in the SHIFT group, 6% (12/205) of patients received therapy for over 14 days to treat residual extensive skull base osteomyelitis or surgically non-amenable orbital abscess. In the LIFT group, the median duration of intravenous therapy was 22 days (IQR, 8–28). Nineteen patients received intravenous therapy for <14 days: twelve died before completing intravenous therapy and seven were switched to oral therapy because of limiting side effects (acute kidney injury, 3; CLABSI, 4).
Fourteen (6%) died before starting posaconazole tablets. All surviving patients (237/251 [94%]) received step-down oral posaconazole therapy for a median of 4·5 months (IQR, 3–6; range, 1–10·5). Nasal endoscopy was performed on 224 patients during the 3-month follow-up, revealing normal results for 219 patients and residual disease for 5, while 26 patients died and 1 was unable to undergo endoscopy.
Outcome
Primary Outcome
The overall treatment success rate at 3 months was 88% (217/248; 95% CI, 83%–91%). The treatment success rate in the SHIFT group was 93% (189/203; 89%–96%), while in the LIFT group it was 62% (28/45; 47%–76%).
Secondary Outcome
The overall 3-month survival rate was 90% (222/248) [95% (192/203) in SHIFT group; 67% (30/45) in LIFT group], while 6-month survival rate was 88% (211/241) [93% (184/197); 61% (27/44). There were high rates of CLABSI (25% [62/251]) [SHIFT:19·5% (40/205); LIFT:48% (22/46)]. Thirty patients died during the follow-up period: fourteen from progressive mucormycosis; sixteen from other causes. The all-cause mortality was 12% (30/251) [LIFT group, 37% (17/46); SHIFT group, 6% (13/205)].
Post-surgery, 215/251 (86%) had significant residual disease and 41/251 (16%) required a second surgery despite antifungal therapy (SHIFT:15% [31/205], LIFT:22% [10/46]) (Table 2 ). The median trough posaconazole plasma concentration at week 2 was 2,746 ng/ml (IQR, 1,981–3,570). Two patients had levels less than 1,000 ng/ml.
Table 2.
Univariate analysis of treatment outcomes
| Outcomes | Total (N=251) | SHIFTa (N=205) | LIFTb (N=46) |
|---|---|---|---|
| Primary outcome | n (%; 95% CI) | n (%; 95% CI) | n (%; 95% CI) |
| Outcome at 3 months | (N=248) | (N=203) | (N=45) |
| Successful outcome at 3 months | 217 (88; 83 to 91) | 189 (93; 89 to 96) | 28 (62; 47 to 76) |
| Outcome at 6 months | (N=241) | (N=197) | (N=44) |
| Successful outcome at 6 months | 211 (88; 83 to 91) | 184 (93; 89 to 96) | 27 (61; 45 to 76) |
| Secondary outcome | n/N (%; 95% CI) | n/N (%; 95% CI) | n/N (%; 95% CI) |
| Survival at 3 months, | 222/248 (90; 85 to 93) | 192/203 (95; 91 to 97) | 30/45 (67; 51 to 80) |
| Survival at 6 months | 211/241 (88; 83 to 91) | 184/197 (93; 89 to 96) | 27/44 (61; 45 to 76) |
| Alive with persistent disease at 3 months | 5/248 (2; 0·7 to 4·6) | 3/203 (1·5; 0·3 to 4·3) | 2/45 (4·4; 0·5 to 15) |
| Alive with persistent disease at 6 months | 0/241 (0; 0 to 1·5) | 0/197 (0; 0 to 1·9) | 0/44 (0; 0 to 8) |
| All-cause mortality, n (%) | 30 (12) | 13 (6) | 17 (37) |
| Mucormycosis-related death, n (%)c | 14 (6) | 1 (0·5) | 13 (28) |
| In-hospital mortality, n (%) | 17 (7) | 5 (2) | 12 (26) |
| Central line associated bloodstream infection (CLABSI), n (%)d | 62 (25) | 40 (20) | 22 (48) |
| Rescue intravenous therapy, n (%) | 11 (4) | 7 (3) | 4 (9) |
| Post-surgery significant residual disease, n (%) | 215 (86) | 169 (82) | 46 (100)) |
| Requiring second surgery, n (%) | 41 (16) | 31 (15) | 10 (22) |
| Posaconazole plasma concentration at 2 weeks (ng/ml), median (IQR) | (N=216) 2,746 (1,981 to 3,570) | (N=185) 2,755 (2,007 to 3,575) | (N=31) 2,437 (1,934 to 3,537) |
| Posaconazole trough level (>1000 ng/ml), n/N (%) | 214/216 (99) | 183/185 (99) | 31/31 (100) |
SHIFT, short intravenous antifungal treatment group.
