JAC Advance Access originally published online on April 27, 2007
Journal of Antimicrobial Chemotherapy 2007 59(6):1076-1083; doi:10.1093/jac/dkm095
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Acquired resistance to echinocandins in Candida albicans: case report and review
1 Université Paris Descartes, Faculté de Médecine, AP-HP, Hôpital Européen Georges Pompidou, Unité de Parasitologie—Mycologie, 75015 Paris, France 2 Service d'Immunologie Clinique, Hôpital Européen Georges Pompidou, AP-HP, Paris, France 3 Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, CNRS URA 3012, Institut Pasteur, 75724 Paris Cedex 15, France
* Correspondence address. Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, CNRS URA3012, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France. Tel: +33-1-40-61-32-50; Fax: +33-1-45-68-84-20; E-mail: dannaoui{at}pasteur.fr
Received 4 January 2007; returned 18 February 2007; revised 7 March 2007; accepted 7 March 2007
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Abstract |
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Objectives: A patient with Candida albicans thrush and oesophagitis was treated with high doses of caspofungin but treatment eventually failed. Four C. albicans isolates were serially recovered before and after caspofungin treatment. A microbiological study was performed to characterize these four isolates.
Methods: In vitro antifungal susceptibility testing was performed by the EUCAST reference method in RPMI and AM3 and by Etest®. Molecular typing of the four isolates was done by sizing three polymorphic microsatellite markers. To look for specific mutations, sequencing of a region of the gene encoding the 1-3-ß-D-glucan synthase was performed for the four isolates.
Results: In vitro antifungal susceptibility testing showed an increase in both caspofungin and micafungin MICs for the two isolates recovered after caspofungin treatment failure. The best discrimination between the pre-treatment and post-treatment isolates was obtained with Etest®. Molecular typing of the four isolates showed that the post-treatment isolates with reduced susceptibility were identical to a susceptible pre-treatment isolate, suggesting the acquisition of caspofungin resistance. Sequencing of the gene encoding the 1-3-ß-D-glucan synthase showed a mutation responsible for an amino acid change at Phe-641 that could confer reduced susceptibility to both echinocandins.
Conclusions: Our results indicate that is it useful to perform in vitro susceptibility testing in the cases of clinical failure during caspofungin therapy.
Keywords: caspofungin , micafungin , 1-3-ß-D-glucan synthase , Etest
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Introduction |
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Echinocandins are a new class of antifungal drugs with broad-spectrum activity.1 They inhibit 1-3-ß-D-glucan synthesis, leading to damage of the cell wall of many fungal species.2 Caspofungin is the first antifungal agent from this class to be available in European countries. It is fungicidal in vitro and in vivo against most isolates of Candida spp. including Candida spp. with fluconazole resistance.1,2 It has been successfully used to treat oropharyngeal and oesophageal candidiasis, invasive candidiasis and invasive aspergillosis.1 Caspofungin provides a generally well-tolerated parenteral therapeutic option. Recommended doses are 50 mg/day after a loading dose of 70 mg on day 1.
Few cases of Candida spp. isolates with reduced susceptibility to caspofungin have been reported to date.3–13 We report a case of acquisition of caspofungin resistance in Candida albicans in an HIV patient treated for oesophageal candidiasis and show that clinical failure during caspofungin therapy was associated with an increase in MIC of this drug. A molecular analysis of the gene encoding the target enzyme was performed and showed the presence of a specific amino acid substitution.
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Case report |
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A 34-year-old male (weight 49 kg), with AIDS (CD4 count of 6 cells/mm3), was admitted with a diagnosis of thrush and Candida oesophagitis lasting 3 months. Previous therapy with fluconazole had failed. Antifungal treatments received by the patient and clinical responses are summarized in Figure 1.
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On day 1, he was treated with voriconazole (400 mg/day) with rapid clinical improvement by day 4. On day 11, treatment for a Mycobacterium avium infection was started (rifabutin, ethambutol and clarithromycin) and Candida infection relapsed on day 15. From day 24 to day 37, he was treated with caspofungin (70 mg daily). His oesophagitis responded partially with persistent oral confluent plaques. By the end of treatment (day 38), thrush and oesophagitis relapsed. Treatment with amphotericin lipid complex (3 mg/kg) once weekly was done (39th and 45th day) and stopped for systemic intolerance after two injections (chills and fever). At the same time (day 39), antiretroviral treatment was started (ritonavir, fosamprenavir, abacavir and tenofovir). From day 55 to day 65, a second course of caspofungin (70 mg/day) was initiated without clinical efficacy. At day 66, treatment with high doses of voriconazole (800 mg/day followed by 600 mg/day) was initiated. Thrush and oesophagitis resolved completely on the third day.
