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JAC Advance Access published online on September 17, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm350
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Correlation of posaconazole minimum fungicidal concentration and time–kill test against nine Candida species

G. Sóczó1, G. Kardos1, P. M. McNicholas2, E. Balogh1, L. Gergely1, I. Varga3, B. Kelentey3 and L. Majoros1,*

1 Department of Medical Microbiology, Medical and Health Science Center, University of Debrecen, Hungary 2 Schering-Plough Research Institute, Kenilworth, NJ, USA 3 Faculty of Dentistry, Medical and Health Science Center, University of Debrecen, Hungary

* Corresponding author. Tel: +36-52-411-717/4501; Fax: +36-52-414-948; E-mail: major{at}dote.hu

Received 13 March 2007; returned 21 May 2007; revised 30 July 2007; accepted 15 August 2007


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Objectives: We evaluated the in vitro activity of posaconazole against nine Candida species using minimum fungicidal concentration (MFC) measurements and time–kill methods.

Methods: MFCs of posaconazole were determined for 209 clinical isolates (32 Candida albicans, 30 Candida glabrata, 21 Candida tropicalis, 29 Candida krusei, 28 Candida parapsilosis sensu stricto, 50 Candida inconspicua, 13 Candida kefyr, 3 Candida lusitaniae and 3 Candida guilliermondii) and 7 ATCC Candida strains. The following strains were tested in time–kill studies: 3 strains each of C. glabrata, C. kefyr, C. guilliermondii and C. lusitaniae; 2 C. tropicalis; 4 C. albicans; 4 C. inconspicua; 9 C. krusei; 12 C. parapsilosis; and 7 ATCC strains.

Results: Posaconazole was fungicidal in both MFC and time–kill experiments (at 2 mg/L within 48 h in time–kill assays) against each C. krusei, C. inconspicua and C. lusitaniae strain and was fungistatic against each C. albicans, C. glabrata, C. tropicalis and C. guilliermondii strain. For the C. parapsilosis strains, posaconazole MFCs were ≤2 mg/L for 20 of the 28 isolates tested; however, in the time–kill tests, even at drug concentrations of 32–64 x MIC, posaconazole was fungistatic against all C. parapsilosis strains tested.

Conclusions: MFC values were good predictors of the fungistatic or fungicidal activity of posaconazole, as determined by time–kill curves, for all tested species except C. parapsilosis. Our results highlight the fungicidal action of posaconazole against a number of clinically relevant Candida species.

Key Words: MFCs , antifungals , triazoles


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The fungicidal activity of an antifungal agent can be measured either by determining the minimum fungicidal concentration (MFC) or using time–kill methodology.1 Although the time–kill method provides information on the rate of killing of a drug, it is both cumbersome and time-consuming and is therefore not suitable for routine laboratory work. Measurement of the MFC value is a useful alternative; however, the method has not yet been standardized.1 Cantón et al.2 observed a good correlation between the results of time–kill experiments and MFC values for amphotericin B against a large panel of Candida species. Similar data for other agents (e.g. triazoles and echinocandins) do not appear to be available.

Triazoles are commonly regarded as being fungistatic; however, some triazoles (e.g. voriconazole and posaconazole) exhibit fungicidal activity against moulds.1 In addition, several previous studies, using either MFC measurements or time–kill studies, suggested that triazoles may also show fungicidal activity against certain Candida species.3–6

Posaconazole is an extended-spectrum triazole that is active in vitro against a wide range of fungal pathogens including most Candida spp. and the majority of organisms responsible for causing aspergillosis, cryptococcosis, chromoblastomycosis, mycetoma and phaeohyphomycosis.7 Posaconazole is also active against many of the zygomycetes, organisms that were previously regarded as being resistant to most azoles, including the most widely used fluconazole and voriconazole.7,8 Using a variety of techniques, posaconazole was shown to be fungicidal against Aspergillus spp., Cryptococcus neoformans and dermatophytes.9–13 This potent in vitro activity has translated into clinical efficacy against a wide spectrum of mycoses.9,10

The aim of this study was to determine whether posaconazole was fungicidal against both common (Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis and Candida krusei) and less common (Candida inconspicua, Candida kefyr, Candida lusitaniae and Candida guilliermondii) Candida species using both MFC determinations and time–kill studies; we also investigated the correlation between the two techniques.


