Correlation of in Vitro Susceptibility Test Results with in Vivo Response: Flucytosine Therapy in a Systemic Candidiasis Model

Stiller, Robert L.; Bennett, John E.; Scholer, H. J.; Wall, Michael; Polak, Annemarie; Stevens, David A.

doi:10.1093/infdis/147.6.1070

Cited by 91 publications

(50 citation statements)

References 11 publications

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“…That a consistent rank order of susceptibility might exist for yeasts has been suggested in previous reports (3,4,8,12). Unfortunately, in some of those studies identical results were produced by many isolates, and in others values were beyond the highest or lowest drug dilutions tested.…”

supporting

confidence: 66%

Comparison of relative susceptibilities of Candida species to three antifungal agents as determined by unstandardized methods

Galgiani

Reiser

Brass

et al. 1987

Antimicrob Agents Chemother

104

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Three groups of isolates, each comprising four isolates of Candida species, were selected for their diversity of susceptibilities to amphotericin B, flucytosine, or ketoconazole. The isolates were distributed in duplicate and in blinded fashion to three laboratories where a total of eight procedures were performed for each drug. From the decoded results, intralaboratory variability among replicate determinations was found usually to fall within a fourfold range. Interlaboratory variation, however, was 16-fold or greater for all isolates, ranging to 50,000-fold differences for some isolates. Relative susceptibilities of isolates within each method could be determined in 11 of the 24 drug-method combinations and agreed with the reference rank order in all but one instance. Our findings underscore the lack of agreement among laboratories for the susceptibility testing of yeasts but indicate that such differences could likely be resolved by standardization without loss of clinical value.Susceptibility testing of fungi, including yeasts such as Candida species, is unstandardized. Numerous broth and agar dilution methods and the application of these methods in specific laboratories under differing test conditions may produce significantly divergent test results (7). Little information has been published concerning differences in results produced by broth and agar dilution procedures. However, a recent interlaboratory comparison testing the reproducibility of a single broth dilution method found an unacceptable discordance of results (3). This lack of agreement undermines the interpretation of in vitro results and raises the question of which method correlates best with the results of treatment.It is possible for the susceptibility of an isolate, relative to others, to be similar even when there exist wide differences in endpoint results when tested under different conditions. That a consistent rank order of susceptibility might exist for yeasts has been suggested in previous reports (3,4,8,12). Unfortunately, in some of those studies identical results were produced by many isolates, and in others values were beyond the highest or lowest drug dilutions tested. Both circumstances restricted detailed determination of rank order. However, if relative sensitivities were constant, even by widely diverse methodology, then each method could be expected to produce equivalent correlations with clinical responses, and the standardization process would thus be significantly simplified.

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supporting

confidence: 66%

Comparison of relative susceptibilities of Candida species to three antifungal agents as determined by unstandardized methods

Galgiani

Reiser

Brass

et al. 1987

Antimicrob Agents Chemother

104

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“…Animal infection models have documented the efficacy of 5FC alone and in combination with other systemically active antifungal agents against various Candida spp. (4,16,27), and several studies have demonstrated concordance between in vitro susceptibility and in vivo endpoints (1,30,35). Recent in vitro pharmacodynamic studies have determined that 5FC exhibits concentration-independent fungistatic activity against Candida spp.…”

Section: Resultsmentioning

confidence: 89%

“…Although not used as monotherapy, 5FC may be a useful adjunct to amphotericin B or azoles in the treatment of hematogenous candidiasis (11,29,38). Despite a general consensus regarding the clinical efficacy of 5FC when used in combination with amphotericin B (11), clinicians are often hesitant to use 5FC due to concerns about toxicity (13,39) and either primary or secondary resistance (8,22,34,35,39). Although primary resistance to 5FC is stated to occur among 10 to 15% of Candida albicans isolates and even higher among other Candida species (31), there is very little recent data explicitly addressing this issue by using the standardized National Committee for Clinical Laboratory Standards (NCCLS) antifungal susceptibility testing method (24) against a large geographically diverse collection of contemporary clinical isolates of Candida spp.…”

mentioning

confidence: 99%

In Vitro Activities of 5-Fluorocytosine against 8,803 Clinical Isolates of Candida spp.: Global Assessment of Primary Resistance Using National Committee for Clinical Laboratory Standards Susceptibility Testing Methods

