Therapy For Invasive Candidiasis Research Articles

Candidemia in cancer patients: phenotypical and molecular-genetic characteristics of antifungal drug resistance, pathogenic factor genes of Candida spp.

Relevance. The global trend of rapid increase in resistance to antifungal drugs due to multiple factors, dictates the need for continuous monitoring of taxonomic structure and susceptibility of nosocomial pathogens, causing invasive fungal infections, for permanent correction of the optimal prevention and treatment strategies. Purpose: to determine antifungal susceptibility of the main yeast pathogens in candidemia in cancer patients, as well as to determine resistance genes and pathogenic factor genes. Material and Methods. Eighty-two strains of Candida spp. isolated from blood of cancer patients from 2015 to 2021 were analyzed. Minimum inhibitory concentrations of fuconazole, voriconazole, posaconazole, anidulafungin and micafungin were determined by a gradient method (E-test, BioMerieux, France). The EUCAST and CLSI criteria were used for MIC value assessment. The genes, associated with pathogenicity factors, and resistance to antifungal drugs were identifed. Results. Our study results based on EUCAST 2020, v.10.0 criteria showed that triazoles, especially fuconazole, were the least effective drugs in empirical therapy for invasive candidiasis (including candidemia). Resistance of Candida spp. fuconazole was superior to that of voriconazole (47.2 % vs 23.2 %, respectively, p<0.01) and posaconazole (47.2 % vs 30.4 %, respectively, p><0.05). The highest in vitro activity was observed in echinocandins, and anidulafungin was 2 times more active than micafungin (4.1 % of resistant strains vs 11.4 %, respectively), with no statistically signifcant difference (p>0.05). The ERG11 and FKS1 genes associated with resistance to antifungal drugs were detected in 28.6 % of Candida spp. strains. The ERG11 gene was detected in 8.6 % of cases, exclusively in Candida albicans strains. The FKS1 gene was identifed in 20.0 % of strains (85.7 % of them were C. parapsilosis, 7.1 % each were C. tropicalis and C. glabrata). Pathogenic factor genes were identifed in 78.6 % of C. albicans and in 79.1 % of C. parapsilosis strains. Conclusion. Molecular genetic methods for the detection of Candida spp strains carrying resistance genes to antifungal drugs, and the determination of pathogenicity factors are promising trends in searching for biomarkers. They facilitate interpretation of results of microbiological study to assess the ability of Candida spp. strains to develop invasive mycoses.

Pharmacoeconomic evaluation of micafungin versus caspofungin as definitive therapy for candidaemia and invasive candidiasis (IC) in Turkey

Micafungin was shown to be as efficacious as caspofungin in treating patients with candidaemia and invasive candidiasis (IC). However, it remains unknown if micafungin or caspofungin is a cost-effective definitive therapy for candidaemia and IC in Turkey. The present study aimed to determine the economic impact of using micafungin versus caspofungin for treatment of candidaemia and IC in the Turkish setting. A decision analytic model was constructed and was populated with data (i.e. transition probabilities, duration of initial antifungal treatment, reasons for treatment failure, percentage of patients who stepped down to oral fluconazole, and duration on oral fluconazole) obtained from a published randomised clinical trial. Cost inputs were derived from the latest Turkish resources while data that were not readily available in the literature were estimated by expert panels. One-way sensitivity analyses, threshold analyses, scenario analyses and probabilistic sensitivity analyses were conducted. Caspofungin (€2693) incurred a lower total cost than micafungin (€4422), with a net cost saving of €1729 per treated patient. Drug acquisition cost was the main cost driver for both study arms. The model outcome was robust over wide variations (of ±100.0% from the base case value) for all input parameters except for micafungin drug cost and the duration of initial treatment with micafungin. Caspofungin appears to be a cost-saving option in treating candidaemia and IC from the Turkish hospital perspective.

Potential clinical and economic outcomes of active beta-D-glucan surveillance with preemptive therapy for invasive candidiasis at intensive care units: a decision model analysis.

