|ORIGINAL RESEARCH ARTICLE
|Year : 2022 | Volume
| Issue : 6 | Page : 417-422
Pharmacovigilance study of amphotericin B for mucormycosis in post-COVID and non-COVID patients at a tertiary care hospital in Eastern India
Suparna Chatterjee1, Manjari Bhattacharjee1, Avijit Hazra1, Pradip Mukhopadhyay2, Biman Kanti Ray3, Sayan Chatterjee1, Souvik Dubey4
1 Department of Pharmacology, Institute of Postgraduate Medical Education and Research, West Bengal, India
2 Department of Endocrinology and Metabolism, Institute of Postgraduate Medical Education and Research and SSKM Hospital, West Bengal, India
3 Department of Neuromedicine, Bangur Institute of Neurosciences (Under Institute of Postgraduate Medical Education and Research), Kolkata, West Bengal, India
4 Department of Neuromedicine, Bangur Institute of Neurosciences (Under Institute of Postgraduate Medical Education and Research and SSKM Hospital), Kolkata, West Bengal, India
|Date of Submission||02-Jul-2022|
|Date of Decision||03-Dec-2022|
|Date of Acceptance||05-Dec-2022|
|Date of Web Publication||31-Jan-2023|
Department of Pharmacology, Institute of Postgraduate Medical Education and Research, 244B, AJC Bose Road, Kolkata - 700 020, West Bengal
Source of Support: None, Conflict of Interest: None
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.
Keywords: Adverse drug reaction, amphotericin B, COVID-19, mucormycosis, pharmacovigilance
|How to cite this article:|
Chatterjee S, Bhattacharjee M, Hazra A, Mukhopadhyay P, Ray BK, Chatterjee S, Dubey S. Pharmacovigilance study of amphotericin B for mucormycosis in post-COVID and non-COVID patients at a tertiary care hospital in Eastern India. Indian J Pharmacol 2022;54:417-22
|How to cite this URL:|
Chatterjee S, Bhattacharjee M, Hazra A, Mukhopadhyay P, Ray BK, Chatterjee S, Dubey S. Pharmacovigilance study of amphotericin B for mucormycosis in post-COVID and non-COVID patients at a tertiary care hospital in Eastern India. Indian J Pharmacol [serial online] 2022 [cited 2023 Mar 22];54:417-22. Available from: https://www.ijp-online.com/text.asp?2022/54/6/417/368841
| » Introduction|| |
Mucormycosis is a serious but rare fungal infection caused by a group of molds called mucormycetes (Mucorales) whose spores are widely disseminated in the environment. Human infection is uncommon but is serious and can be fatal. Clinically, mucormycosis may manifest in rhino-orbito-cerebral, pulmonary, cutaneous, abdominal, and disseminated forms with varying symptoms like fever, headache, nasal or sinus congestion, black lesions of the nasal bridge or buccal cavity, cough, chest pain, abdominal pain, and skin ulcers., Recently, there has been a dramatic rise of mucormycosis cases in India among post-COVID-19 patients. Many of them are diabetic or have a history of long duration of steroid use which are known risk factors for the disease., Medical management, as of now, includes liposomal amphotericin B (L-amB) in a dose of 5–10 mg/kg/day or amphotericin B deoxycholate (amphoB) in a dose of 1–1.5 mg/kg/day and posaconazole in amphoB resistant cases. Posaconazole is also being used for follow-up oral treatment in patients who have received amphotericin B.
