Antifungal prophylaxis with nebulized amphotericin-B in solid-organ transplant recipients with severe COVID-19: a retrospective observational study.

COVID-19-associated pulmonary aspergillosis (CAPA) has emerged as a frequent complication in the intensive care unit (ICU). However, little is known about this life-threatening fungal superinfection in solid organ transplant recipients (SOTRs), including whether targeted anti-mold prophylaxis might be justified in this immunosuppressed population. We performed a multicentric observational retrospective study of all consecutive ICU-admitted COVID-19 SOTRs between August 1, 2020 and December 31, 2021. SOTRs receiving antifungal prophylaxis with nebulized amphotericin-B were compared with those without prophylaxis. CAPA was defined according the ECMM/ISHAM criteria. Sixty-four SOTRs were admitted to ICU for COVID-19 during the study period. One patient received antifungal prophylaxis with isavuconazole and was excluded from the analysis. Of the remaining 63 SOTRs, nineteen (30.2%) received anti-mold prophylaxis with nebulized amphotericin-B. Ten SOTRs who did not receive prophylaxis developed pulmonary mold infections (nine CAPA and one mucormycosis) compared with one who received nebulized amphotericin-B (22.7% vs 5.3%; risk ratio 0.23; 95%CI 0.032-1.68), but with no differences in survival. No severe adverse events related to nebulized amphotericin-B were recorded. SOTRs admitted to ICU with COVID-19 are at high risk for CAPA. However, nebulized amphotericin-B is safe and might reduce the incidence of CAPA in this high-risk population. A randomized clinical trial to confirm these findings is warranted.

Treatment of pulmonary mucormycosis with adjunctive nebulized amphotericin B (MUCONAB trial): Results of an open-label randomized controlled trial.

BACKGROUND: The role of nebulized amphotericin B (NAB) in managing pulmonary mucormycosis (PM) is unknown. METHODS: In this open-label trial, we randomized PM subjects to receive either intravenous liposomal amphotericin B (control arm, 3-5 mg/kg/day) alone or along with nebulized amphotericin B deoxycholate (NAB, 10 mg twice a day, every alternate day). The primary outcomes were: (1) overall response ('success' [complete or partial response] or 'failure' [stable disease, progressive disease, or death]) at 6 weeks; and (2) the proportion of subjects with adverse events (AE). The key secondary outcome was 90-day mortality. We performed a modified intention-to-treat (mITT) analysis where we included only subjects receiving at least a single dose of NAB. RESULTS: Fifteen and 17 subjects were randomized to the control and NAB arms; two died before the first dose of NAB. Finally, we included 30 subjects (15 in each arm; mean age 49.8 years; 80% men) for the mITT analysis. Diabetes mellitus (n = 27; 16/27 were COVID-19-associated PM) was the most common predisposing factor. The overall treatment success was not significantly different between the control and the NAB arms (71.4% vs. 53.3%; p = .45). Twenty-nine subjects experienced any AE, but none discontinued treatment. The 90-day mortality was not significantly different between the control (28.6%) and NAB arm (53.3%; p = .26). CONCLUSION: Adjunctive NAB was safe but did not improve overall response at 6 weeks. A different dosing schedule or nebulized liposomal amphotericin B may still need evaluation. More research is needed to explore other treatment options for PM.

Utility of itraconazole and terbinafine in mucormycosis: a proof-of-concept analysis.

