|CLINICAL RESEARCH ARTICLES
|Year : 2022 | Volume
| Issue : 2 | Page : 90-96
Sinonasal mucormycosis and liposomal amphotericin B: A quest for dose optimization
Smile Kajal1, Syed Shariq Naeem2, Pooja Gupta2, Arvind Kumar Kairo1, Anam Ahmed3, Prankur Verma4, Ashish Saini1
1 Department of Otorhinolaryngology and Head-Neck Surgery, All India Institute of Medical Sciences, New Delhi, India
2 Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
4 Department: Otorhinolaryngology and Head-Neck Surgery, Government Medical College and Hospital, Sector 32, Chandigarh, India
|Date of Submission||10-Aug-2021|
|Date of Decision||24-Mar-2022|
|Date of Acceptance||24-Mar-2022|
|Date of Web Publication||10-May-2022|
Dr. Pooja Gupta
Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
OBJECTIVES: Sinonasal mucormycosis is a serious fungal infection. Early diagnosis and prompt antifungal therapy along with surgical intervention is the key to its management. Liposomal amphotericin B (LAmB) given intravenously is the antifungal agent of choice. However, the current literature is not clear on its optimum dosage. We did a retrospective study to find the optimum dose of LAmB in cases with sinonasal mucormycosis.
MATERIALS AND METHODS: Thirty patients diagnosed with mucormycosis involving sinonasal, rhino-orbital, or rhino-orbito-cerebral regions and receiving only LAmB as pharmacotherapy were included in our retrospective study from 2017 to 2020. A multiple logistic regression model was developed to correlate the total dose of LAmB and other parameters with the final outcome which was defined clinico-radiologically as improved, worsened, or death. The dose of LAmB which led to the first significant change in urea, creatinine, and potassium levels was also determined.
RESULTS: The model showed a good fit in goodness-to-fit analysis (Pearson = 0.999, deviance = 0.995), while the likelihood ratio was statistically significant (0.001). The overall model prediction was 83.3%. However, the correlation of outcome with any of the variables, including mean LAmB dose per kilogram (82.2 ± 13.02 mg/kg), was statistically not significant.
CONCLUSION: Many patient-related factors (such as age, comorbidities, extent of the disease, and side effects from LAmB therapy), which vary on a case-to-case basis, contribute to the outcome in a mucormycosis patient. The optimum dose of LAmB for improved outcome still requires individualization guided by experience, till well-designed studies address the question.
Keywords: Liposomal amphotericin B, mucormycosis, optimum dose, sinonasal
|How to cite this article:|
Kajal S, Naeem SS, Gupta P, Kairo AK, Ahmed A, Verma P, Saini A. Sinonasal mucormycosis and liposomal amphotericin B: A quest for dose optimization. Indian J Pharmacol 2022;54:90-6
|How to cite this URL:|
Kajal S, Naeem SS, Gupta P, Kairo AK, Ahmed A, Verma P, Saini A. Sinonasal mucormycosis and liposomal amphotericin B: A quest for dose optimization. Indian J Pharmacol [serial online] 2022 [cited 2022 May 23];54:90-6. Available from: https://www.ijp-online.com/text.asp?2022/54/2/90/344963
| » Introduction|| |
Mucormycosis is a life-threatening infection caused by a variety of fungal species in the order Mucorales, most common being Rhizopus, Lichtheimia, and Mucor., In tropical regions like India, Apophysomyces elegans is also commonly seen., It is an invasive fungal infection (IFI) that usually occurs in patients who are immunocompromised, those with diabetes mellitus, neutropenic conditions, hematological malignancies, solid organ or stem cell transplantation, or skin-penetrating injuries.,, Clinically, it can involve different regions which include rhino-orbito-cerebral, cutaneous, pulmonary, gastrointestinal, and disseminated (involving 2 or more regions). Rarely, it may be isolated from a single organ as well (renal/lymph node/parotid/ear/heart).,
Early diagnosis is the key to treatment and management approaches including prompt antifungal therapy, surgical debridement, and addressing the underlying predisposing condition. In most situations, intravenous amphotericin B is used as the first line of antifungal treatment, with the liposomal form being less nephrotoxic than the conventional form, and thus able to be given for longer periods.
