International Journal of Antimicrobial Agents 26 (2005) 247–253 Voriconazole activity against clinical yeast isolates: a Istituto di Microbiologia, Universit`a degli Studi di Milano, Via C. Pascal, 36 – 20133 Milan, Italy b Dipartimento di Patologia e Medicina di Laboratorio, Sezione di Microbiologia, Universit`a degli Studi di Parma, Parma, Italy Received 16 March 2005; accepted 3 June 2005 Abstract
The activity of voriconazole was tested in vitro against 1996 clinical yeast isolates collected in 20 Italian microbiology laboratories.
Voriconazole susceptibility testing was carried out with the broth microdilution (NCCLS M27-A2), Etest and disk diffusion methods. Theminimum inhibitory concentrations at which 90% of the isolates were inhibited (MIC90) obtained with the NCCLS method were 0.03 mg/Lfor Candida albicans, 0.5 mg/L for Candida non-albicans and 0.25 mg/L for other genera; those obtained with Etesting were, respectively,0.032 mg/L, 0.125 mg/L and 0.125 mg/L. With the disk diffusion method, the majority of isolates (92.3%) showed inhibition zone diametersbetween 21 mm and 40 mm. Using a tentative MIC cut-off of 1 mg/L as indicative of in vitro susceptibility, 98.1% of the isolates tested in ourstudy would be classified as susceptible, and only 28 (1.4%) of the isolates, with MICs higher than 2 mg/L, would be classified as resistant tothe drug. Our findings confirm the broad-spectrum in vitro activity of voriconazole against yeasts, including Candida species that are generallyless susceptible to other azoles.
2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Keywords: Voriconazole; Yeast susceptibility testing; Comparative methods 1. Introduction
fungal drugs, and for this reason therapy must be tailoredto the susceptibility characteristics of the infecting agent.
Since the early 1990s, mortality rates related to candidi- Non-albicans species are increasingly frequent causes of can- asis among non-HIV-infected subjects have been declining, didemia, and these infections are generally associated with although the rates of nosocomial Candida infections, espe- higher mortality rates than those for other types of candidemia cially bloodstream infections, are still on the rise is particularly true for bloodstream infections caused The current frequency of systemic Candida infections is by Candida krusei, which is innately resistant to flucona- the result of various factors such as the growing number of zole, or Candida glabrata, which currently ranks third or patients with impaired immunity (caused by HIV infection, fourth on the list of species most commonly isolated from neutropenia provoked by antineoplastic therapy, or immuno- blood cultures. The increasing incidence of C. glabrata can- suppressive therapy related to organ transplantation) and the didemia has been related to the widespread use of antifungal many advances in modern medicine The symptoms of systemic Candida infections are similar, but the species are well documented, particularly in the United States, while that cause them differ markedly in their responses to anti- resistance to amphotericin B seems to be more common inEurope This epidemiological scenario has prompted the pharma- Corresponding author. Tel.: +39 02 5031 5065; fax: +39 02 5031 5070.
E-mail address: (G. Morace).
ceutical industry to develop new drugs with a broad spectrum 1 Italian Group for In Vitro Study of Antifungals (see of action against yeasts and filamentous fungi. Most of these 0924-8579/$ – see front matter 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
doi:10.1016/j.ijantimicag.2005.06.005 G. Morace, L. Polonelli / International Journal of Antimicrobial Agents 26 (2005) 247–253 agents are triazoles or members of the new echinocandin class of antifungals. They represent potential therapeutic tools that Species distribution of yeasts isolated in the GISIA 2 study may be used as a valid alternative to other well established antifungal drugs in the incidence of species responsible for candidiasis and the introduction of new drugs to combat these infections has heightened interest in in vitro antifungal susceptibility testing, which can provide valu- able guidance in the clinical management of these infections Voriconazole, a new triazole derived from fluconazole, has been shown to display a broad spectrum of activity against yeasts It has been approved for primary treatment of aspergillosis and for salvage therapy in cases of seri- ous infections caused by unusual moulds. More recently, voriconazole has also been approved for the treatment of severe yeast infections. In light of the strong scientific inter- est in this molecule, we conducted a multicentre study to evaluate the in vitro voriconazole sensitivity of clinical yeast isolates recovered in 20 microbiology laboratories located in a C. intermedia, C. lambica, C. norvegensis, C. rugosa, Candida spp., different parts of Italy. Each participating laboratory provided Rhodotorula glutinis and R. rubra (two isolates of each); C. colliculosa, ca. 100 fresh clinical yeast isolates (Candida spp., Cryptococ- C. zeylanoides, Cryptococcus albidus, Geotrichum penicillatum, Hansenula