Version Changes
Revised. Amendments from Version 1
This version addresses the reviewer comments and includes some minor typesetting and referencing corrections. The inclusion criteria was explained in more detail and the Results and Discussion sections were merged into one, pending editorial approval. A more detailed explanation on how Candida drug resistance in sub-Saharan Africa differs from the rest of the world is also given in the Results/Discussion section.
Abstract
Background: Candida infections are responsible for increased morbidity and mortality rates in at-risk patients, especially in developing countries where there is limited access to antifungal drugs and a high burden of HIV co-infection. Objectives: This study aimed to identify antifungal drug resistance patterns within the subcontinent of Africa. Methods: A literature search was conducted on published studies that employed antifungal susceptibility testing on clinical Candida isolates from sub-Saharan African countries using Pubmed and Google Scholar. Results: A total of 21 studies from 8 countries constituted this review. Only studies conducted in sub-Saharan Africa and employing antifungal drug susceptibility testing were included. Regional differences in Candida species prevalence and resistance patterns were identified. Discussion: The outcomes of this review highlight the need for a revision of antifungal therapy guidelines in regions most affected by Candida drug resistance. Better controls in antimicrobial drug distribution and the implementation of regional antimicrobial susceptibility surveillance programmes are required in order to reduce the high Candida drug resistance levels seen to be emerging in sub-Saharan Africa.
Keywords: Candida, antifungal drug resistance, Africa
Introduction
Candida species are known to shift from commensal to opportunistic infectious agents when triggered by factors such as immunosuppression, continuous usage of antibiotics and poor nutrition, leading to increased patient morbidity and mortality 1– 3. In severely immunocompromised patients, Candida species can spread through the bloodstream and gastrointestinal tract. This can lead to systemic candidiasis, with a reported mortality rate in developed countries of 38% 4 and 44% 5. Candida is currently the 4 th most commonly isolated microorganism in nosocomial bloodstream infections 6 and has been implicated in >78% of cancerous and precancerous oral lesions 7.
Various antifungal drugs with different modes of action have been developed over the years. These include polyene antifungals (e.g. nystatin and amphotericin B), which interfere with ergosterol synthesis, thereby causing cell membrane leakage; the imidazoles (e.g. miconazole, clotrimazole, econazole and ketoconazole), which also interfere with ergosterol and other cell membrane sterol synthesis; the echinocandins (e.g. anidulafungin, micafungin and caspofungin), which inhibit β 1–3 glucan synthesis, affecting the fungal cell wall and 5-flucytosine that in turn interferes with fungal RNA and DNA synthesis 8. The triazoles (including fluconazole, posaconazole, voriconazole and itraconazole) interfere with the synthesis of ergosterol and have been shown to have fewer side effects than some of the other antifungal drug classes 9.
Resistance to available antifungal therapies is widespread 10, 11, probably due to the widespread and repeated use of these drugs 12. Different Candida species have varying resistance patterns, which appear to be geographically determined 13, 14. Therefore early recognition of resistance facilitates the selection of an appropriate antifungal drug, with the use of oral antifungals in oropharyngeal candidiasis reserved for cases where there is no response to topical antifungal treatment 15. Resistance pattern surveillance to avoid an even higher number of improperly treated, and therefore resistant fungal infections, is imperative 16. This is a cause for concern in the case of immunocompromised patients, who are at a much higher risk of developing opportunistic complications. Importantly, sub-Saharan Africa is the region most affected by HIV, with approximately 25.8 million infected people in 2014 and accounting for almost 70% of the global number of new HIV infections ( http://www.who.int/mediacentre/factsheets/fs360/en/).
Programmes on species prevalence and antifungal surveillance have been successfully developed and introduced in Europe, Asia-Pacific, Latin America and North America 17– 19. The gap in antifungal drug resistance surveillance in Africa has been documented 20. Surveillance programmes are crucial tools in the transition from empirical antifungal treatment, which often does not work due to the diverse resistance levels seen in different regions, and the presence of species that are intrinsically resistant to certain antifungal drugs. The non-existence of routine diagnostics laboratories in most African countries has meant that many African patients are treated without the knowledge of which species they harbour and without any updated guideline data that could be used as a reference in prescribing antifungals. Possible causes for the lack of Candida surveillance programmes in Africa include lack of funding, the limited number of research collaborations and the existence of conflict areas within the continent. This prompted the need for a review of the current situation in Africa regarding the drug susceptibility profiles of Candida species available from different regions.
