CRYPTOCOCCOSIS: A bibliographic narrative review on antifungal resistance

KAKIZAKI, MARIA ISMÊNIA T.; MELHEM, MARCIA DE S.C.

doi:10.1590/0001-3765202320220862

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MICROBIOLOGY • An. Acad. Bras. Ciênc. 95 (suppl 1) • 2023 • https://doi.org/10.1590/0001-3765202320220862 copy

CRYPTOCOCCOSIS: A bibliographic narrative review on antifungal resistance

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Cryptococcosis is an infectious fungal disease widely studied for its epidemiological importance in the context of public health, given the high morbidity and mortality associated with this invasive fungal infection. Many cases of the disease present clinical resistance and progress to death, even in the presence of antifungal therapy. The prolonged use of triazole drugs to maintain the treatment of cryptococcosis in AIDS patients, can lead to selective pressure from mutant strains, among other resistance mechanisms, justifying the poor clinical evolution of some cases. In this study, a narrative review of the literature on the occurrence of antifungal resistance in cryptococcosis agents was performed. Publications from 2010 to 2022 that address this topic were selected using Google Scholars and Scopus website. Data from the studies were analyzed for the values of minimum inhibitory concentration (MIC) of drugs used in the management of cryptococcosis. The review showed that the highest MIC values occurred for voriconazole, especially against C. neoformans. It is concluded that there is a lack of studies with statistical analysis of the data obtained, in order to provide a better dimensioning of the resistance rates of cryptococcosis agents to different antifungal agents, both in geographical and temporal context.

Key words
Azole; Cryptococcus; resistance; susceptibility

Author and year	Country	Types of study	Agent Etiological (number of isolates)	Minimum Inhibitory Concentration (MIC; mg/L)								Method used for MIC test	Conclusions
				fluconazole		amphotericin B		Itraconazole		Voriconazole
				MIC ₅₀	MIC ₉₀	MIC ₅₀	MIC ₉₀	MIC ₅₀	MIC ₉₀	MIC ₅₀	MIC ₉₀
Govender et al. 2011GOVENDER NP, PATEL J, WYK MV, CHILLER TM & LOCKHART SR. 2011. Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates obtained through population- based surveillance in South Africa in 2002-2003 and 2007-2008. Antimicrob Agents Chemother 55(6): 2606-2611.	South Africa	Prospective (clinical)	C. neoformans (237)	MIC range (mg/mL) 0,25-16		MIC range (mg/mL) 0,008-0,94		MIC range (mg/mL) 0,015-1		MIC range (mg/mL) 0,008-0,25		CLSI M27-A3	Fluconazole resistance not shown in isolates from South Africa.
Pfaller et al. 2011	USA	Retrospective and Prospective (clinical)	C. neoformans (285)	MIC range (mg/mL) 0,25-32		------------		----------------		MIC range (mg/mL) 0,008-0,5		CLSI M27-A3	Almost all the isolates were classified as wild and without resistance mechanisms to fluconazole (96.9%) and voriconazole (95.1%).