Amphotericin B is a polyene antifungal antibiotic produced by Streptomyces nodosus. It binds to ergosterol, an essential component of the fungal cell membrane, altering membrane permeability and leading to leakage of intracellular components, membrane disintegration, and eventually cell death. This agent may also induce oxidative damage in fungal cells and has been reported to stimulate host immune cells. Amphotericin B, as a broad-spectrum parenteral antifungal, is used in the management of invasive fungal infections such as aspergillosis, blastomycosis, invasive candidiasis, coccidioidomycosis, cryptococcosis, and mucormycosis. Its action may be fungistatic or fungicidal depending on the concentration at the target site and the susceptibility of the fungus. Amphotericin B is also used for the treatment of visceral leishmaniasis and mainly the liposomal preparation is being used for this purpose. L-amB is the preferred formulation as it causes fewer adverse reactions,, but it is far more expensive than the conventional formulation i.e., amphotericin B deoxycholate and is not readily available in resource-limited settings. The conventional formulations are known to cause several adverse drug reactions (ADRs) like infusion-related problems, nephrotoxicity, and electrolyte disturbances, especially hypokalemia and hypomagnesemia.
Our hospital is a tertiary care teaching hospital that is serving as the apex hub for the treatment of mucormycosis cases in Eastern India. During the recent spurt in COVID-19 linked mucormycosis cases, we encountered a large enough patient pool to conceive this focused pharmacovigilance study on amphotericin B in mucormycosis with or without a background of confirmed COVID-19 infection in the recent past. There is a paucity of safety data on amphotericin B used for mucormycosis treatment. The objectives of this prospective study from Eastern India were to characterize the nature, severity, and outcome of the ADRs associated with the use of amphotericin B in a cohort of hospitalized patients with mucormycosis.
| » Materials and Methods|| |
We initiated this prospective, observational, targeted pharmacovigilance study with approval from the institutional ethics committee (IPGME&R/IEC/2021/325). It was conducted in accordance with the Indian Council of Medical Research National Guidelines for Biomedical Research on human participants. Patients, irrespective of age and gender, admitted with a clinical diagnosis of mucormycosis and administered amphotericin B during the period April to September 2021 were recruited. Informed consent was obtained from the patient or a legally acceptable representative.
The patients hailed from different districts of West Bengal in Eastern India, and few from neighboring states of Bihar or Jharkhand. No formal sample size calculation was done and all patients fulfilling the selection criteria were enrolled.
The clinical condition, investigations, amphotericin B use, and other concomitant drug therapy were monitored during the entire hospital stay from admission until discharge or death of the patient. Since the study site is a government teaching hospital with the mandate of providing free services to all patients, the entire cost of drug treatment and diagnostic tests was free from the patient's perspective. Hence, cost was not a limiting factor in monitoring the patients. Collected data were all part of the routine care and no additional research-specific investigations were performed. The monitoring team comprised a multidisciplinary group of clinicians, pharmacologists, and a pharmacist trained in pharmacovigilance. A study-specific case record form was designed to capture the information. Study variables included sociodemographic data, detailed present and past medical history with emphasis on COVID-19 and diabetes, systemic corticosteroid intake, investigations, and treatment of mucormycosis. Details of amphotericin B use (formulation type, dose, frequency, and duration) and other medications were recorded by the team comprising of attending doctors and nurses. Information about all suspected amphotericin B-related treatment emergent adverse events (nature of the event, onset, severity, seriousness, and outcome) were noted. Causality assessment of the suspected ADRs was done by the study team using the World Health Organization-Uppsala Monitoring Center (WHO-UMC) categorization. All recruited patients who had been administered at least one dose of amphotericin B were considered evaluable. Attempts were also made to follow-up these patients over the phone until 2 weeks after discharge. For the few patients who left against medical advice (LAMA) or those who died, data were limited to their period of hospital stay.