An epidemic of mucormycosis followed the second wave of COVID 19 in the state of Uttar Pradesh, India in May 2021. This epidemic, however, had additional challenges to offer in the form of acute shortage of all forms of amphotericin B, posaconazole and isavuconazole. It was, therefore, planned to assess the trends in minimum inhibitory concentration (MIC) of antifungal agents, viz itraconazole and terbinafine, and provide a template for personalized therapy to see whether the results could be translated clinically. This is an observational, single-center study. Samples comprising nasal swab, nasal and paranasal sinus tissue, brain tissue, brain abscess and orbital content, derived from 322 patients from northern India with mucormycosis, of whom 215 were male and 107 were female, were used for analysis. Cultures were identified both by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and conventional methods of identification. Antifungal susceptibility was done for amphotericin B, posaconazole, isavuconazole, itraconazole and terbinafine as per Clinical Laboratory Standard Institute M38-A2. The outcome was identification of the species of mucormycosis and susceptibility to itraconazole and terbinafine besides other primary antifungal agents. Patients or the public were not involved in the design, or conduct, or reporting or in the dissemination plans of our research. Of 322 patients, 203 were culture-positive, of whom 173 were positive by both MALDI-TOF and conventional methods of identification. Final antifungal susceptibility testing was available for 150 patients. The most common Mucorales found to cause this epidemic was Rhizopus oryzae, followed by R. microsporus Amphotericin B, posaconazole and isavuconazole had low MIC values in 98.8% of all Mucorales identified. The MIC of itraconazole was species-dependent. 97.7% of Roryzae had MIC ≤2 µg/mL. However, only 36.5% of Rmicrosporus had MIC ≤2 µg/mL. For terbinafine, 85.2% of R. microsporus had MIC ≤2 µg/mL. We conclude that identification at the species level is required as antifungal susceptibilities seem to be species-dependent. Assessment of the efficacy of itraconazole and terbinafine warrants further studies with clinical assessment and therapeutic drug monitoring as they seem to be potential candidates especially when the primary agents are not available.

Mucormycosis: The hidden and forgotten disease.

Mucormycosis is a rare but serious fungal infection caused by a group of moulds called mucormycetes. More attention has recently been paid to it due to its association with coronavirus disease 2019 (COVID-19). Thus, it is important to review the progress of studies on mucormycosis and highlight the important findings in relation to epidemiology, clinical manifestation, major risk factors, diagnostic strategies and management. An electronic literature search was performed in PubMed using the keywords: Rhizopus, Mucorales, mucormycosis, zygomycosis, zygomycetes, COVID-19, the drugs (azoles, posaconazole, isavuconazole, amphotericin B pharmaceutical preparations and caspofungin), combination therapy, diagnosis and clinical manifestations. Studies written in the English language from January 1960 to 2021 were considered for this review article. All search results were reviewed, and the relevance of each article was determined by the authors independently. The review emphasized the fact that the diagnosis of mucormycosis is difficult, it is necessary to have a high index of suspicion to identify it, surgical debridement should be done prior to the dissemination of infection to improve clinical outcomes and identifying underlying risk factors is important for proper treatment. Moreover, antifungal therapeutic options are few with polyenes and their combinations should be appropriate for empirical therapy while posaconazole and isavuconazole are best reserved for de-escalation, refractory cases or patients intolerant to amphotericin B.

To evaluate the efficacy of topical anti-fungal therapy in postoperative cases of COVID Associated Mucormycosis (CAM): A single-blinded randomized control trial.

PURPOSE: To compare the efficacy of 0.1 % w/w Liposomal Amphotericin-B gel with 10 % w/w Povidone-Iodine and saline nasal douching in preventing revision surgery in patients with CAM. STUDY DESIGN: Multi-arm, parallel randomized control trial. STUDY SETTING: The trial was conducted in the Department of ENT, All India Institute of Medical Sciences (AIIMS) Bhubaneswar. METHODS: Participants: Microbiologically and histologically proven cases of mucormycosis who underwent surgical debridement were included in the study. INTERVENTIONS: Postoperatively, patients were randomized into three groups based on the type of topical intervention received, in the form of Lipid-based Amphotericin B gel, povidone­iodine ointment or saline nasal douching. OUTCOME: Requirement of revision surgery in postoperative cases of CAM. RANDOMIZATION: Participants were allotted to one of the three arms by block randomization. BLINDING: Single-blinded trial. RESULTS: Numbers randomized: 15 participants were randomized to each group. Recruitment: Completed recruiting. Numbers analyzed: 15 participants were analyzed in each group. OUTCOMES: Control arm's risk of revision surgery was 4.50 (95 % CI: 1.16-17.44) times than Lipid-based Amphotericin B gel arm and 1.50 (95 % CI: 0.71-3.16) times that of the Povidone- Iodine arm. The difference was statistically significant (p = 0.02) for Amphotericin but not for Povidone-Iodine. CONCLUSIONS: Topical Amphotericin-B gel application in the postoperative cavity can decrease the need for revision surgery and help in early recovery. TRIAL REGISTRATION: CTRI/2021/10/037257. Clinical Trials Registry of India.

Endogenous Fungal Endophthalmitis following COVID-19 Hospitalization: Evidence from a Year-Long Observational Study.