Other therapies used were valaciclovir started on day 9 for herpes zoster of the hand, gabapentin and clonazepam for post-herpetic neuralgia and he also had a prophylactic treatment with sulfamethoxazole/trimethoprim.
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Materials and methods |
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Yeast strains
C. albicans isolates were recovered from the oral cavity 12 days before admission (isolate 1) and on days 18, 63 and 131 (isolates 2, 3 and 4, respectively). Isolates were identified by colony pigmentation on CandiSelect4 (Bio-Rad, Marnes la Coquette, France) and by carbohydrate assimilation profile on ID32C strips (bioMerieux, Marcy l'Étoile, France). Specific Candida dubliniensis PCR amplification14 was negative for all four isolates.
Antifungal susceptibility testing was performed by a commercial agar diffusion test (Etest®) and by the EUCAST microdilution broth reference method.15
Etest® strips for amphotericin B, fluconazole, voriconazole and caspofungin were supplied by AB Biodisk (Solna, Sweden) and used as recommended by the manufacturer. The yeast inoculum was adjusted in sterile 0.9% NaCl to the turbidity of a 0.5 McFarland standard. The surface of agar plates containing RPMI medium buffered to pH 7.0 with 0.165 M MOPS and containing 2% glucose (AES Chemunex, Bruz, France) was inoculated by using a swab dipped in the cell suspension. When the surface was completely dry, the Etest® strips were applied. The plates were incubated at 35°C and read at 48 h. For caspofungin and amphotericin B, the MIC was defined as the lowest concentration at which the zone of complete inhibition intersected the strip. For fluconazole and voriconazole, the MIC was read as the lowest concentration at which the border of the elliptical inhibition zone intercepted the scale on the strip; any growth such as microcolonies throughout a discernible inhibition ellipse was ignored. MIC determination was done at least twice. Micafungin susceptibility was not performed by Etest® as strips for this drug are not commercially available.
Antifungal susceptibility was also determined by the EUCAST broth microdilution reference method.15 Amphotericin B (Sigma-Aldrich, Saint Quentin Fallavier, France), fluconazole (Pfizer Central Research, Sandwich, UK), voriconazole (Pfizer), caspofungin (Merck & Co., Inc., Rahway, NJ, USA) and micafungin (Astellas Pharma, Osaka, Japan) were obtained as powders of known potency. For all antifungals except for amphotericin B, RPMI 1640 medium with L-glutamine but without sodium bicarbonate (Sigma-Aldrich) buffered to pH 7.0 with 0.165 M MOPS (Sigma-Aldrich) was used as the test medium. Amphotericin B was tested in antibiotic medium 3 (AM3, Difco, Le Pont de Claix, France) supplemented with 2% glucose. Additionally, caspofungin was also tested in AM3 medium. The final concentrations of the antifungal agents were 0.015–8 mg/L for amphotericin B, voriconazole, caspofungin and micafungin and 0.125–64 mg/L for fluconazole. Isolates were grown on Sabouraud glucose agar for 24 h at 30°C and yeast suspensions were prepared in sterile water and adjusted to a turbidity equivalent to that of a 0.5 McFarland standard. After inoculation, microplates were incubated at 35°C for 24 h and spectrophotometric readings were performed at 492 nm with an automated microplate reader spectrophotometer (Rosys Anthos ht3, Anthos Labtec Instruments GmbH, Salzburg, Austria). MIC endpoints were defined as the lowest drug concentration that led to an inhibition of 
95% for amphotericin B and the echinocandins and to an inhibition of 50% for the azoles. Reference strains, Candida krusei ATCC 6258 and Candida parapsilosis ATCC 22019, were included to ensure quality control.
Strain genotyping was performed by multiplex PCR amplification of three polymorphic microsatellite markers (CDC3, EF3 and HIS3), as described previously.16 Briefly, primers were labelled with different dyes: 4,7,2',4',5',7'-hexachloro-6-carboxyfluorescein (HEX), 6-carboxyfluorescein (6-FAM) and 4,7,2',7'-tetrachloro-6-carboxyfluorescein (TET) for primers CDC3, EF3 and HIS3, respectively. PCR products were sized by an automatic ABI 310 capillary genetic analyser (Applied Biosystems) and data analysed with the Genescan 3.0 software (Applied Biosystems). C. albicans B311 (ATCC 32354) reference strain was used as the quality control.
