Fungal Infections, Treatment and Antifungal Resistance: The Sub-Saharan African Context

Abstract

Fungal pathogens cause a wide range of infections in humans, from superficial to disfiguring, allergic syndromes, and life-threatening invasive infections, affecting over a billion individuals globally. With an estimated 1.5 million deaths annually attributable to them, fungal pathogens are a major cause of mortality in humans, especially people with underlying immunosuppression. The continuous increase in the population of individuals at risk of fungal infections in sub-Saharan Africa, such as HIV patients, tuberculosis patients, intensive care patients, patients with haematological malignancies, transplant (haematopoietic stem cell and organ) recipients and the growing global threat of multidrug-resistant fungal strains, raise the need for an appreciation of the region’s perspective on antifungal usage and resistance. In addition, the unavailability of recently introduced novel antifungal drugs in sub-Saharan Africa further calls for regular evaluation of resistance to antifungal agents in these settings. This is critical for ensuring appropriate and optimal use of the limited available arsenal to minimise antifungal resistance. This review, therefore, elaborates on the multifaceted nature of fungal resistance to the available antifungal drugs on the market and further provides insights into the prevalence of fungal infections and the use of antifungal agents in sub-Saharan Africa.

Introduction

Fungi are a major threat to the lives of immunocompromised individuals. ¹ They can colonise different sites of their human hosts, including the gastrointestinal tract, respiratory tract, bloodstream, and female genitals, ² which are of public health concern. Fungal infections could either be endogenous in origin or be transmitted via inhalation, direct skin contact with humans or animals, or close proximity to contaminated surfaces. ³

The prevalence of invasive fungal infections (IFIs) is increasing worldwide due to the expansion of existing at-risk populations and the emergence of new at-risk groups, such as persons with recent COVID-19 infections. ⁴ The global attributable death toll from these infections exceeds 2.5 million, with more than seven million individuals affected annually. ⁵ In sub-Saharan Africa, fungal infections significantly contribute to the overall disease burden, primarily driven by factors such as HIV, tuberculosis, admission to intensive care, haematological malignancies, transplantation (haematopoietic stem cells and organs) and poverty. ⁶ Available data from epidemiological and other studies suggest a high burden of fungal infections in sub-Saharan Africa.^5,7

The impact of fungal infections has been exacerbated by the increasing occurrence of antifungal-resistant strains, which can be attributed to the widespread suboptimal and inappropriate use of antifungal drugs, as well as the agricultural application of analogues of these drugs. ⁸ Although fungi are also implicated in a variety of infections in sub-Saharan Africa, a greater attention has been given to bacteria, with very little interest shown in fungal species. ⁹ This is largely attributed to inadequate awareness and poor access to essential diagnostics and antifungal drugs. ¹⁰ Consequently, these historical challenges have led to a decreased focus on efforts that ensure early detection and optimal management of fungal infections in the region. The continuous increase in populations in sub-Saharan Africa that are at risk for fungal infections ¹¹ and the growing global threat of multidrug-resistant fungal strains ¹² raise the need for an appreciation of the region’s perspective on antifungal usage and resistance. This review, therefore, aimed to summarise the prevalence of fungal infections, the use of antifungal agents, and antifungal resistance, in the context of sub-Saharan Africa, focusing on the major fungal species associated with IFIs.

Methods

A detailed search was conducted in multiple databases, including PubMed, Scopus, ScienceDirect, Google Scholar and African Journal Online, for each of the 48 countries in the sub-Saharan Africa, using the following keywords: (‘fungal infections’ OR ‘tinea capitis’ OR ‘cryptococcosis’ OR ‘pneumocystosis’ OR ‘disseminated histoplasmosis’ OR ‘chronic pulmonary aspergillosis’ OR ‘candidiasis’ OR ‘candidaemia’ OR ‘mucormycosis’ OR ‘fungal keratitis’) AND (‘antifungal agents’) AND (‘antifungal resistance’) AND (‘Angola’ OR ‘Benin’ OR ‘Botswana’ OR ‘Burkina Faso’ OR ‘Burundi’ OR ‘Cabo Verde’ OR ‘Cameroon’ OR ‘Central African Republic’ OR ‘Chad’ OR ‘Comoros’ OR ‘Democratic Republic of the Congo’ OR ‘Republic of Congo’ OR ‘Cote d’Ivoire’ OR ‘Djibouti’ OR ‘Equatorial Guinea’ ‘Eritrea’ OR ‘Eswatini’ OR ‘Ethiopia’ OR ‘Gabon’ OR ‘Gambia’ OR ‘Ghana’ OR ‘Guinea’ OR ‘Guinea-Bissau’ OR ‘Kenya’ OR ‘Lesotho’ OR ‘Liberia’ OR ‘Madagascar’ OR ‘Malawi’ OR ‘Mali’ OR ‘Mauritania’ OR ‘Mauritius’ OR ‘Mozambique’ OR ‘Namibia’ OR ‘Niger’ OR ‘Nigeria’ ‘Rwanda’ OR ‘Sao Tome and Principe’ OR ‘Senegal’ OR ‘Seychelles’ OR ‘Sierra Leone’ OR ‘Somalia’ OR ‘South Africa’ OR ‘South Sudan’ OR ‘Sudan’ OR ‘Tanzania’ OR ‘Togo’ OR ‘Uganda’ OR ‘Zambia’ OR ‘Zimbabwe’). The search was limited to articles published in English up to 2023, focusing on the most recent data on IFIs in each country. Apart from epidemiological data on IFIs, articles presenting the treatment of fungal infections and the mechanism of resistance exhibited by common pathogenic fungal species were included in this review. The references of the articles were also screened for relevant studies.

The burden of fungal infections in sub-Saharan Africa

In many sub-Saharan African countries, surveillance and available data on fungal disease burden are limited, contributing to challenges in determining the precise prevalence of IFIs. Despite these challenges, individual countries have reported high burdens of severe or serious fungal infections. In Ghana, for example, approximately 4% of the population, equivalent to 1,147,228 individuals, is affected by severe fungal infections, with 35,000 experiencing severe morbidity and mortality related to these infections. ¹³ This prevalence is higher than the reported 3% in Tanzania ¹⁴ but lower than the projected 11.8% in Nigeria. ¹⁵ In the Democratic Republic of the Congo (DRC), it is estimated that approximately 5,177,000 people (5.4% of the general population) suffer from serious fungal infections each year. ¹⁶ Elsewhere in Senegal, approximately 12.5% of the population (approximately 1,743,507 individuals) is affected by fungal infections. ¹⁷ In Sierra Leone, however, 4.92% of the population is affected by serious fungal infections, and a prevalence of 2.9% has been observed among people living with HIV. ¹⁸ Moreover, research conducted in Zimbabwe indicates that approximately 14.9% of the inhabitants experiences fungal infections annually, with tinea capitis accounting for 80% of these cases. ¹⁹ A summary of the prevalence of fungal infections in sub-Saharan Africa is provided in Table 1, and the burden of the major fungal infections in the subregion is detailed in Table 2.

Table 1.

Summary of the prevalence of fungal infections in sub-Saharan Africa.

