Antibiotics Improve Survival in Severe Malnutrition Oral antibiotics amoxicillin and cefdinir show efficacy in a randomized study of children with severe acute malnutrition. Linda MacArthur, PhD February 14, 2013—In children with severe acute malnutrition, a one week course of amoxicillin or cefdinir, combined with ready-to-use therapeutic food (RUTF), improved nutritional recovery and
Tablets-au.com Available ED Pharmacy is an 1st. pharmacy providing a individual service to the community in Australia. Over 80,000 extremely satisfied customers! We're your medication drug store kamagra australia and have provided trusted service to families in Australia for over 15 years.
Art. 1.1320European Review for Medical and Pharmacological Sciences
Fluconazole resistance in Candida albicans:
a review of mechanisms
I.A. CASALINUOVO, P. DI FRANCESCO, E. GARACI Department of Experimental Medicine and Biochemical Sciences, Microbiology University of Rome “Tor Vergata” – Rome (Italy) A b s t r a c t . – Antifungal agents have
Resistance to azole antifungals was reported greatly contributed to the improvement of pub-
in the late 1980s in C. albicans after prolonged lic health. Nevertheless, antifungal resistant
therapy with miconazole and ketoconazole.
pathogens have increased during the past
Fluconazole is a bis-triazole discovered in decade, becoming a serious concern. Candida
the 1990s. This compound has been shown to albicans has been the most extensively stud-
ied pathogen in antifungal resistance because
possess potent antifungal activity against of their morbidity and mortality associated
with infections in immunocompromised pa-
such as C. immitis, H. capsulatum, B. dermati- tients. This review describes the antifungal
tidis, P. brasiliensis and S. schenckii1.
mechanims of the azole fluconazole widely
In spite of its widespread use in the med- used for the prophylaxis and treatment of can-
ical community, many reports described the didal infections. The specific molecular path-
clinical failure of fluconazole therapy in indi- ways occurring in fluconazole-resistance of C.
albicans and some issues about new antifun-
gal agents are also discussed.
Recently, fluconazole-resistant C. albicans strains and intrinsically resistant Candida species such as C. glabrata and C. krusei are Fluconazole, Candida albicans, Ergosterol, Antifungal treated for therapy or prophylaxis5-8.
These and other data have led to research on the molecular mechanisms operating toconfer fluconazole resistance.
In this article we review the current knowl- edge on the principal resistance mechanisms Introduction
to fluconazole (Table I). In addition, otherpotential explanations resulting from new ex- In recent years, fungal infections have in- perimental data about the above-mentioned mechanisms are discussed. The findings have lead to a new therapeutic approach in the prevention or control of Candida infections.
mune disease and organ or tissue transplan-tion. Candida albicans, a commensal fungusof the oral cavity and gastrointestinal tractin humans, represents one the major causes Fluconazole
of mucosal infection and systemic infection,which can be life threatening if not treated.
into imidazoles and triazoles (Figure 1).
(azoles, allylamines and morpholines), di- mazole and ketoconazole) consist of a five- membered ring structure containing two ni- (polyenes) or target cell wall biosynthesis trogen atoms with a complex side chain at- tached to one of the nitrogen atoms.
I.A. Casalinuovo, P. Di Francesco, E. Garaci Table I. Overview of fluconazole resistance mechanisms in C. albicans.
Molecular basis of
Final change accounting
Reduced drug affinity for the target enzyme aAllelic differences elimination by gene conversion or mitotic recombination lead to identical mutations in two al-leles; the resulting phenotype is significantly more resistant.
bCDRs genes are associated with cross-resistance to other azoles.
Figure 1. Chemical structures of azole antifungal agents.