LIFT, long intravenous antifungal treatment group.
Other-cause deaths were 9% (4/46) and 6% (13/205) in the LIFT group and SHIFT group respectively.
The most common organism was ESBL-producing Klebsiella pneumoniae.
Factors associated with outcome
Univariate analysis was performed on 248/251 patients (three were lost to follow-up) to determine the factors associated with the outcome at 3 months. On multivariable analysis, age (adjusted risk ratio with 95% CI [aRR], 1.02; 1.00–1.05; p=0.027), DKA at presentation (aRR, 2.32; 1.20–4.46; p=0·012), stroke (aRR, 3.93; 1.94–7.95; p=0·0001), and brain parenchymal involvement (aRR, 5.67; 3.05–10.54; p<0.0001) were independently associated with unsuccessful outcomes after adjusting for the effect of the study group (Table 3 ).
Table 3.
Factors associated with treatment failure at 3 months
| Factors | Univariate analysis |
Multivariable analysis |
||
|---|---|---|---|---|
| Risk Ratio (95% CI) | p-value | Adjusted Risk Ratio (95% CI) | p-value | |
| Age a (years) | 1.02 (1.00–1.05) | 0.070 | 1.02 (1.00–1.05) | 0.027 |
| Sex | ||||
| Male | Reference | |||
| Female | 0.89 (0.41–1.97) | 0.78 | ||
| Comorbidity | ||||
| Hypertension (Yes) | 1.09 (0.56–2.10) | 0.81 | ||
| Recently diagnosed diabetes mellitus (Yes) | 1.57 (0.81–3.05) | 0.18 | ||
| Diabetic ketoacidosis at presentation a (Yes) | 4.44 (2.04–9.68) | 0.0002 | 2.32 (1.20–4.46) | 0.012 |
| HbA1c ab (%) | 1.28 (1.10–1.49) | 0.0014 | 1.19 (1.03–1.39) | 0.019 |
| Recent or concurrent COVID-19c infection (Yes) | 1.05 (0.46–2.43) | 0.91 | ||
| Steroid Use (Yes) | 0.98 (0.49–1.96) | 0.96 | ||
| Laboratory parameters | ||||
| Positive fungal culture (Yes) | 1.84 (0.91–3.75) | 0.091 | ||
| Mucorales Species - R. arrhizus (Yes) | 1.63 (0.84–3.15) | 0.15 | ||
| Serum ferritin a (ng/mL) | 0.87 (0.87–0.87) | ≤0.0001 | 1.00 (1.00–1.00) | 0.064 |
| C-reactive protein a (mg/L) | 1.00 (1.00–1.01) | 0.005 | 1.00 (1.00–1.01) | 0.055 |
| Organ involvement | ||||
| Orbital apex involvement a (Yes) | 3.32 (1.72–6.42) | 0.0004 | 2.04 (1.00–4.15) | 0.049 |
| Dural involvement (Yes) | 0.22 (0.03–1.54) | 0.13 | ||
| Brain Parenchymal involvement d (Yes) | 5.48 (2.92–10.28) | <0.0001 | 5.67 (3.05–10.54) | <0.0001 |
| Stroke a (Yes) | 9.36 (5.79–15.14) | <0.0001 | 3.93 (1.94–7.95) | 0.0001 |
| Extensive osteomyelitis (Yes) | 1.29 (0.43–3.86) | 0.65 | ||
| Internal carotid artery thrombosis a (Yes) | 6.47 (3.59–11.65) | <0.0001 | 2.83 (0.95–8.44) | 0.062 |
Adjusted for study group.