Country	Estimated prevalence (%)	Population affected	Year of study	Reference
Burkina Faso	7.51	1,400,000	2018	Bamba et al. 20
Cameroon	–	1,236,332	2018	Mandengue et al. 21
Côte d’Ivoire	7.25	1,800,000	2021	Koffi et al. 22
Republic of the Congo	5.6	293,918	2020	Amona et al. 23
Democratic Republic of the Congo	5.4	5,177,000	2021	Kamwiziku et al. 16
Ethiopia	8	–	2019	Tufa et al. 24
Ghana	4	1,147,228	2019	Ocansey et al. 13
Kenya	11.57	–	2023	Ratemo et al. 25
Malawi	7.54	1,338,523	2018	Kalua et al. 26
Mali	12.8	2,729,670	2023	Doumbo et al. 27
Mozambique	6.9	1,834,947	2018	Sacarlal et al. 28
Namibia	5	112,870	2019	Dunaiski et al. 29
Nigeria	11.8	–	2014	Oladele et al. 15
Senegal	12.5	1,743,507	2015	Badiane et al. 17
Sierra Leone	4.92	–	2021	Lakoh et al. 18
Sudan	10	5,000,000	2023	Ahmed et al. 30
Tanzania	3	–	2015	Faini et al. 14
Togo	5.29	7,265,286	2021	Dorkenoo et al. 31
Zimbabwe	14.9	–	2021	Pfavayi et al. 19
South Africa	5.7	3,220,014	2019	Schwartz et al. 32

Table 2.

Burden of major fungal infections in sub-Saharan Africa.

Country	Tinea capitis (in children) (cases per year)	Cryptococcosis (cases per year)	Pneumocystosis (cases per year)	Disseminated histoplasmosis (cases per year)	Chronic pulmonary aspergillosis (cases per year)	Vulvovaginal candidiasis (cases per year)	Candidaemia (cases per year)	Mucormycosis (cases per year)	Fungal keratitis (cases per year)	References
Burkina Faso	1,132,781	459	1013	–	1120	–	906	–	–	Bamba et al. 20
Cameroon	721,000	6720	9000	1800	1265	350,000	–	5	–	Mandengue et al. 21
Democratic Republic of the Congo	3,551,900	9265	2800	–	54,700	1,202,640	–	–	–	Kamwiziku et al. 16 Zono et al. 33
Côte d’Ivoire	–	4590	2640	513	6568	421,936	–	–	3350	Koffi et al. 22
Ethiopia	7,051,700	9900	11,500	1	15,200	1,469,100	5300	–	–	Tufa et al. 24
Ghana	598,840	6275	12,610	724	12,620	442,621	1,446	58	810	Ocansey et al. 13
Kenya	4,905,249	8975	25,429	2,244	100,570	915,795	2,804	109	7929	Ratemo et al. 25
Malawi	670,900	8200	10,800	–	2911	326,960	–	30	1825	Kalua et al. 26
Mali	2,300,000	611	1393	180	7290	272,460	>1060	43	2820	Doumbo et al. 27
Mozambique	1,181,686	18,640	33,380	153	18,475	348,179	1321	53	–	Sacarlal et al. 28
Namibia	53,784	543	836	–	453	37,390	125	5	–	Dunaiski et al. 29
Nigeria	15,581,400	57,894	74,594		120,753	1,521,520	9284	300		Oladele et al. 15
Senegal	1,523,700	366	1149	–	2700	191,228	–	26	–	Badiane et al. 17
Sierra Leone	266,450	302	643	0	1275	85,440	382	15	1017	Lakoh et al. 18
Sudan	4,127,760	462	571	–	14,950	631,300	2340	94	6550	Ahmed et al. 30
Tanzania	420,000	6394	9600	135	10,437	759,500	2181	–	–	Faini et al. 14
Togo	232,271	1,342	1650	330	191	108,979	–	–	981	Dorkenoo et al. 31
Zimbabwe	1,806,700	6086	9429	57	2448	203,585	743	–	2080	Pfavayi et al. 19
Republic of the Congo	178,400	560	830	120	3420	85,440	–	–	–	Amona et al. 23
South Africa	1,003,490	8357	4452	60	89,416	1,002,499	5421	113	–	Schwartz et al. 32

Tinea capitis

Tinea capitis, a fungal infection that affects the scalp, skin, and hair, is the most prevalent type of dermatophyte infection and constitutes 52% of all fungal infections. ³⁴ African children are particularly susceptible, with an estimated 138 million cases recorded among them. ³⁵ In Ghana, tinea capitis is the predominant fungal disease, accounting for 44% of fungal infections. ¹³ The prevalence among Ghanaian school children ranges from 8.4% to 8.7%, which is lower than the prevalence reported in other sub-Saharan African countries. ³⁶ Another study revealed that 598,840 Ghanaian children, or 2070 cases per 100,000 individuals, have tinea capitis. ¹³ In Nigeria, at least 20% of school-aged children were reported to have tinea capitis. ³⁷ Zimbabwe has approximately 1,806,700 affected children, ¹⁹ while Senegal has a 25% prevalence among children, corresponding to approximately 1.5 million individuals. ¹⁷ In Malawi, 670,900 cases of tinea capitis were reported among school children in 2018. ²⁶ Similarly, in Rwanda, approximately 21% or 34,995 school children were identified to have tinea capitis. ³⁶ The DRC detected approximately 3,551,900 cases of tinea capitis out of the 5,177,000 cases of fungal infections. ¹⁶ Approximately 178,400 school children in the Republic of the Congo (RC) suffer from tinea capitis of the 293,918 cases of fungal infections. ²³

Cryptococcosis

Cryptococcosis, caused by Cryptococcus neoformans and Cryptococcus gattii complexes, is a leading cause of meningitis in HIV-infected patients in sub-Saharan Africa. ³⁸ On average, 152,100 HIV patients worldwide were estimated to contract cryptococcal meningitis in 2020, leading to 112,000 deaths, which constituted 19% of all AIDS-related deaths. ⁷ In sub-Saharan Africa, 61,000–101,000 people living with HIV were diagnosed with cryptococcal meningitis in 2020, resulting in 71,000 deaths. ⁷ The prevalence of cryptococcosis among HIV patients is notably high in sub-Saharan Africa. ⁷ For instance, one study estimated that 21.7 per 100,000 cases of cryptococcal meningitis occurred among AIDS patients in Ghana. ¹³ Another study, conducted in Zimbabwe, projected an annual prevalence of 6086 cases of cryptococcal meningitis among HIV/AIDS patients, with an estimated rate of 41/100,000 people per year. ¹⁹ In Senegal, 366 of 59,000 HIV-positive individuals developed cryptococcal meningitis. ¹⁷ In addition, the DRC has an annual prevalence of 9265 cases of cryptococcal meningitis in adults. ¹⁶

Candidiasis

Candidiasis, whose spectrum of manifestations includes oral, vaginal and vulvovaginal candidiasis (VVC), as well as systemic candidiasis (such as candidaemia), is a severe and potentially fatal disease that poses a significant threat to critically ill individuals, with mortality rates ranging from 29% to 76%. ³⁹ In sub-Saharan Africa, a study by Mushi et al. ⁴⁰ found that 33.5% of people living with HIV had oral candidiasis, which was caused by various Candida species, including both albicans and non-albicans, such as Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, and others.