Data were summarized using appropriate summary statistics (mean, standard deviation, median, interquartile range [IQR], frequency, and percentage) depending on the nature of the data. Key variables were expressed with 95% confidence interval (CI). Statistical analysis was done using SPSS (Statistical Package for Social Sciences, IBM, USA) software version 20 and 95% CI for proportion was calculated without continuity correction using VassarStats online calculator.
| » Results|| |
During the study period, a total of 77 patients were evaluated, of whom 88.32% were directly admitted and the rest referred from other hospitals. The sociodemographic and clinical characteristics of the patients are listed in [Table 1]. There was a male preponderance (64.94%) among the cases and about 79.22% hailed from rural (panchayat area) or semiurban areas (municipality areas). Age-wise, 61.04% of the patients belonged to 36–59 years category, 32.47% were above 60 years, and none were below the age of 18 years. The study cohort had 50 patients (64.94%) with confirmed diagnosis (reverse transcription polymerase chain reaction or rapid antigen test positive) of prior COVID-19 disease. Majority of the patients had rhino-orbital cerebral mucormycosis and only 3 had pulmonary disease.
|Table 1: Demography and clinical characteristics of the study participants (n=77)|
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Analysis of comorbidities showed that the majority (96%) had one or more comorbidities. Sixty-eight patients (88.31%) had history of diabetes, of whom 8 developed it after COVID-19 infection and the rest were long-standing patients of diabetes. Other comorbidities were hypertension (19), chronic kidney disease (CKD) (10), anemia (26), and thyroid disorders (7). Among those with CKD, there was one who had undergone renal transplant 3 years back and two were on renal replacement therapy. Of the patients who had prior COVID, 35 had a documented history of systemic steroid intake for COVID-19 disease. However, we could not elicit detailed history of dose and duration of systemic steroid use from those patients who could not produce prior hospital admission records.
Antifungal drugs were administered as per the national guidelines for the management of mucormycosis., All patients were hydrated with normal saline before administration of amphotericin B. Participants received amphotericin B deoxycholate at a dose of 1 mg/kg body weight by intravenous infusion in 5% dextrose over 4 to 6 hours for a period of up to 2–3 weeks or longer as per the treatment protocol. However, there were 3 patients with pulmonary mucormycosis who received amphotericin B lipid complex (ABLC) in a dose of 5mg/kg body weight and one patient was on L-amB (procured drug on his own) in a dose of 5 mg/kg. There were two patients who had repeated severe infusion-related reactions despite prophylactic treatment with antiallergic agents and steroids. In them, amphotericin B had to be discontinued and posaconazole was administered instead.
A summary of the ADR profile in the study cohort is provided in [Table 2] and [Figure 1]. Out of 77 patients, 75 (97.4%) experienced at least one suspected ADR during the hospital stay. The number of suspected ADRs per patient varied from 0 to 6 with the median (IQR) at 3 (2 to 4). [Table 3] depicts the different ADRs observed in the study. Out of a total of 214 ADRs, the three most common ones were hypokalemia, infusion-related reactions, and anemia. In patients who had preexisting anemia, further reduction in hemoglobin level was considered as ADR. All ADRs were expected, i.e., listed in the prescribing literature. Of the infusion-related reactions, there were infusion-related chills, rigor, and fever. Although all patients received prophylactic promethazine injection, the incidence of infusion-related reactions was high. Most could be managed conservatively by temporary stoppage of infusion and medications. In 29 out of the 48 infusion-related reactions, rechallenge was positive. There were no cases of anaphylaxis or skin rashes. In two patients, the drug had to be withdrawn due to severe infusion-related fever, chills, and rigor and one patient refused to take any further doses of the drug and were switched over to posaconazole. The latter drug was also used for follow-up domiciliary treatment in discharged cases as needed.
|Table 2: Summary of suspected adverse drug reactions (ADR) to amphotericin B|
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|Table 3: Spectrum of observed adverse drug reaction with suspected drug amphotericin B (n=214)|
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Analysis of the electrolyte abnormalities observed following amphotericin B administration showed that out of the 68 patients who had developed hypokalemia, 33 had quite low levels (serum potassium <2.5mEq/L). Out of the 2 patients who had baseline hyperkalemia due to CKD, one developed hypokalemia following amphoB administration. Majority of the hypokalemia incidences were detected by investigations, i.e., serum level estimation, and some had ECG changes. These patients were treated with potassium chloride supplementation either orally or as intravenous infusion. Of the 17 patients with hypomagnesemia, 11 had a serum magnesium levels <1.25 mg/dL. Review of concomitant medications in these patients revealed that two had CKD and were on diuretics that are known to cause hypokalemia and hypomagnesemia.