Previously described specific primers 5'-GAAATCGGCATATGCTGTGTC-3' and 5'-AATGAACGACCAATGGAGAAG-3' were used for PCR amplification and sequencing of the fks gene.8 These primers amplified a fragment of 
450 bp of the CaFKS1 locus. This fragment contains the hot-spot region 1 in which mutations are known to confer reduced susceptibility to echinocandins.8 Reaction volumes of 50 µL contained 3 µL of genomic DNA, 1.25 U of AmpliTaq gold (Roche), 5 µL of PCR buffer 10 x (Roche), 5 µL of MgCl2 25 mM (Roche), 5 µL of 2.5 mM dNTP and 1.25 µL of each 20 µM concentrated primers. The PCR products were amplified in an ICycler Thermocycler (Bio-Rad) setup with a first cycle of denaturation for 10 min at 95°C, followed by 30 cycles of denaturation at 94°C for 30 s, annealing at 50°C for 30 s and elongation at 72°C for 30 s, with a final extension step of 10 min at 72°C. After purification of PCR products, both strands were sequenced with the same primer set used for amplification. Reaction products were analysed on an ABI Prism 3700 automated DNA analyser (Applied Biosystems). Sequences were determined twice in independent experiments. Sequences were translated and analysed with BioEdit sequence alignment editor (Isis Therapeutics, Carlsbad, CA, USA).
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Results |
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Comparison of the length of PCR products for the three microsatellite markers for each isolate showed that all four isolates shared identical patterns and were thus considered to belong to the same strain. The only difference was that isolate 1 was heterozygous for the CDC3 locus, as shown in Figure 2.
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By Etest® method, all four isolates showed high MICs of fluconazole (from 48 to 64 mg/L). For voriconazole MICs were 0.50 mg/L for isolates 1, 2 and 3 and 2 mg/L for isolate 4. All four isolates showed similar MICs for amphotericin B of 0.064 mg/L. There were no major discrepancies between results by Etest® and the EUCAST reference method (MIC differences were within two 2-fold dilutions). MICs of echinocandins are shown in Table 1. There was a 1024-fold increase (i.e. 10 doubling dilutions) in caspofungin MIC as determined by Etest® for isolates 3 and 4 recovered after clinical failure of caspofungin therapy when compared with isolates 1 and 2. As shown in Figure 3 for two isolates, inhibition patterns with Etest® were easy to read with a clear inhibition ellipse for the pre-treatment isolate 1 and complete absence of inhibition zone for post-treatment isolate 4. These results were corroborated by the EUCAST reference method on RPMI and AM3 media. Nevertheless, increase in MICs by this method was less significant than by Etest®. The use of AM3 medium allowed better discrimination between the isolates recovered before and after failure treatment (i.e. five dilutions) than the RPMI medium (i.e. three dilutions). Isolates 3 and 4 also demonstrated increased MICs of micafungin (i.e. four dilutions).
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Alignment of the deduced Fks protein sequences for the four isolates in comparison with the sequence of a wild-type C. albicans (CaFks1p, accession number D88815 [GenBank] ) is shown in Figure 4. Pre-treatment isolates 1 and 2 did not exhibit mutation in the sequenced region. In contrast, both post-treatment resistant isolates contain the same F641S mutation.
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Discussion |
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Caspofungin is active in vitro against most species of Candida17,18 and has shown good in vivo efficacy for treatment of candidaemia19 and oesophageal candidiasis.20 Surveillance programmes showed a low level of elevated MICs for caspofungin in Candida spp.18 Nevertheless, there are minimal data available regarding the development of echinocandin resistance in Candida spp. during therapy with these antifungal drugs. A limited number of cases have reported infections with isolates showing decreased susceptibility to caspofungin,3–13 and in a few instances, acquisition of resistance under caspofungin treatment has been demonstrated for C. albicans, Candida glabrata, C. parapsilosis and C. krusei.
In the present case, acquisition of resistance was demonstrated in a patient treated with caspofungin. Clinical resistance was associated with increased MICs in vitro and related to a new mutation of the target enzyme. A high dose of caspofungin (70 mg/day) was used, as currently recommended,2 because the patient received rifabutin, a drug closely related to rifampicin that is known to interact with caspofungin. Indeed, it has been shown that caspofungin trough concentrations were decreased by 14–30% in healthy volunteers in the case of co-administration with rifampicin.21 There was no drug interaction reported with the other molecules, particularly antiretroviral therapy administered to the patient at the same time than the second course of caspofungin.