cus neoformans, Saccharomyces cerevisiae and Trichosporon anomala, Pichia carsonii, P. ohmeri and Trichosporon inkin (one isolate of spp.) recovered from hospitalised patients with normal or impaired immunity, or from immunocompromised patientsbeing followed in outpatient settings. Each isolate was sub- The isolates were identified by standard procedures jected to in vitro voriconazole susceptibility testing using the i.e. morphology on cornmeal agar plates, germ tube produc- broth microdilution method recommended by the National tion in serum, and biochemical analysis with the Vitek sys- Committee for Clinical Laboratory Standards (NCCLS; now tem, API 20CAUX or ATB 32C panels (Bio-Merieux, Rome, Clinical and Laboratory Standards Institute) the Etest Italy). Prior to susceptibility testing (described below), each isolate was subcultured at least twice on Sabouraud DextroseAgar to ensure viability, purity and optimal growth character-istics. After testing, each isolate was frozen at −70 ◦C. Tested 2. Materials and methods
isolates were periodically transferred to one of the studygroup’s two co-ordinating centres, where they were stored under appropriate conditions until the study was completedand statistical analysis was performed. After all isolates had The study was conducted on a total of 1996 yeast iso- been assayed (initial testing, Phase 1), each centre re-tested lates (1120 (56%) C. albicans, 801 (40%) C. non-albicans each of its isolates (repeat testing, Phase 2) and the results and 75 (4%) other genera) which had been col- were compared to evaluate the intralaboratory reproducibility lected in participating laboratories between November 2001 and June 2002. Each participating laboratory provided ca.
100 isolates, freshly and consecutively isolated from clinicalspecimens (primarily blood, genitourinary tract and respi- ratory tract specimens) collected from inpatients (with orwithout impaired immunity) or outpatients (only those with immune impairment). Isolates recovered from immunocom- After overnight growth on Sabouraud Dextrose Agar at promised patients (transplant patients, neutropenic patients, 35 ◦C, each isolate was suspended in 5 mL of sterile distilled AIDS and Intensive Care Unit patients at risk for fungal infec- water and thoroughly vortexed to achieve a smooth suspen- tions) could account for no more than 60% of the total number sion. Turbidity (at a wavelength of 530 nm) was adjusted of isolates collected by a given centre, and at least 40% of to a 0.5 McFarland standard with water. This suspension the collected isolates had to be species other than C. albi- (ca. 1 × 106 to 5 × 106 colony-forming units/mL) was used cans. This choice was made because voriconazole could be for susceptibility testing with the Etest and disk diffusion considered a valid therapeutic alternative against yeasts dis- methods. For assays performed using the broth microdilu- playing a reduced susceptibility to fluconazole. However, all tion method (NCCLS reference method), the suspension was isolates collected from blood cultures were included in the used after appropriate dilution according to the standardised G. Morace, L. Polonelli / International Journal of Antimicrobial Agents 26 (2005) 247–253 2.2.2. Voriconazole susceptibility testing methods also subjected to parallel Etesting on Casitone agar plates The products and materials used by the 20 participat- (Biolife Italiana srl, Milan, Italy). Both types of plates were ing laboratories came from identical lots. Each laboratory used by the participating laboratories within the expiration was equipped with the following instruments: a spectropho- date indicated by the suppliers (on average, 3 months after tometer for measuring inoculum turbidity (McFarland stan- the date of receipt by the laboratory).
dards from 0.5 to 1); a second spectrophotometer for reading The plates were inoculated with undiluted inoculum sus- microtitre plates at a wavelength of 540 nm; and mirror read- pension (0.5 McFarland) using sterile non-toxic cotton swabs ers for visual readings of microtitre plates.
that had been rolled against the side of the tube to remove theexcess suspension. The surface of the plate was streaked in at NCCLS reference method. Ninety-six-well micro- least three different directions with the side of the swab. Once titre panels were prepared by one of the co-ordinating cen- the inoculum had been absorbed, an Etest strip was applied to tres in accordance with NCCLS standards packed in each plate and pressed lightly to ensure good contact with the dry ice. Within 24 h of preparation the plates were delivered agar. The plates were then incubated at 35 ◦C and read after to participating laboratories where they were suitably stored 24 h and 48 h. The drug concentration shown on the Etest at −70 ◦C and were used for testing within 6 months of the strip at the outer border of the elliptical inhibition halo was preparation date. Each panel allowed simultaneous in vitro recorded as the MIC. The growth of microcolonies within voriconazole susceptibility testing of eight yeast isolates.
this inhibition zone was disregarded.