For most patients, 5–7.5 mg/kg/day of liposomal Amphotericin B (LAmB) is considered reasonable for most patients. In case of central nervous system involvement, a higher dose of 10 mg/kg/day is recommended. Based on literature and international consensus, the European Organization for Research and Treatment of Cancer (EORTC)/Mycosis Study Group (MSG) proposed research-oriented definitions for the IFI and categorized them as “proven,” “probable,” and “possible.” However, a clear guideline on the dose and duration of LAmB therapy is lacking. The dose varies on a case-to-case basis depending on factors such as comorbidities, patient age, extent of disease, need for surgical intervention, and treating physician's experience. Therefore, the recommended dose of 5–7 mg/kg/day may not result in improved outcomes for all cases.
We retrospectively reviewed data of patients with mucormycosis involving sinonasal/rhino-orbital/rhino-orbito-cerebral region, who presented at our tertiary care institution, and aimed at finding the most appropriate dosage of LAmB in such cases.
| » Materials and Methods|| |
This was a retrospective study done in the department of otolaryngology and pharmacology at an apex tertiary care institution. The hospital medical records were perused after clearance from the Institute Ethics committee (IEC-59/8.1.21, RP-07/2021). The first and last patients included were hospitalized in June 2017 and November 2020, respectively.
Patients diagnosed with “Proven” and “Probable” invasive mucormycosis infection (as per the EORTC/MSG definition) involving sinonasal/rhino-orbital/rhino-orbito-cerebral regions and receiving only LAmB as pharmacotherapy were included. The patients receiving any other antifungal drug in addition to LAmB were excluded [Figure 1]. The microbiological diagnosis was established either by examination of 10% potassium hydroxide mount of nasal/palatal crust/tissue biopsy specimen or by a histopathological diagnosis of tissue. None of the patients enrolled in our study had laboratory-diagnosed coronavirus disease of 2019 (COVID-19).
The final outcome was categorized into the following three categories:
- Improved: Both clinical and radiological improvement
- Clinical improvement: No clinical evidence of residual disease (necrotic tissue or bone/residual fungal debris/osteomyelitic bone)
- Radiological improvement: No evidence of residual disease on computed tomography (CT) in all cases or magnetic resonance imaging (MRI) in cases involving orbital apex or those with intracranial extension.
Worsened: Either clinical or radiological deterioration
- Clinical deterioration: Progression of disease (involvement of new regions/progression of necrosis) or no clinical improvement despite giving LAmB and/or possible surgical intervention
- Radiological deterioration: Progression of disease (involvement of new regions) or persistent residual disease on CT or MRI despite giving LAmB and/or possible surgical intervention.
Death: Patients who expired during inhospital treatment.
The data were retrieved, cleaned, and entered into MS Excel. Analysis was done using IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. A multiple logistic regression model was developed to correlate dependent variables such as duration of symptoms, comorbidities, extent of the disease, surgical intervention done, duration of hospital stay, and total dose of LAmB with the independent variable which was the final outcome of the patients (improved, worsened or death). Results were presented as mean ± standard deviation.
| » Results|| |
The demographic details, clinical parameters evaluated, and mean total dose of LAmB in our study participants are given in [Table 1]. The baseline serum urea, creatinine, and electrolytes (sodium and potassium) levels were analyzed for all the patients. [Table 2] shows mean of baseline levels and significant change in the levels of urea (>50% increase from baseline), creatinine (>50% increase from baseline), and potassium (<3.5 mmol/L), for the first-time, during treatment with a certain dose of LAmB. Raised serum urea and creatinine levels (>50% increase from baseline) were seen in 50% of patients. Out of these 15 patients, 9 had complete recovery and 4 had partial recovery (see discussion). Two patients with preexisting chronic kidney disease had raised baseline serum urea and creatinine levels. Hypokalemia (K + levels <3.5 mmol/L) was seen in 80% of the patients.