Fluconazole resistance in Candida albicans: a review of mechanisms Fluconazole and itraconazole are triazole compounds containing an additional nitrogen rhoea, hepatotoxicity, have rarely been re- in the ring9. Other antifungals of new genera- tion such as posaconazole, ravuconazole and Prophylactic administration of fluconazole voriconazole, also belong to triazoles.
has been reserved for selected patients con- The azole compounds inhibit the lanosterol sidered to be at high risk of candidemia13. In demethylase enzyme (or 14α-sterol demethy- particular, invasive fungal infections have be- lase); this enzyme converts lanosterol to er- come increasingly prevalent in individuals from lanosterol. The 14α-sterol demethylase neutropenic patients, HIV-infected patients and transplant recipients. The agreement for the fluconazole-prophylaxis is still controver- heme moiety in its active site. The azoles sial14. However, there is a general consensus bind to the heme iron through an unhindered that resistant strains are related to drug expo- nitrogen, thus inhibiting the enzymatic reac- tion. In addition, a second nitrogen of the Fluconazole is fungistatic; this makes it azoles interacts directly with the apoprotein clear that host factors contribute to the out- of lanosterol-demethylase. It is thought that the affinity of different azoles for the enzymeis also determined by the position of this sec-ond nitrogen10-12.
ERG11 and Other ERG Genes
fungal plasma membranes; it is important formembrane integrity and for the activity of The inhibition of 14α-sterol demethylase leads to the accumulation of 14α-methylated demethylase, an essential enzyme for ergos- sterols, resulting in a defective cell membrane terol synthesis. Resistance to azole antifungal with decreased availability of ergosterol and drugs has been associated with ERG11 gene overexpression and/or point mutations and also alterations in the ergosterol biosynthetic cholesterol. However, the azoles used in ther- apeutic concentrations demonstrate greater lanosterol 14α-demethylase and results in in- affinity for fungal P-450 demethylase than for the mammalian enzyme. Fluconazole appears whelms the capacity of the antifungal drug.
to be free of adverse effects on steroid hor- The effect of ERG11 gene overexpression on mone production1 and it is available in both antifungal susceptibility has been described intravenous and oral formulations. Because by several studies in C. albicans15-17 and also of the low toxicity and ready distribution into in C. glabrata and C. dubliniensis clinical iso- aqueous body fluids such as cerebrospinal fluid (CSF), fluconazole has been used in the treatment of both superficial and systemic in C. albicans as a consequence of azoles ex- posure was observed in matched sets of clini- cal isolates from the same strain20,21. In vitro discovered in the early 1950s), a favourable demonstrated in additional Candida species pharmacokinetic profile (metabolic stability, such as C. tropicalis, C. glabrata and C. water solubility) and availability as an oral and parenteral formulation. These factors Recently, in an analysis of unmatched sets have contributed to its therapeutic use in of clinical isolates it was found that resistance both normal and immunocompromised hosts.
zole therapy such as nausea, headache, skin that depletion of the ERG11 gene in C. I.A. Casalinuovo, P. Di Francesco, E. Garaci glabrata results in the accumulation of 4,14- merase was associated with fluconazole resis- demethylzimosterol, which did not cause de- tance22,34,35. In contrast, other studies found fective growth of fungal cells in vitro and in that the ERG1 gene was repressed in resis- has also been associated with point mutations was observed first in S. cerevisiae43. Defective of the ERG11 gene25-27; these mutations re- sterol C5,6-desaturase was attributed as the sult in conformational changes that reduce ef- cause of fluconazole resistance in C. albicans fective binding between azoles and their tar- clinical isolates from AIDS patients44. Such isolates accumulated ergosterol precursors in- Several investigators found sequence dif- ferences of the ERG11 gene in fluconazole- dienol. The molecular mechanisms associated resistant C. albicans and in S. cerevisiae with ERG3 defects are still unclear45,46.
transformants28-30. A list of differentaminoacid exchanges has been provided bydifferent studies that could simply reflect al-lelic variations31. In fluconazole-resistant C. Expression of Two Major
albicans isolates frequently observed nu- Efflux Pumps
cleotide changes were concerned with twoaminoacids located near the heme binding site (R467K [arginine 467 replaced by lysine] and G464S [glycine 464 replaced by serine]); this probably resulted in structural or func- tional alterations reducing fluconazole affini- The correlation between decreased suscep- porters operate through a proton gradient.