The wells contained voriconazole (Pfizer Pharmaceuticals,Groton, CT) dissolved in dimethylsulphoxide (DMSO) and Disk diffusion test. Voriconazole disks (1 ␮g) were diluted in RPMI 1640 medium buffered with morpholino- supplied by Becton Dickinson (Franklin Lakes, NJ) and propansulphonic acid (MOPS) 0.165 M and supplemented assays were performed with the experimental method with 2% glucose panel contained 11 scalar concen- of Kirby–Bauer The test entailed preparation of trations of voriconazole ranging from 0.015 mg/L to 16 mg/L.
Mueller–Hinton agar plates containing 2% glucose and For each isolate, the inoculum suspension was diluted 5 mg/L methylene blue (Eurolab SNC), which were sent to twice with RPMI 1640 medium (1:50 and then 1:20).
each participating centre and were used within the spec- Aliquots (0.1 mL) of the latter dilution were then placed in the ified expiration data (4–5 months after preparation). The 12 wells of a single row (11 wells containing voriconazole and plates were inoculated as described for the Etest assays. Once the 12th used for evaluation of control growth) and the sealed the inoculum had been absorbed, a voriconazole disk was plates were incubated at 35 ◦C. An initial visual reading was applied to the surface of the agar and pressed lightly to ensure made after 24 h of incubation, and the lowest voriconazole good contact. The plates were incubated at 35 ◦C. After 24 h concentration that had inhibited visible growth was recorded and 48 h, the diameters of the inhibition zones were mea- as the minimum inhibitory concentration (MIC). After 48 h of sured in millimetres from the points where growth abruptly incubation, the panels were analysed spectrophotometrically (after shaking) and the MIC was recorded as the voricona-zole concentration that produced a 50% reduction in turbidity Quality control yeasts. Three quality control strains compared with that of the control well growth (MIC50).
were included in each daily assay session: C. krusei ATCC® Minimum fungicidal concentrations (MFCs) were also 6258 (tentative voriconazole MIC range for the NCCLS ref- determined for each isolate. For this analysis, the contents erence method, 0.25–1.0 mg/L; voriconazole MIC range for of all wells were subcultured on Sabouraud agar plates with Etesting declared by the manufacturer, 0.125–0.5 mg/L; ten- voriconazole concentrations greater than or equal to that of tative range for inhibition zone diameters in disk diffusion the MIC. In most cases the subculture was done with 0.01 mL testing, 16–25 mm); Candida parapsilosis ATCC® 22019 of the well content; in some cases the entire content of the (tentative voriconazole MIC range for the NCCLS refer- well (0.2 mL) was used. Subcultures were read after 24 h of ence method, 0.03–0.25 mg/L; voriconazole MIC range for incubation at 37 ◦C and the lowest voriconazole concentra- Etesting declared by the manufacturer, 0.016–0.125 mg/L; tion that had inhibited all visible growth at all was recorded tentative range for inhibition zone diameters in disk diffusion testing, 28–37 mm); and C. albicans ATCC® 90028 (tentativevoriconazole MIC range for the NCCLS reference method, Etest. Etest strips containing a continuous gradient unavailable; voriconazole MIC range for Etesting declared by of voriconazole (range, 0.002–32 mg/L) were sent directly the manufacturer, 0.008–0.032 mg/L; tentative range for inhi- to participating centres by the manufacturer (AB BIODISK, bition zone diameters in disk diffusion testing, 31–42 mm) Solna, Sweden) and used for testing within the declared expi- ration date (on average, almost 24 months after the date ofreceipt). All Phase 1 and Phase 2 Etest assays were performed with RPMI agar (RPG plates containing RPMI 1640, MOPSand 2% of glucose; Eurolab SNC, Avezzano, Italy), as rec- Complete data for each yeast isolate tested were recorded ommended by the manufacturer. In Phase 2, each isolate was on a Paper Data Report Form and an Electronic Data Report G. Morace, L. Polonelli / International Journal of Antimicrobial Agents 26 (2005) 247–253 Form (E-DRF) by the investigator. The E-DRF was supplied and the very elderly) represented 65.5% of the 1546 subjects as a portable document format (.pdf) file to be completed by from whom complete sets of clinical background data were the investigator using Adobe Acrobat 4.0 software. The form contained an ‘Enter’ key that could be clicked with the mouse The majority of the isolates were susceptible to voricona- to E-mail the completed form to the Central Data Manage- zole, with minimum inhibitory concentrations at which 90% ment