As summarized in Table 2, few cases of Candida spp. isolates with reduced susceptibility to caspofungin have been reported to date.3–13 These infections included oesophageal candidiasis in HIV patients3,5,6 and candidaemia or invasive candidiasis in both neutropenic and non-neutropenic patients.7–13 Isolates with reduced susceptibility were C. albicans,3–6,8 C. glabrata,4,10–13 C. krusei,8,9 and C. parapsilosis.7 In several cases, pre- and post-treatment isolates were available and typing methods were employed to show identity of the isolates, suggesting acquisition of caspofungin resistance during treatment with this drug.3,5,7–13
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In the present study, genotyping was performed to determine whether the four isolates studied were closely related or independent. Using three polymorphic microsatellite markers,16 we clearly showed that isolates 2–4 had identical genotype and that caspofungin resistance was acquired without modification of these three markers. Interestingly, we were able to genotype isolate 1, collected 75 days before isolate 3, the first with reduced susceptibility to caspofungin. Isolate 1 was heterozygous, whereas the other isolates were homozygous for the CDC3 marker. This observation suggests two things. First, the loss of heterozygosity (LOH) can be selected and persist over time under caspofungin pressure. However, the probability of having both homozygous and heterozygous colonies in the same clinical sample and picking the same one three times depends on the unknown ratio of both genotypes. Second, LOH has been coupled with azole resistance in C. albicans.22 Here, we show that LOH can precede and not be concomitant with antifungal resistance. The fact that both CDC3 and the glucan-synthase gene are located on chromosome 1 suggests that LOH promoted reduced susceptibility to caspofungin. We have already shown that LOH for one marker located on chromosome 5 is associated with duplication of the homozygous marker and not loss of one copy.23 It is hypothesized that recombination between the involved portions of chromosome or duplication of the entire chromosome can be responsible for this LOH.22
Although susceptibility breakpoints have not been defined for caspofungin, most of the reported cases in the literature involved isolates with high in vitro MICs when compared with MICs generally observed for Candida spp.17,18 In some instances, in vitro decreased susceptibility was also confirmed in experimental animal models of candidiasis.3,8,10 Moreover, when pre- and post-treatment isolates were available, MIC increase was linked to clinical failure, indicating a correlation between in vitro results and in vivo efficacy of the drug.
The best methodological parameters to be used for in vitro susceptibility testing of caspofungin are still under debate.24,25 In the present case, different techniques were used. A better discrimination between pre- and post-treatment isolates was obtained with the EUCAST method when AM3 medium was used instead of RPMI. Moreover, the discrimination between pre- and post-treatment isolates was much better with Etest®, suggesting that Etest® could be a reliable and efficient technique to detect Candida spp. isolates with reduced susceptibility to caspofungin. Although CLSI (formerly NCCLS) methodology26 recommends RPMI as a test medium, alternative medium such as AM3 has been tested for susceptibility testing of caspofungin and has proven to be useful.25 Alternative methods such as Etest® have also been evaluated for caspofungin susceptibility testing against Candida spp. In a previous study,27 a high agreement (95%) between Etest® method and the EUCAST reference method with RPMI medium was found. Nevertheless, this study did not include C. albicans isolates with high MICs to caspofungin. Significant differences were observed between the two test methods for species such as Candida guillermondii that exhibited high MICs27; lower MIC values were obtained with Etest®, compared with CLSI and EUCAST techniques. Further studies with Candida spp. isolates known to be resistant to caspofungin are needed to compare Etest® and microdilution broth techniques for their ability to detect isolates with reduced susceptibility to caspofungin.