tibility to azole drugs and nucleotide changes CDR2 (Candida Drug Resistance), as well as that encoding a major facilitator, CaMDR1 Recently, other nucleotide substitutions in ERG11 gene were identified (K143R [lysine have been shown to be overexpressed47-51 in 143 replaced by arginine], E266D [glutamic C. albicans azole-resistant isolates. CaMDR1 acid 266 replaced by aspartic acid], V404L is specific for fluconazole resistance but not [valine 404 replaced by leucine], V488I [va- for other azoles48. Upregulation of these ef- line 488 replaced by isoleucine]) in three C. flux pumps reduces the effective concentra- albicans isolates33; these mutations were asso- tions of fluconazole in the fungal cell and is ciated with the fluconazole resistance pheno- correlated to azole resistance in C. albicans.
type. As suggested by investigators, a single Genetic deletion of the CDR1 gene resulted aminoacid change, not interacting with the in hypersusceptibility to azole drugs52, where- active site of ERG11p, was unrelated to drug as CDR2 gene disruption did not cause hy- resistance. Moreover, mesh membrane struc- persusceptibility to these agents. The latter ture developments were observed in the en- gene is closely related to CDR1 and disrup- doplasmic reticula of resistant cells33.
Several molecular and genetic studies have creased hypersusceptibility to azole antifun- described other ERG genes involved in the complex ergosterol biosynthesis as alterna- tive pathways, which were more or less corre- ed with benomyl resistance in S. cerevisiae) lated to fluconazole exposure: ERG1, ERG2, gene deletion in resistant strains of C. albi- cans does not result in increased susceptibili- In C. albicans, increased expression of through CDR4) correlated with increased re- sistance to fluconazole, ketoconazole and Fluconazole resistance in Candida albicans: a review of mechanisms itraconazole37. This resistance, however, Some of the C. albicans cell wall glycopro- arose rapidly after fluconazole exposure and teins have been found to be highly immuno- was transient. In fact, susceptibility resulted genic and differently modulated according to in azole-free media and also in vivo after the drug was no longer administered to the pa- In vitro studies on the cell wall of flucona- zole-susceptible and -resistant C. albicans To date, the molecular mechanisms involv- strains detected altered distribution of cell wall glucan-associated proteins63. These re- CaMDR) have not yet been elucidated.
sults suggest that fluconazole treatment could Recently, it has been shown that Cdr1p and have an effect on fungal cell wall metabolism and structure63,64, and these effects may be CDR2 genes) in C. albicans act as phospho- stably incorporated into the cell wall upon ac- lipids translocators eliciting in-to-out transbi- The asexual and diploid nature of C. albi- membrane. It is interesting that fluconazole cans65,66 complicates the characterization of could inhibit this transbilayer movement54.
gene expression in antifungal drug resistance.
Several studies investigating changes in chro- mosome copy number, loss (or not) of het- Recent results show that in vitro acquired erozygosity, gene disruption at definite loci resistance to fluconazole of C. albicans and other genetic strategies have been linked strains was associated with variation in mem- to fluconazole resistance67-70. These studies brane lipid fluidity and asymmetry56.
show that other factors may contribute to flu- conazole resistance development. However, a differences in gene expression identified new detailed analysis of these and other promising genes associated or not with drug resistance in C. albicans. Several of these genes werecoordinately regulated with both CDR genesand CaMDR1, whereas others appeared notto be coordinately regulated with known re- Different Targets and New
sistance genes35,36. These data suggest that Therapeutic Approaches
the efflux pumps may be regulated by com-bined expression of several genes. Analysis of these differentially regulated genes re- regulatory patterns and new antifungal treat- quires further investigation and opens up the ments are currently being undertaken.
possibility of finding new targets for antifun- pathway and modulation of the susceptibilityto antifungal azoles have been examined. C.
albicans mutants in the genes encoding theproteins responsible for cAMP synthesis Other Changes in Fluconazole
fluconazole and other sterol biosynthesis in-hibitors71. The addition of cAMP conferred Recently, antifungal resistance results in partial-to-complete reversal of this hypersus- biofilm-associated infections57-59. Efflux ceptibility. These data suggest that antifungal pumps do not appear to contribute to flu- susceptibility could be modulated by adeny- conazole resistance in C. albicans at late (in- termediate and mature) stages in biofilm for- mation60, but solely in the early-phase. On (CsA) and tacrolimus hydrate (FK506, a 23- the contrary, changes in sterol profile were member macrolide) are promising candidates expressed by resistant phenotypes at interme- for antifungal therapy, due to their synergis- diate and mature phases. Therefore, phase- tic fungicidal effect in combination with specific mechanisms are suggested to be op- azoles and non-azole antifungal agents72,73.