Methods
Data collection
A literature search was conducted on 21 published studies that employed antifungal susceptibility testing on clinical Candida isolates from 8 sub-Saharan African countries, with the aim of identifying antifungal drug resistance patterns within different regions of the subcontinent and included resistance data for 14 antifungal drugs. Searches were performed on PubMed and Google Scholar between August and November 2016 using the keywords ‘ Candida’, ‘Susceptibility Testing’, ‘Drug Resistance’ and ‘Antifungal’.
Data extracted from the individual studies included the regions within the different countries, patient health information, the methods used for antifungal susceptibility testing, the frequency of Candida species and their susceptibilities to antifungal drugs ( Dataset 1 21).
Inclusion criteria
We attempted to keep the review recent, and with the exception of a few earlier studies which provided an important comparison, only studies conducted in sub-Saharan Africa between the years 1998 and 2016 employing antifungal drug susceptibility testing were included.
Exclusion criteria
Studies conducted in Africa which reported on the prevalence of Candida but did not describe antimicrobial susceptibility were excluded from this review.
Results and discussion
The study populations included healthy 22, 23, HIV-positive 22– 35 and cancer patients 23, as well as patients with genitourinary tract infections 36– 39, respiratory tract infections 32, 39, meningitis 39 and candidemia 40, 41. Most studies relied on broth microdilution or disk diffusion for antimicrobial susceptibility testing, while one of the publications was a retrospective clinical study based on the patients’ response to antifungal therapy.
This review included seven studies from two regions in South Africa 22– 25, 36, 40, 41, three studies from different regions in Ethiopia 33– 35, three studies from two regions in Cameroon 25– 27, three studies from different regions in Nigeria 28, 29, 37, two studies from the same region in Ivory Coast 30, 38, one study from Tanzania 31, one study from Kenya 32 and one study from Ghana 39. Due to the paucity of studies and differences in isolation and antifungal susceptibility testing, a meta-analysis could not be conducted.
Non-albicans species, such as C. glabrata and C. krusei are reported to have innate resistance to antifungal drugs. C. krusei resistance has been reported from South Africa 22, 25, Cameroon 25, Nigeria 28, 37, Ghana 39, Tanzania 31 and Ethiopia 34. Initially thought to have innate resistance to azoles, C. glabrata resistance has been reported in Cameroon 25, Ethiopia 34 and Tanzania 31, while susceptibility has been reported in South Africa 22, 25 and Nigeria 28. This discrepancy may be explained by the phenotypic similarity between C. glabrata, C. nivariensis and C. bracarensis, which could possibly be confused in the absence of molecular typing methods and show different antifungal profiles 42. Resistant C. glabrata has increased in patients presenting with candidiasis in recent years 43, with increased mortality rates 44, and echinocandins have been recommended for the treatment of invasive C. glabrata infections showing resistance to azoles. However, co-resistance to both echinocandins and azoles in clinical isolates of C. glabrata have been reported 45, with two cases of echinocandin-resistant C. glabrata infections recently reported from South Africa 36.
A new multi-drug resistant species, C. auris is taking the world by storm. First discovered in Japan 46, this species has been found in nine other countries on four continents. The Centre for Disease Control and Prevention (CDC) has issued a warning for increased awareness of C. auris in healthcare settings. This nosocomial pathogen is frequently misdiagnosed, shows resistance to different classes of antifungals routinely administered, and is associated with high mortality rates 47. The isolation of this species in South Africa 40 appears to be the only report in Africa at the time of writing this paper.
Regional differences in Candida susceptibility profiles have been observed. In South Africa, earlier reports of baseline data demonstrated a high susceptibility (100%) of C. albicans to fluconazole, along with intrinsically resistant non-albicans species 22, 24, with more recent studies in South Africa showing an emerging resistance to azoles 23, 25, 48. The reasons for this change in susceptibility patterns is not clear, but it is worth noting that the earlier studies were done before the 2002 introduction of fluconazole as prophylaxis to patients attending HIV-AIDS clinics in South Africa 49.
Studies from abroad have reported cross-resistance to fluconazole in patients receiving itraconazole prophylaxis 50 and other previously administered azole therapies, such as ketoconazole and miconazole 51, 52. Similar cross-resistance was recently reported in South Africa where 37% of C. parapsilosis isolates were susceptible to fluconazole and voriconazole, and 44% of fluconazole-resistant isolates were voriconazole cross-resistant 41.