Espinel-Ingroff et al. 2012a	Global	Prospective (clinical)	C. neoformans (3.590) C. Gatti (985)	--------------	MIC range (mg/mL) ≤0,03-4 ≤0,03-2	--------------	--------------	CLSI M27-A3	The epidemiological cut-off point for amphotericin B was proposed at MIC ≥ 2ug/ml.
Pan et al. 2012PAN W ET AL. 2012. Resistance of Asian Cryptococcus neoformans serotype a is confined to few microsatellite genotypes. PLoS ONE 7(3): e32868.	China, Japan, India, Indonesia, Thailand, Kuwait and Qatar	Retrospective and Prospective (clinical and environmental)	C. neoformans (493)	MIC range (mg/mL) 0,125-32	MIC range (mg/mL) 0,063-1	MIC range (mg/mL) <0,016-0,5	MIC range (mg/mL) <0,016-0,5	CLSI M27-A3	High sensitivity of the isolates for several antifungals, both clinical and environmental, but resistance was found to flucytosine (<0.063- >64 ug/mL) and to fluconazole (0.125-32 ug/mL).
Trpkovic et al. 2012TRPKOVIC A, PEKMEZOVIC M, BARAC A, CRNCEVIC L & ARSENIJEVIC VA. 2012. In vitro antifungal activies of amphotericin B, 5- flurocytosine, fluconazole and itraconazole against Cryptococcus neoformans isolated from cerebrospinal fluid and blood from patients in Serbia. J Mycol Med 22: 243-248.	Serbia	Prospective (clinical)	C. neoformans (31)	16 64	0,125 0,25	0,25 0,38	-------------	E-test®	The isolates were highly sensitive to amphotericin B (100%) and flucytosine (87.1%) but little sensitive to fluconazole (48.4%).
Espinel-Ingroff et al. 2012bESPINEL-INGROFF A ET AL. 2012a. Cryptococcus neoformans- Cryptococcus gattii species complex: an international study of wild-type susceptibility endpoint distributions and epidemiological cutoff values for amphotericin B and flucytosine. Antimicrob Agents Chemother 56(6): 3107-3113.	Global	Prospective (clinical)	C. neoformans (5733) C. gattii (975)	MIC range (mg/mL) <0,12- ≥64 0,25- ≥64	------------	MIC range (mg/mL) ≤0,008- ≥4 ≤0,008-2	MIC range (mg/mL) ≤0,008- ≥4 ≤0,008-1	CLSI M27-A3	ECVs have been proposed for fluconazole (8-32 ug/ml), itraconazole (0.25-1 ug/ml), posaconazole (0.25-0.5 ug/ml) and voriconazole (0.12-0.25 ug/ml).
Lee et al. 2012LEE CH, CHANG TY, LIU JW, CHEN FJ, CHIEN CC, TANG YF & LU CH. 2012. Correlation of anti-fungal susceptibility with clinical outcomes in patients with cryptococcal meningitis. BMC Infect Dis 12: 361.	Taiwan	Retrospective (clinical)	C. neoformans (46)	MIC range (mg/mL) 2-32	MIC range (mg/mL) 0,25-2	--------------	MIC range (mg/mL) 0,06-0,5	CLSI M27-A3	Isolates with primary resistance to amphotericin B (MIC >1 ug/mL) (17.4%) or to fluconazole (>8 ug/mL) (26.1%), with recommendation of additional and larger studies to confirm the data.
Gast et al. 2013GAST CE, BASSO JUNIOR LR, BRUZUAL I & WONG B. 2013. Azole resistance in Cryptococcus gattii from the Pacif Northwest: investigation of the role of ERG11.Antimicrob Agents Chemother 57(11): 5478-5485.	USA	Retrospective e Prospective (clinical)	C. gattii (25) (Pacific Northwest) C. gattii (34) C. neoformans (20)	16 64 8 32 8 32	0,5 1 0,5 1 0,5 1	1 1 0,5 1 0,5 2	0,5 1 0,25 1 0,25 0,5	CLSI M27-A3	The MIC values of azoles against 25 isolates of C. gattii from the Pacific Northwest (western Canada and Northwestern United States) were higher than those obtained from 34 from other regions and from 20 of C. neoformans.

Ferreira et al. 2015FERREIRA GF, SANTOS JRA, COSTA MC, HOLANDA RA, DENADAI AML, FREITAS GJC, SANTOS ARC, TAVARES PB, PAIXÃO TA & SANTOS DA. 2015. Heteroresistance to itraconazole alters the morphology and increases the virulence of Cryptococcus gattii. Antimicrob Agents Chemother (8): 4600-4609.	Brazil	Prospective (clinical)	C. gattii (11)	-------------	--------------	MIC range 0,06-0,25 mg/L	--------------	CLSI M27-A3	Heteroresistance to itraconazole was observed, as an adaptive phenomenon and intrinsic to C. gattii strains.
Smith et al. 2015SMITH KD ET AL. 2015. Increased antifungal drug resistance in clinical isolates of Cryptococcus neoformans in Uganda. Antimicrob Agents Chemother 59(12).	Uganda	Prospective (clinical)	C. neoformans (198)	MIC range (mg/L) 0,125-64	MIC range (mg/mL) 0,125-2	----------------	------------	CLSI M27-A3	Fluconazole MIC values tended to increase over the course of drug treatment, but a correlation with clinical failure has not been established.