Candidaemia is a common bloodstream infection characterised by the presence of Candida species in the blood. ⁴¹ The most prevalent Candida species associated with candidaemia include Candida albicans, C. krusei, C. parapsilosis, C. tropicalis, C. glabrata, and the usually multidrug-resistant, biofilm-forming species Candida auris. ⁴² In a single-site surveillance of Candida bloodstream infections conducted in Kenya over a six-year period, C. auris comprised 38% of all isolates, closely followed by C. albicans, which accounted for 25% of the isolates. ⁴³ By contrast, a retrospective study conducted in South Africa between 2009 and 2010 indicated that C. albicans was the predominant cause of candidaemia, accounting for 23.8% of cases. ⁴⁴ Similarly, retrospective studies conducted in hospitals in both South Africa and Nigeria found C. albicans to be the primary cause of candidaemia, accounting for 73% and 77% of cases, respectively. ⁴⁵

Regarding vulvovaginal candidiasis, one study reported its diagnosis among 21% of patients receiving care at a gynaecological clinic in the Middle Belt of Ghana. ⁴⁶ VVC has a pooled prevalence of 33%, affecting both pregnant and non-pregnant women in sub-Saharan Africa. ⁴⁷ The projected prevalence of recurrent vulvovaginal candidiasis (RVVC) among adult women in Ghana’s overall healthy population is estimated to be approximately 442,621 cases, occurring annually at a rate of 1530 females per 100,000 persons. ¹³ Elsewhere in Namibia, RVVC affects 37,390 adult women (33.1% of 112,870 cases of fungal infections), ²⁹ while in Zimbabwe, its burden is 2739 cases per 100,000 people. ¹⁹ Moreover, it is predicted that each year, 1,000,000 South African women will be affected by RVVC out of every 56,521,947 persons diagnosed with fungal infections. ³² Furthermore, the reported prevalence of RVVC in the DRC is 1,202,640 of the total 5,177,000 fungal infections, ¹⁶ while in the RC, RVVC is estimated to account for approximately 85,440 of the 293,918 cases of fungal infections, occuring among adult women. ²³

Oral candidiasis, the most common opportunistic fungal infection among immunocompromised individuals, affects 7.6%–75.0% of HIV patients in sub-Saharan Africa. ⁴⁰ Although C. albicans is the predominant cause, non-albicans Candida species account for more than 30% of the cases. ⁴⁰ Similarly, oesophageal candidiasis is considered an AIDS-defining condition and affects approximately 12% of HIV/AIDS patients in the region. ⁴⁸ In Senegal, 1946 of 59,000 HIV-positive individuals were determined to develop oesophageal candidiasis. ¹⁷ Additionally, a Zimbabwean study among persons living with HIV reported that oral candidiasis affects 77,143 patients, while oesophageal candidiasis affects 63,571 patients. ¹⁹ In the DRC, oral and oesophageal candidiasis were observed in 50,470 and 28,800 HIV-infected patients, respectively, ¹⁶ whereas in Ghana, they were reported to account for 27,100 of the 1,147,228 cases of fungal infections. ¹³

Invasive aspergillosis

Invasive aspergillosis (IA) is a potentially fatal infection that primarily affects individuals with a weakened immune system. ⁴⁹ It is caused by Aspergillus spp., which are ubiquitous and release airborne conidia into the environment. Inhaling these conidia can lead to various clinical manifestations, including allergies, chronic pulmonary aspergillosis (CPA) and IA. ⁵⁰

The prevalence of IA in Africa varies across different regions, with rates ranging from 0.05 to 10.9 cases per 100,000 people. ⁵¹ In Ghana, there were 12,620 estimated cases of CPA and 1254 cases of IA out of the 1,147,228 cases of fungal infections. ¹³ Southern Africa has a prevalence of 4.8–16 per 100,000 people, Western Africa has 0.3–6.25 per 100,000 people, Northern Africa has 7.1–10.7 per 100,000 people and Central Africa has 3.2–6.9 per 100,000 people. ⁵¹ Among AIDS patients, the prevalence of invasive aspergillosis was found to be 380 cases per year in the DRC. ¹⁶ Histological evaluations indicated a prevalence of 2.6% in South Africa and 1.15% in Uganda. ⁵² An estimated 2448 cases of IA occur annually in Zimbabwe, with a rate of 16 cases per 100,000 people. ¹⁹ The primary Aspergillus species identified are Aspergillus flavus and Aspergillus niger, which are more predominant in sub-Saharan Africa, given that the tropical climate of the region is ideal for their survival. ⁵³ To a lesser extent, other species, such as Aspergillus fumigatus, Aspergillus ochraceus, Aspergillus tubingensis, and Aspergillus westerdijkiae have also been identified in the region. ⁵⁴

Pneumocystis jirovecii pneumonia

Pneumocystis jirovecii, a member of the Ascomycota fungal group, is known for causing severe pneumonia in individuals with a weakened immune system. ⁵⁵ A comprehensive analysis of studies conducted in hospitals across 18 sub-Saharan African countries revealed that the overall occurrence of Pneumocystis jirovecii pneumonia (PJP) among persons living with HIV was 15.4%, with high prevalence among individuals exhibiting respiratory symptoms (18.8%), hospitalised patients (22.4%) and hospitalised patients with respiratory symptoms (24%). ⁵⁶ In Ghana, it was estimated that there were 12,610 cases of Pneumocystis jirovecii among individuals living with HIV/AIDS. ¹³ Screening of randomly selected patients in a facility in Cameroon revealed that 82% of these patients had significant antibody titres and were, therefore, exposed to Pneumocystis jirovecii. ⁵⁷ Zimbabwe reported an annual prevalence of 63 cases per 100,000 people for PJP among HIV/AIDS patients. ¹⁹ In Senegal, it was predicted that out of 59,000 HIV-positive individuals, 1149 would develop PJP. ¹⁷ Moreover, South Africa reported 4452 cases of PJP out of 56,521,947 cases of fungal infections, ³² while the DRC had an estimated annual prevalence of 2800 cases of PJP among adults out of the 5,177,000 cases of fungal infection. ¹⁶

Histoplasmosis

Histoplasmosis is a fungal infection that primarily affects individuals living in endemic regions. ⁵⁸ It is particularly problematic for people with advanced HIV disease, as it can cause opportunistic infections. ⁵⁸ Infection occurs when individuals inhale spores of Histoplasma capsulatum, which has two variants: Histoplasma capsulatum var. capsulatum (HCC) and Histoplasma capsulatum var. duboisii (HCD). ⁵⁹

Histoplasmosis has significantly expanded in Africa alongside the HIV epidemic but remains largely underestimated. Limited information and epidemiological data are available for histoplasmosis in Ghana; however, a recent study reported a prevalence of 4.7% (5 out of 107) among HIV patients. ⁶⁰ A comprehensive analysis of histoplasmosis in Africa revealed a total of 470 documented cases spanning a period of six decades (1952–2017). Among these cases, 38% (178) was reported in HIV-infected individuals. ⁶¹ A study also reported that West Africa had the highest number of histoplasmosis cases in Africa, followed by Southern Africa. ⁶¹ Research conducted in Cameroon revealed that 13% of HIV-positive individuals who presented with persistent fever, cough, and skin lesions were diagnosed with histoplasmosis. ⁶² Specific studies reported 17 of the 7,265,286 cases of fungal infections in Lomé, Togo, between 2002 and 2016 ⁶³ and 36 patients infected with HCD out of the 5,177,000 fungal infection cases in Kimpese, DRC. ⁶⁴

Sporotrichosis

Sporotrichosis, caused by the Sporothrix schenckii complex, is a chronic fungal infection primarily transmitted through traumatic inoculation, such as thorn pricks or scratches, among individuals involved in occupations or recreational activities, such as gardening, farming, fishing, hunting and, horticulture. ⁶⁵ Although sporotrichosis in Africa has received limited attention, it has been reported in some countries, particularly Madagascar. ⁶⁶ In South Africa, sporotrichosis cases have primarily been documented among mine workers, with an estimated number of undocumented cases surpassing 3300. ⁶⁷ The infection has been observed in various regions in the southern part of Africa, such as Pretoria, Botswana, Mpumalanga, and the Northwest Province, particularly among employees in gold mines. ⁹ However, due to the limited availability of medical mycology laboratories in sub-Saharan Africa, the true extent of sporotrichosis spread across the continent remains poorly documented. ⁹