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Clinical isolates

Two hundred and nine yeast isolates (32 C. albicans, 30 C. glabrata, 21 C. tropicalis, 29 C. krusei, 28 C. parapsilosis sensu stricto, 50 C. inconspicua, 13 C. kefyr, 3 C. lusitaniae and 3 C. guilliermondii) were studied. We also tested seven ATCC Candida strains (C. albicans ATCC 14053, C. tropicalis ATCC 750, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, C. inconspicua ATCC 16783, C. guilliermondii ATCC 6260 and Candida norvegensis ATCC 22977). Strains were identified using CHROMagar Candida, morphology on rice extract agar and the API ID32C panel. Species identities of C. inconspicua and C. parapsilosis isolates were confirmed by PCR-ribotyping14 and restriction fragment length polymorphism of the SADH gene,15 respectively.

Drug

Posaconazole was obtained as the reagent grade powder from the Schering-Plough Research Institute. Stock solutions were prepared in DMSO as specified by the CLSI (formerly NCCLS) M27-A2 document.16 Final concentration ranges were 0.015–8 mg/L.

Susceptibility testing

Posaconazole MICs for these isolates with the exception of C. lusitaniae and C. guilliermondii have been published elsewhere.17 For measurement of MFCs, the inoculum recommended in the CLSI M27-A2 document16 was increased 10-fold to ~104 cells/mL.2 Inoculum densities were confirmed by plating serial dilutions on Sabouraud dextrose agar (SDA). All other test procedures followed the approved CLSI broth microdilution method. Microdilution trays were incubated for 48 h and read visually; the MIC was the lowest concentration of drug that produced a prominent decrease in turbidity when compared with the drug-free control.

After MICs were read, the entire contents (200 µL) of each well with drug concentrations above the MIC were plated onto two drug-free SDA plates (100 µL aliquots/plate).2 Aliquots were placed in a single spot on the agar plate and, after drying, the cells were dispersed by streaking. Plates were incubated at 35°C for 48 h; the MFC was defined as the lowest drug concentration that resulted in a 99.9% reduction in the starting inoculum. All assays were performed in duplicate and repeated at least twice.

Time–kill studies

In time–kill experiments, the method described by Klepser et al.18 was used. The starting inoculum was 105 cells/mL and drug concentrations ranged from 0.5 to 16 times the MIC; C. parapsilosis strains were also tested at concentrations 32 and 64 times the MIC. Test tubes were incubated with agitation in the dark at 35°C. At predetermined time points, samples (100 µL) were removed and serially diluted 10-fold in sterile saline; four 30 µL aliquots were subsequently plated onto SDA (if colony counts were suspected to be <1000 cfu/mL, undiluted samples were plated). On the basis of our preliminary results with C. albicans ATCC 14053 and C. krusei ATCC 6258 strains, the following sampling points were chosen: 0, 6, 18, 24, 36 and 48 h. Colony counts were determined after incubation of the plates at 35°C for 48 h. All assays were performed in duplicate and repeated at least twice. Time–kill curves were prepared using the computer curve-fitting software GraphPad Prism 4.03 for Windows. The limit of exact quantification using this methodology is 50 cfu/mL. Fungicidal activity was defined as a 99.9% (3 log10) reduction in viable cfu/mL of the starting inoculum.


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MFCs

Fungicidal activity is routinely defined as a 99.9% reduction in cfu over a fixed sampling period. The standard inoculum of 103 cfu/mL (which equates to 102 cells/well when using 100 µL/well), described in the CLSI document M27-A2,16 is too low to permit an accurate measurement of a 99.9% reduction in viable cells. Therefore, as recommended by Cantón et al.,2 in this study, MIC and MFC determinations were performed using a 10-fold higher inoculum, 104 cfu/mL. The MICs obtained using the higher inoculum were the same as, or one dilution higher, those obtained using the standard CLSI inoculum (data not shown); all MIC values in the following sections were obtained using the higher inoculum. MFC distributions, geometric mean values and MFC50/90 values (MFCs for 50% and 90% of the isolates, respectively) are shown in Table 1.