erative in antifungal resistance of biofilm Cyclosporine has several cellular targets in- I.A. Casalinuovo, P. Di Francesco, E. Garaci transporters and the cyclophilin-calmodulin- 5) CASE CP, MACGOWAN AP, BROWN NM, REEVES DS, calcineurin pathway. The mechanism of this WHITEHEAD P, FELMINGHAM D. Prophylactic oral flu-conazole and candida fungaemia. Lancet 1991; fungicidal synergism is unknown and was re- cently reported not to be involved with mul-tidrug efflux transporters74.
6) MARTINS MD, LOZANO-CHIU M, REX JH. Point preva- lence of oropharyngeal carriage of fluconazole- resistant Candida in human immunodeficiency tifungal drugs could also be another thera- virus-infected patients. Clin Infect Dis 1997; 25: 7) RANGEL-FRAUSTO MS, WIBLIN T, BLUMBERG HM, et al.
are cell wall biosynthesis inhibitors.
National epidemiology of mycoses survey (NE- MIS): variations in rates of bloodstream infections spectrum of susceptibility are being proposed due to Candida species in seven surgical inten-sive care units and six neonatal intensive care to circumvent cross-resistance within the fun- units. Clin Infect Dis 1999; 29: 253-258.
In conclusion, in this review we have sum- RCMERY V, BARNES AJ. Non-albicans Candida spp.
causing fungaemia: pathogenicity and antifungal marized the mechanisms of resistance to flu- resistance. J Hosp Infect 2002; 50: 243-260.
conazole in C. albicans. Excellent reviews, 9) BODEY GP. Antifungal agents. In: GP Bodey, ed.
which the reader is referred to, have been published concerning this matter77-83. Our Treatment. Raven Press, Ltd, New York: 1993: 10) HITCHCOCK CA. Cytochrome P-450-dependent 14 and/or correlated to antifungal resistance in alpha-sterol demethylase of Candida albicans this organism. The resistant phenotype ap- and its interaction with azole antifungals.
pears to result from different mechanisms Biochem Soc Trans 1991; 19: 782-787.
not always arising. However it is possible 11) VANDEN BOSSCHE H, MARICHAL P, ODDS FC.
Molecular mechanisms of drug resistance in fun-gi. Trends Microbiol 1994; 2: 393-400.
known. It could be interesting to investigatethe cause of this variability and, if it exists, 12) JOSEPH-HORNE T, HOLLOMON DW. Molecular mecha- the specific step responsible for fluconazole resistance. Yet, a combination of different,not only antifungal, drugs could be a promis- 13) EDWARDS JE JR, BODEY GP, BOWDEN RA, et al.
International Conference for the Development of a Consensus on the Management and Preventionof Severe Candidal Infections. Clin Infect Dis1997; 25: 43-59.
14) SNYDMAN DR. Shifting patterns in the epidemiology References
of nosocomial Candida infections. Chest 2003;123 (5 Suppl): 500S-503S.
1) GRANT SM, CLISSOLD SP. Fluconazole: A review of 15) LAMB DC, KELLY DE, SCHUNCK WH, et al. The muta- its pharmacodynamic and pharmacokinetic prop- tion T315A in Candida albicans sterol 14α- erties, and therapeutic potential in superficial and demethylase causes reduced enzyme activity systemic mycoses. Drugs 1990; 39: 877-916.
and fluconazole resistance through reduced affin- ity. J Biol Chem 1997; 272: 5682-5688.