Early initiation of antifungal treatment for invasive candidiasis is associated with change in mortality. Beta-D-glucan (BDG) is a fungal cell wall component and a serum diagnostic biomarker of fungal infection. Clinical findings suggested an association between reduced invasive candidiasis incidence in intensive care units (ICUs) and BDG-guided preemptive antifungal therapy. We evaluated the potential cost-effectiveness of active BDG surveillance with preemptive antifungal therapy in patients admitted to adult ICUs from the perspective of Hong Kong healthcare providers. A Markov model was designed to simulate the outcomes of active BDG surveillance with preemptive therapy (surveillance group) and no surveillance (standard care group). Candidiasis-associated outcome measures included mortality rate, quality-adjusted life year (QALY) loss, and direct medical cost. Model inputs were derived from the literature. Sensitivity analyses were conducted to evaluate the robustness of model results. In base-case analysis, the surveillance group was more costly (1387 USD versus 664 USD) (1 USD = 7.8 HKD), with lower candidiasis-associated mortality rate (0.653 versus 1.426 per 100 ICU admissions) and QALY loss (0.116 versus 0.254) than the standard care group. The incremental cost per QALY saved by the surveillance group was 5239 USD/QALY. One-way sensitivity analyses found base-case results to be robust to variations of all model inputs. In probabilistic sensitivity analysis, the surveillance group was cost-effective in 50% and 100% of 10,000 Monte Carlo simulations at willingness-to-pay (WTP) thresholds of 7200 USD/QALY and ≥27,800 USD/QALY, respectively. Active BDG surveillance with preemptive therapy appears to be highly cost-effective to reduce the candidiasis-associated mortality rate and save QALYs in the ICU setting.

Training should be the first step toward an antifungal stewardship program

The frequency of use of systemic antifungal agents has increased significantly in most tertiary centers. However, antifungal stewardship has received very little attention. The objective of this article was to assess the knowledge of prescribing physicians in our institution as a first step in the development of an antifungal stewardship program. Attending physicians from the departments that prescribe most antifungals were invited to complete a questionnaire based on current guidelines on diagnosis and therapy of invasive candidiasis and invasive aspergillosis (IA).The survey was completed by 60.8% (200/329) of the physicians who were invited to participate. The physicians belonged to the following departments: medical (60%), pediatric (19%), intensive care (15.5%), and surgical (5.5%). The mean (±SD) score of correct responses was 5.16±1.73. In the case of candidiasis, only 55% of the physicians clearly distinguished between colonization and infection, and 17.5% knew the local rate of fluconazole resistance. Thirty-three percent knew the accepted indications for antifungal prophylaxis, and 23% the indications for empirical therapy. However, most physicians knew which antifungals to choose when starting empirical therapy (73.5%). As for aspergillosis, most physicians (67%) could differentiate between colonization and infection, and 34.5% knew the diagnostic value of galactomannan. The radiological features of IA were well recognized by 64%, but only 31.5% were aware of the first line of treatment for IA, and 36% of the recommended duration of therapy. The usefulness of antifungal levels was known by 67%. This simple, easily completed questionnaire enabled us to identify which areas of our training strategy could be improved.

Invasive candidiasis in intensive care unit; consensus statement from an Iranian panel of experts, July 2013.

Invasive candidiasis (IC) is associated with high mortality in intensive care unit (ICU) patients. Timely diagnosis of this potentially fatal condition remains a challenge; on the other hand, the criteria for initiating empirical antifungal therapy in critically ill patients are not well defined in different patient population and ICU settings. Alongside the international guidelines, reaching regional and local consensus on diagnosis and management of IC in ICU setting is essential. This report summarizes our present status of IC management in ICU, considered by a group of Iranian experts in the fields of intensive care and infectious diseases. A round table of 17 experts was held to review the available data and discuss the optimal treatment strategies for IC in critical care setting. Comparative published data on the management of IC were analytically reviewed and the commonly asked questions about the management of IC in ICU were isolated. These questions were interactively discussed by the panel and audience responses were taken to consolidate point-to-point agreement with the panel arriving at consensus in many instances. The responses indicated that patients’ risk stratification, clinical discretion, fungal diagnostic techniques and the empirical therapy for IC are likely to save more patients. Treatment options were recommended to be based on the disease severity, prior azole exposure, and the presence of suspected azole-resistant Candida species. This report was reviewed, edited and discussed by all participants to include further evidence-based insights. The panel expects such endorsed recommendations to be soon formulated for implementation across the country.