Chromoblastomycosis

Chromoblastomycosis (CBM) is a fungal infection caused by melanised fungi, specifically Fonsecaea pedrosoi and Cladophialophora carrionii. ⁶⁸ The extent of the impact of CBM in Africa is not accurately understood due to a lack of thorough epidemiological studies. However, it is noteworthy that Madagascar has the highest number of reported CBM cases among African countries. ⁶⁸ In one study in the country, chromoblastomycosis was diagnosed in 50 out of 148 patients who had chronic subcutaneous lesions suggestive of dermatomycosis. ⁶⁶ A recent study examining the global burden of CBM spanning from 1914 to 2020 revealed that Africa ranks as the second highest region in terms of documented cases, following South America. Across 22 countries in Africa, a total of 1875 out of 7740 CBM cases were reported. ⁶⁹

Other fungal infections

Emergomycosis, previously known as Emmonsia, is a fungal infection caused by a fungus of the genus Emergomyces that can spread throughout the body. There are five recognised species of Emergomyces worldwide, namely, Emergomyces pasteurianus, Emergomyces africanus, Emergomyces canadensis, Emergomyces orientalis and Emergomyces europaeus. Of these, Es. pasteurianus and Es. africanus are notably prevalent in Africa, with numerous cases reported in Lesotho, Uganda, and South Africa. ⁷⁰ Mucormycosis and fungal keratitis are two other significant diseases affecting the African population. Approximately 58 out of 100,000 individuals in Ghana are affected by mucormycosis, while fungal keratitis affects approximately 810 people out of 100,000. ¹³ However, in Namibia, only five cases of mucormycosis have been reported. ²⁹

Mode of action of the different antifungal agents

In ancient times, plant extracts were utilised to treat skin and nail fungal infections, contributing to the development of antifungal agents as drugs for combating fungal infections. ⁷¹ The earliest available pharmacologic agents for the treatment of fungal infections included undecylenic acid, phenolic dye and weak acid. ⁷¹ The modern era of antifungal therapy began in the mid-20th century, ⁷¹ following the discovery of griseofulvin in 1939, the first synthetic antifungal drug, which was approved for clinical use in early 1960 and became available for oral use that year. ⁷¹ Griseofulvin belongs to the antifungal class of polyenes, was isolated from the fungus Penicillium griseofulvum, ⁷² and remains effective against dermatophyte infections. ⁷³ Besides being available for oral use, antifungal medications, are available as topical and intravenous agents as well, and are used to treat different types of fungal infections; however, all these routes of administration have their respective limitations and side effects. ⁷⁴

Numerous antifungals have since been developed after the discovery of the first antifungal agent in the 20th century. ⁷⁵ These are grouped into classes including azoles, echinocandins, polyenes, and flucytosine, with each class exhibiting different mechanisms of action. ⁷⁶ Therefore, appropriate combination therapy may ultimately yield a positive outcome, even for patients who have drug-resistant fungal infections. However, not all these antifungals are readily available in sub-Saharan African countries. In Ghana, for instance, the antifungals that are easily accessible are 5-flucytosine ⁷⁷ and fluconazole, ⁷⁸ while amphotericin B is available only in Benin, Zambia, South Africa, and Ethiopia. ⁷⁷

Azoles

Azoles are heterocyclic compounds within whose chemical structures are imidazole or triazole rings, which are bound to the rest of the structure via nitrogen-carbon bonds. ⁷⁹ This structure confers a weak basic character to azole antifungals. ⁷⁹ It is believed that the nitrogen atoms N-3 and N-4 in the imidazoles and triazoles, respectively, bind to the heme portion of cytochrome P-450, inhibiting the demethylation of lanosterol. ⁸⁰ The balance of the lipophilicity/hydrophilicity of azoles is determined by the number of aromatic rings and halogen substituents, with the latter imparting a hydrophilic character and the former imparting a lipophilic character. ⁸⁰ These azoles exhibit antifungal activity by blocking the synthesis of ergosterol, a key constituent of the fungal cell membrane, which leads to disruptions in permeability, membrane stability, and the function of membrane-bound enzymes. ⁸¹ The blockage of ergosterol synthesis occurs by inhibiting lanosterol 14-α-demethylase encoded by ERG11 in C. albicans and Cryptococcus neoformans, Cyp51A/Cyp51B in moulds, ⁸² and cyp51B and cyp51A in A. fumigatus, ⁸¹ leading to the build-up of dangerous sterol intermediates, such as the product of Erg3, 14-methyl-3,6-diol. ⁸³ When incorporated into the fungal membrane, this creates membrane stress ⁸² and ultimately inhibits proliferation. ⁸⁴

Azoles are the most frequently and widely used antifungals in clinical practice for the treatment of fungal infections. ⁸¹ They are fungistatic and are often administered long-term. ⁸⁵ The currently available azoles that are clinically approved are isavuconazole, voriconazole, itraconazole, fluconazole and posaconazole, and they primarily possess fungistatic activity against yeasts, such as Cryptococcus and Candida spp. ⁸⁴ Compared to other antifungals, many azole drugs have excellent oral bioavailability and are offered in both intravenous and oral formulations. ⁷⁹ However, this does not make azoles harmless consumable drugs, as they have a high potential to interact with other drugs. In addition, they inhibit mammalian cytochrome P450 enzymes, which are responsible for drug metabolism. ⁸⁶ New azoles that have a higher specificity for fungal enzymes (VT-1161, VT-1129 and VT-1598) are currently being developed to address this restriction. ⁸¹

Considering that fluconazole (an azole) has been recommended by previous guidelines as the initial treatment for Candida infections, ⁸⁷ it is worth noting that fungal resistance to azoles (including fluconazole) has risen over time following the continuous exposure of the drugs to fungi. For instance, C. parapsilosis resistance to fluconazole has increased over time. ⁸⁸

A recent study demonstrated increased efficacy of combination therapy involving azoles and a target of rapamycin (TOR) inhibitor (AZD8055) against azole-resistant A. fumigatus and multidrug-resistant C. auris. ⁸⁹ The authors further reported that both TORC1 and TORC2 are inhibited by the binding of AZD8055 to the adenosine triphosphate (ATP)-binding cleft of TOR kinase. Investigations have shown that in the pathogenesis of fungal infections, the TOR signalling pathway plays important roles. ⁹⁰ The expression of genes associated with cellular adhesion, aggregation and morphogenesis, which are attributed to the virulence of C. albicans, is regulated by TOR ⁹¹ and the DNA damage response “machinery”. ⁹²

Despite the promise of this class of antifungals in contemporary fungal treatment regimens, its overuse, particularly in sub-Saharan Africa, has driven the emergence of resistance. Additionally, the widespread use of azole fungicides (14a-demethylase inhibitors) in agricultural fields in Africa could be a contributing factor to the selection of azole-resistant isolates. ⁹³ For example, multiazole-resistant A. fumigatus strains have been isolated from the environment in Tanzania, ⁹⁴ and azole-resistant C. parapsilosis strains causing bloodstream infection have been isolated in South Africa. ⁹⁵ Hamdy et al. considered numerous novel azoles, such as S-alkylated azole derivatives (UoST5, 7, 8, and 11), for further development due to their low MIC₅₀ and safety in mammalian cells. ⁹⁶

Echinocandins

Echinocandins have a cyclic hexapeptide as their core and are acylated by having a different fatty acid attached to the dihydroxyornithine amino group ⁷⁵ ; this lipid residue is necessary for bioactivity because it anchors the drug to the cell membrane. ⁹⁷ Filamentous fungi naturally produce echinocandins, such as echinocandin B. ⁷⁵ Semisynthetic cyclic lipopeptides with antifungal activity include rezafungin, anidulafungin, micafungin, and caspofungin. ⁷⁵