PURPOSE: To describe cases of endogenous fungal endophthalmitis (EFE) post-recovery from or hospitalization for coronavirus disease 2019 (COVID-19). METHODS: This prospective audit involved patients with suspected endophthalmitis referred to a tertiary eye care center over a one-year period. Comprehensive ocular examinations, laboratory studies, and imaging were performed. Confirmed cases of EFE with a recent history of COVID-19 hospitalization±intensive care unit admission were identified, documented, managed, followed up, and described. RESULTS: Seven eyes of six patients were reported; 5/6 were male, and the mean age was 55. The mean duration of hospitalization for COVID-19 was approximately 28 days (14-45); the mean time from discharge to onset of visual symptoms was 22 days (0-35). All patients had underlying conditions (5/6 hypertension; 3/6 diabetes mellitus; 2/6 asthma) and had received dexamethasone and remdesivir during their COVID-related hospitalization. All presented with decreased vision, and 4/6 complained of floaters. Baseline visual acuity ranged from light perception (LP) to counting fingers (CF). The fundus was not visible in 3 out of 7 eyes; the other 4 had "creamy-white fluffy lesions" at the posterior pole as well as significant vitritis. Vitreous taps were positive for Candida species in six and Aspergillus species in one eye. Anti-fungal treatment included intravenous amphotericin B followed by oral voriconazole and intravitreal amphotericin B. Three eyes underwent vitrectomy; the systemic health of two patients precluded surgery. One patient (with aspergillosis) died; the others were followed for 7-10 months - the final visual outcome improved from CF to 20/200-20/50 in 4 eyes and worsened (hand motion to LP) or did not change (LP), in two others. CONCLUSION: Ophthalmologists should maintain a high index of clinical suspicion for EFE in cases with visual symptoms and a history of recent COVID-19 hospitalization and/or systemic corticosteroid use - even without other well-known risk factors.

Pharmacovigilance study of amphotericin B for mucormycosis in post-COVID and non-COVID patients at a tertiary care hospital in Eastern India.

BACKGROUND: Mucormycosis is a rare but serious fungal infection which has dramatically increased in post-COVID patients. There is a paucity of safety data on amphotericin B (amphoB) used for mucormycosis treatment. OBJECTIVES: The objective of this prospective, observational, active safety surveillance study was to evaluate the safety profile of amphoB in a cohort of hospitalized patients who were on the drug for suspected mucormycosis. MATERIALS AND METHODS: All suspected adverse drug reactions (ADRs) in hospitalized mucormycosis patients who had received amphoB were analyzed. The nature, severity, outcome of the ADRs were recorded and analyzed. RESULTS: Of the 77 patients enrolled, 70% had documented history of prior COVID-19 infection. 96% had comorbidities, the most common being diabetes. Majority received conventional amphotericin B deoxycholate formulation. 97% experienced at least one suspected ADR and the median ADR/patient was 3. Out of 214 ADRs, 91 were serious but there were no ADR-related deaths. The most common ADRs were hypokalemia (31.78%), infusion-related reactions (22.43%), and anemia (17.29%). Thirty-three patients had serum potassium <2.5 mEq/L, while 11 had serum magnesium <1.25 mg/dL. Doubling of pretreatment creatinine level was noted in 15 patients. Seventy percent ADRs were of "possible" category as per the World Health Organization Uppsala Monitoring Centre categorization. CONCLUSION: AmphoB deoxycholate use in mucormycosis patients was associated with a high incidence of electrolyte abnormalities and infusion-related reactions. All ADRs subsided with medical management and none were fatal. The safety data generated from this study may be useful in resource-limited settings where the far more expensive liposomal formulation is not being used.

Long-term outcomes of transcutaneous retrobulbar amphotericin B in COVID-19-associated mucormycosis.