Studies from Bamenda 25 and Douala 26 in Cameroon showed high resistance of C. albicans isolates to azoles (>50% and 70% respectively), with low resistance reported from Mutegene 27 and Bamenda 25 for amphotericin B (4.9 and 4.3%) and 5-flucytosine (10.7 and 6.5%), respectively. The Douala study, on the other hand, reported increased C. albicans resistance to amphotericin B (52.6%) and 5-flucytosine (70%). A comparison of the Mutengene and Bamenda studies further revealed that C. dubliniensis and C. tropicalis susceptibilities differed between the two groups, with C. dubliniensis showing susceptibility to fluconazole and 100% resistance to amphotericin B in the Bamenda group, and increased resistance (66%) to fluconazole and no resistance to amphotericin B in the Mutengene group. C. tropicalis showed resistance to amphotericin B in the Bamenda group (50%) and only 4.3% resistance in the Mutegene group.
C. albicans resistance to amphotericin B has also been reported in Kenya (25.6%) 32 and Ghana (23.4%) 39, while no resistance was seen in studies from Ivory Coast 30, 38 nor Nigeria 29. Intermediate resistance values observed for clotrimazole and amphotericin B in studies from South West Cameroon, may indicate the need for administering higher doses to effectively treat these patients. This raises some concern, since both drugs are toxic at high concentrations and might have various side effects, such as the increase of blood pressure caused by clotrimazole therapy 53.
The application of topical antifungals, such as econazole and nystatin, is recommended for the localized treatment of Candida infections. Candida isolates from the Ivory Coast showed good susceptibility to nystatin with an increasing resistance noted in Ethiopia (1.3–4.7%), Kenya (36%), Gauteng, South Africa (67%) and Mutengene, Cameroon (68%). Resistance to econazole was reported in South West Cameroon 26, 27. Overall, Candida isolates from Eastern African countries demonstrated the lowest resistance levels, with the exception of Kenya where resistance values for clotrimazole (74%) and nystatin (35.6%) were high 32. Systemic antifungals are usually reserved for patients who are unresponsive to topical treatment in cases such as these.
Copyright: © 2017 Africa CWJ and Abrantes PMdS
Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).
The prevalence of Candida species isolated from sub-Saharan Africa appeared to follow the same trend as in other regions, with C. albicans being the predominant species, followed by C. glabrata. However, in a study from Cameroon 27 and two studies from Nigeria 28, 29, C. tropicalis was the second most prevalent species. When comparing the drug resistance patterns with those in the rest of the world, C. albicans resistance to azoles was seen to be noticeably higher in Southwest South Africa 25 and two distinct regions in Cameroon 25, 26, while C. glabrata resistance to azoles was found to be generally low. However, in a study from South Africa 41, C. glabrata resistance to fluconazole was found to be similar to the high resistance levels seen in North America 19. C. tropicalis resistance to fluconazole was seen to be noticeably high in East African countries, with up to 50% resistance seen in Tanzania 31. Such high levels of resistance have not been documented in other regions.
Fluconazole is widely used in public health settings in the African continent and is used empirically in the treatment of systemic or localized Candida infections 54, as it is less toxic and regarded as more effective than imidazole antifungals, such as ketoconazole or amphotericin B, even though it is a teratogenic drug 55, 56. Although still somewhat effective in other regions, the use of azoles as first line drugs for systemic infection should be revisited in certain areas of South and West Africa, due to their increasing inefficacy. Regular monitoring of Candida at a regional level could therefore be an important tool to aid in the prescription of antifungals based on the prevalent species and their susceptibilities to antifungal drugs in areas where routine microbiological laboratory testing is not available.
The sale of antimicrobial medications is largely unregulated in Africa and is exacerbated by the influx of fake and adulterated drugs with little or no active ingredients, often available both in pharmacies and on the streets. This problem is aggravated by practitioners who prescribe antimicrobial medications empirically based on clinical presentation, without prior knowledge of which microbial agent(s) are causing infections in their patients. These issues pose a serious public health threat, as they are largely responsible for more and more antimicrobial drugs being rendered ineffective in treating life-threatening infections. This is especially true in the case of the antifungal armamentarium, which is already very limited 57, especially in resource-poor settings. Limitations of this study include the paucity of available data from African regions, differences in sample sourcing, as well as techniques for isolation and susceptibility profiles from different regions, all of which complicate a comparison of outcomes of the cited studies.