This class of antifungals has lipopeptide molecules that execute their antifungal activity by noncompetitively inhibiting β-1,3-D-glucan synthase in the fungal cell wall, ⁹⁸ which oversees the production of β-1,3-D-glucan, a key structural element of fungal cell walls. ⁹⁹ Caspofungin, micafungin, and anidulafungin are some of the accepted antifungal agents, and they are fungicidal against most Candida species, including those resistant to polyenes and azoles. ⁸⁸ Rezafungin (CD101), a novel echinocandin with a prolonged half-life, is currently being evaluated in Phase 3 trials. ¹⁰⁰ A study conducted by Song et al. ¹⁰¹ revealed that isolates of C. krusei, C. albicans, C. tropicalis, and C. parapsilosis resistant to one or more echinocandins are notably rare. However, resistance to anidulafungin, caspofungin, and micafungin was most noticeable among C. glabrata isolates. While the echinocandin class is fungicidal, ¹⁰² it is fungistatic to some pathogenic filamentous fungi, including Aspergillus spp. ¹⁰¹

Unlike polyenes, which are toxic owing to their slight affinity for human cholesterol, the therapeutic potential of echinocandins is outstanding, and they are unlikely to cause serious drug interactions or renal or hepatic toxicity. ¹⁰³ In most cases, when caspofungin and posaconazole were combined, they worked well in a synergistic manner. ¹⁰⁴ Interestingly, synergistic effects were also detected in azole-resistant isolates of A. fumigatus. ¹⁰⁴

The wide availability of the accepted antifungal agents in this class in sub-Saharan Africa has not been determined, but studies in South Africa, ¹⁰⁵ Ethiopia, ¹⁰⁶ and Cameroon ¹⁰⁷ have indicated the availability of caspofungin and anidulafungin.

Polyenes

The oldest class of antifungal medications used to treat systemic fungal infections are polyenes, which are organic, amphipathic molecules. The most widely used polyene, amphotericin B, was first used in medicine in the 1950s and has potent activity against a variety of clinically important fungal species, including several species of Aspergillus, Cryptococcus, and Candida. ¹⁰⁸ The distinguishable feature of polyenes that characterises and differentiates them from other antifungal classes is the multiple conjugated double bonds of the hydroxylated chromophore. ⁸⁰ Depending on the quantity of conjugated double bonds they contain, amphotericin B and natamycin are categorised as heptaene and tetraene polyene antifungal drugs, respectively. ⁸⁰ The all-trans conformation of the conjugated double-bond lactone chromophore is necessary for the stability and antifungal activity of natamycin and amphotericin B. ¹⁰⁹ The aforementioned polyene antifungals are lipophilic because of the conjugated double bonds and hydrophilic because of the hydroxylation of the chromophore. ⁸⁰ Hydrophilicity allows the drug to dissolve in water, while lipophilicity impacts drug uptake, metabolism, and drug interactions with the target protein. ⁸⁰

Traditionally, polyenes are believed to directly bind to ergosterol to form drug-lipid complexes that intercalate into the membranes of fungal cells, resulting in leakage of intracellular components and eventually cell death. ¹¹⁰ Recent structural and biophysical studies, however, cast doubt on this model, showing that amphotericin B forms extra membranous aggregates that act as a fungicidal ‘sterol sponge’ to draw ergosterol from fungal cell membranes, as shown in Figure 1. ¹¹¹

Figure 1.

Illustration showing the mechanism of action of the three classes of antifungal agents.

Source: Figure adopted from Lee et al. ⁸³

Polyenes have a wide range of fungicidal effects. The target of amphotericin B is ergosterol, which is a sterol lipid; unlike proteins, it is not encoded by genes; hence, resistance to polyenes is relatively infrequent. ¹¹² Its resistance may arise when there is ergosterol replacement or depletion that results in alteration of the cell membrane composition. ⁸⁴ According to a recent study, clinicians found that a single high dose of amphotericin B is as effective as a one-week course of daily amphotericin B. ⁶⁰ The administration of polyenes, such as amphotericin B, is disfavoured due to nephrotoxicity, ¹¹³ dose-dependent toxic effects towards the host and poor oral bioavailability. ¹¹⁰

Flucytosine

Flucytosines are pyrimidine analogues that are antimycotic, lack intrinsic antifungal capacity and have limited clinical uses. ⁸¹ After intake, flucytosine is transformed into the toxic substance 5-fluorouracil (via the activity of cytosine deaminase, which is absent in humans), which inhibits RNA and DNA synthesis, as well as various metabolic pathways. ⁸¹ Flucytosines are rarely used alone owing to the rapid emergence of drug resistance during monotherapy, and they are combined with amphotericin B when used to treat cryptococcal meningitis and other fungal infections. ⁸¹ Flucytosine monotherapy is used only for treating chromoblastomycosis and vaginal and lower urinary tract candidiasis. ¹¹⁴ Unlike some other antifungals, flucytosines are currently not widely available in sub-Saharan Africa. ¹¹⁵

Tolerance and resistance mechanism of different antifungal classes

Numerous environmental and clinical fungal isolates can resist or tolerate antifungal drugs. The ability of fungi to grow at antifungal drug concentrations that stop growth or kill most fungal isolates is known as antifungal resistance. ¹¹⁶ On the other hand, tolerance refers to the capacity of drug-sensitive cells to proliferate at drug concentrations greater than the minimum inhibitory concentration (MIC), and it involves a variety of general stress responses, spore formation and/or epigenetic pathways. ¹¹⁶ Some fungal species exhibit intrinsic resistance, resulting from the inability of drugs to effectively bind to their target or the removal of the drug by efflux pumps, as observed in C. krusei, Aspergillus spp., and intrinsic (100.0%) fluconazole resistance in C. krusei. ¹¹⁷ In contrast to intrinsic resistance, some fungal species exhibit acquired resistance – acquisition of resistance mechanisms that give them an upper hand in thriving and proliferating in higher antifungal drug concentrations than their corresponding wild types. ⁸⁵ This resistance can be acquired via evolution or vertical or horizontal gene transfer from the resistant mutant to the wild type. ¹¹⁸

As fungi are eukaryotes, they are usually multicellular and have multinucleate genomic organisation, which increases the potential for genetic changes promoting adaptations and the development of resistance. Some genetic alterations that confer antifungal resistance include hypermutator fungal lineages in C. glabrata and Cryptococcus spp., gene duplications, transposon insertions (~10⁻³ to 10⁻⁴ per cell per generation) and point mutations (~10⁻⁶ to 10⁻⁸ per cell per generation). ⁸⁵

The environmental resistance of fungi to antiungal agents can emerge following the prior exposure of human pathogenic fungi to fungicides in nature. ¹¹⁹ Resistance to all major classes of fungicides, including anilinopyrimidines, benzimidazoles, strobilurins, sterol demethylation inhibitors, including azoles and succinate dehydrogenase inhibitors, is evolving due to environmental pressure from fungicides. ¹²⁰ Furthermore, some species exhibit a nongenetic route of conferring resistance or tolerance via a physiologically sessile state of multimorphic cells known as biofilm formation. ⁸⁵ The extracellular matrix produced by the collective fungal cells in biofilms serves as a drug sink, lowering the effective drug concentration for the cells in the biofilm. ¹²¹ Alterations at the molecular level and in the environment result in many adaptive mechanisms of antifungal resistance and tolerance. This includes overexpression or drug target alteration, activation of stress responses and upregulation of multidrug transporters. ¹²² Due to these multiple ways of obtaining resistance, resistance to azoles and echinocandins is much more common, ⁸² but resistance to polyenes is still incredibly rare. ¹²³

Resistance to polyenes

Fungal resistance to polyenes is mediated by alterations in enzymes, such as ERG2 and ERG11, ¹²⁴ which deplete ergosterol from the membrane or reduce drug-binding affinity, ⁸³ as illustrated in Figure 2.

Figure 2.

A picture showing the mechanism of antifungal resistance.