Fluconazole-resistant recurrent oral candidiasis in 16) PEREA S, LÓPEZ-RIBOT JL, KIRKPATRICK WR, et al.
human immunodeficiency virus-positive patients: Prevalence of molecular mechanisms of resis- persistence of Candida albicans strains with the tance to azole antifungal agents in Candida albi- same genotype. J Clin Microbiol 1994; 32: 1115- cans strains displaying high-level fluconazole re- sistance isolated from human immunodeficiency virus-infected patients. Antimicrob Agents EX JH, RINALDI MG, PFALLER MA. Resistance of Candida species to fluconazole. Antimicrob 17) LUPETTI A, DANESI R, CAMPA M, DEL TACCA M, KELLY S.
Molecular basis of resistance to azole antifun- EREA S, LÒPEZ-RIBOT JL, WICKES BL, et al. Molecular mechanisms of fluconazole resistance in Candida gals. Trends Mol Med 2002; 8: 76-81.
dubliniensis isolates from human immunodefi- 18) MARICHAL P, VANDEN BOSSCHE H, ODDS FC, et al.
ciency virus-infected patients with oropharyngeal Molecular biological characterization of an azole- candidiasis. Antimicrob Agents Chemother 2002; resistant Candida glabrata isolate. Antimicrob Agents Chemother 1997; 41: 2229-2237.
Fluconazole resistance in Candida albicans: a review of mechanisms 19) HOLMBERG K, STEVENS DA. Resistance to antifungal 31) MORSCHHÄUSER J. The genetic basis of fluconazole drugs: current status and clinical implications.
resistance development in Candida albicans.
Curr Opin Anti-Infective Invest Drugs 1999; 1: Biochim Biophys Acta 2002; 1587: 240-248.
32) MARICHAL P, KOYMANS L, WILLEMSENS S, et al.
20) LÓPEZ-RIBOT JL, MCATEE RK, LEE NL, et al. Distinct Contribution of mutations in the cytochrome P450 patterns of gene expression associated with de- 14alpha-demethylase (Erg11p, Cyp51p) to azole velopment of fluconazole resistance in serial resistance in Candida albicans. Microbiology Candida albicans isolates from human immuno- deficiency virus-infected patients with oropharyn- geal candidiasis. Antimicrob Agents Chemother Proliferation of intracellular structure correspond- ing to reduced affinity of fluconazole for cy- 21) WHITE TC, PFALLER MA, RINALDI RG, SMITH J, REDDING tochrome P-450 in two low-susceptibility strains SW. Stable azole drug resistance associated with of Candida albicans isolated from a Japanese a substrain of Candida albicans from an HIV-in- AIDS patient. Microbiol Immunol 2003; 47: 117- fected patient. Oral Dis 1997; 3: S102-S109.
22) HENRY KW, NICKELS JT, EDLIND TD. Upregulation of 34) SMITH WL, EDLIND TD. Histone deacetylase in- ERG genes in Candida species by azoles and hibitors enhance Candida albicans sensitivity to other sterol biosynthesis inhibitors. Antimicrob azoles and related antifungals: correlation with re- Agents Chemother 2000; 44: 2693-2700.
duction in CDR and ERG upregulation. AntimicrobAgents Chemother 2002; 46: 3532-3539.
23) WHITE TC, HOLLEMAN S, DY F, MIRELS LF, STEVENS DA.
Resistance mechanisms in clinical isolates of 35) ROGERS PD, BARKER KS. Evaluation of differential Candida albicans. Antimicrob Agents Chemother gene expression in fluconazole-susceptible and - resistant isolates of Candida albicans by cDNA mi-croarray analysis. Antimicrob Agents Chemother 24) NAKAYAMA H, NAKAYAMA N, ARISAWA M, AOKI Y. In vitro and in vivo effects of 14α-demethylase (ERG11)depletion in Candida glabrata. Antimicrob Agents 36) ROGERS PD, BARKER KS. Genome-wide expression profile analysis reveals coordinately regulatedgenes associated with stepwise acquisition of 25) WHITE TC. The presence of an R467K aminoacid azole resistance in Candida albicans clinical iso- substitution and loss of allelic variation correlate lates. Antimicrob Agents Chemother 2003; 47: with an azole-resistant lanosterol 14α-demethy- lase in Candida albicans. Antimicrob AgentsChemother 1997; 41: 1488-1494. 37) MARR KA, LYONS CN, RUSTAD TR, BOWDEN RA, WHITE TC. Rapid, transient fluconazole resistance in 26) FRANZ R, KELLY SL, LAMB DC, KELLY DE, RUHNE M, Candida albicans is associated with increased MORSCHHÄUSER J. Multiple molecular mechanisms contribute to a stepwise development of flucona- zole resistance in clinical Candida albicansstrains. Antimicrob Agents Chemother 1998; 42: 38) DE BACKER MD, ILYINA T, MA XJ, VANDONINCK S, LUYTEN WH, VANDEN BOSSCHE H. Genomic profiling of theresponse of Candida albicans to itraconazole treat- 27) WHITE TC, MARR KA, BOWDEN RA. Clinical, cellular, ment using a DNA microarray. Antimicrob Agents and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev 1998; 11:382-402.
