IMPLEMENTATION CONSIDERATIONS Treatment Access to essential antifungal drugs remains inadequate, and drug toxicity and laboratory monitoring costs continue to be important barriers. Lack of local generic manufacturers, lack of in-country registration and high prices are some of the main barriers (72,73). Liposomal amphotericin B is included in the 2021 WHO List of Essential Medicines and WHO Prequalification Expression of Interest list. Although liposomal amphotericin B has been off patent since 2016, and despite preferential pricing from the originator for some countries, the current price of liposomal amphotericin B remains substantially higher than that of amphotericin B deoxycholate in most countries. Lack of registration and inclusion in national essential medicines lists and national treatment guidelines can also be barriers to access. For example, as of February 2022, liposomal amphotericin B was only registered in two countries in sub-Saharan Africa (Ethiopia and South Africa). Fluconazole is widely registered and is available in low- and middle-income countries. However, several countries have not included fluconazole in their national list of essential medicines. Flucytosine is not widely registered nor available in most low- and middle-income countries. Although registering standard formulations of flucytosine is the current priority, 100 mg/kg per day dosages of flucytosine given four times a day are problematic. Antifungal medications for treating cryptococcal meningitis are increasingly more affordable, and barriers to access can be overcome by:

• increasing advocacy for reducing drug prices and promoting generic production, especially for liposomal amphotericin B and oral flucytosine;
• carrying out quality assurance of newly available generic formulations;
• ensuring national registration of all cryptococcal meningitis drugs and including them in national essential medicine lists (amphotericin B deoxycholate, liposomal amphotericin B, flucytosine and fluconazole are included in the WHO Model List of Essential Medicines);
• ensuring adequate supply chains at the national level;
• developing proper drug-forecasting and -monitoring systems; and
• improving access to liposomal amphotericin B by integrating it in the national package of drugs to treat severe fungal diseases. The new 10 mg/kg liposomal amphotericin B–based induction regimen could enable people to be discharged from hospital earlier since intravenous treatment is not required after the initial dose and the need for toxicity monitoring is reduced. However, because of the severity of illness of many people with advanced HIV disease and cryptococcal meningitis, very early discharge (before day seven) should only be considered for clinically stable individuals, with provisions in place for outpatient follow-up and management of raised intracranial pressure if required. In exceptional circumstances, the single high-dose liposomal amphotericin B induction regimen could be administered to ambulatory patients in outpatient settings, but this should only be considered when no option for safe inpatient treatment is available. Monitoring The recommended package for preventing, monitoring and managing amphotericin B toxicity sets the standard that should be followed when resources permit. However, in settings in which applying all monitoring requirements is not possible, this should not limit provision of amphotericin B since the benefits of treatment will still outweigh the toxicity risks. The monitoring package should be informed by resource availability, local data and clinical experience.