Source: Image adapted from Lee et al. ⁸³

Furthermore, a study by Vandeputte et al. ¹²⁵ on clinical isolates of C. glabrata that were less susceptible to polyenes revealed a nonsense mutation in the ERG6 gene, which encodes an enzyme involved in the final stages of the pathway for ergosterol biosynthesis and has been attributed to be the cause of this reduction in susceptibility. Additionally, the ERG6 mutation caused the overexpression of almost all the genes that catalyse the final stages of the ergosterol biosynthesis pathway, supporting the idea that this metabolic pathway is blocked in the wild type. ¹²⁵

Resistance to echinocandins

Fungal resistance to the echinocandin class is principally mediated by mutations in the FKS genes, as shown in Figure 2. These mutations increase the MIC, resulting in cross-resistance to various echinocandins and significantly reducing the IC₅₀ of the glucan synthase enzyme. ¹²⁶ Pfaller et al. ⁸⁸ confirmed variable cross-resistance between voriconazole and fluconazole when examining the common species of Candida that cause invasive candidiasis.

Although prolonged exposure to two different classes of agents occurs when the multidrug resistance (MDR) phenotype is most frequently found, ⁸⁸ recent studies have shown that under stressful circumstances, mutations in the MSH2 DNA mismatch repair gene may result in a hypermutable state and accelerate the development of resistance to echinocandin, amphotericin B, and fluconazole. ¹²⁷ These findings may provide a potential explanation for why some studies reported echinocandin resistance in Candida strains exposed to fluconazole, even though the drugs have different targets and resistance mechanisms. ¹²⁸

A study conducted by Pfaller et al. ⁸⁸ revealed that drug-resistant strains of C. albicans, which are specifically resistant to caspofungin and micafungin, exhibited mutations in the FKS1 HS1 gene. These mutations included F641I, F641S, S654P, S629P and S645P (each present in four isolates). Additionally, all C. glabrata isolates analysed in the study showed modifications in the FKS HS genes. The most prevalent alterations observed were F659S/V/Y in FKS2 HS1 and S663P in FKS2 HS1. ⁸⁸ Another study on C. albicans revealed that mutations occurring at positions S641 and S645 are not only the most frequently observed but also result in the most pronounced resistance phenotypes. ⁹⁸ According to earlier reports by Pfaller et al., ⁸⁸ isolated C. glabrata harbouring the S663F mutation did not respond to high doses of anidulafungin in vivo but responded to high doses of micafungin or caspofungin under similar conditions. By contrast, isolates carrying the S629P mutation were insensitive to any of the three echinocandins, even at the highest dose. ¹²⁹ Echinocandin therapy typically has positive results for patients whose C. glabrata infections are caused by strains with the I1379V and I634V mutations (susceptible to both caspofungin and anidulafungin). ¹³⁰ Echinocandin-resistant strains displayed either FKS1 or FKS2 hotspot mutations. ¹²⁷ Perlin et al. further reported that the main cause of clinical resistance to echinocandins is FKS1 or FKS2 hotspot mutations. ⁹⁸

Resistance to azoles

Fungistatic azoles exert strong directional selection pressure on fungal pathogens, such as Cryptococcus and Candida pathogens, without causing their death, thereby facilitating the development of antifungal drug resistance. As a result, different Candida species exhibit varying levels of susceptibility to azoles. C. krusei is inherently resistant to the commonly used azole fluconazole, whereas resistance in C. glabrata is increasing, and C. albicans generally remains susceptible. ⁸³

Numerous mechanisms of azole resistance have been identified; one of the most common involves the drug target gene ERG11/CYP51A/CYP51B being altered or overexpressed, with resistant isolates of Candida and Aspergillus frequently having amino acid substitutions in regions close to the enzyme’s heme-binding site. ¹³¹ It has also been reported that the transcription factors SRE1 and SRBA in C. neoformans and A. fumigatus, respectively, are involved in resistance to this antifungal agent. ¹³² Furthermore, azole resistance can be enabled following alterations to the other steps in the biosynthesis of ergosterol, such as loss of function of the Δ-5,6-desaturase enzyme ERG3. Cross-resistance to azoles and polyenes frequently results from the depletion of ergosterol and the accumulation of alternative sterols, all of which result from ERG3 mutations. ¹³³

The overexpression of CDR1 and CDR2, which are transporters, is often associated with azole resistance, ⁸² as shown in Figure 2. Among these two transporters, CDR1 plays a more significant role in determining azole resistance. Removing CDR1 from a clinical isolate reduces azole resistance by fourfold to eightfold. Conversely, deleting CDR2 typically has a comparatively weaker impact. ¹³⁴ SNQ2 is also involved in azole resistance. ¹³⁵ C. albicans acquires azole resistance by altering the ergosterol biosynthesis pathway through loss of function mutations in ERG3. These mutations affect the 5,6-desaturase enzyme encoded by ERG3, preventing the cellular accumulation of 14-α-methyl-3,6-diol, a toxic sterol intermediate generated as a result of the inhibition of ERG11 by azoles. ¹³⁶ Alternatively, fungal growth and replication in the presence of azoles are made possible and enhanced by the incorporation of 14-α-methyl-fecosterol into the fungal cell membrane. Another study by Spettel et al. ¹³⁷ revealed that C. albicans resistance to azoles can be attributed to five missense mutations in ERG3 (A353T, G261E, S191P, T329S and A168V) and two additional nonsense mutations (Y190* and Y325*), leading to loss of function.

Resistance to flucytosine

Flucytosine enters fungal cells through cytosine permease, where it is converted into fluorouracil, which then interferes with pyrimidine salvage pathways, subsequently inhibiting DNA, RNA and protein synthesis. ¹³⁸ Primarily, resistance to flucytosine arises from mutations in the FCY2 gene, which encodes a cytosine permease enzyme, leading to decreased uptake of the drug by the enzyme. ¹³⁹ Fungal pathogens can also acquire resistance to flucytosine by suppressing the conversion of 5-fluorocytosine (5FC) to 5-fluorouracil (5FU) or by inhibiting the binding of 5-fluorouracil to uracil phosphoribosyl transferase. ¹³⁸ The genes involved in this resistance mechanism are FCY1 and FUR1, which encode the enzymes cytosine deaminase and uracil phosphoribosyl transferase, respectively. ¹³⁸ These resistance mechanisms have been identified in Candida spp., S. cerevisiae, Cryptococcus spp. and other fungal pathogens. ¹³⁸ Kern et al. ¹⁴⁰ reported that the R134S mutation in the FUR1 gene of S. cerevisiae confers resistance to 5FU. Furthermore, the G28D/S29L and A176G mutations in C. albicans as well as the A15D/G11D/W148R/G210D/L136R/T84L/I384F and G246S/I384F mutations in C. glabrata result in defective cytosine deaminase and cytosine permease enzymes. ¹⁴¹ Billmyre et al. ¹⁴² reported that the D306G/Y217C/1520delT/1182insC mutation in the UXS1 gene of C. deuterogattii leads to the accumulation of UDP glucuronic acid and the alteration of nucleotide metabolism, resulting in the inhibition of both 5FC and 5FU toxicity. Additionally, defective DNA mismatch repair pathways frequently contribute to acquired 5FC resistance in C. deuterogattii isolates. ¹⁴²