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  		Table 1. Posaconazole MFC distributions, geometric means of MFC and MFC50/90 values for test isolates

 
Posaconazole was fungicidal at low concentrations (≤2 mg/L) against all of the C. inconspicua and C. lusitaniae strains and against the majority of C. krusei (24/29, 83%), C. parapsilosis (20/28, 71%) and C. kefyr (9/13, 69%) strains. In contrast, the drug was fungistatic (MFC > 8 mg/L) against all of the C. albicans, C. glabrata, C. tropicalis and C. guilliermondii strains tested. MFC values for the five ATCC strains showed the same species disposition as the clinical isolates (Table 1).

Time–kill study results

To further characterize the fungicidal activity of posaconazole, time–kill assays were performed. Strains from a given species were chosen to represent the entire MFC range of that species; in those instances where there was a lack of concordance between the MFC and time–kill experiments, additional strains were tested. Time–kill curves of all reference strains used were also determined. The isolates and reference strains tested together with their MIC and MFC ranges are listed in Table 2; representative kill curves are shown in Figure 1.


Figure 1
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  		Figure 1. Representative time–kill plots. Cells were incubated with the indicated amount of posaconazole and samples withdrawn at the indicated time points and plated on drug-free medium to quantify cfu. The dashed line indicates a 99.9% reduction in the starting inoculum. Each data point represents the mean ± SD (error bar) for two independent experiments, each performed in duplicate. The concentrations of drug tested were as follows: drug-free control, filled triangles; 0.5 x MIC, open squares; 1 x MIC, open triangles; 2 x MIC, open inverted triangles; 4 x MIC, open diamonds; 8 x MIC, open circles; and 16 x MIC, asterisks.

 


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  		Table 2. Candida spp. tested in time–kill assays

 
Posaconazole appeared to exhibit the strongest fungicidal activity against the C. lusitaniae, C. inconspicua and C. kefyr clinical isolates; at 1 mg/L, the drug resulted in 99.9% killing within 24 h against two of three C. lusitaniae, three of four C. inconspicua and two of three C. kefyr isolates (Figure 1). At 48 h, posaconazole was fungicidal against all of the C. lusitaniae, C. inconspicua and C. kefyr isolates (with the exception of the single C. kefyr isolate with an MFC of >8 mg/L). Posaconazole also exhibited fungicidal activity against seven out of nine C. krusei isolates at concentrations 4-fold higher than the MIC after 48 h (but not after 36 h). The remaining two isolates, with MFC values of 4 and 8 mg/L, exhibited a 99.9% reduction in cfu at concentrations 8-fold higher than their respective MICs after 48 h. The only C. krusei strain to exhibit a 99.9% reduction in cfu within 24 h was the ATCC strain 6258; the drug concentration was 4 mg/L. Finally, against the C. norvegensis ATCC 22977 strain, posaconazole displayed good fungicidal activity after 36 h at concentrations 1–16-fold higher than the MIC.

With the exception of the C. albicans strain exhibiting reduced susceptibility to posaconazole (MIC > 8 mg/L), growth of all strains of C. albicans, C. tropicalis and C. guilliermondii was strongly inhibited at drug concentrations ranging from 2- to 16-fold higher than the respective MICs. In contrast, there was little or no growth inhibition of the C. glabrata strains at concentrations of posaconazole 16-fold above the MIC. Twelve C. parapsilosis isolates with MFCs ranging from 0.5 to >8 mg/L were tested. Although posaconazole did not exhibit fungicidal activity against any of the strains, growth of all isolates was strongly inhibited at low (0.06–0.12 mg/L; Figure 1) drug concentrations.


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The standard CLSI susceptibility testing method for yeasts recommends an incubation time of 48 h when testing Candida species.16 As MFC measurements are frequently extensions of the MIC test—the contents of the optically clear wells in the MIC test are plated on drug-free medium to quantify changes in cfu—the same drug exposure time is used when measuring MFCs. In contrast, time–kill measurements are generally made over 24 h,1 and this discrepancy makes direct comparisons between the two methods problematic. To address this problem, Cantón et al.2 recommended that the incubation time for time–kill experiments be extended from 24 to 48 h; with the extended incubation time, they observed a good correlation between MFCs and time–kill results when examining the activity of amphotericin B against seven Candida species.