Interestingly, acquisition of caspofungin resistance in the present isolates was associated with an increase in micafungin MIC, suggesting cross-resistance between these two echinocandins. In vitro study of a large number of isolates has shown that for those species with high MICs of caspofungin (e.g. C. parapsilosis), MICs of micafungin and anidulafungin were also elevated.17 Similarly, in previous clinical cases, resistance to caspofungin was associated with increased micafungin and/or anidulafungin MICs,7,9 and in a case of clinical failure of micafungin treatment, the post-treatment isolate showed elevated MICs of all three echinocandins.5
It has been shown in laboratory mutants of C. albicans with reduced susceptibility to caspofungin that mutations in selected regions of fks1, the gene encoding the echinocandin target enzyme 1-3-ß-D-glucan synthase, were responsible for the increase in caspofungin MICs.8 In particular, mutations of the serine at position 645 have been shown to be associated with decreased susceptibility to caspofungin. Recently, sequencing of this region for 85 spontaneous mutants confirmed that mutations mainly occurred at position 645 and also, in some cases, at position 641.28 Up to now, a very limited number of echinocandin-resistant clinical isolates have been screened for Fks mutations.4–6,8 Both S645P and S645F mutations have been reported5,6,8 and in one case, an F641Y substitution has been observed.4 In the present case, an F641S substitution, which has not been reported previously, was associated with the acquisition of caspofungin resistance. Fks mutations have also been reported in echinocandin-resistant isolates of C. glabrata4 and C. krusei.8 It has to be noticed that in one case, resistance of a C. krusei was not related to an alteration of Fks,9 suggesting that other mechanisms could be responsible for resistance.
In summary, we report a clinical case of oesophagitis with acquired clinical resistance to caspofungin in spite of high doses of caspofungin. The resistance was associated with an increase in echinocandin MICs and with a new mutation of the fks gene. The Etest® method allowed easy detection of elevated MIC, suggesting that it could be used to perform susceptibility testing in cases of clinical failure during caspofungin therapy.
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None to declare.
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Acknowledgements |
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We thank Damien Hoinard and Dorothée Raoux for their excellent technical assistance.
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3
Hernandez S, Lopez-Ribot JL, Najvar LK, et al. Caspofungin resistance in Candida albicans: correlating clinical outcome with laboratory susceptibility testing of three isogenic isolates serially obtained from a patient with progressive Candida esophagitis. Antimicrob Agents Chemother (2004) 48:1382–3.
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Katiyar S, Pfaller M, Edlind T. Candida albicans and Candida glabrata clinical isolates exhibiting reduced echinocandin susceptibility. Antimicrob Agents Chemother (2006) 50:2892–4.
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Laverdiere M, Lalonde RG, Baril JG, et al. Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis. J Antimicrob Chemother (2006) 57:705–8.
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Moudgal V, Little T, Boikov D, et al. Multiechinocandin- and multiazole-resistant Candida parapsilosis isolates serially obtained during therapy for prosthetic valve endocarditis. Antimicrob Agents Chemother (2005) 49:767–9.
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Park S, Kelly R, Kahn JN, et al. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother (2005) 49:3264–73.
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Hakki M, Staab JF, Marr KA. Emergence of a Candida krusei isolate with reduced susceptibility to caspofungin during therapy. Antimicrob Agents Chemother (2006) 50:2522–4.
10 Krogh-Madsen M, Arendrup MC, Heslet L, et al. Amphotericin B and caspofungin resistance in Candida glabrata isolates recovered from a critically ill patient. Clin Infect Dis (2006) 42:938–44.[CrossRef][Web of Science][Medline]
11 Daneman N, Chan AK, Rennie R, et al. The emergence of caspofungin resistance during treatment of recurrent Candida glabrata candidemia. Abstracts of the 16th European Congress of Clinical Microbiology and Infectious Diseases, Nice, France, 2006. (2006) 12(Suppl_4):386. Abstract P1204. Clin Microb Infect.
12 Villareal NC, Fother-Gill AW, Kelly C, et al. Candida glabrata resistance to caspofungin during therapy. In: Abstracts of the Forty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2004. Washington, DC, USA: American Society for Microbiology. p. 417. Abstract M-1034.
13 Dodgson KJ, Dodgson AR, Pujol C, et al. Caspofungin resistant C. glabrata. Abstracts of the 15th European Congress of Clinical Microbiology and Infectious Diseases, Copenhagen, Denmark, 2005 (2005) 11(Suppl 2):364. Abstract P1158. Clin Microb Infect.
14
Donnelly SM, Sullivan DJ, Shanley DB, et al. Phylogenetic analysis and rapid identification of Candida dubliniensis based on analysis of ACT1 intron and exon sequences. Microbiology (1999) 145:1871–82.
15 Rodríguez-Tudela JL, Barchiesi F, et al, Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). Method for the determination of minimum inhibitory concentration (MIC) by broth dilution of fermentative yeasts. EUCAST Discussion Document E.Dis 7.1. Clin Microbiol Infect (2003) 9:i–viii.[CrossRef]
16
Botterel F, Desterke C, Costa C, et al. Analysis of microsatellite markers of Candida albicans used for rapid typing. J Clin Microbiol (2001) 39:4076–81.