HbA1c, glycated hemoglobin A1c.
COVID-19, coronavirus disease 2019.
Adjusted for age and sex as potential natural confounders.
Adverse events
Among 251 patients, 235 (94%) experienced at least one adverse event, with deoxycholate amphotericin B at 94%, lipid emulsion B at 72%, liposomal amphotericin B at 97%, and intravenous posaconazole at 33%. (Table 4A, Table 4B A, 4B). Most common adverse event experienced following intravenous therapy (≥10% of patients) included mild hypokalemia (69%;173/251), acute kidney injury (41%; 104/251) and CLABSI (25%; 62/251). Out of the 21 patients with severe hypokalemia, 16 also had hypomagnesemia. Most patients (193/234 [82%]) had at least one side effect after oral posaconazole therapy which could be managed without treatment interruption. Majority presented with mild hypokalemia, 161/234 (69%) and gastrointestinal symptoms (nausea, vomiting, and diarrhea), 85/234 (36%). Patients with gastrointestinal symptoms had high median posaconazole trough concentration levels at 2 weeks (3,051 ng/ml; IQR, 2,395–4,312 ng/ml).
Table 4A.
Adverse events due to intravenous and oral antifungal therapy
| Adverse events | Total (N=251) n (%) | SHIFTa (N=205) n (%) | LIFTb (N=46) n (%) |
|---|---|---|---|
| Patients with one or more adverse eventsc | 235 (94) | 194 (95) | 41 (89) |
| Patients with one or more side effects after intravenous therapyd | 219 (87) | 179 (87) | 40 (87) |
| Patients with one or more side effects after oral posaconazolee | (N=237) 193/234 (82) | (N=201) 163/199 (82) | (N=36) 30/35 (86) |
| Side effects to intravenous therapy: | |||
| Worsening renal function (creatinine >1·5 mg/dL) | 104 (41) | 83 (40) | 21 (46) |
| Anemia (decrease in hemoglobin >1g/dL) | 17 (7) | 10 (5) | 7 (15) |
| Renal tubular acidosis | 2 (1) | 2 (1) | 0 (0) |
| Infusion reactions | 43 (17) | 32 (16) | 11 (24) |
| Mild hypokalemia (2·5–3·5 meq/L) | 173 (69) | 141 (69) | 32 (70) |
| Severe hypokalemia (<2·5 meq/L) | 13 (5) | 8 (4) | 5 (11) |
| Diarrhea | 6 (2) | 5 (2) | 1 (2) |
| Central line-associated bloodstream infection | 62 (25) | 40 (20) | 22 (48) |
| Central line-related thrombosis | 25 (10) | 20 (10) | 5 (11) |
| Oroantral fistula | 40 (16) | 35 (17) | 5 (11) |
| Side effects of oral posaconazole: | (N=237) | (N=201) | (N=36) |
| Worsening renal function (creatinine >1·5 mg/dL), n (%) | 19/234 (8) | 17/199 (8.5) | 2/35 (6) |
| Mild hypokalemia (2·5–3·5meq/L), n/N (%) | 161/234 (69) | 137/199 (69) | 24/35 (69) |
| Severe hypokalemia (<2·5 meq/L), n/N (%) | 16/234 (7) | 13/199 (7) | 3/35 (9) |
| Hyperkalemia (>5 meq/L), n/N (%) | 25/234 (11) | 21/199 (11) | 4/35 (11) |
| Gastrointestinal symptoms, n/N (%) | 85/234 (36) | 72/199 (36) | 13/35 (37) |
| New onset hypertension, n/N (%) | 38/234 (16) | 33/199 (17) | 5/35 (14) |
| Anemia (decrease in hemoglobin >1g/dL), n/N (%) | 6/234 (3) | 5/199 (3) | 1/35 (3) |
SHIFT, short intravenous antifungal treatment.
LIFT, long intravenous antifungal treatment.
Side effects to both intravenous and oral posaconazole therapy were present in 177 patients; 10/14 who died before starting oral posaconazole experienced one or more side effects to intravenous therapy.