Nephrotoxicity observed with amphotericin B included a rise in serum creatinine and acute kidney injury (AKI). Doubling of pretreatment creatinine level was noted in 15 patients and 14 had AKI. Detailed analysis of the patients who had AKI revealed that 12 of them had at least one comorbidity like CKD, hypertension, or diabetes and one had a history of renal transplant and was on tacrolimus and mycophenolate mofetil. Hemodialysis was given to five of the 14 AKI patients. Analysis of the electrolyte profiles showed that 8 out of 10 CKD patients developed hypokalemia and 3 had hypomagnesemia. The 4 CKD patients who developed AKI underwent hemodialysis and were treated accordingly. All CKD patients except one had diabetes and five had hypertension.
Hematological ADRs observed in the study were anemia and pancytopenia. Although 26 patients had anemia before amphotericin B, which may be attributed to several causes, their hemoglobin levels fell further following amphotericin B administration. Out of 37 patients with anemia and 7 patients with pancytopenia, blood transfusions were given to 20. However, it is noteworthy that all these patients had undergone major surgical intervention and four had preexisting advanced stage CKD.
The ADR frequency rates in those with past history of COVID were comparable to those without the disease. There were no deaths attributable to drug-induced reactions. Of the observed ADRs, 91 (42.52%) were considered serious in nature in that they caused significant disability and required medical intervention to avert more serious consequences. Analysis of outcome showed that 82.74% of the patients recovered but complete recovery from hypokalemia and anemia was not noted in 14 patients until the study closed out.
ADR causality analysis was done using the WHO-UMC criteria as already stated; 14.01% were certain, 15.88% probable, and 70.09% were possible. None mapped to other categories. Majority of the instances of hypokalemia, hypomagnesemia, AKI, and raised creatinine levels were of the 'possible' category since dechallenge (drug stoppage or dose reduction) was not clinically warranted in most of the cases, although clinically the reactions were deemed drug related. In contrast, for infusion-related reactions, temporary stoppage of the infusion was often done, and the reactions recurred with reinstitution. Hence, they were categorized as “certain.” Infusion-related reactions often became less frequent or of lesser intensity after 7 to 10 doses.
| » Discussion|| |
The use of the conventional formulation of amphotericin B, the deoxycholate form, is known to be accompanied by various ADRs, most importantly infusion-related reactions and nephrotoxicity, which can be dose limiting. Experience has been gained in a wide variety of invasive fungal infections and, to a lesser extent, in visceral leishmaniasis. However, the clustering of mucormycosis cases offered us the opportunity to undertake a pharmacovigilance study in this condition and till date we have not come across a similar published study. Around 65% of the study cohort had a background history of COVID-19 and about 90% were not vaccinated.
In addition to amphotericin B deoxycholate, there are three formulations of amphotericin B which have been introduced in an attempt to circumvent toxicity, including ABLC, L-amB, and amphotericin B colloidal dispersion. Of these ABLC and L-amB are available in India though they were not in use in our hospital during the study period. It has been reported that the few controlled clinical trials that have been done with the lipid-associated formulations have not demonstrated important clinical differences among these agents and conventional amphotericin B for efficacy, although there are significant safety benefits of the lipid products. Interestingly, a study in children failed to substantiate that the liposomal formulation is safer than the conventional formulation. This study with 76 children reported that when appropriately administered, L-amB was associated with more hepatotoxicity than the conventional formulations with no difference in infusion-related reactions or nephrotoxicity. In our study, of the 77 cases evaluated, 73 received the conventional formulation, leaving us with no scope to compare the ADR profile of the conventional deoxycholate versus lipid-based formulations.