Purpose: To describe the long-term outcomes of transcutaneous retrobulbar amphotericin B (TRAMB) in COVID-19-associated mucormycosis. Methods: In total, 18 cases of COVID-19-associated mucormycosis were reviewed. In addition to the recommended treatment protocol, all patients were to be given 3.5 mg/ml/day of TRAMB for five days. Results: Of the 18 patients, 2 presented with stage 3a disease, 13 had stage 3c disease, and 3 patients had central nervous system (CNS) involvement (stage 4a and 4c). In addition to planned retrobulbar doses, five patients were given more while two patients received fewer injections (i.e., <5). At the last mean follow-up of 34.67 (±8.88) weeks, 11 patients were in radiological regression and 4 had stable disease while 2 patients had to undergo exenteration; one mortality was observed because of disease progression. Clinical regression in terms of visual and ptosis improvement was seen in seven and nine patients, respectively. Conclusion: Rhino-orbito-cerebral mucormycosis is a serious condition which warrants an aggressive treatment strategy. In unprecedented situations witnessed recently, TRAMB turned out to be an effective and economical alternative. Though large randomized studies are needed to establish its efficacy, TRAMB still manages to halt progression and salvage the globe in significant number of patients, and hence its use should be encouraged on a case-to-case basis especially in developing countries with limited resources.

Mortality and its determinants after an outbreak of post COVID-19 associated rhino-orbito-cerebral mucormycosis in Central India.

AIM: To report cumulative mortality rates using survival analysis from an outbreak of 211 patients with post COVID-19 rhino-orbito-cerebral mucormycosis (ROCM) in central India. METHODS: Case files of eligible patients were evaluated and mucor was identified from deep nasal swabs using freshly prepared KOH mount. All patients underwent contrast enhanced MRI and disease staging was done based on the extent of anatomical involvement. All patients received intravenous Amphotericin B and sinus debridement was done when possible. Orbital exenteration was reserved for patients with advanced orbital disease. RESULTS: The mean age was 50.7 ± 10.2 of which 147 (70%) were men. At presentation, ROCM was limited to sinuses in 72 (34%), orbital extension was seen in 102 (48%) and 31 (15%) had CNS extension. Sinus debridement was possible in 82% cases (n = 173). Thirty-five (16.6%) patients died due to ROCM. The mean follow-up of patients who survived was 126.6 ± 16.4 days. The cumulative mortality rate at day 10 was 4.8% (95%CI = 2.6-8.8%) and increased 13.1% (95%CI = 9.1-18.7%) at day 30 and to 18.4% (95%CI = 13.6-24.8%) at day 60. Majority of deaths (n = 26, 75%) occurred within 1-month of ROCM presentation. Multivariable hazards analysis showed that patients with CNS involvement had a 6.5 times higher risk of death (Hazard Ratio = 6.71, 95% CI = 2.9-15.5, p < 0.001). CONCLUSION: We report significantly lower mortality rates compared to recent literature that varies from 30 to 80% at 1-month follow-up. Timely sinus debridement and systemic Amphotericin B can help reduce mortality. Presence of CNS extension significantly increased the mortality risk with patients with ROCM.

Rhizopus microsporus as Causative Agent of Mucormycosis in COVID-19 Patient.

BACKGROUND: The pandemic of coronavirus disease (COVID-19) emerged as a fatal infection, especially in immunocompromised patients. Currently, this infection is managed with systemic corticosteroids. Co-infection of CO-VID-19 with opportunistic fungi is increasingly recognized. METHODS: We describe a case of rhino-cerebral mucormycosis 12 days following severe COVID-19 in a diabetic patient. RESULTS: He received 50 mg amphotericin B and surgical debridement. The patient's symptoms improved following medical and surgical intervention. CONCLUSIONS: Mucormycosis is an uncommon but serious infection that complicates the course of severe COVID-19. Subjects with diabetes mellitus and multiple risk factors may be at a higher risk for developing mucormycosis.

Microbiology Profile of COVID-19-Associated Rhino-Orbital Mucormycosis Pathogens in South India.