Yang et al. 2015YANG ML, UHRIG J, VU K, SINGAPURI A, DENNIS M, GELLI A & THOMPSON III GR. 2015. Fluconazole susceptibility in Cryptococcus gattii is dependent on the ABC transporter Pdr 11. Antimicrob Agents Chemother 60(3): 1202-1207.	USA	Prospective (clinical)	C. gattii VGII (1)	MIC (mg/L) 32 ( >128 )	MIC (mg/L) 0,125	MIC (mg/L) 2	MIC (mg/L) 1	CLSI M27-A3 and E- test®	Increased production of PDR11 efflux pumps was responsible for fluconazole resistance in the studied strain.
Córdoba et al. 2016CÓRDOBA S, ISLA MG, SZUSZ W, VIVOT W, ALTAMIRANO R & DAVEL G. 2016. Susceptibility profile and epidemiological cut-off values of Cryptococcus neoformans species complex from Argentina. Mycoses 59(6): 351-356.	Argentina	Retrospective (clinical)	C. neoformans (707)	8 16	0,25 0,5	0,03 0,25	0,13 0,25	EUCAST E.Def7.2	New ECV values were proposed for azoles and amphotericin B and for isolates from Argentina.

Rossi et al. 2016ROSSI SA, TREVIJANO-CONTADOR N, SCORZONI L, MESA-ARANGO AC, OLIVEIRA HC, WERTHER K, RASO TF, MENDES-GIANNINI MJS, ZARAGOZA O & FUSCO-ALMEIDA AM. 2016. Impact of resistance to fluconazole on virulence and morphological aspects of Cryptococcus neoformans and Cryptococcus gattii isolates. Front Microbiol (7): 153.	Brazil	Prospective (clinical and environmental)	C. neoformans (3) C. gattii (2)	MIC range (mg/L) 2-64 4-64	MIC range (mg/L) 0,125-0,0625 0,125-0,0625	-----------	-----------	CLSI M27-A3	The adaptation of strains to the stress produced by exposure to drugs led to loss of virulence, and morphological changes.
Lomes et al. 2016LOMES NR, MELHEM MSC, SZESZS MW, MARTINS MA & BUCCHERI R. 2016. Cryptococcosis in non- HIV/ non- transplant patients: a Brazilian case series. Med Mycol 54(7): 669-676.	Brazil	Retrospective (clinical)	C. neoformans (2) C. gattii (7)	MIC range (mg/L) 1 – 4 (50%) 32 (28,5%) 64 (14,3%)	--------------	-----------	----------	CLSI M27-A3	Lower sensitivity to fluconazole was observed among C. gatti isolates when compared to C. neoformans.
Alves 2016ALVES GSB. 2016. Genotyping of Cryptococcus neoformans and C. gattii isolated from house dust and assessment of susceptibility to antifungal agents and the presence of the antigen in residents of a rural community in Amazonas. 2016. 71f. Dissertation (Master’s Health, Society and Endemic Diseases in the Amazon) - Federal University of Amazonas, Manaus. (Unpublished).	Brazil	Prospective (environmental)	C. neoformans (10) C. gattii (4)	------ 24 ------ 256	------ 0,25 ------ 0,38	------- 0,38 ------- 3	-----------	E-test®	Most isolates were sensitive to amphotericin B, itraconazole, ketoconazole, and posaconazole. Half of the C. gattii isolates were resistant to fluconazole.
Figueiredo et al. 2016FIGUEIREDO TP, LUCAS RC, CAZZANIGA RA, FRANÇA CN, SEGATO F, TAGLIALEGNA R & MAFFEI CML. 2016. Antifungal susceptibility testing and genotyping characterization of Cryptococcus neoformans and gattii isolates from HIV-infected patients of Ribeirão Preto, São Paulo, Brazil. Rev Inst Med Trop São Paulo, vol. 58.	Brazil	Prospective (clinical)	C. neoformans (39 ) C. gattii (11)	------- 2 -------- 4	------ 0,5 ------ 0,5	------ 0,5 ------ 1,0	-----------	CLSI M27-A2	No increase in fluconazole resistance was observed over the years.