|Table 2: Baseline level and first significantly changed level of Urea, Creatinine and Potassium after administration of LAmB|
Click here to view
The model showed a good fit in goodness-to-fit analysis (Pearson = 0.999, deviance = 0.995), as shown in [Table 3], while the likelihood ratio was statistically significant (0.001). The overall model prediction was 83.3%. The prediction for improved and expired outcomes was 100%, while for the worsened was 16.7%. The correlation of outcome with any of the variables was not statistically significant [Table 4]. The model also did not show any correlation between the mean LAmB dose per kilogram with the outcome. [Table 5] shows the dose and duration of LAmB therapy.
|Table 5: Dose and duration of liposomal amphotericin B expressed as mean±standard deviation with reference to the outcome|
Click here to view
| » Discussion|| |
Mucormycosis is a life-threatening condition that can progress rapidly. A comprehensive systemic review and meta-analysis of case reports of mucormycosis by Jeong et al. concluded amphotericin to be the mainstay antifungal agent for pharmacotherapy of mucormycosis. Lipid-based amphotericin B has less renal toxicity and can be given for a longer duration of time., However, international consensus for dose and duration of LAmB is lacking. A prospective study in 40 patients used a relatively higher dose of LAmB (10 mg/kg/day) for the treatment of mucormycosis in the initial stages and showed no change in mortality at high dose during the first 7 days of treatment. According to the AmBiLoad trial in IFI, 10 mg/kg/day dose of LAmB did not improve efficacy but increased the toxicity and cost of treatment as compared to 3 mg/kg/day. This trial, however, included only three and two patients, in the respective treatment arms, who had IFI due to Zygomycetes. Most of the patients having IFI were due to Aspergillus (91 in 10 mg/kg/day arm and 103 in 3 mg/kg/day arm). There was a statistically significant difference in toxicity between the two arms – nephrotoxicity and hypokalemia being higher in 10 mg/kg/day arm.
In our study, the duration and dose of LAmB varied from case to case. A high SD of the LAmB, almost approaching the mean, suggests wide variation in the dose of LAmB administered on a case-to-case basis. The observation re-emphasizes the fact that the dose and duration of amphotericin for mucor have not been standardized or systematically studied. We further tried to estimate the total dose of LAmB required for clinical and/or radiological improvement. However, we did not find any statistically significant contributor to the outcome, and the total dose of LAmB administered did not have any correlation with the outcome. In addition, the mean total dose administered in our patients was 2.1 mg/kg/day which was lower than the general recommendation of 5–7 mg/kg/day. Our data suggest a cautious approach while deciding the daily dose of LAmB to prevent life-threatening hypokalemia or nephrotoxicity. As discussed later, none of our patients required dialysis or developed life-threatening hypokalemia.
In India, most cases of mucormycosis are seen during monsoon and autumn. In our study, 70% of the patients presented in the months of July to November. A tertiary care center in India shared its experience with Zygomycosis over 10 years and reported that rhino-orbito-cerebral mucormycosis was the most common type (44.2%) among 129 patients. Analysis of the outcome of the therapy was done in 33 patients (24 rhino-orbito-cerebral cases). Of these, 15 patients received amphotericin B alone (total dose 3–4 g) and 16 were treated by surgical debridement along with amphotericin B (dose not specified). Amphotericin-B given along with aggressive debridement was found to work best in more than 80% of patients improved with the combination.