39) BAMMERT GF, FOSTEL JM. Genome-wide expression patterns in Saccharomyces cerevisiae: compari- 28) SANGLARD D, ISCHER F, KOYMANS L, BILLE J. Amino son of drug treatments and genetic alterations af- acid substitutions in the cytochrome P-450 fecting biosynthesis of ergosterol. Antimicrob lanosterol 14α-demethylase (CYP51A1) from Agents Chemother 2000; 44: 1255-1265.
azole-resistant Candida albicans clinical isolatescontribute to resistance to azole antifungal 40) MUKHOPADHYAY K, KOHLI A, PRASAD R. Drug suscepti- agents. Antimicrob Agents Chemother 1998; 42: bilities of yeast cells are affected by membrane lipid composition. Antimicrob Agents Chemother2002; 46: 3695-3705.
29) KELLY SL, LAMB DC, KELLY DE. Y132H substitution in Candida albicans sterol 14alpha-demethylase 41) DIMSTER-DENK D, RINE J, PHILLIPS J, et al. Comprehensive confers fluconazole resistance by preventing evaluation of isoprenoid biosynthesis regulation binding to haem. FEMS Microbiol Lett 1999; 180: in Saccharomyces cerevisiae utilizing the Genome Reporter Matrix. J Lipid Res 1999; 40:850-860. 30) LAMB DC, KELLY DE, WHITE TC, KELLY SL. The R467K amino acid substitution in Candida albicans sterol 42) COWEN LE, NANTEL A, WHITEWAY MS, et al.
14α-demethylase causes drug resistance through Population genomics of drug resistance in reduced affinity. Antimicrob Agents Chemother Candida albicans. Proc Natl Acad Sci U S A I.A. Casalinuovo, P. Di Francesco, E. Garaci 43) WATSON PF, ROSE ME, ELLIS SW, ENGLAND H, KELLY 55) DOGRA S, KRISHNAMURTHY S, GUPTA V, et al.
SL. Defective sterol C5-6 desaturation and azole Asymmetric distribution of phosphatidylethanol- resistance: a new hypothesis for the mode of ac- amine in C. albicans: possible mediation by tion of azole antifungals. Biochem Biophys Res CDR1, a multidrug transporter belonging to ATP binding cassette (ABC) superfamily. Yeast 1999;15: 111-121.
44) KELLY SL, LAMB DC, KELLY DE, et al. Resistance to fluconazole and cross-resistance to amphotericin 56) KOHLI A, SMRITI, MUKHOPADHYAY K, RATTAN A, PRASAD R.
B in Candida albicans from AIDS patients caused In vitro low-level resistance to azoles in Candida by defective sterol delta5,6-desaturation. FEBS albicans is associated with changes in membrane lipid fluidity and asymmetry. Antimicrob AgentsChemother 2002; 46: 1046-1052.
45) JACKSON CJ, LAMB DC, MANNING NJ, KELLY DE, KELLY SL. Mutations in Saccharomyces cerevisiae sterol 57) CHANDRA J, KUHN DM, MUKHERJEE PK, HOYER LL, C5-desaturase conferring resistance to the MCCORMICK T, GHANNOUM MA. Biofilm formation by CYP51 inhibitor fluconazole. Biochem Biophys the fungal pathogen Candida albicans: develop- ment, architecture, and drug resistance. JBacteriol 2001; 183: 5385-5394.