Studies have proposed that each fungal pathogen may possess different mechanisms of resistance to 5-fluorocytosine other than the Fcy2-Fcy1-Fur1 pathway. ¹³⁹ In a chemogenomic analysis by Costa et al., ¹⁴³ it was discovered that 183 genes contribute to resistance to flucytosine by affecting various stages of fungal metabolic processes. Notably, within the domain of DNA metabolism, 13 genes were found to be associated with flucytosine resistance, comprising eight genes responsible for chromatin remodelling and five genes involved in DNA repair. Although flucytosine does not primarily target the cell membrane, eight lipid metabolism genes are required for 5-flucytosine tolerance. ¹⁴³ These genes included the ergosterol biosynthetic genes ERG4 and ERG3, as well as six others that affect plasma membrane phospholipid composition, such as the transcription factor encoding gene MGA2, which has a role in regulating the desaturase-encoding genes OLE1, and OPI1, which is a negative regulator of phospholipid biosynthesis genes. ¹⁴³ The authors also discovered that cell wall-encoding genes, specifically CWP2 and SED1, play a role in conferring resistance to flucytosine. Moreover, the deletion of CGFPS1 and CGFPS2 was found to increase the susceptibility of fungi to flucytosine, ¹⁴³ suggesting that these genes play a major role in resistance because they are related to osmotic stress resistance. ¹⁴⁴ The discovery of five genes encoding arginine metabolic enzymes that confer 5-flucytosine resistance within these processes suggested that arginine itself may be required for 5-flucytosine resistance. ¹⁴³

Antifungal resistance cases reported in sub-Saharan Africa

Microbiological resistance occurs when antifungal medications are unable to effectively eliminate or hinder the growth of fungi under controlled laboratory conditions. ¹⁴⁵ This resistance can either be inherent to fungi or acquired over time. ¹⁴⁶ The emergence of resistance is a major factor contributing to treatment failures and the high mortality rates observed in systemic fungal infections. ¹⁴⁷ The efficacy of available antifungal therapies is compromised due to the widespread presence of resistance, which is likely a result of the extensive and repeated use of these drugs. ¹⁴⁸ Additionally, factors such as limited systemic usage due to toxicity concerns and the emergence of new strains of fungal infections further undermine the effectiveness of antifungal medications. ¹⁴⁹ Notably, fungal pathogens belonging to Candida, Aspergillus, Cryptococcus, and Pneumocystis species demonstrate significant rates of resistance to antifungal agents. ¹⁴⁶

Candida

The global prevalence of antifungal resistance in yeasts is on the rise, particularly due to the emergence of non-albicans Candida species. ¹²⁸ Similar to bacteria, there is growing concern over multidrug-resistant yeasts, such as C. auris and C. glabrata. ¹⁵⁰ A study conducted in Ghana revealed that C. albicans was the most frequently isolated species from clinical samples, with resistance levels ranging from 4.5% to 22.2%. ¹⁵¹ However, another study focusing on 267 HIV-infected individuals with oropharyngeal candidiasis in Ghana revealed a shift in the distribution of Candida species, with an increase in non-albicans species that often exhibit resistance to fluconazole. ¹⁵² Recent research conducted in Ghana demonstrated that Candida species showed the highest rates of resistance to fluconazole (48.1%), followed by voriconazole (37.0%) and nystatin (9.3%). ¹⁵³ The significant resistance to fluconazole among Candida isolates may be attributed to its predominant use for the empirical treatment of vulvovaginal candidiasis. ¹⁵³ As a result, current treatment guidelines recommend the use of alternative effective antifungals, such as amphotericin B and flucytosine. ¹⁵⁴

Resistance to antifungal drugs has been observed in non-albicans Candida species, such as C. glabrata and C. krusei, in several African countries, including South Africa, ¹⁵⁵ Cameroon, ¹⁰⁷ Nigeria, ¹⁵⁶ Ghana, ¹⁵¹ Tanzania, ¹⁵⁷ and Ethiopia. ¹⁵⁸ Azole resistance has increased in candidiasis patients, leading to increased mortality rates, ¹⁵⁹ and echinocandins have been recommended as alternative treatments. However, coresistance to both echinocandins and azoles has been reported in clinical isolates of C. glabrata, ¹³⁰ and cases of echinocandin-resistant C. glabrata infections have been documented in South Africa. ⁴⁵ Fluconazole resistance in C. glabrata and C. tropicalis has been observed in various sub-Saharan African countries, including Tanzania. ¹⁶⁰ Amphotericin B resistance has also been identified in Kenya ¹⁶¹ and Ghana. ¹⁵¹

Studies from Southwest Cameroon have indicated intermediate resistance to clotrimazole and amphotericin B, suggesting the need for higher dosages for effective treatment. ¹⁰⁷ Topical antifungals, such as econazole and nystatin, are recommended for localised Candida infections, but resistance to nystatin has been reported in Ivory Coast, Ethiopia, Kenya, South Africa, and Cameroon, ¹⁶² while econazole resistance has been found in Southwest Cameroon. ¹⁶³ A new multidrug-resistant species, C. auris, has been isolated in South Africa. ¹⁶⁴ When comparing drug resistance patterns in South Africa and Cameroon, C. albicans showed significantly greater resistance to azoles, while C. glabrata generally exhibited low azole resistance. ¹⁰⁷ A recent systematic review by Mushi et al. ⁴⁷ on VVC in sub-Saharan Africa revealed that resistance to fluconazole in C. albicans ranged from 6.8% in Cameroon to 53.7% in Ethiopia.

Cryptococcus

Treatment of cryptococcosis involves a combination of amphotericin B deoxycholate and flucytosine for at least two weeks, followed by fluconazole for a minimum of eight weeks. ¹⁶⁵ However, due to the widespread unavailability and inaccessibility of flucytosine in sub-Saharan Africa, treatment primarily relies on amphotericin B deoxycholate and fluconazole, despite their limited effectiveness. ¹⁶⁶ Fluconazole is the most commonly prescribed antifungal drug for treating cryptococcal meningitis in the region, although it is less effective than amphotericin B. ¹⁶⁷ Moreover, reports indicate the emergence of fluconazole resistance in C. neoformans, with associated chromosomal changes in the fungus. ¹⁶⁸ Widespread resistance to fluconazole and, to a lesser extent, amphotericin B deoxycholate has significantly impacted treatment outcomes. ¹⁶⁹ The C. gattii species complex generally exhibits greater resistance to azoles than isolates from the C. neoformans species complex. ¹⁷⁰

Studies conducted in different sub-Saharan African countries have reported an increase in antifungal drug resistance among clinical isolates of C. neoformans. In Uganda, resistance to amphotericin B is rare, while resistance to fluconazole appears to be emerging. ¹⁷¹ According to the research conducted by Atim et al., ¹⁷² 43.9% of the 310 clinical isolates of C. neoformans had IC₅₀ values ⩾8 µg/ml. In vitro susceptibility testing of C. neoformans isolates from Egypt revealed that out of 29 isolates, only three exhibited resistance to the tested antifungal drugs. ¹⁷³ Another study reported a decrease in fluconazole susceptibility among clinical isolates of C. neoformans in South Africa over a decade. ¹⁷⁴ Similarly, a study in Cameroon found that 92.7% of C. neoformans with reduced susceptibility to fluconazole. ¹⁷⁵ Recently, Bive et al. ¹⁷⁶ found that two C. neoformans isolates out of 23 (8.7%) were resistant to fluconazole and one isolate out of 23 (4.3%) isolates was resistant to flucytosine. Research conducted in Nairobi, Kenya, highlighted the presence of azole resistance in C. neoformans isolates from clinical sources. ¹⁷⁷ These findings emphasise the challenges faced in effectively treating cryptococcosis in sub-Saharan Africa due to the development of antifungal drug resistance.