The angiotropism of Mucorales species causes blood vessel thrombosis and finally necrosis, resulting in low drug penetration., Therefore, surgical removal of the devitalized tissue, whenever possible, forms an important part of the management of mucormycosis and has improved outcomes when compared to those getting only antifungal therapy.,, In our study, all patients except one underwent surgical procedures in addition to LAmB therapy. Therefore, there was no group to compare the effect of surgical intervention on the outcome. The one patient who did not undergo surgery had multiple comorbidities (diabetes mellitus, chronic kidney disease, and chronic liver disease) and was not fit to undergo surgery under general anesthesia. The number of surgical debridement or number of surgical procedures performed had no correlation with the extent of the disease or outcome. Every patient was assessed clinically on daily basis and if there was suspicion of significant residual disease after first surgery or recurrence of disease (evident either clinically or radiologically), then he/she was taken for revision surgery or debridement.
LAmB has significantly less renal toxicity as compared to conventional amphotericin B (amphotericin B deoxycholate), as the drug gets locked in the liposomes and the particles have small size and negative charge., Although LAmB offers less toxicity than conventional amphotericin B, the reduction in adverse events, particularly nephrotoxicity, comes at a significantly higher cost., Such formulation may not be affordable in large quantities at the community level. Recently, there was an epidemic of COVID-19-associated mucormycosis in India., Many hospitals had to revert to conventional amphotericin B during this time due to high demand, short supply, and relatively higher cost of LAmB. The effect of COVID-19 or steroids used during the pandemic on dose and duration of LAmB or conventional amphotericin B are not known, as there is insufficient literature focusing on the difference in dosage of amphotericin used in COVID-19-associated mucormycosis versus non-COVID-19 mucormycosis. What is known is that there are less nephrotoxicity and fewer infusion-related reactions with continuous infusion of conventional amphotericin B over 24 h as compared to four-hourly to six-hourly infusions.,, Conventional amphotericin B can also be admixed with locally prepared lipid emulsions. Although there is no standardized protocol for making such extemporized mixture, a meta-analysis has shown its efficacy to be similar to LAmB and nephrotoxicity lower than conventional amphotericin B. This meta-analysis also compared LAmB with conventional amphotericin B and concluded that liposomes reduce nephrotoxicity of amphotericin by 18.1% ([99% confidence interval, 0.36–0.64]; n = 1233).
The dose of LAmB at which renal toxicity starts is unclear, but it has been shown in animal studies that even at a higher dose range of 10–15 mg/kg/day, LAmB causes less toxicity as opposed to conventional amphotericin.,, LAmB has been found to have a minimal effect on renal function of critically ill patients who had elevated baseline serum creatinine, suggesting that LAmB can be used in such patients, independent of the renal function status at the time of treatment initiation. In our study, 50% of the patients developed acute kidney injury which was defined as >50% increase in serum creatinine levels in accordance with the previously published studies., In these patients, LAmB therapy was halted for 24 h and 0.9% sodium chloride was given for salt loading as a toxicity-prevention strategy described widely.,,, LAmB therapy was resumed after 24 h, at a reduced dose than the previous day, after re-checking the creatinine levels. Four patients did not recover completely, but nine patients had complete recovery which was defined as a return to within 10% of pretreatment serum creatinine. None of the patients required dialysis. In a study to assess renal recovery following LAmB nephrotoxicity, the results suggested that the dose of LAmB dose had no impact on the probability of renal recovery. Currently, salt loading by infusion of normal saline, avoidance of dehydration, or concomitant use of other nephrotoxic drugs appears to be a safe and effective strategy to prevent LAmB-induced nephrotoxicity. N-acetyl cysteine has been tried for prophylaxis in animal studies, but the evidence is inconclusive in humans.,,
Hypokalemia (K + levels <3.5 mmol/L) was seen in 80% of the patients in our study, but none of the patient (including those who worsened or expired) developed life-threatening hypokalemia. It has been shown in the studies that early supplementation of potassium, within 2 days of starting LAmB, is an independent factor for reducing the risk of LAmB induced hypokalemia and it is necessary to start potassium supplementation before the levels drop to <2.83 mEq/l., We also started our patients on either intravenous or regular oral potassium chloride syrup (20–40 mEq/day) after detection of first significantly lower potassium value (<3.5 mmol/L) and dose of LAmB therapy was adjusted daily to maintain potassium levels above 3.5 mmol/L. No other adverse effects such as allergic reaction or anaphylaxis were seen in our patients. The dose of LAmB was altered daily in 80% of the patients based on daily urea, creatinine, and potassium levels. The amphotericin blood levels were not checked in any of the patient.