46) SANGLARD D, ISCHER F, PARKINSON T, FALCONER D, BILLE J. Candida albicans mutations in the ergos- 58) CHANDRA J, MUKHERJEE PK, LEIDICH SD, et al.
terol biosynthetic pathway and resistance to sev- Antifungal resistance of candidal biofilms formed eral antifungal agents. Antimicrob Agents on denture acrylic in vitro. J Dent Res 2001; 80: 47) PRASAD R, DE WERGIFOSSE P, GOFFEAU A, BALZI E.
59) KUHN DM, CHANDRA J, MUKHERJEE PK, GHANNOUM Molecular cloning and characterization of a novel MA. Comparison of biofilms formed by Candida gene of Candida albicans, CDR1, conferring mul- albicans and Candida parapsilosis on biopros- tiple resistance to drugs and antifungals. Curr thetic surfaces. Infect Immun 2002; 70: 878-888.
60) MUKHERJEE PK, CHANDRA J, KUHN DM, GHANNOUM 48) SANGLARD D, KUCHLER K, ISCHER F, PAGANI JL, MONOD MA. Mechanism of fluconazole resistance in M, BILLE J. Mechanisms of resistance to azole an- Candida albicans biofilms: phase-specific role of tifungal agents in Candida albicans isolates from efflux pumps and membrane sterols. Infect AIDS patients involve specific multidrug trans- porters. Antimicrob Agents Chemother 1995; 39: PAGNOLI GC, AUSIELLO C, CASALINUOVO I, ANTONELLI G, DIANZANI F, CASSONE A. Candida albicans and a 49) SANGLARD D, ISCHER F, MONOD M, BILLE J. Cloning of phosphorylated glucomannan-protein fraction of Candida albicans genes conferring resistance to its cell wall induce production of immune interfer- azole antifungal agents: characterization of on by human peripheral blood mononuclear cells.
CDR2, a new multidrug ABC transporter gene.
50) FRANZ R, RUHNKE M, MORSCHHÄUSER J. Molecular as- CASALINUOVO I, CASSONE A. Biochemical and anti- pects of fluconazole resistance development in genic characterization of mannoprotein con- Candida albicans. Mycoses 1999; 42: 453-458.
stituents released from yeast and mycelial formsof Candida albicans. J Med Vet Mycol 1991; 29: 51) WIRSCHING S, MICHEL S, MORSCHHÄUSER J. Targeted gene disruption in Candida albicans wild-typestrains: the role of the MDR1 gene in fluconazole 63) ANGIOLELLA L, MICOCCI MM, D'ALESSIO S, GIROLAMO A, resistance of clinical Candida albicans isolates.
MARAS B, CASSONE A. Identification of major glucan- associated cell wall proteins of Candida albicansand their role in fluconazole resistance. Antimicrob 52) SANGLARD D, ISCHER F, MONOD M, BILLE J.
Agents Chemother 2002; 46: 1688-1694.
Susceptibilities of Candida albicans multidrugtransporter mutants to various antifungal agents 64) HAZEN KC, MANDELL G, COLEMAN E, WU G.
and other metabolic inhibitors. Antimicrob Agents Influence of fluconazole at subinhibitory concen- trations on cell surface hydrophobicity andphagocytosis of Candida albicans. FEMS 53) MARR KA, WHITE TC, VAN BURIK JA, BOWDEN RA.
Development of fluconazole resistance inCandida albicans causing disseminated infection 65) PUJOL C, REYNES J, RENAUD F, et al. The yeast in a patient undergoing marrow transplantation.
Candida albicans has a clonal mode of reproduc- tion in a population of infected human immunode-ficiency virus-positive patients. Proc Natl Acad 54) SMRITI, KRISHNAMURTHY S, DIXIT BL, GUPTA CM, MILEWSKI S, PRASAD R. ABC transporters Cdr1p,Cdr2p and Cdr3p of a human pathogen Candida 66) LOCKHART SR, DANIELS KJ, ZHAO R, WESSELS D, SOLL albicans are general phospholipid translocators.
DR. Cell biology of mating in Candida albicans.