Side effects of intravenous therapy: worsening renal function, Anemia, renal tubular acidosis, hypersensitivity/infusion reaction, bilirubin >2·0 mg/dL, mild hypokalemia (2·5–3·5 meq/L), severe hypokalemia (<2·5 meq/L), diarrhea, central line-associated bloodstream infection, central line-related thrombosis, and oronasal fistula.
Side effects of oral posaconazole: mild hypokalemia (2·5–3·5 meq/L), severe hypokalemia (<2·5 meq/L), hyperkalemia (>5 meq/L), gastrointestinal symptoms, new onset hypertension, bilirubin >2·0 mg/dL, worsening renal function, anemia.
Table 4B.
Adverse events and outcomes during intravenous antifungal treatment
| Adverse events and outcomes | Predominant class of intravenous drug used |
|||
|---|---|---|---|---|
| Deoxycholate amphotericin B (N=138) n (%) | Lipid emulsion B (N=75) n (%) | Liposomal amphotericin B (N=35) n (%) | Intravenous posaconazole (N=3) n (%) | |
| Patients with at least one side effect to intravenous therapy | 130 (94) | 54 (72) | 34 (97) | 1 (33) |
| Adverse events | ||||
| Mild hypokalemia (2·5–3·5 meq/L) | 106 (77) | 36 (48) | 30 (86) | 1 (33) |
| Severe hypokalemia (<2·5 meq/L) | 7 (5) | 2 (3) | 4 (11) | 0 (0) |
| Anemia (decrease in hemoglobin >1 g/dL) | 11 (8) | 5 (7) | 1 (3) | 0 (0) |
| Worsening renal function (creatinine >1·5 mg/dL) | 84 (61) | 10 (13) | 10 (29) | 0 (0) |
| Reversible renal injury, n/N (%) | 70/85 (82) | 8/12 (67) | 7/12 (58) | 0/1 (0) |
| Infusion reactions | 25 (18) | 12 (16) | 6 (17) | 0 (0) |
| Renal tubular acidosis | 2 (1) | 0 (0) | 0 (0) | 0 (0) |
| Gastrointestinal symptoms/diarrhea | 2 (1·5) | 3 (4) | 1 (3) | 0 (0) |
| Central line-related bloodstream infection | 40 (29) | 12 (16) | 9 (26) | 1 (33) |
| Central line-related thrombosis | 18 (13) | 4 (5·3) | 3 (9) | 0 (0) |
| Oronasal fistula | 20 (14) | 12 (16) | 8 (23) | 0 (0) |
| Requiring second surgery | 24 (17) | 12 (16) | 4 (11) | 1 (33) |
| Successful outcome | 121 (88) | 66 (88) | 29 (83) | 1 (33) |
| All-cause mortality | 15 (11) | 8 (11) | 6 (17) | 1 (33) |
Discussion
As the optimal treatment of diabetes or COVID-19 associated ROCM is unclear, guidelines suggest using intravenous therapy until disease stability is achieved [2]. In this study, patients with ROCM without CNS involvement were administered intravenous therapy for less than 14 days followed by step-down posaconazole tablets to reduce inpatient stay, CLABSI, and amphotericin-related toxicity. The overall 6-month mortality rate in our study was 12% (30/251); 6% (13/205) in the SHIFT group, which is lower than 25%–50% of most studies [[6], [7], [8]]. A recent multicentric study of 287 patients, the majority having COVID-associated mucormycosis, showed a case fatality rate of 45·7% at 12 weeks [9]. Several novel observations have emerged on studies reporting on COVID 19 associated mucormycosis. Firstly, in many reports the mortality associated with COVID 19, appears to be lower than mucormycosis with other risk factors [[10], [11], [12]]. Few meta-analyses report a lower proportion of CNS involvement among COVID-19 associated mucormycosis, but not others [10]. There is also increased awareness and earlier presentation to the hospital setting. Novel associations in addition to steroids have also been noted - zinc supplementation, rural residence etc..[13]. One retrospective collection of 28 patients with various extents of involvement, reported favorable outcomes with upfront posaconazole or isavuconazole without any preceding intravenous antifungal therapy [14]. These observations need to be studied more for wider use. The reduced mortality and improved treatment success rates in our study may be related to the reductions in the duration of hospital stay, central line-related complications, and polyene-related toxicities.