The regional differences in antifungal drug susceptibility of Candida species, often seen within the same country, are an important finding that justifies the implementation of Candida species prevalence and susceptibility testing programmes in the African continent, notably in at-risk population groups, such as HIV patients. With the emergence of inherently drug resistant non-albicans species, more studies on Candida prevalence and drug susceptibility are needed throughout sub-Saharan Africa. This is most critical in resource-poor areas where there is little or no information available, such as southern (with the exception of South Africa) and central African countries and countries bordering the Sahara.
We would like to conclude by adding that Candida identification to species level is rarely made in clinical settings in Africa, and patients are treated empirically based on their clinical symptoms. The introduction of routine antimicrobial susceptibility testing before initiation of therapy can be relatively expensive, but is certainly a long-term cost effective solution in preventing the progression of drug resistance. Changes in drug susceptibility over time serve as a reminder for the need to test clinical Candida isolates for sensitivity to antifungal drugs in the effort to improve patient care and reduce patient morbidity and mortality.
Data availability
The data referenced by this article are under copyright with the following copyright statement: Copyright: © 2017 Africa CWJ and Abrantes PMdS
Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). http://creativecommons.org/publicdomain/zero/1.0/
Dataset 1: Antifungal drug resistance of Candida species per region. DOI, 10.5256/f1000research.10327.d145319 21
Funding Statement
This study was supported by the Research Office of the University of the Western Cape (project registration no. ScRIRC2012/10/72).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[version 2; referees: 2 approved]
References
- 1. Akpan A, Morgan R: Oral candidiasis. Postgrad Med J. 2002;78(922):455–9. 10.1136/pmj.78.922.455 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Jabra-Rizk MA, Falkler WA, Jr, Enwonwu CO, et al. : Prevalence of yeast among children in Nigeria and the United States. Oral Microbiol Immunol. 2001;16(6):383–5. 10.1034/j.1399-302X.2001.160611.x [DOI] [PubMed] [Google Scholar]
- 3. Owotade FJ, Patel M, Ralephenya TR, et al. : Oral Candida colonization in HIV-positive women: associated factors and changes following antiretroviral therapy. J Med Microbiol. 2013;62(Pt 1):126–32. 10.1099/jmm.0.047522-0 [DOI] [PubMed] [Google Scholar]
- 4. Gudlaugsson O, Gillespie S, Lee K, et al. : Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis. 2003;37(9):1172–7. 10.1086/378745 [DOI] [PubMed] [Google Scholar]
- 5. Almirante B, Rodríguez D, Park BJ, et al. : Epidemiology and predictors of mortality in cases of Candida bloodstream infection: results from population-based surveillance, Barcelona, Spain, from 2002 to 2003. J Clin Microbiol. 2005;43(4):1829–35. 10.1128/JCM.43.4.1829-1835.2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Budhavari S: What’s new in diagnostics? Fungitell ®: 1,3 beta-D Glucan assay. South Afr J Epidemiol Infect. 2009;24(1):37–8. Reference Source [Google Scholar]
- 7. Mohd Bakri M, Mohd Hussaini H, Rachel Holmes A, et al. : Revisiting the association between candidal infection and carcinoma, particularly oral squamous cell carcinoma. J Oral Microbiol. 2010;2:5780. 10.3402/jom.v2i0.5780 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Odds FC, Brown AJ, Gow NA: Antifungal agents: mechanisms of action. Trends Microbiol. 2003;11(6):272–9. 10.1016/S0966-842X(03)00117-3 [DOI] [PubMed] [Google Scholar]
- 9. Khan ZK, Jain P: Antifungal agents and immunomodulators in systemic mycoses. Indian J Chest Dis Allied Sci. 2000;42(4):345–55. [PubMed] [Google Scholar]
- 10. Luque AG, Biasoli MS, Tosello ME, et al. : Oral yeast carriage in HIV-infected and non-infected populations in Rosario, Argentina. Mycoses. 2009;52(1):53–9. 10.1111/j.1439-0507.2008.01542.x [DOI] [PubMed] [Google Scholar]