Fluconazole resistance in Candida albicans: a review of mechanisms 67) PEREPNIKHATKA V, FISCHER FJ, NIIMI M, et al. Specific 76) BACHMANN SP, PATTERSON TF, LOPEZ-RIBOT JL. In vitro chromosome alterations in fluconazole-resistant activity of caspofungin (MK-0991) against mutants of Candida albicans. J Bacteriol 1999; Candida albicans clinical isolates displaying dif- ferent mechanisms of azole resistance. J ClinMicrobiol 2002; 40: 2228-2230.
68) PUJOL C, MESSER SA, PFALLER M, SOLL DR. Drug re- sistance is not directly affected by mating type lo- 77) ODDS FC, BROWN AJ, GOW NA. Antifungal agents: cus zygosity in Candida albicans. Antimicrob mechanisms of action. Trends Microbiol 2003; Agents Chemother 2003; 47: 1207-1212.
69) RUSTAD TR, STEVENS DA, PFALLER MA, WHITE TC.
78) GHANNOUM MA, RICE LB. Antifungal agents: mode Homozygosity at the Candida albicans MTL locus of action, mechanisms of resistance, and correla- associated with azole resistance. Microbiology tion of these mechanisms with bacterial resis- tance. Clin Microbiol Rev 1999; 12: 501-517.
70) DE BACKER MD, VAN DIJCK P. Progress in functional 79) PEREA S, PATTERSON TF. Antifungal resistance in genomics approaches to antifungal drug target pathogenic fungi. Clin Infect Dis 2002; 35: 1073- discovery. Trends Microbiol 2003; 11: 470-478.
71) JAIN P, AKULA I, EDLIND T. Cyclic AMP signaling 80) SANGLARD D. Clinical relevance of mechanisms of pathway modulates susceptibility of Candida antifungal drug resistance in yeasts. Enferm species and Saccharomyces cerevisiae to anti- Infecc Microbiol Clin 2002; 20: 462-469.
fungal azoles and other sterol biosynthesis in- 81) COWEN LE, ANDERSON JB, KOHN LM. Evolution of hibitors. Antimicrob Agents Chemother 2003; 47: drug resistance in Candida albicans. Annu Rev 72) CRUZ MC, GOLDSTEIN AL, BLANKENSHIP JR, et al.
82) SANGLARD D, ODDS FC. Resistance of Candida Calcineurin is essential for survival during mem- species to antifungal agents: molecular mecha- brane stress in Candida albicans. EMBO J 2002; nisms and clinical consequences. Lancet Infect 73) ONYEWU C, BLANKENSHIP JR, DEL POETA M, HEITMAN J.
83) LOEFFLER J, STEVENS DA. Antifungal drug resistance.
Ergosterol biosynthesis inhibitors become fungici- Clin Infect Dis 2003; 36 (Suppl 1): S31-S41.
dal when combined with calcineurin inhibitorsagainst Candida albicans, Candida glabrata, andCandida krusei. Antimicrob Agents Chemother2003; 47: 956-964.
74) MARCHETTI O, MOREILLON P, ENTENZA JM, et al.
Fungicidal synergism of fluconazole and cy-closporine in Candida albicans is not dependent onmultidrug efflux transporters encoded by the CDR1,CDR2, CaMDR1, and FLU1 genes. AntimicrobAgents Chemother 2003; 47: 1565-1570.
75) DI FRANCESCO P, GAZIANO R, CASALINUOVO IA, et al.
We thank Emanuele Rodolà for his excellent tech- Combined effect of fluconazole and thymosin al- nical assistance. This work was supported by MI- pha 1 on systemic candidiasis in mice immuno-suppressed by morphine treatments. Clin Exp UR, 60% and progetto FIRB n° RBNE01P4B5-
OPEN UNIVERSITY OF MAURITIUS EMPLOYABILITY SKILLS PROGRAMME: (EDUCATION IN NUTRITION) COURSE TITLE: HEALTH AND NUTRITION- [OUES012] LECTURER: DR. VISHNEE BISSONAUTH JUNE 2013 1. Introduction Every day we are faced with an abundance of food choices and nutritional information. Whether to maintain a balanced diet at a restaurant, to browse the aisles of grocery store or