Worasilchai et al. 2017WORASILCHAI N, TANGWATTANACHULEEPORN M, MEESILPAVIKKAI K, FOLBA C, KANGOGO M, GROß V, WEIG M, BADER O & CHINDAMPORN A. 2017. Diversity and antifungal drug susceptibility of Cryptococcus isolates in Thailand. ISHAM- Med Mycol 55: 680-685.	Thailand	Prospective (clinical and environmental)	C. neoformans (73 clinical) C. deuterogattii VGII (1) C. neoformans (52 environmental)	MIC range (mg/L) 0,5-4 2 0,25-2	MIC range (mg/L) 0,125-1 0,5 0,125-0,5	--------------	-------------------	EUCASTE. Def 7.1 and CLSI M27-A3	No strains resistant to the evaluated antifungals were found, similarly to eastern Thailand and other non-Asian countries.
Nascimento et al. 2017NASCIMENTO E, VITALI LH, KRESS MRZ & MARTINEZ R. 2017. Cryptococcus neoformans and C. gattii isolates from both HIV- infected and uninfected patients: antifungal susceptibility and outcome of cryptococcal disease. Rev Inst Med Trop São Paulo 59.	Brazil	Prospective (clinical)	C. neoformans variety grubbii (80) C. gattii (7)	4,0 8,0 8,0 8,0	0,25 0,50 0,06 0,13	0,06 0,25 0,13 0,25	0,25 0,50 0,50 0,50	CLSI M27-A2 and E-test ®	High sensitivity of isolates from both species complexes.
Chang et al. 2018CHANG M, SIONOV E, LAMICHHANE AK, KWON-CHUNG KJ & CHANG YC. 2018. Roles of three Cryptococcus neoformans and Cryptococcus gattii efflux pump-coding genes in response to drug treatment. Antimicrob Agents Chemother 62(4).	USA	Prospective (clinical)	C. neoformans (1) C.gattii (1)	MIC range (mg/L) 2 4	MIC range (mg/L) 0,125 0,5	MIC range (mg/L) 0,031-0,063 0,063-0,125	MIC range (mg/L) 0,031 0,063-0,125	CLSI M27-A3	The AFR1 efflux pump is responsible for intracellular expulsion of azole drugs as a resistance mechanism.
Rocha et al. 2018ROCHA DFS, CRUZ KS, SANTOS CSS, MENESCAL LSF, SILVA NETO JR, PINHEIRO SB, SILVA LM, TRILLES L & SOUZA JVB. 2018. MLST reveals a clonal population structure for Cryptococcus neoformas molecular type VNI isolates from clinical sources in Amazonas, Northern- Brazil. PLoS ONE 13(6): e0197841.	Brazil	Prospective (clinical)	C. neoformans VNI (34) C. gattii VGII (4)	MIC range (mg/L) 2-8 8-32	MIC range (mg/L) 0,03-0,25 0,03-0,125	MIC range (mg/L) 0,03-0,25 0,125-0,5	---------------	CLSI M27-A3	All isolates were sensitive to the 3 antifungals evaluated, but fluconazole presented the highest MIC values for VGII.
Berejnoi et al. 2019	Argentina	Prospective (clinical)	C. gattii VGIII (1) C. gattii VGIV (1)	MIC (mg/L) 16 4	MIC (mg/L) 0,25 0,25	MIC (mg/L) 0,12 0,12	MIC (mg/L) 0,12 0,06	EUCAST E.Def 7.3.1	A high MIC value for fluconazole was found against the first clinical strain of C. decagattii described in South America.
Pinheiro 2019PINHEIRO SB. 2019. Clinical and molecular aspects of cryptococcosis in non-HIV patients in the state of Amazonas, Brazil. 2019, 89 f. Dissertation (Master’s in Pharmaceutical Sciences) Federal University Amazonas, Manaus. (Unpublished).	Brazil	Retrospective and Prospective (clinical)	C. gattii VGII (7)	MIC range (mg/L) 1-8	MIC range (mg/L) < 0,03-0,25	MIC range (mg/L) < 0,03-0,25	---------------	CLSI M27-A3	C. gattii isolates were sensitive to the antifungals analyzed.

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[1] Correspondence to: Maria Ismênia Teixeira Kakizaki E-mail: ismeniakakizaki@gmail.com