Aspergillus

Azole-resistant Aspergillus species have emerged as a growing problem in sub-Saharan Africa. ¹⁷⁸ In a Tanzanian study, all five clinical isolates of A. fumigatus were found to be resistant to triazole antifungal drugs, indicating a prevalence rate of 100%. ¹⁷⁹ Surveillance studies conducted in various regions have also reported an increase in triazole-resistant A. fumigatus, raising concerns about the management of fungal diseases caused by this particular species. ¹⁸⁰ The presence of azole-resistant A. fumigatus isolates has been documented in Tanzania, ⁹⁴ and the first isolate of A. fumigatus resistant to azole antifungal agents was identified in Burkina Faso. ¹⁸¹ The resistance of filamentous fungi, notably A. fumigatus, to antifungal drugs, particularly azoles, has been attributed to their increased use in both clinical and environmental settings. ¹⁸² The increase in azole-resistant Aspergillus species poses significant challenges for the effective treatment of fungal infections in sub-Saharan Africa.

Dermatophytes

A study conducted in Nigeria revealed that every single isolate (100.0%) of T. rubrum, which is one of the main fungi responsible for tinea capitis, demonstrated resistance to ketoconazole, fluconazole, itraconazole, griseofulvin, and terbinafine. ¹⁸³ There are limited data on T. rubrum resistance in sub-Saharan Africa.

Current and future interventions

Diagnosis and surveillance

Fungal diseases often receive insufficient attention in terms of funding, research, and health policies, with medical mycology accounting for only approximately 3% of infectious disease research expenditures. ¹⁸⁴ Although effective species prevalence and antifungal monitoring programmes have been successfully implemented in Europe, the Asia-Pacific region, Latin America, and North America, comprehensive epidemiological data on fungal infections worldwide, particularly in sub-Saharan Africa, are lacking. For instance, a recent assessment of clinical mycology in Africa involving 40 institutions from 21 countries revealed that the majority of institutions (n = 39, 97.5%) reported having microbiology laboratories. However, regarding mycological diagnostic tools, three institutions (7.5%) reported no access to such services at all. ¹⁸⁵ In cases of suspected fungal infection, 21 institutions (52.5%) conducted direct microscopy on clinical specimens, 34 (85.0%) used microscopy for diagnosing cryptococcosis, and only eight (20.0%) employed silver staining when pneumocystosis was suspected. ¹⁸⁵ Similarly, data collected in 48 African countries revealed that a significant portion of the population in 14 sub-Saharan African countries, approximately 74% or 1.041 billion people, lacked access to histoplasmosis diagnostics, and 78.5% or 1.105 billion people lacked access to Pneumocystis pneumonia diagnostics. ¹⁸⁶ Moreover, fungal culture, another diagnostic method, was available in 41 countries, covering a population of 94% or 1.289 billion people, whereas magnetic resonance imaging was routinely accessible to only 32.2% or 453.59 million people in sub-Saharan Africa. ¹⁸⁶ A recent study investigating the diagnostic capacity for cutaneous fungal diseases in sub-Saharan Africa revealed that skin biopsies were regularly collected in 46% (22) of the 47 countries studied, while direct microscopy and histopathological examination of tissue were frequently performed in 42% (20) and 40% (19) of the countries, respectively. ¹⁸⁷ The cost of diagnostics for patients was identified as a significant hindrance to the utilisation of these diagnostic methods. ¹⁸⁷ Additionally, a study focusing on diagnostic options for pulmonary fungal diseases in sub-Saharan African countries with populations exceeding one million revealed that chest X-rays and computed tomography were frequently utilised in the public sector, while bronchoscopy and spirometry were commonly conducted in tertiary health facilities. ¹⁸⁸

In sub-Saharan Africa, there is a deficiency in surveillance of antifungal medication resistance. ¹⁶² Surveillance programs play a vital role in the transition from empirical antifungal therapy, which often faces challenges due to varying resistance levels and the presence of inherently resistant organisms. ¹⁶² The optimal selection of effective medication and accurate identification of the causative fungal species are crucial for the management of many fungal infections. C. auris, a multidrug-resistant pathogen first discovered in South Africa ¹⁶⁴ in 2009 and Kenya ⁴³ in 2011, serves as a notable example. However, only a few laboratories in sub-Saharan Africa can accurately identify C. auris using current technologies, such as matrix-assisted laser desorption or ionisation time of flight (MALDI-ToF), or molecular techniques. ¹⁸⁹ In a study focused on identifying fungi at the species level, biochemical tests were the predominant method utilised for species-level identification of fungi in 28 out of the 40 institutions (70%), while seven institutions (17.5%) employed MALDI-ToF, eight institutions (20%) used DNA sequencing and 19 institutions (47.5%) had access to automated blood culture monitoring. ¹⁸⁵ These studies have revealed notable variations in both the accessibility and quality of diagnostic tests throughout sub-Saharan Africa. While a few instances showcased exceptional diagnostic capabilities and superior care, such occurrences were infrequent. Due to the limited availability of routine diagnostic facilities in most sub-Saharan African countries, many patients receive treatment without knowledge of the specific fungal species they are infected with, and there is a lack of updated guideline data for the appropriate prescription of antifungal medications. ¹⁶² Establishing diagnostic molecular microbiology laboratories, particularly in underdeveloped nations, such as those in Africa, presents significant challenges. ¹⁹⁰ However, strengthening healthcare laboratories and overall system capacity is urgently needed in sub-Saharan Africa to address the burden of fungal infections.

Treatment

Unlike bacterial infections, which have more promising alternative treatments, ¹⁹¹ fungal infections still face limitations because there are currently limited therapeutic and combination options, thereby emphasising the importance of exploring new targets for the development of antifungal therapies. Africa encounters various challenges concerning fungal infections, including inadequate awareness among healthcare professionals and policymakers, as well as concerns regarding the cost, toxicity, availability, and accessibility of antifungal treatments. ¹⁹² The WHO Essential Medicines List presently includes amphotericin B, clotrimazole, fluconazole, flucytosine, griseofulvin, itraconazole, nystatin, and voriconazole. These medications have been identified and approved by the World Health Organisation as essential treatments for various fungal infections. ¹⁹³ The scarcity of these essential medications in sub-Saharan Africa is a worrisome issue. One potential approach to address the emergence of antifungal resistance is the utilisation of combination therapies, which involve combining antifungal drugs with different mechanisms of action. ¹⁹⁴ These combinations can synergistically enhance the elimination of pathogens, potentially enabling lower dosages of the drugs to mitigate toxicity concerns. ⁸ For instance, in the treatment of cryptococcal meningitis, the addition of flucytosine to amphotericin B has proven effective in preventing the selection of resistant colonies and improving treatment outcomes. ¹⁹⁵ Combinations of flucytosine, fluconazole, and amphotericin B have also shown promise in accelerating infection clearance and reducing mortality rates. ¹⁹⁶ The extensive use of antifungal medications is believed to contribute to the development of drug resistance, emphasising the need for a deeper understanding of resistance mechanisms and underlying biological processes.

A significant challenge faced in the sub-Saharan Africa region is the lack of comprehensive and current data regarding the burden of fungal infections, as well as management and treatment practices and antifungal resistance. This scarcity is due to limited research conducted on fungal infections within the region. As a result, this review falls short of capturing the full impact of these infections in the region and recommending treatment strategies to mitigate their burden.

Conclusion

This extensive review has revealed significant evidence on fungal infections in sub-Saharan Africa, a considerable proportion of which remain untreated or unreported. Most antifungal susceptibility tests have focused on species of the Candida genus. Given the increasing populations at risk of fungal infections, however, it is crucial to evaluate antifungal resistance in various invasive fungal diseases across the region. Giving additional attention to fungal infections is crucial to overcoming the multifaceted resistance of fungi to the limited spectrum of antifungal arsenals. Regulatory bodies need to monitor the use of antifungal agents across sub-Saharan Africa, allowing the use of potent antifungals and further discouraging the overuse of some antifungal agents. Additionally, active surveillance needs to be implemented to keep track of the diagnosis and antifungal treatment of fungal infections.