- 11. Manzano-Gayosso P, Méndez-Tovar LJ, Hernández-Hernández F, et al. : [Antifungal resistance: an emerging problem in Mexico]. Gac Med Mex. 2008;144(1):23–6. [PubMed] [Google Scholar]
- 12. Jia XM, Ma ZP, Jia Y, et al. : RTA2, a novel gene involved in azole resistance in Candida albicans. Biochem Biophys Res Commun. 2008;373(4):631–6. 10.1016/j.bbrc.2008.06.093 [DOI] [PubMed] [Google Scholar]
- 13. Pfaller MA, Jones RN, Doern GV, et al. : International surveillance of bloodstream infections due to Candida species: frequency of occurrence and antifungal susceptibilities of isolates collected in 1997 in the United States, Canada, and South America for the SENTRY Program. The SENTRY Participant Group. J Clin Microbiol. 1998;36(7):1886–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Falagas ME, Roussos N, Vardakas KZ: Relative frequency of albicans and the various non-albicans Candida spp among candidemia isolates from inpatients in various parts of the world: a systematic review. Int J Infect Dis. 2010;14(11):e954–66. 10.1016/j.ijid.2010.04.006 [DOI] [PubMed] [Google Scholar]
- 15. Powderly WG, Mayer KH, Perfect JR: Diagnosis and treatment of oropharyngeal candidiasis in patients infected with HIV: a critical reassessment. AIDS Res Hum Retroviruses. 1999;15(16):1405–12. 10.1089/088922299309900 [DOI] [PubMed] [Google Scholar]
- 16. Godoy P, Tiraboschi IN, Severo LC, et al. : Species distribution and antifungal susceptibility profile of Candida spp. bloodstream isolates from Latin American hospitals. Mem Inst Oswaldo Cruz. 2003;98(3);401–5. 10.1590/S0074-02762003000300020 [DOI] [PubMed] [Google Scholar]
- 17. Adriaenssens N, Coenen S, Muller A, et al. : European Surveillance of Antimicrobial Consumption (ESAC): outpatient systemic antimycotic and antifungal use in Europe. J Antimicrob Chemother. 2010;65(4):769–74. [DOI] [PubMed] [Google Scholar]
- 18. Cuenca-Estrella M, Rodríguez-Tudela JL, Córdoba S, et al. : [Regional laboratory network for surveillance of invasive fungal infections and antifungal susceptibility in Latin America]. Rev Panam Salud Publica. 2008;23(2):129–34. 10.1590/S1020-49892008000200014 [DOI] [PubMed] [Google Scholar]
- 19. Pfaller MA, Moet GJ, Messer SA, et al. : Geographic variations in species distribution and echinocandin and azole antifungal resistance rates among Candida bloodstream infection isolates: report from the SENTRY Antimicrobial Surveillance Program (2008 to 2009). J Clin Microbiol. 2011;49(1):396–9. 10.1128/JCM.01398-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. The World Health Organization: Antimicrobial resistance global report on surveillance.WHO Press, Geneva, Switzerland. ISBN 978 92 4 156474 8.2014. Reference Source [Google Scholar]
- 21. Africa CWJ, Dos Santos Abrantes PM: Dataset 1 in: Candida antifungal drug resistance in sub-Saharan African populations: A systematic review. F1000Research. 2016. Data Source [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Blignaut E, Messer S, Hollis RJ, et al. : Antifungal susceptibility of South African oral yeast isolates from HIV/AIDS patients and healthy individuals. Diagn Microbiol Infect Dis. 2002;44(2):169–74. 10.1016/S0732-8893(02)00440-6 [DOI] [PubMed] [Google Scholar]
- 23. Owotade FJ, Gulube Z, Ramla S, et al. : Antifungal susceptibility of Candida albicans isolated from the oral cavities of patients with HIV infection and cancer. SADJ. 2016;71(1):8–11. Reference Source [Google Scholar]
- 24. Blignaut E, Botes ME, Nieman HL: The treatment of oral candidiasis in a cohort of South African HIV/AIDS patients. SADJ. 1999;54(12):605–8. [PubMed] [Google Scholar]
- 25. Dos Santos Abrantes PM, McArthur CP, Africa CWJ: Multi-drug resistant oral Candida species isolated from HIV-positive patients in South Africa and Cameroon. Diagn Microbiol Infect Dis. 2014;79(2):222–7. 10.1016/j.diagmicrobio.2013.09.016 [DOI] [PubMed] [Google Scholar]