Although the definitive dose and duration of LAmB for expecting an improved outcome in sinonasal mucormycosis remain debatable, its dose in visceral leishmaniasis or Kala-azar is well defined. It is currently recommended as a first-line antileishmanial drug. The recommended dosage regimen is intravenous administration of 3 mg/kg/d LAmB on days 1–5, 14, and 21. The regimen accounts for a total dose of 21 mg/kg and 20 mg/kg has been shown to have a 99% initial cure and low relapse rates. The National Kala-Azar Elimination Programme of India uses 10 mg/kg LAmB as a single dose which also has a more than 95% cure rate. Conventional amphotericin B also has similar efficacy to LAmB and can be used as a short-course regimen.,
Our study focussed on sinonasal mucormycosis, but we included patients with orbital and intracranial extensions as these were extension of the infection from sinonasal region only. The study was limited by small sample size and retrospective review. Large-scale randomized controlled trials are needed to define the optimum dose which can lead to a decrease in mortality of patients with invasive fungal disease.
| » Conclusion|| |
Sinonasal mucormycosis is a disease with a high mortality rate. Amphotericin B is an established pharmacotherapy, and its liposomal form has less toxicity than the conventional form. Surgery remains the cornerstone of management in such patients in addition to pharmacotherapy. The optimum dose of LAmB required for complete response in invasive fungal disease is not well established. There are many patient-related factors (such as age, comorbidities, extent of the disease, and side effects from antifungal therapy) which contribute to the response of the patient and should be considered in estimating the total dose of LAmB therapy. However, all these factors vary on a case-to-case basis and our study did not find any significant correlation between any of these factors and final outcome of the patient. Hence, the optimum dose of LAmB required for the improved outcome should be estimated on an individual basis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, et al.
Epidemiology and outcome of zygomycosis: A review of 929 reported cases. Clin Infect Dis 2005;41:634-53.
Chakrabarti A, Dhaliwal M. Epidemiology of mucormycosis in India. Curr Fungal Infect Rep 2013;7:287-92.
Chakrabarti A, Chatterjee SS, Das A, Panda N, Shivaprakash MR, Kaur A, et al
. Invasive zygomycosis in India: Experience in a tertiary care hospital. Postgrad Med J 2009;85:573-81.
Lanternier F, Dannaoui E, Morizot G, Elie C, Garcia-Hermoso D, Huerre M, et al.
A global analysis of mucormycosis in France: The RetroZygo Study (2005-2007). Clin Infect Dis 2012;54 Suppl 1:S35-43.
Spellberg B, Ibrahim AS. Recent advances in the treatment of mucormycosis. Curr Infect Dis Rep 2010;12:423-9.
Lanternier F, Poiree S, Elie C, Garcia-Hermoso D, Bakouboula P, Sitbon K, et al.
Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis. J Antimicrob Chemother 2015;70:3116-23.
Jeong W, Keighley C, Wolfe R, Lee WL, Slavin MA, Chen SC, et al.
Contemporary management and clinical outcomes of mucormycosis: A systematic review and meta-analysis of case reports. Int J Antimicrob Agents 2019;53:589-97.
De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al.
Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46:1813-21.