This study describes the microbiological and histopathological features of patients with COVID-19-associated rhino-orbital mucormycosis (ROM) seen at the L V Prasad Eye Institute between May and August 2021. Diagnosed clinically and radiologically, 24 patients with ROM were included in the study. Deep nasal swabs or endoscopically collected nasal swabs or orbital tissues were submitted for microbiological evaluation and in vitro susceptibility testing by microbroth dilution for natamycin, amphotericin B, caspofungin, posaconazole, ketoconazole, and voriconazole. Cultures were processed by 28S ribosomal DNA polymerase chain reaction and molecular sequencing. A portion of orbital tissues was also sent for histopathological evaluation. The age of the patients ranged from 27 to 75 (mean 48.58 ± 14.09) years and the majority (79%) were male. Nineteen patients were known to be diabetic prior to developing ROM and 18 patients had recovered from active COVID-19 infection. Thirteen patients had a history of hospitalization during COVID-19 infection and eight received steroids. Of the 24 samples, microbiological evaluation identified Rhizopus arrhizus in 12, Rhizopus microsporus in 9, Lichtheimia ramosa in 2, and Rhizopus delemar in 1. Twelve isolates were tested for antifungal susceptibility and all were susceptible to natamycin and amphotericin B. The susceptibility to posaconazole was high, with minimum inhibitory concentration (MIC) < 2 µg/mL for 10/12 (84%) isolates, whereas the MIC of other drugs varied. Histopathological examination of tissues showed acute fulminant disease, granuloma formation, and vascular invasion by the fungal pathogens in these specimens. Rhizopus arrhizus was predominantly associated with ROM and most isolates were susceptible to amphotericin B and posaconazole. Further studies are needed to corroborate the findings and explain possible underlying links.

Corneal manifestations and treatment among patients with COVID-19-associated rhino-orbito-cerebral mucormycosis.

Purpose: TO report the corneal manifestations in patients with COVID-19-associated rhino-orbito-cerebral mucormycosis (ROCM). Methods: This study was a retrospective, observational, and record-based analysis of patients of ROCM with corneal involvement. Results: A total of 220 patients were diagnosed with ROCM over a period of 3 months. Thirty-two patients had developed corneal manifestations. The mean age at diagnosis was 52.84 ± 12.8 years. The associated risk factors were systemic mucormycosis, uncontrolled diabetes, recent COVID-19 infection, and injudicious use of systemic steroids. Twenty-nine patients were known diabetics, 32 had recent COVID-19 infection, and 13 gave a history of injudicious use of steroids. The right eye (RE) was affected in nine patients, the left eye (LE) in 20 patients, and both eyes in three patients. Nine patients had a round-oval corneal ulcer. One patient each had a perforated corneal ulcer with uveal prolapse, sealed perforated corneal ulcer, spontaneously healed limbal perforation, diffuse corneal haze with hyphemia, panophthalmitis, diffuse corneal stromal abscess, limbal ischemia, anterior uveitis with posterior synechiae, inferior corneal facet, and filamentary keratitis. Three patients each had a corneal melt and inferior conjunctival xerosis with chemosis. Orbital exenteration was performed in six patients. Five patients with corneal ulcers healed. Topical eye drops of amphotericin (0.5 mg/ml) cycloplegic, antiglaucoma medications, and lubricant eye drops were started along with systemic antifungals. Conclusion: Central corneal ulcer was the most common manifestation of mucormycosis. A concentration as low as 0.5 mg/ml of amphotericin eye drops was effective in the treatment.

Retrospective analysis of the role of retrobulbar amphotericin-B injection in the management of COVID-19 associated rhino-orbito-cerebral-mucormycosis.

Introduction: Rhino-orbito-cerebral-mucormycosis (ROCM) is the most common form of mucormycosis observed during the second wave of COVID-19 where a steep rise in the number of cases was seen. The orbital form is almost always associated with fungal sinusitis. Among the various treatment modalities available, the role of retrobulbar Amphotericin-B injections is under-reported. This study is conducted to determine the role of transcutaneous retrobulbar amphotericin-B (TRAMB) in the management of COVID-19 associated ROCM. Methods: a retrospective analysis of 61 patients of COVID-19 associated ROCM was done, who met the inclusion criteria and presented to a tertiary care center, between May to August 2021. These patients were administered TRAMB (deoxycholate/emulsion form) along-with systemic amphotericin B. All the patients were evaluated for clinical improvement. Results: out of 61 patients, 58 (95.08%) showed overall improvement. 40 patients (65.57%) stabilized or improved clinically and 3 patients succumbed to the illness due to advanced systemic mucormycosis and acute kidney failure. Sixteen out of 58 patients underwent orbital exenteration. Out of remaining 43 patients, 35 showed complete recovery of orbital and ocular disease and the disease stabilized in eight patients. Seven patients demonstrated TRAMB associated ocular complications which however completely resolved in six patients. Conclusion: to the best of the author´s knowledge, regression of orbital mucormycosis with improvement in ptosis, proptosis, ocular motility and stabilization of visual acuity are scarcely reported in literature. Further TRAMB as a globe non-deforming treatment modality is an option available for ROCM.