Unit. Before being sent, the E-DRF was automatically of the isolates were inhibited (MIC90) of 0.25 mg/L using checked by an electronic validation program to verify the NCCLS reference method testing and 0.125 mg/L using consistency of data. If the E-DRF passed this check, it was Etesting; 92.2% of the isolates displayed inhibition zone automatically saved, printed and sent to the Data Manage- diameters between 21 mm and 40 mm with the disk diffu- ment Unit; otherwise the user was prompted to make the sion method. As shown in slight differences were appropriate corrections. The printed copy of the E-DRF was observed among the three broad species categories exam- signed by the investigator and filed on site. Using the same ined: C. albicans, C. non-albicans and the other genera of automated procedure, the Data Management Unit then for- yeasts. The MFC90 was greater than 8 mg/L, which indicates warded a copy of the E-DRF to the co-ordinating centre that the activity of voriconazole against yeasts is predom- responsible for the laboratory in which the isolates had been inantly fungistatic. The same MFC90 emerged when assays were carried out on the total content of the investigated wells.
In accordance with the manufacturers’ instructions, the The highest MIC90 values were recorded for C. glabrata, results of the first readings (24 h) of Etest and disk diffu- C. krusei and C. tropicalis isolates (0.5 mg/L with the refer- sion results were used in the analyses unless these readings ence method). For C. tropicalis isolates, the reference method showed no growth. In this case, the second reading (48 h) results were discordant with those obtained with Etesting was used. For the NCCLS reference method, results from the (MIC90 of 0.047 mg/L). This difference did not reflect diffi- second reading were used, as recommended in the M27-A2 culty in reading the 48 h end-point for the reference method, document. Yeast susceptibility data reported below are based because only seven isolates showed a MIC value greater than exclusively on Phase 2 test results.
three-fold the MIC value obtained at 24 h visual reading. Ingeneral, the disk diffusion results showed good correlationwith those of the reference method: small diameter inhi- 3. Results
bition zones were observed for all of the isolates with thehighest MIC values. Only 12 isolates with MIC values less A total of 1996 yeast clinical isolates were collected dur- than 0.5 mg/L showed inhibition diameters less than 14 mm, ing the study period (Other than C. albicans, the whilst an inhibition diameter greater than 25 mm was dis- most common species was C. glabrata (15.5%), followed played by two isolates with MIC values greater than 2 mg/L.
by Candida tropicalis (7.5%), C. parapsilosis (7.4%) and C. No significant differences were observed when the results krusei (3.2%). Among the other genera of yeasts, S. cere- were analysed with regard to the types of clinical sample from visiae accounted for 1.7% of all isolates and C. neoformans which the isolates had been recovered. As shown in for 1.1%. Most of our isolates had been recovered from the majority of the isolates were collected from blood, urine lower respiratory tract specimens (48.6%), urine (14.5%) or or lower respiratory tract specimens, and for most species, blood (11.3%). Patients with impaired immunity (all causes, the MIC90 values and inhibition zone diameters recorded for including exclusively age-related impairments in newborns specimen-based subgroups were similar or identical to those Table 2In vitro voriconazole susceptibility, as determined by the reference broth microdilution, Etest and disk diffusion methods MIC, minimum inhibitory concentration.
G. Morace, L. Polonelli / International Journal of Antimicrobial Agents 26 (2005) 247–253 Table 3Voriconazole susceptibility results for the most commonly isolated yeast species grouped according to isolation site (blood, urine and lower respiratory tract) Species (no. of isolates) recovered from: MIC, minimum inhibitory concentration.
reported for the species as a whole (The only excep- discordant results with disk diffusion testing. The low con- tion was C. glabrata, where isolates derived from blood and cordance characterising Etest reproducibility involved 246 urine had MIC90 values that were considerably higher than C. albicans and 10 C. tropicalis isolates, which presented a those observed for C. glabrata isolates in general.
MIC greater than 32 mg/L in Phase 1 and a MIC ≤ 1 mg/L in For the most common species studied, MIC90 values based on Etesting with RPMI versus Casitone agar were: C.
