Amphotericin B, itraconazole, posaconazole and isavuconazole minimum inhibitory concentration against 85 strains of Rhizopus spp, isolated from the patients having COVID-19 associated mucormycosis in North India
DOI:
https://doi.org/10.18203/2394-6040.ijcmph20240276Keywords:
CAM, R. homothallicus, R. arrhizus, R. microsporus, SARS-CoV-2Abstract
Background: Mucormycosis cases are managed by extensive debridement of the affected tissues, with correction of predisposing risk factors and antifungal drugs. Amphotericin B is the drug of choice; however, few azoles also have a good activity against Mucorales. Therefore, the present study was done to determine the minimum inhibitory concentration (MIC) of antifungal drugs against Mucorales, causing COVID-19 associated mucormycosis in North India.
Methods: After obtaining written and informed consent, we processed the received tissue, sputum, and gastric lavage samples as per standard mycological procedures. Subsequently, we determined itraconazole, posaconazole, isavuconazole and amphotericin B MIC against the isolated Mucorales (one from each patient) by broth microdilution using CLSIM38A3 guidelines.
Results: We received 615 samples from the enrolled 269 patients with CAM. We observed broad aseptate hyphae in 329 fresh tissues, ten sputum and one gastric lavage sample, whereas 163 follow-up excised tissue had broad aseptate hyphae. In addition, 209 Mucorales were isolated with a predominance of Rhizopus arrhizus (n=183), followed by Rhizopus microsporus (n=21) and Rhizopus homothallicus (n=5). We determined MIC against 77 and 8 strains of R. arrhizus and R. microsporus, respectively. Posaconazole had the least MIC. 0.25, 1, 0.5, and 2µg/ml were the MIC50 of posaconazole, amphotericin B, isavuconazole and itraconazole against R. arrhizus strains, respectively, whereas it was 0.125, 0.1875, 0.5 and 2 µg/ml against R. microsporus, respectively.
Conclusions: Lower posaconazole MIC makes it a preferred drug for managing the mucormycosis cases; however, availability and cost are the limitations. Thus, amphotericin B and itraconazole may be used in such conditions.
References
Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India. Diabetes Metab Syndr. 2021;15(4):102146.
Patel A, Kaur H, Xess I, Michael JS, Savio J, Rudramurthy S, et al. A multicentre observational study on the epidemiology, risk factors, management and outcomes of mucormycosis in India. Clin Microbiol Infect. 2020;26(7):944.e9-944.e15.
Chakravarty J, Gupta MK, Tilak R, Maurya RP, Kumar N, Agarwal SK, et al. J Diabetes Complications. 2022;36(9):108284.
Banerjee M, Pal R, Bhadada SK. Intercepting the deadly trinity of mucormycosis, diabetes and COVID-19 in India. Postgrad Med J. 2022;98(e2):e108-9.
Nett JE, Andes DR. Antifungal agents: spectrum of activity, pharmacology, and clinical indications. Infect Dis Clin North Am. 2016;30(1):51-83.
Preserving yeast and mold isolates. Available at: https://www.cdc.gov/fungal/lab-professionals/preserving-yeasts.html. Accessed on 6 April 2023.
Clinical and Laboratory Standards Institute (CLSI) Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi. 3rd ed. CLSI; Wayne, PA, USA. 2017;M38-A3.
Espinel-Ingroff A, Chakrabarti A, Chowdhary A, Cordoba S, Dannaoui E, Dufresne P, et al. Multicenter evaluation of MIC distributions for epidemiologic cutoff value definition to detect amphotericin B, posaconazole, and itraconazole resistance among the most clinically relevant species of Mucorales. Antimicrob Agents Chemother. 2015;59:1745-50.
Gupta MK, Kumar N, Dhameja N, Sharma A, Tilak R. Laboratory diagnosis of mucormycosis: Present perspective. Fam. Med. Prim. Care Rev Care. 2022;11(5):1664.
Samprathi M, Jayashree M. Biomarkers in COVID-19: an up-to-date review. Front. Pediatr. 2021;8:972.
Ghuman H, Voelz K. Innate and adaptive immunity to mucorales. J Fungi. 2017;3(3):48
Lecube A, Pachón G, Petriz J, Hernández C, Simó R. Phagocytic activity is impaired in type 2 diabetes mellitus and increases after metabolic improvement. PloS One. 2011;6(8):e23366.
Gupta M, Chandra A, Prakash P, Banerjee T, Maurya OP, Tilak R. Fungal keratitis in north India; Spectrum and diagnosis by Calcofluor white stain. Indian J Med Microbiol. 2015;33(3):462.
Gupta P, Malhotra HS, Saxena P, Singh R, Shukla D, Hasan MS, et al. Utility of itraconazole and terbinafine in mucormycosis: a proof-of-concept analysis. J Investig Med. 2022;70:914-8.
Ponce-Rosas L, Gonzales-Zamora J, Diaz-Reyes N, Alarco-Cadillo O, Alave-Rosas J. Rhino-Orbital-Cerebral Mucormycosis in a Post-COVID-19 Patient from Peru. Case Rep Infect Dis. 2022;2022.
Mehta RM, Bansal S, Kalpakkam H. Critical COVID-19-associated pulmonary mucormycosis: The underreported life-threatening spectrum of the mucormycosis epidemic. Lung India. 2022;39(2):187-90.
Kaur H, Kanaujia R, Rudramurthy SM. Rhizopus homothallicus: An emerging pathogen in era of COVID-19 associated mucormycosis. Indian J Med Microbiol. 2021;39(4):473-4.
Heykants J, Van Peer A, Van de Velde V, Van Rooy P, Meuldermans W, Lavrijsen K, et al. The clinical pharmacokinetics of itraconazole: an overview. Mycoses 1989;32(1):67-87.
Borman AM, Fraser M, Patterson Z, Palmer MD, Johnson EM. In vitro antifungal drug resistance profiles of clinically relevant members of the mucorales (mucoromycota) especially with the newer triazoles. J Fungi. 2021;7(4):271.
SM G, Clissold SP. Itraconazole. Itraconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs. 1989;37(3):310-44.
Greenberg RN, Mullane K, Van Burik JA, Raad I, Abzug MJ, Anstead G, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother. 2006;50(1):126-33.
Kanafani ZA, Perfect JR. Resistance to antifungal agents: mechanisms and clinical impact. Clin. Infect. Dis. 2008;46(1):120-8.