Candida Albicans Sub-Retinal Abscess following COVID-19.

A 42-year-old male post-renal transplantation presented with sudden diminution of vision in the left eye. The right eye was lost following a failed vitreoretinal surgery 5 years ago. The patient had been hospitalized 4 months prior for coronavirus disease 2019 infection with a good recovery. The presenting visual acuity was 20/600 in the right eye and 20/250 in the left eye. Fundus examination revealed a sub-macular sub-retinal abscess in the left eye. Sub-retinal aspiration of the abscess revealed Candida albicans. The patient was managed with repeated intravitreal amphotericin B injections, following which the abscess resolved with scarring and vision improving to 20/60.

Exploring the globe salvaging treatment options in patients of COVID-19-associated mucormycosis with orbital involvement.

Purpose: To explore the various globe salvaging treatment strategies for patients with coronavirus disease 2019-associated mucormycosis (CAM). Methods: This was a prospective: interventional analytical study conducted at a Medical College in rural India. A total of 84 patients of CAM admitted between May 2021 and August 2021 were enrolled for the study. Patients with histologically proven CAM with clinical and/or radiological evidence of orbital involvement were divided into three treatment categories based on the site and extent of the lesion. Re-assessment was performed after 7 days. For patients who worsened with the primary approach, orbital exenteration was considered based on a Sion Hospital Scoring System. A novel approach to intra-orbital anti-fungal therapy, site-centered peri-bulbar injection of amphotericin B (SCPeriAmB), was also explored. All the patients were followed up for at least 3 months. Convenience sampling with descriptive statistics was used. Results: Six patients had to finally undergo exenteration by the end of the study period. The rest of the patients were reported to be stable or improved. No mortalities were reported on delaying the exenteration. No adverse events were noted in patients who were given SCPeriAmB. Conclusion: Globe salvaging treatment options should be advocated as a primary approach in patients with CAM. Site-centered peri-bulbar injections can be considered as an approach for delivering intra-orbital anti-fungal therapy in selected patients.

Indications that the Antimycotic Drug Amphotericin B Enhances the Impact of Platelets on Aspergillus.

Platelets are currently thought to harbor antimicrobial functions and might therefore play a crucial role in infections, e.g., those caused by Aspergillus or mucormycetes. The incidence of invasive fungal infections is increasing, particularly during the coronavirus disease 2019 (COVID-19) pandemic, and such infections continue to be life-threatening in immunocompromised patients. For this reason, the interaction of antimycotics with platelets is a key issue to evaluate modern therapeutic regimens. Amphotericin B (AmB) is widely used for the therapy of invasive fungal infections either as deoxycholate (AmB-D) or as a liposomal formulation (L-AmB). We showed that AmB strongly activates platelets within a few minutes. AmB concentrations commonly measured in the blood of patients were sufficient to stimulate platelets, indicating that this effect is highly relevant in vivo. The stimulating effect was corroborated by a broad spectrum of platelet activation parameters, including degranulation, aggregation, budding of microparticles, morphological changes, and enhanced adherence to fungal hyphae. Comparison between the deoxycholate and the liposomal formulation excluded the possibility that the liposomal part of L-Amb is responsible for these effects, as no difference was visible. The induction of platelet activation and alteration by L-AmB resulted in the activation of other parts of innate immunity, such as stimulation of the complement cascade and interaction with granulocytes. These mechanisms might substantially fuel the antifungal immune reaction in invasive mycoses. On the other hand, thrombosis and excessive inflammatory processes might occur via these mechanisms. Furthermore, the viability of L-AmB-activated platelets was consequently decreased, a process that might contribute to thrombocytopenia in patients.

Retrobulbar Injection of Amphotericin B in Patients With COVID-19 Associated Orbital Mucormycosis: A Systematic Review.