0.03 versus 0.047 mg/L; C. tropicalis 0.047 versus 4. Discussion
0.094 mg/L; C. parapsilosis 0.016 versus 0.032 mg/L; Can-dida lusitaniae 0.008 versus 0.012 mg/L; C. glabrata 0.125 In assays performed with the NCCLS broth microdilu- versus 0.125 mg/L (only 263 of the 309 isolates of this species tion method, voriconazole displayed high activity against the displayed visible growth on Casitone agar after 48 h of incu- majority of our yeast isolates (MIC90, 0.25 mg/L). Fewer than bation); C. krusei 0.25 versus 0.25 mg/L (only 9 of 63 grew on 20% of the isolates presented MFCs that were equal to or no Casitone agar); S. cerevisiae 0.094 versus 2 mg/L (over 60% more than two concentrations higher than the corresponding of the isolates showed no growth in Casitone agar); and C. MICs, indicating that voriconazole action was predominantly neoformans 0.047 versus 0.047 mg/L (only 16 isolates grew fungistatic. Interestingly enough, this percentage was close to 50% for three species: C. krusei, C. lusitaniae and S. cere- With a few exceptions, the daily results reported for the three quality control strains (C. albicans ATCC® 90028, C. Etest results obtained with both types of growth medium krusei ATCC® 6258 and C. parapsilosis ATCC® 22019) were (RPMI and Casitone agar) were comparable with those pro- all within expected limits. Comparison of results obtained in duced by the NCCLS method, although the MIC90 values Phase 1 (initial testing) and Phase 2 (repeat testing) assays for the most common Candida non-albicans species were revealed a good level of intralaboratory reproducibility for the lower (These results probably reflect characteris- NCCLS method. Low concordance rates were found in a few tics of the single species, as well as those of the growth centres and were probably related to the fact that this method medium used. Casitone agar, for example, does not allow is not used routinely in these laboratories. Much wider vari- optimal growth of C. krusei, C. glabrata, C. neoformans or ability was observed with Etesting, but there were no cases of S. cerevisiae. In addition, there could be problems related to G. Morace, L. Polonelli / International Journal of Antimicrobial Agents 26 (2005) 247–253 Casitone interbatch variation. Etest results were also compli- ble to the drug. Only 28 (1.4%) of the isolates had MICs cated to read: interpretation of the results is highly subjective higher than 2 mg/L. The susceptibility of these isolates to and highly dependent on the experience of the examiner. As other antifungal drugs (amphotericin B, fluconazole, itra- noted above, some important and potentially pathogenic yeast conazole, ketoconazole and flucytosine) was evaluated with species grow poorly on Casitone agar, but for C. albicans the Sensititre method: cross-resistance to other azoles was and C. tropicalis this medium facilitates Etest MIC read- identified in 17 isolates of C. glabrata, as noted in one of ing (especially for staff members who are unfamiliar with our previous reports and in 6 isolates of C. albicans this method) by eliminating the problem of double inhibition and 5 of C. tropicalis. The majority of these isolates were halos. Indeed, for 24 isolates of C. albicans with reference derived from blood or urine, thus confirming the need of per- method MICs of less than 1 mg/L, Casitone Etest MICs forming antifungal susceptibility testing only on clinically also fell within this range, whereas RPMI Etest MICs were significant isolates to help physicians in their therapeutic In disk diffusion testing, the largest voriconazole inhi- In conclusion, the efficacy of voriconazole was confirmed bition zones were observed with C. lusitaniae isolates, by the results of the reference method, as well as those which are known for their resistance to amphotericin B.
of the Etest and the disk diffusion tests. All methods indi- The voriconazole MICs for this species in both NCCLS cated that the majority of the isolates were susceptible to and Etesting were also the lowest observed in this study.