Muñoz P, Guinea J, Narbona MT, Bouza E. Treatment of invasive fungal infections in immunocompromised and transplant patients: AmBiLoad trial and other new data. Int J Antimicrob Agents 2008;32 Suppl 2:S125-31.
Chakrabarti A, Sakhuja V. Ten years' experience in zygomycosis at a tertiary care centre in India. J Infect 2001;42:261-6.
Stone NR, Bicanic T, Salim R, Hope W. Liposomal amphotericin B (AmBisome(®)): A review of the pharmacokinetics, pharmacodynamics, clinical experience and future directions. Drugs 2016;76:485-500.
Hamill RJ. Amphotericin B formulations: A comparative review of efficacy and toxicity. Drugs 2013;73:919-34.
Kleinberg M. What is the current and future status of conventional amphotericin B? Int J Antimicrob Agents 2006;27 Suppl 1:12-6.
Bates DW, Su L, Yu DT, Chertow GM, Seger DL, Gomes DR, et al.
Mortality and costs of acute renal failure associated with amphotericin B therapy. Clin Infect Dis 2001;32:686-93.
Sen M, Honavar SG, Bansal R, Sengupta S, Rao R, Kim U, et al.
Epidemiology, clinical profile, management, and outcome of COVID-19-associated rhino-orbital-cerebral mucormycosis in 2826 patients in India – Collaborative OPAI-IJO Study on Mucormycosis in COVID-19 (COSMIC), Report 1. Indian J Ophthalmol 2021;69:1670-92.
] [Full text]
Patel A, Agarwal R, Rudramurthy SM, Shevkani M, Xess I, Sharma R, et al.
Multicenter epidemiologic study of coronavirus disease-associated mucormycosis, India. Emerg Infect Dis 2021;27:2349-59.
Falagas ME, Karageorgopoulos DE, Tansarli GS. Continuous versus conventional infusion of amphotericin B deoxycholate: A meta-analysis. PLoS One 2013;8:e77075.
Maharom P, Thamlikitkul V. Implementation of clinical practice policy on the continuous intravenous administration of amphotericin B deoxycholate. Med Assoc Thai 2006;89:118-24.
Falci DR, dos Santos RP, Wirth F, Goldani LZ. Continuous infusion of amphotericin B deoxycholate: An innovative, low-cost strategy in antifungal treatment. Mycoses 2011;54:91-8.
Mistro S, Maciel Ide M, de Menezes RG, Maia ZP, Schooley RT, Badaró R. Does lipid emulsion reduce amphotericin B nephrotoxicity? A systematic review and meta-analysis. Clin Infect Dis 2012;54:1774-7.
Boswell GW, Bekersky I, Buell D, Hiles R, Walsh TJ. Toxicological profile and pharmacokinetics of a unilamellar liposomal vesicle formulation of amphotericin B in rats. Antimicrob Agents Chemother 1998;42:263-8.
Lee JW, Amantea MA, Francis PA, Navarro EE, Bacher J, Pizzo PA, et al.
Pharmacokinetics and safety of a unilamellar liposomal formulation of amphotericin B (AmBisome) in rabbits. Antimicrob Agents Chemother 1994;38:713-8.
Bekersky I, Boswell GW, Hiles R, Fielding RM, Buell D, Walsh TJ. Safety and toxicokinetics of intravenous liposomal amphotericin B (AmBisome®
) in beagle dogs. Pharm Res 1999;16:1694-701.
Alvarez-Lerma F, Soriano MC, Rodríguez M, Catalán M, Llorente AM, Vidart N, et al
. Impact of liposomal amphotericin B on renal function in critically ill patients with renal function impairment. Rev Esp Quimioter 2012;25:206-15.
Bates DW, Su L, Yu DT, Chertow GM, Seger DL, Gomes DR, et al.
Correlates of acute renal failure in patients receiving parenteral amphotericin B. Kidney Int 2001;60:1452-9.