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Ostrosky-Zeichner L, Rex JH, Pappas PG, et al. Antifungal susceptibility survey of 2,000 bloodstream Candida isolates in the United States. Antimicrob Agents Chemother (2003) 47:3149–54.
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Pfaller MA, Boyken L, Hollis RJ, et al. In vitro susceptibilities of Candida spp. to caspofungin: four years of global surveillance. J Clin Microbiol (2006) 44:760–3.
19
Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med (2002) 347:2020–9.
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Kartsonis NA, Saah A, Lipka CJ, et al. Second-line therapy with caspofungin for mucosal or invasive candidiasis: results from the caspofungin compassionate-use study. J Antimicrob Chemother (2004) 53:878–81.
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Stone JA, Migoya EM, Hickey L, et al. Potential for interactions between caspofungin and nelfinavir or rifampin. Antimicrob Agents Chemother (2004) 48:4306–14.
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Coste A, Turner V, Ischer F, et al. A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics (2006) 172:2139–56.
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Foulet F, Nicolas N, Eloy O, et al. Microsatellite marker analysis as a typing system for Candida glabrata. J Clin Microbiol (2005) 43:4574–9.
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Odds FC, Motyl M, Andrade R, et al. Interlaboratory comparison of results of susceptibility testing with caspofungin against Candida and Aspergillus species. J Clin Microbiol (2004) 42:3475–82.
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Bartizal C, Odds FC. Influences of methodological variables on susceptibility testing of caspofungin against Candida species and Aspergillus fumigatus. Antimicrob Agents Chemother (2003) 47:2100–7.
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Chryssanthou E, Cuenca-Estrella M. Comparison of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing proposed standard and the E-test with the NCCLS broth microdilution method for voriconazole and caspofungin susceptibility testing of yeast species. J Clin Microbiol (2002) 40:3841–4.
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M. A. Pfaller, D. J. Diekema, L. Ostrosky-Zeichner, J. H. Rex, B. D. Alexander, D. Andes, S. D. Brown, V. Chaturvedi, M. A. Ghannoum, C. C. Knapp, et al. Correlation of MIC with Outcome for Candida Species Tested against Caspofungin, Anidulafungin, and Micafungin: Analysis and Proposal for Interpretive MIC Breakpoints J. Clin. Microbiol., August 1, 2008; 46(8): 2620 - 2629. [Abstract] [Full Text] [PDF]
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M. Desnos-Ollivier, F. Dromer, and E. Dannaoui Detection of Caspofungin Resistance in Candida spp. by Etest J. Clin. Microbiol., July 1, 2008; 46(7): 2389 - 2392. [Abstract] [Full Text] [PDF]
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M. A. Pfaller, V. Chaturvedi, D. J. Diekema, M. A. Ghannoum, N. M. Holliday, S. B. Killian, C. C. Knapp, S. A. Messer, A. Miskov, and R. Ramani Clinical Evaluation of the Sensititre YeastOne Colorimetric Antifungal Panel for Antifungal Susceptibility Testing of the Echinocandins Anidulafungin, Caspofungin, and Micafungin J. Clin. Microbiol., July 1, 2008; 46(7): 2155 - 2159. [Abstract] [Full Text] [PDF]
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J. D. Cleary, G. Garcia-Effron, S. W. Chapman, and D. S. Perlin Reduced Candida glabrata Susceptibility Secondary to an FKS1 Mutation Developed during Candidemia Treatment Antimicrob. Agents Chemother., June 1, 2008; 52(6): 2263 - 2265. [Abstract] [Full Text] [PDF]
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S. Hodgetts, L. Nooney, R. Al-Akeel, A. Curry, S. Awad, R. Matthews, and J. Burnie Efungumab and caspofungin: pre-clinical data supporting synergy J. Antimicrob. Chemother., May 1, 2008; 61(5): 1132 - 1139. [Abstract] [Full Text] [PDF]
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E. Dannaoui, O. Lortholary, D. Raoux, M. E. Bougnoux, G. Galeazzi, C. Lawrence, D. Moissenet, I. Poilane, D. Hoinard, F. Dromer, et al. Comparative In Vitro Activities of Caspofungin and Micafungin, Determined Using the Method of the European Committee on Antimicrobial Susceptibility Testing, against Yeast Isolates Obtained in France in 2005-2006 Antimicrob. Agents Chemother., February 1, 2008; 52(2): 778 - 781. [Abstract] [Full Text] [PDF]
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