In this study, we also used a 48 h incubation time to evaluate the fungicidal activity of posaconazole. Posaconazole exhibited concentration- and time-dependent fungicidal activity against several Candida species, including fluconazole-resistant C. krusei isolates, as shown by both MFC measurements and time–kill curves. Similarly, posaconazole showed excellent and rapid fungicidal activity against C. inconspicua and C. lusitaniae strains (with MFCs ≤ 2 mg/L); two species that are reported to exhibit decreased susceptibility to fluconazole and amphotericin B, respectively.3,14

The correlation between MFCs (read at 48 h) and the time–kill results was far better at 48 h than at 24 h. This was most clearly evident for the C. krusei isolates; at 24 h, posaconazole appeared fungistatic at 4 mg/L against 9 of the 10 isolates tested (the exception was the ATCC 6258 strain), but at 48 h, it (at 2 mg/L) was fungicidal against all isolates tested. The correlation between MFC values and 48 h time–kill results was excellent for all Candida species, except C. parapsilosis; posaconazole was fungistatic (by time–kill assays) against this species regardless of the MFC values. Generally, in time–kill studies, it was fungicidal within 48 h at a lower concentration than the MFC against all of the C. krusei, C. lusitaniae and C. inconspicua isolates as well as the two C. kefyr isolates with MFC values ≤2 mg/L.

To date, only one other study compared MFCs with time–kill results when testing the fungicidal action of azoles.19 In this study, posaconazole exhibited concentration- and time-dependent fungicidal activity against an Aspergillus fumigatus strain at concentrations of 4 mg/L and lower; a 99.9% reduction in cfu required 8 mg/L posaconazole and 48 h of incubation. The exact MFC value for this strain was not provided; nonetheless, the time–kill results appear to correlate with the MFC range of the A. fumigatus strains examined (4.45 ± 2.70 mg/L).

For antifungal drugs, there are limited data correlating the in vitro fungicidal/fungistatic activities of the drugs with clinical outcomes. The most compelling data, summarized by Pfaller et al.,1 are from patients treated with amphotericin B; in a series of studies, microbiological failures (with both yeast and mould pathogens) appeared to be correlated with elevated in vitro MFC values. However, in clinical trials comparing a fungicidal drug, the echinocandins (micafungin and anidulafungin), with a fungistatic drug, fluconazole, for the treatment of oesophageal candidiasis (the predominant pathogen was C. albicans), there were no significant differences in either clinical or mycological cures.20,21 Furthermore, despite being fungistatic against C. glabrata, in clinical trials posaconazole was effective in treating oropharyngeal candidiasis in people with human immunodeficiency virus, including subjects infected with fluconazole-resistant C. glabrata isolates.22 Clearly, further studies are required to determine whether there are clinical settings in which a fungicidal drug may provide an improved response when compared with a fungistatic drug in the treatment of invasive fungal infection.

In summary, the present study is the first to examine the correlation between MFCs and time–kill results in the determination of the fungicidal activity of an azole antifungal against Candida species. With the exception of C. parapsilosis, MFC values proved to be a good predictor of the fungicidal activity of posaconazole, as measured by time–kill studies, against Candida species.


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The study did not receive any financial support from third parties.


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None to declare.


   Acknowledgements
 
We would like to thank Cecília Miszti and Erzsébet Falusi for their valuable help. We are grateful to Dr Rudolf Gesztelyi for his help with the graphs. We thank Schering-Plough for providing the posaconazole powder. A part of this work was presented at the Forty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 2006 (abstract A-2151).


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1 . Pfaller MA, Sheehan DJ, Rex JH. Determination of fungicidal activities against yeasts and molds: lessons learned from bactericidal testing and the need for standardization. Clin Microbiol Rev (2004) 17:268–80.[Abstract/Free Full Text]

2 . Cantón E, Pemán J, Gobernado M, et al. Patterns of amphotericin B killing kinetics against seven Candida species. Antimicrob Agents Chemother (2004) 48:2477–82.[Abstract/Free Full Text]

3 . Ernst EJ, Yodoi K, Roling EE, et al. Rates and extents of antifungal activities of amphotericin B, flucytosine, fluconazole, and voriconazole against Candida lusitaniae determined by microdilution, Etest, and time–kill methods. Antimicrob Agents Chemother (2002) 46:578–81.[Abstract/Free Full Text]

4 . Girmenia C, Venditti M, Martino P. Fluconazole in combination with flucytosine in the treatment of fluconazole-resistant Candida infections. Diagn Microbiol Infect Dis (2003) 46:227–31.[CrossRef][Web of Science][Medline]

5 . Morace G, Polonelli L, for the GISIA group. Voriconazole activity against clinical yeast isolates: a multicentre Italian study. Int J Antimicrob Agent (2006) 26:247–53.