The ADR spectrum we encountered was in line with the known toxicity profile of the drug., Hypokalemia, infusion-related reactions, anemia, hypomagnesemia, raised serum creatinine, and AKI were encountered at a frequency over 5%. Fortunately, most could be managed with supportive treatment, and although some of the ADRS were deemed serious, deaths in our study participants were attributed to disease severity rather than drug toxicity. Although the spectrum revealed no surprise, the overall frequency of ADR was high compared with some earlier studies., This may logically be attributed to the longer duration of drug use (69% for at least 2 and 30% for at least 3 weeks) in mucormycosis cases compared to other indications for amphotericin B usage.
All reactions captured in this study were attributable to amphotericin B through expert judgment. However, because of the inherent difficulty in formal dechallenge and rechallenge, the causality status of most reactions remained at either probable (15.88%) or possible (70.09%) by WHO-UMC criteria. 'Certain' status was attributable to only 14.01% of instances, mostly of infusion-related reactions where rechallenge occurred automatically with subsequent doses. This is a situation common to hospital-based pharmacovigilance studies., We used the WHO-UMC criteria to deduce causality. Review of the expectedness has revealed that the ADR profile conforms to the known spectrum of Amphotericin B reactions when used in invasive fungal infections, although the frequency of occurrence varied. We also observed that the frequencies of ADR (hypokalemia, infusion-related reactions, anemia, hypomagnesemia, and raised creatinine level) were similar among those with or without documented history of Covid. Due to inadequacies in archival of documents pertaining to history of Covid, we feel that the number of participants with past history of COVID could be marginally more. However, this is an inherent limitation of all real world studies.
| » Conclusion|| |
To the best of our knowledge, this study is perhaps the first pharmacovigilance study on amphotericin B conducted on a relatively large cohort of mucormycosis patients from Eastern India. Significant proportions of patients were post-COVID who had preexisting comorbidities, and underwent major surgical interventions. We could also compute the frequency of occurrence of different ADRs unlike spontaneous ADR reporting strategies where such computation is not possible.
Liposomal and lipid complex formulations of amphotericin B are more widely used globally than the deoxycholate formulation because of better safety profile. However, the newer formulations are far more expensive than conventional amphotericin B. Therefore, in resource-limited settings where L-amB may not be affordable, especially for indications which require a long duration of therapy, our study has generated robust safety data of amphotericin B deoxycholate formulation
Our study also has its share of limitations. Patients were receiving multiple medicines for comorbidities and it is possible that some reactions may be attributed to drug–drug interactions, rather than due to amphotericin B alone, which aspect may have eluded us. As already stated, we are not in a position to say whether lipid formulations of amphotericin B would have been better tolerated than the conventional formulation in this setting. Despite these limitations, we can say that, overall, this study has generated a profile of adverse reactions to amphotericin B in the setting of hospitalized mucormycosis patients who were managed both surgically and medically. The clinical and diagnostic profile of patients who were admitted until June 2021 in our institution has been reported elsewhere. This study adds information related to likely ADR in critically ill mucormycosis patients. Opportunities for such reporting will be seldom and the information may be particularly useful in resource-limited settings where conventional amphotericin B is still used instead of the more expensive lipid formulations.
Finally, we may conclude that the ADR spectrum we encountered was in line with the known toxicity profile of the drug. However, it might be worth having safety data specifically in this patient population and where long-term drug administration is required.
We wish to thank the:
- Director of Institute of Postgraduate Medical Education and Research and the Medical Superintendent cum Vice Principal of SSKM
- Entire Mucormycosis treating team- doctors, nursing personnel, paramedical staff of the wards and ITU for their assistance in data collection
- National Coordinating Centre of the PVPI as Miss Manjari Bhattacharjee is a Pharmacovigilance Associate under the Pharmacovigilance Program of India.
Financial support and sponsorship
The resources of the Department of Pharmacology of the Institute were utilized.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]