- 26. Njunda AL, Nsagha DS, Assob JCN, et al. : In vitro antifungal susceptibility patterns of Candida albicans from HIV and AIDS patients attending the Nylon Health District Hospital in Douala, Cameroon. J Pub Health Afr. 2012;3(1):4–7. 10.4081/jphia.2012.e2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Njunda LA, Assob JCN, Nsagha SD, et al. : Oral and urinary colonization of Candida species in HIV/AIDS patients in Cameroon. Basic Sci Med. 2013;2(1):1–8. Reference Source [Google Scholar]
- 28. Enwuru CA, Ogunledun A, Idika N, et al. : Fluconazole resistant opportunistic oro-pharyngeal Candida and non- Candida yeast-like isolates from HIV-infected patients attending ARV clinics in Lagos, Nigeria. Afr Health Sci. 2008;8(3):142–8. [PMC free article] [PubMed] [Google Scholar]
- 29. Nweze EI, Ogbonnaya UL: Oral Candida isolates among HIV-infected subjects in Nigeria. J Microbiol Immunol Infect. 2011;44(3):172–7. 10.1016/j.jmii.2011.01.028 [DOI] [PubMed] [Google Scholar]
- 30. Nébavi F, Arnavielhe S, Le Guennec R, et al. : Oropharyngeal candidiasis in AIDS patients from Abidjan (Ivory Coast): antifungal susceptibilities and multilocus enzyme electrophoresis analysis of Candida albicans isolates. Pathol Biol (Paris). 1998;46(5):307–14. [PubMed] [Google Scholar]
- 31. Hamza OJ, Matee MI, Moshi MJ, et al. : Species distribution and in vitro antifungal susceptibility of oral yeast isolates from Tanzanian HIV-infected patients with primary and recurrent oropharyngeal candidiasis. BMC Microbiol. 2008;8:135. 10.1186/1471-2180-8-135 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Bii CC, Ouko TT, Amukoye E, et al. : Antifungal drug susceptibility of Candida albicans. East Afr Med J. 2002;79(3):143–5. 10.4314/eamj.v79i3.8894 [DOI] [PubMed] [Google Scholar]
- 33. Wabe NT, Hussein J, Suleman S, et al. : In vitro antifungal susceptibility of Candida albicans isolates from oral cavities of patients infected with human immunodeficiency virus in Ethiopia. J Exp Integr Med. 2011;1(4):265–71. 10.5455/jeim.260911.or.012 [DOI] [Google Scholar]
- 34. Mulu A, Kassu A, Anagaw B, et al. : Frequent detection of ' azole' resistant Candida species among late presenting AIDS patients in northwest Ethiopia. BMC Infect Dis. 2013;13:82. 10.1186/1471-2334-13-82 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Moges B, Bitew A, Shewaamare A: Spectrum and the in vitro antifungal susceptibility pattern of yeast isolates in Ethiopian HIV patients with oropharyngeal candidiasis. Int J Microbiol. 2016;2016: 3037817. 10.1155/2016/3037817 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Naicker SD, Magobo RE, Zulu TG, et al. : Two echinocandin-resistant Candida glabrata FKS mutants from South Africa. Med Mycol Case Rep. 2016;11:24–6. 10.1016/j.mmcr.2016.03.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Akortha EE, Nwaugo VO, Chikwe NO: Antifungal resistance among Candida species from patients with genitourinary tract infection isolated in Benin City, Edo state, Nigeria. Afr J Microbiol Res. 2009;3(11):694–9. Reference Source [Google Scholar]
- 38. Djohan V, Angora KE, Vanga-Bosson AH, et al. : [ In vitro susceptibility of vaginal Candida albicans to antifungal drugs in Abidjan (Ivory Coast)]. J Mycol Med. 2012;22(2):129–33. 10.1016/j.mycmed.2011.11.005 [DOI] [PubMed] [Google Scholar]
- 39. Feglo PK, Narkwa P: Prevalence and antifungal susceptibility patterns of yeast isolates at the Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana. British Microbiol Res J. 2012;2(1):10–22. 10.9734/BMRJ/2012/861 [DOI] [Google Scholar]
- 40. Magobo RE, Corcoran C, Seetharam S, et al. : Candida auris: An emerging, azole-resistant pathogen causing candidemia in South Africa. IJID. 2014;21(S1):215 10.1016/j.ijid.2014.03.869 [DOI] [Google Scholar]
- 41. Govender NP, Patel J, Magobo RE, et al. : Emergence of azole-resistant Candida parapsilosis causing bloodstream infection: results from laboratory-based sentinel surveillance in South Africa. J Antimicrob Chemother. 2016;71(7):1994–2004. 10.1093/jac/dkw091 [DOI] [PubMed] [Google Scholar]