PURPOSE: Following COVID-19 infection a rising count of rhino-orbito-cerebral mucormycosis is observed, requiring orbital exenteration, a disabling lifetime affecting surgery. One of the potential interventions for globe salvage in these patients is retrobulbar injections of amphotericin B. This study was conducted to review protocols, outcomes, and side effects of retrobulbar injection of amphotericin B in patients with COVID-19 associated rhino-orbito-cerebral mucormycosis (CAM). METHODS: The PubMed, Scopus, Web of Science, and Embase databases were searched using a comprehensive string of relevant keywords. All English studies with the confirmed diagnosis of CAM infection were included. We excluded all studies in which retrobulbar injection of amphotericin B was not implemented in any of the patients or there was a lack of clarified and detailed data about this procedure among participants. RESULTS: A total of 647 cases had a history of retrobulbar injection(s) of amphotericin B in 13 reviewed studies with 3,132 subjects of CAM. The most common protocol was the retrobulbar injection of 1 ml of 3.5 mg/ml liposomal amphotericin B for 3 doses daily or on alternate days. We discerned that the globe salvage rate was 95.0% in eyes with a history of retrobulbar injection(s). The total rate of orbital exenteration was 14.9%, regardless of the history of retrobulbar injection of the drug. Other outcomes of this intervention were vision salvage and reduced major ophthalmic complaints, including pain, swelling, chemosis, ptosis, and ophthalmoplegia. The side effects of this intervention were not serious, and most of them were transient. They included swelling at the injection site, restriction of ocular motilities, exacerbation of orbital inflammation, and even intensification of visual impairment in a few cases. CONCLUSIONS: Retrobulbar injection of amphotericin B should be considered a nearly safe and protective intervention against orbital exenteration in patients with CAM. It may also be effective in saving vision. Since the effectiveness of orbital exenteration in the survival of patients is not ascertained, retrobulbar injections can be considered an alternative intervention.

[Postcovid sino-orbital mucormycosis: a case report]. / Sluchai postkovidnogo sinoorbital'nogo mukormikoza.

We describe a case of postcovid sino-orbital mucormycosis in a 74-year-old patient with diabetes mellitus. Orbital symptoms appeared after discharge from the covid hospital, in the third week of the disease and were represrnted by ptosis, proptosis, ophthalmoplegia, blindness and pain in the right eye, numbness of the right half of the face, edema of the periorbital region and cheek. The diagnosis of mucormycosis was confirmed by fluorescence microscopy of the discharge from the middle nasal meatus. SCT of the paranasal sinuses revealed pansinusitis with predominant destructive changes in the right maxillary, ethmoid and sphenoid sinuses. The patient underwent emergency endoscopic debridment, orbital decompression, orbitotomy; treatment with amphotericin B intravenously was started. 10 days after due to the deterioration of the patient's condition, more aggressive debridment of paranasal sinuses was performed: right maxillary sinus anterior, posterior and medial walls resection, medial orbital wall resection, necrectomy of the nasal cavity, paranasal sinuses, orbit, pterygopalatine fossa. Antifungal treatment was continued in the postoperative period. The patient was discharged on the 22nd day of stay in the ENT hospital.

Development and application of amphotericin B immunoassay for pharmacokinetic studies and therapeutic drug monitoring in critically ill patients.

Amphotericin B (ATB) is a broad spectrum antibiotic used to combat severe systemic fungal and protozoan infections. Existing and new ATB formulations designed to address the problem of poor solubility and side effects of ATB require pharmacokinetic (PK) studies and dosing controls, especially in critically ill patients. Given that, the present study was devoted to development of competitive immunoassay of ATB and its testing on real human serum samples. A novel immunogen design was based on alternative ATB carboxyl-mediated conjugation to tetanus toxoid (TTd). The resulting conjugates retained antifungal (C.albicans) activity, which indicates the preservation and spatial availability of the ergosterol-binding site, bioactive polyene epitope. Antibody generated against click reaction product, TTd-ATB(cuaac), was able to recognize a group of polyenes ATB, nystatin, natamycin and deoxycholate ATB in heterologous ELISA as 100%, 255%, 99% and 70%, respectively. The sensitivity (IC50), detection limit (IC10) and dynamic range of assay (IC20-IC80) were 6.0, 0.1 and 0.6-46 ng/mL, respectively, and made it possible to quantify total and unbound ATB in the therapeutic range of concentrations in serum. ATB recovery from spiked serum samples was in the range of 95-106% and unbound ATB fractions in ultrafiltrates were about 12%. PK parameters were estimated in single COVID-19 patient with secondary lung Rhizopus microspores infection who was treated with ATB and received veno-venous extracorporeal membrane oxygenation.