Pfaller¹,

Messer²,

Boyken³

et al. 2002

Antimicrob Agents Chemother

116

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MICs were determined by broth microdilution tests performed according to NCCLS guidelines by using RPMI 1640 as the test medium and the following interpretive breakpoints: susceptible (S), <4 g/ml; intermediate (I), 8 to 16 g/ml; resistant (R), >32 g/ml. 5FC was very active against the 8,803 Candida isolates (MIC 90 , 1 g/ml), 95% S. A total of 99 to 100% of C. glabrata (MIC 90 , 0.12 g/ml), C. parapsilosis (MIC 90 , 0.25 g/ml), C. dubliniensis (MIC 90 , 0.12 g/ml), C. guilliermondii (MIC 90 , 0.5 g/ml), and C. kefyr (MIC 90 , 1 g/ml) were susceptible to 5FC at the NCCLS breakpoint. C. albicans (MIC 90 , 1 g/ml; 97% S) and C. tropicalis (MIC 90 , 1 g/ml; 92% S) were only slightly less susceptible. In contrast, C. krusei was the least susceptible species: 5% S; MIC 90 , 32 g/ml. Primary resistance to 5FC is very uncommon among Candida spp. (95% S, 2% I, and 3% R), with the exception of C. krusei (5% S, 67% I, and 28% R). The in vitro activity of 5FC, combined with previous data demonstrating a prolonged post-antifungal effect (2.5 to 4 h) and concentration-independent activity (optimized at 4؋ MIC), suggest that 5FC could be used in lower doses to reduce host toxicity while maintaining antifungal efficacy.

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“…Although not used as monotherapy, 5FC may be a useful adjunct to other systemically active antifungal agents in the treatment of hematogenous candidiasis (68, 189, 293). Despite a general consensus regarding the clinical efficacy of 5FC when used in combination with other agents (68), clinicians are often hesitant to use this antifungal agent due to concerns about toxicity (78,297) and either primary or secondary resistance (155,280,281,297). The older literature has stated that primary resistance to 5FC occurred among 10% to 15% of C. albicans isolates and was even higher among other species (265,280).…”

Section: Trends In Antifungal Susceptibility In Relation To Time Geomentioning

confidence: 99%

Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem

2007

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SUMMARY Invasive candidiasis (IC) is a leading cause of mycosis-associated mortality in the United States. We examined data from the National Center for Health Statistics and reviewed recent literature in order to update the epidemiology of IC. IC-associated mortality has remained stable, at approximately 0.4 deaths per 100,000 population, since 1997, while mortality associated with invasive aspergillosis has continued to decline. Candida albicans remains the predominant cause of IC, accounting for over half of all cases, but Candida glabrata has emerged as the second most common cause of IC in the United States, and several less common Candida species may be emerging, some of which can exhibit resistance to triazoles and/or amphotericin B. Crude and attributable rates of mortality due to IC remain unacceptably high and unchanged for the past 2 decades. Nonpharmacologic preventive strategies should be emphasized, including hand hygiene; appropriate use, placement, and care of central venous catheters; and prudent use of antimicrobial therapy. Given that delays in appropriate antifungal therapy are associated with increased mortality, improved use of early empirical, preemptive, and prophylactic therapies should also help reduce IC-associated mortality. Several studies have now identified important variables that can be used to predict risk of IC and to help guide preventive strategies such as antifungal prophylaxis and early empirical therapy. However, improved non-culture-based diagnostics are needed to expand the potential for preemptive (or early directed) therapy. Further research to improve diagnostic, preventive, and therapeutic strategies is necessary to reduce the considerable morbidity and mortality associated with IC.

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Correlation of in Vitro Susceptibility Test Results with in Vivo Response: Flucytosine Therapy in a Systemic Candidiasis Model

Cited by 91 publications

References 11 publications

Comparison of relative susceptibilities of Candida species to three antifungal agents as determined by unstandardized methods

Comparison of relative susceptibilities of Candida species to three antifungal agents as determined by unstandardized methods

In Vitro Activities of 5-Fluorocytosine against 8,803 Clinical Isolates of Candida spp.: Global Assessment of Primary Resistance Using National Committee for Clinical Laboratory Standards Susceptibility Testing Methods

Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem

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