The efficacy and safety of lipid emulsion amphotericin B in treating diabetes or COVID-19 associated mucormycosis was also studied. We intentionally did not pre-specify the agent to be used because liposomal amphotericin B is not a feasible option in resource-limited areas and the toxicity of deoxycholate amphotericin B could be minimized by shortening the duration of therapy. Most patients received deoxycholate amphotericin B (55%; 138/251), many of whom developed renal toxicity (61%; 84/138). In most patients (82% [70/85]), renal injury reversed on stopping therapy. Renal replacement therapy was not required. Interestingly, renal toxicity was less with lipid emulsion than liposomal amphotericin B [13% (10/75) versus 29% (10/35)] as reported earlier [15]. Although lipid emulsion is safer than conventional and liposomal preparations, its clinical efficacy is not known in patients with diabetes or COVID-19 associated mucormycosis or CNS involvement [16,17]. Of the 41 studies reporting at least ten patients with diabetes-associated mucormycosis (Appendix 1), only eight included patients receiving lipid complexes, and none reported outcomes specific to the agents used. Of those with CNS involvement, 15/70 (21%) received lipid emulsion amphotericin, and 13/15 (87%) saw treatment success. Hence, lipid emulsion is efficacious and safe for treating patients with all forms of diabetes or COVID-19 associated ROCM [18]. Being cost-effective, it is a promising frontline drug for diabetes or COVID-19 associated mucormycosis, particularly in resource-limited settings.
Although accumulating evidence shows that step-down with posaconazole is effective and safe [5,19], there is no consensus on when to initiate or stop therapy. We continued treatment with sustained release posaconazole tablets for 3–6 months in most patients. Posaconazole tablets showed good efficacy and achieved adequate therapeutic levels in all except two patients. Therapeutic monitoring of posaconazole levels may not be routinely indicated in patients with diabetes or COVID-19 associated mucormycosis as opposed to those with severe immunocompromise [20]. Mild hypokalemia and gastrointestinal disturbances were common side effects. About a fifth of patients developed new onset, or significant worsening of pre-existing hypertension, probably related to pseudo hyperaldosteronism [21]. These patients can be identified by regular monitoring of blood pressure while on posaconazole therapy.
Despite being a single-center observational study, the practical design and execution increased the potential for external validation. Nevertheless, our approach needs to be validated in other centers. The absence of a control arm restricted comparison in the same clinical environment. Many of our patients had recent SARS-CoV-2 infection, which may have affected their final outcomes. Further, although allowing therapy switches between polyenes during the initial phase of management added to the pragmatism of the study, some of the toxicities seen may have been spillovers from previously used agents.
In summary, this study found that short intravenous antifungal therapy followed by sustained release posaconazole tablets was a simple and effective regimen for diabetes or COVID-19 associated mucormycosis involving the paranasal sinuses.
Authors Contribution
GMV and AM conceptualized the study and developed the study protocol. GMV, AM, KB, BM and ED developed the methodology. GMV acquired funding. GMV, AM, SSK, LV, BSM and DD provided oversight and supervision. MM, PP, PS and ED did the statistical analysis. ED and KB did project administration, oversaw data collection and management. ED, KB, AM, GMV, SSK and MMG accessed and verified the data. GMV, AM, ED and KB wrote the original draft of the manuscript.LV, ReK, LMC, DD, MMG, SSK, RK, HV, JP, JSM, MT, BSM and VR provided critical review and edited the original draft. All authors had access to the raw data, reviewed and approved the final manuscript, and agreed to the submission for publication.
Funding
This study is supported by the institutional research grant of Christian Medical College, Vellore [grant number 12930/2020]. The funders were not involved in the study design, collection, analysis or interpretation of data, writing of the report, or in the decision to submit the paper for publication.
Conflict of Interest
Authors have no conflicts of interest to declare.
Ethical Approval Statement
The study was approved by the Institutional Review Board and Ethics Committee of Christian Medical College, Vellore (No. 12930/24.06.2020).
Acknowledgements
None.
Handling Editor: Mical Paul
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.cmi.2023.06.017.
Appendix A. Supplementary data
The following is/are the supplementary data to this article:
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