the drug. In addition, our findings indicate that the Etest As previously noted with fluconazole disk diffusion testing and disk diffusion methods are suitable commercial tests voriconazole inhibition zones for C. glabrata isolates for antifungal sensitivity evaluation of yeasts in clinical were much smaller than the average observed for all other species (The same phenomenon was observed whenvoriconazole was tested against C. krusei. These observationsshould be kept in mind during any evaluation of regression Acknowledgments
Analysis of the results of quality control testing for each This study was made possible by the financial support of of the three methods showed that most centres recorded Pfizer Italia, srl. We thank Massimiliano Borelli from Dimen- results within the expected ranges during each work ses- sione Ricerca for statistical analysis, and Marian Kent for sion. Some centres, however, reported reading difficulties, particularly with the Etest (performed both with RPMI andCasitone agar plates), reflecting the subjectivity of the read-ing method. Out-of-range Etest results were common for Appendix A. The GISIA Group
C. parapsilosis with both growth media, for C. krusei inassays performed with RPMI, and for C. albicans tested on G. Amato, M. Piccirillo, C.M.C. Belli (Ospedale Car- darelli, Naples); S. Andreoni, R. Fanello (Ospedale Maggiore On the whole, the MIC values that emerged from our study della Carit`a, Novara); P. Barbaro, C. Petraroli (Ospedale were very low, indicating that voriconazole should be active Morelli, Reggio Calabria); F. Bistoni, A. Mencacci, L.
against a high percentage of yeast isolates and species, includ- Pitzurra (Universit`a degli Studi, Perugia); P. Cione, S.
ing those with innately low susceptibility to other triazoles.
Cuccurullo (Ospedale Monaldi, Naples); G. Fadda, M.
The highest MIC90 values were seen for C. glabrata, C. kru- Sanguinetti (Universit`a Cattolica del Sacro Cuore, Rome); sei and C. tropicalis isolates, whilst the lowest were those R. Fontana, G. Lo Cascio (Universit`a degli Studi, Verona); recorded for C. albicans, C. parapsilosis and C. lusitaniae. A. Goglio, C. Farina (Ospedali Riuniti, Bergamo); G. Lom- These findings are consistent with MIC values observed in bardi, A. Col`ı (Ospedale del Circolo, Varese); E. Manso, previous studies In general, results obtained C. Paladini (Ospedale Le Torrette, Ancona); P. Marone, C.
with the two commercial assay methods were similar to those Cavanna (Ospedale S. Matteo, Pavia); M. Menozzi, E. Di of the reference method, although some problems emerged Stefano (Ospedale Cervello, Palermo); M.T. Montagna, C.
that can probably be attributed to the fact that some of our Napoli, D. Tat`o (Universit`a degli Studi, Bari); G. Morace, investigators were unfamiliar with the reading criteria used in M. Drago, M.M. Scaltrito (Universit`a degli Studi, Milan); these assays. The results of NCCLS reference method assays A. Nanetti (Ospedale S. Orsola, Bologna); P.L. Nicoletti, P.
clearly showed that the activity of voriconazole against yeasts Pecile (Ospedale Careggi, Florence); S. Oliveri, G. Buscema (Universit`a degli Studi, Catania); L. Polonelli, S. Conti, F.
Clinical studies aimed at establishing definitive break- Fanti (Universit`a degli Studi, Parma); R. Rigoli, M. Niero points for voriconazole susceptibility are nearing completion.
(Ospedale Ca’ Foncello, Treviso); M. Sanna, R. Podda, P.P.
In the meantime, for comparison purposes, some studies have Porcu (Ospedale Oncologico Businco, Cagliari); G.C. Schito, used a tentative MIC cut-off of 1 mg/L as indicative of in vitro O. Soro (Universit`a degli Studi, Genoa); M.A. Viviani, A.M.
susceptibility Using this breakpoint, 98.1% of the Tortorano (Universit`a degli Studi, Milan); S. La Face, I.
isolates tested in our study would be classified as suscepti- Mancuso (Direzione Medica, Pfizer Italia, Rome).
G. Morace, L. Polonelli / International Journal of Antimicrobial Agents 26 (2005) 247–253 References
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Die Heilige Messe zelebriert Rektor Prälat Dr. Ernst Pucher. Alessandro Poglietti (17. Jhdt.): Toccata Rossignolo singen die Wiener Sängerknaben unter der Leitung von Bomi Kim Maria durch ein Dornwald ging, eventuell auch Es wird scho glei dumpa Antonio Caldara (um 1670-1736) Missa in A-Dur Unter Kaiser Karl VI. (1685-1740) erreichte die Musik in Österreich zweifellos einen Höhepu

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2 Day Nuclear Stress Test Stress Day : Date: Rest Day : Date: OVERVIEW The nuclear stress test is a TWO-DAY diagnostic test. An IV or injection will be placed in your arm or hand to allow a radioactive tracer to help image your heart. This helps to determine if your heart is receiving adequate blood supply. Two sets of images will be taken, one day with your heart under st

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