Walsh TJ, Goodman JL, Pappas P, Bekersky I, Buell DN, Roden M, et al.
Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus
species and other filamentous fungi: Maximum tolerated dose study. Antimicrob Agents Chemother 2001;45:3487-96.
Branch RA. Prevention of amphotericin B-induced renal impairment. A review on the use of sodium supplementation. Arch Intern Med 1988;148:2389-94.
Gardner ML, Godley PJ, Wasan SM. Sodium loading treatment for amphotericin B-induced nephrotoxicity. DICP 1990;24:940-6.
Llanos A, Cieza J, Bernardo J, Echevarria J, Biaggioni I, Sabra R, et al.
Effect of salt supplementation on amphotericin B nephrotoxicity. Kidney Int 1991;40:302-8.
Karimzadeh I, Farsaei S, Khalili H, Dashti-Khavidaki S. Are salt loading and prolonging infusion period effective in prevention of amphotericin B-induced nephrotoxicity? Expert Opin Drug Saf 2012;11:969-83.
Personett HA, Kayhart BM, Barreto EF, Tosh P, Dierkhising R, Mara K, et al.
Renal recovery following liposomal amphotericin B-induced nephrotoxicity. Int J Nephrol 2019;2019:8629891.
Feldman L, Efrati S, Dishy V, Katchko L, Berman S, Averbukh M, et al.
N-acetylcysteine ameliorates amphotericin-induced nephropathy in rats. Nephron Physiol 2005;99:p23-7.
Odabasi Z, Karaalp A, Cermik H, Mohr J, Tigen ET, Koc M, et al.
Reduction of amphotericin B-induced renal tubular apoptosis by N-acetylcysteine. Antimicrob Agents Chemother 2009;53:3100-2.
Karimzadeh I, Khalili H, Dashti-Khavidaki S, Sharifian R, Abdollahi A, Hasibi M, et al.
N-acetyl cysteine in prevention of amphotericin- induced electrolytes imbalances: A randomized, double-blinded, placebo-controlled, clinical trial. Eur J Clin Pharmacol 2014;70:399-408.
Okada N, Azuma M, Imanishi M, Zamami Y, Kirino Y, Nakamura T, et al.
Potential usefulness of early potassium supplementation for preventing severe hypokalemia induced by liposomal amphotericin B in hematologic patients: A retrospective study. Clin Ther 2018;40:252-60.
Usami E, Kimura M, Kanematsu T, Yoshida S, Mori T, Nakashima K, et al.
Evaluation of hypokalemia and potassium supplementation during administration of liposomal-amphotericin B. Exp Ther Med 2014;7:941-6.
Balasegaram M, Ritmeijer K, Lima MA, Burza S, Ortiz Genovese G, Milani B, et al.
Liposomal amphotericin B as a treatment for human leishmaniasis. Expert Opin Emerg Drugs 2012;17:493-510.
van Griensven J, Diro E. Visceral leishmaniasis: Recent advances in diagnostics and treatment regimens. Infect Dis Clin North Am 2019;33:79-99.
Burza S, Sinha PK, Mahajan R, Lima MA, Mitra G, Verma N, et al.
Five-year field results and long-term effectiveness of 20 mg/kg liposomal amphotericin B (Ambisome) for visceral leishmaniasis in Bihar, India. PLoS Negl Trop Dis 2014;8:e2603.
Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW. Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med 2010;362:504-12.
Sundar S, Mehta H, Suresh AV, Singh SP, Rai M, Murray HW. Amphotericin B treatment for Indian visceral leishmaniasis: Conventional versus lipid formulations. Clin Infect Dis 2004;38:377-83.
Rodrigo C, Weeratunga P, Fernando SD, Rajapakse S. Amphotericin B for treatment of visceral leishmaniasis: Systematic review and meta-analysis of prospective comparative clinical studies including dose-ranging studies. Clin Microbiol Infect 2018;24:591-8.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]