- 42. Lockhart SR, Messer SA, Gherna M, et al. : Identification of Candida nivariensis and Candida bracarensis in a large global collection of Candida glabrata isolates: comparison to the literature. J Clin Microbiol. 2009;47(4):1216–7. 10.1128/JCM.02315-08 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. Vermitsky JP, Edlind TD: Azole resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-like transcription factor. Antimicrob Agents Chemother. 2004;48(10):3773–81. 10.1128/AAC.48.10.3773-3781.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Yoo JI, Choi CW, Lee KM, et al. : Gene Expression and Identification Related to Fluconazole Resistance of Candida glabrata Strains. Osong Public Health Res Perspect. 2010;1(1):36–41. 10.1016/j.phrp.2010.12.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Alexander BD, Johnson MD, Pfeiffer CD, et al. : Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013;56(12):1724–32. 10.1093/cid/cit136 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46. Satoh K, Makimura K, Hasumi Y, et al. : Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital. Microbiol Immunol. 2009;53(1):41–4. 10.1111/j.1348-0421.2008.00083.x [DOI] [PubMed] [Google Scholar]
- 47. Chowdhary A, Voss A, Meis JF: Multidrug-resistant Candida auris: ‘new kid on the block’ in hospital-associated infections? J Hosp Infect. 2016;94(3):209–12. 10.1016/j.jhin.2016.08.004 [DOI] [PubMed] [Google Scholar]
- 48. Molepo JSE, Blignaut E: Antifungal susceptibility of oral Candida isolates from HIV/AIDS patients. J Dent Res. 2006;85(Spec Issue B):837. [Google Scholar]
- 49. Wertheimer AI, Santella TM, Lauver HJ: Successful public/private donation programs: a review of the diflucan partnership program in South Africa. J Int Assoc Physicians AIDS Care. 2004;3(3):74–9, 84–5. 10.1177/154510970400300302 [DOI] [PubMed] [Google Scholar]
- 50. Goldman M, Cloud GA, Smedema M, et al. : Does long-term itraconazole prophylaxis result in in vitro azole resistance in mucosal Candida albicans isolates from persons with advanced human immunodeficiency virus infection? The National Institute of Allergy and Infectious Diseases Mycoses study group. Antimicrob Agents Chemother. 2000;44(6):1585–7. 10.1128/AAC.44.6.1585-1587.2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Pelletier R, Peter J, Antin C, et al. : Emergence of resistance of Candida albicans to clotrimazole in human immunodeficiency virus-infected children: in vitro and clinical correlations. J Clin Microbiol. 2000;38(4):1563–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52. Rautemaa R, Richardson M, Pfaller M, et al. : Reduction of fluconazole susceptibility of Candida albicans in APECED patients due to long-term use of ketoconazole and miconazole. Scand J Infect Dis. 2008;40(11–12):904–7. 10.1080/00365540802275853 [DOI] [PubMed] [Google Scholar]
- 53. Makita K, Takahashi K, Karara A, et al. : Experimental and/or genetically controlled alterations of the renal microsomal cytochrome P450 epoxygenase induce hypertension in rats fed a high salt diet. J Clin Invest. 1994;94(6):2414–20. 10.1172/JCI117608 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54. Kaplan JE, Benson C, Holmes KK, et al. : Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1–207; quiz CE1-4. 10.1037/e537722009-001 [DOI] [PubMed] [Google Scholar]
- 55. Pursley TJ, Blomquist IK, Abraham J, et al. : Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis. 1996;22(2):336–40. 10.1093/clinids/22.2.336 [DOI] [PubMed] [Google Scholar]
- 56. Lopez-Rangel E, Van Allen MI: Prenatal exposure to fluconazole: an identifiable dysmorphic phenotype. Birth Defects Res A Clin Mol Teratol. 2005;73(11):919–23. 10.1002/bdra.20189 [DOI] [PubMed] [Google Scholar]
- 57. Roemer T, Krysan DJ: Antifungal drug development: challenges, unmet clinical needs, and new approaches. Cold Spring Harb Perspect Med. 2014;4(5): pii: a019703. 10.1101/cshperspect.a019703 [DOI] [PMC free article] [PubMed] [Google Scholar]