6 . Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743872) and LY-303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol (1998) 36:2950–6.[Abstract/Free Full Text]

7 . Sabatelli F, Patel R, Mann PA, et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole and amphotericin B against a large collection of clinically important moulds and yeasts. Antimicrob Agents Chemother (2006) 50:2009–15.[Abstract/Free Full Text]

8 . Chau AS, Chen G, McNicholas PM, et al. Molecular basis for the enhanced activity of posaconazole against Absidia corymbifera and Rhizopus oryzae. Antimicrob Agents Chemother (2006) 50:3917–9.[Abstract/Free Full Text]

9 . Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis (2007) 44:2–12.[CrossRef][Web of Science][Medline]

10 . van Burik JH, Hare RS, Solomon HF, et al. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis (2006) 42:e61–5.[CrossRef][Web of Science][Medline]

11 . Espinel-Ingroff A, Fothergill A, Peter J, et al. Testing conditions for determination of minimum fungicidal concentrations of new and established antifungal agents for Aspergillus spp.: NCCLS collaborative study. J Clin Microbiol (2002) 40:3204–8.[Abstract/Free Full Text]

12 . Perfect JR, Cox GM, Dodge RK, et al. In vitro and in vivo efficacies of the azole SCH56592 against Cryptococcus neoformans. Antimicrob Agents Chemother (1996) 40:1910–3.[Abstract]

13 . Barchiesi F, Arzeni D, Camiletti V, et al. In vitro activity of posaconazole against clinical isolates of dermatophytes. J Clin Microbiol (2001) 39:4208–9.[Abstract/Free Full Text]

14 . Majoros L, Kardos G, Belák Á, et al. Restriction enzyme analysis of ribosomal DNA shows that Candida inconspicua clinical isolates can be misidentified as Candida norvegensis with traditional diagnostic procedures. J Clin Microbiol (2003) 41:5250–3.[Abstract/Free Full Text]

15 . Tavanti A, Davidson AD, Gow NAR, et al. Candida orthopsilosis and Candida metapsilosis spp. nov. to replace Candida parapsilosis groups II and III. J Clin Microbiol (2005) 43:284–92.[Abstract/Free Full Text]

16 . National Committee for Clinical Laboratory Standards. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts—Second Edition: Approved Standard M27-A2 (2002) Wayne, PA, USA: NCCLS.

17 . Sóczó G, Kardos G, McNicholas PM, et al. Posaconazole susceptibility testing against Candida species: comparison of broth microdilution and Etest methods. Mycoses (2007) 50:178–82.[CrossRef][Web of Science][Medline]

18 . Klepser ME, Ernst EJ, Lewis RE, et al. Influence of test conditions on antifungal time–kill curve results: proposal for standardized methods. Antimicrob Agents Chemother (1998) 42:1207–12.[Abstract/Free Full Text]

19 . Manavathu EK, Cutright JL, Loebenberg D, et al. A comparative study of the in vitro susceptibilities of clinical and laboratory-selected resistant isolates of Aspergillus spp. to amphotericin B, itraconazole, voriconazole and posaconazole (SCH 56592). J Antimicrob Chemother (2000) 46:229–34.[Abstract/Free Full Text]

20 . de Wet N, Llanos-Cuentas A, Suleiman J, et al. A randomized, double-blind, parallel-group, dose–response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients. Clin Infect Dis (2004) 39:842–9.[CrossRef][Web of Science][Medline]

21 . Krause DS, Simjee AE, van Rensburg C, et al. A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis. Clin Infect Dis (2004) 39:770–5.[CrossRef][Web of Science][Medline]

22 . Skiest DJ, Vazquez JA, Anstead GM, et al. Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection. Clin Infect Dis (2007) 44:607–14.[CrossRef][Web of Science][Medline]


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