Economic evaluation of micafungin versus caspofungin for the treatment of candidaemia and invasive candidiasis

Micafungin demonstrated non-inferiority to caspofungin as definitive therapy for candidaemia and invasive candidiasis (IC) in a major randomised clinical trial. The aim of this study was to investigate if micafungin is a cost-saving option compared with caspofungin for treating candidaemia and IC. A decision analytical model was constructed to capture downstream consequences of using either agent as initial therapy for candidaemia and IC. The main outcomes were treatment success and treatment failure (i.e. death, mycological persistence, emergent infection, clinical failure but microbiological success). Outcome probabilities and treatment pathways were derived from the literature. Cost inputs were from the latest Australian resources, and resource use was estimated by expert panel. The analysis was from the Australian hospital perspective. Sensitivity analyses using Monte Carlo simulation were conducted. Micafungin (AU$52 816) was associated with a lower total cost than caspofungin (AU$52 976), with a net cost-saving of $160 per patient. This was primarily due to the lower cost associated with alternative antifungal treatment in the micafungin arm. Hospitalisation was the main cost-driver for both arms. The model outcome was most sensitive to the proportion of treatment success in the micafungin arm. Uncertainty analysis demonstrated that micafungin had a 58% chance of being cost-saving compared with caspofungin. Micafungin was cost-equivalent to caspofungin in treating candidaemia and IC, with variation in drug acquisition cost the critical factor.

Are Echinocandins Better Than Azoles for Invasive Candidiasis?

Antifungal therapy has advanced tremendously in the past decade, with multiple new agents for systemic fungal infections that have a broad spectrum of activity and are well-tolerated. There is usually more than one acceptable therapeutic option for many diseases, and this is true in particular of candidiasis. Fluconazole has been the drug of choice for most clinical syndromes of candidiasis, due to its tolerability, effectiveness, and ease of administration. However, the echinocandin class of antifungals, comprised of caspofungin, micafungin and anidulafingin, has emerged as the preferred choice in the therapy of invasive candidiasis and candidemia. Their potent fungicidal activity and minimal toxicity have made them first-line drugs for this indication. In certain clinical settings, they may even be agents of first choice. Nevertheless, recent trends in echinocandin resistance demonstrated with Candida glabrata mandate ongoing surveillance, and continued trends may impact upon future antifungal selection.

Invasive candidiasis in Pakistan: clinical characteristics, species distribution and antifungal susceptibility

This study reports for the first time, to our knowledge, descriptive epidemiological data for 188 invasive Candida isolates from Pakistan, including species identification and antifungal susceptibility against fluconazole, itraconazole, voriconazole, caspofungin, micafungin, anidulafungin and amphotericin. Risk factors for invasive candidiasis (IC) were determined for 96 patients from Karachi, Pakistan. In adults and neonates, Candida tropicalis (38 and 36 %, respectively) was the most common species, followed in adults by Candida parapsilosis (17.8 %), Candida glabrata (15.9 %) and Candida albicans (12.3 %). C. albicans (21 %) was the second most common in neonates. In children, C. albicans (31.9 %), C. tropicalis (26.4 %) and C. parapsilosis (19.4 %) were the most common. C. albicans IC was significantly associated with paediatric age [crude odds ratio (COR) 3.46, 95 % confidence interval (CI) 1.63-7.32]. Rare species made up 17.5 % of the total isolates studied. Resistance to fluconazole was seen in C. glabrata (15 .0%) and Candida krusei (100 .0%). Only one isolate (C. glabrata) was resistant to all three echinocandins. Low MICs of fluconazole for 98 % (184/188) of isolates tested support its continued use as an empiric therapy for IC. Non-C. albicans IC was associated with the use of β-lactam inhibitor combinations (COR 3.16, 95 % CI 1.05-9.57). Use of healthcare devices was documented in 85.4 % of IC patients, whilst 75 .0% had been admitted to special care units. Surprisingly, 66.7 % of patients with IC were not obviously immunosuppressed. The high frequency of modifiable risk factors in this population indicates that candidaemia can be reduced with stringent antibiotic and infection control measures. These data will be useful for empiric selection of antifungals in Karachi, and contribute to global assessments of antifungal resistance.

Is (1→3)-β-D-glucan the missing link from bedside assessment to pre-emptive therapy of invasive candidiasis?

Invasive candidiasis is a frequent life-threatening complication in critically ill patients. Early diagnosis followed by prompt treatment aimed at improving outcome by minimizing unnecessary antifungal use remains a major challenge in the ICU setting. Timely patient selection thus plays a key role for clinically efficient and cost-effective management. Approaches combining clinical risk factors and Candida colonization data have improved our ability to identify such patients early. While the negative predictive value of scores and predicting rules is up to 95 to 99%, the positive predictive value is much lower, ranging between 10 and 60%. Accordingly, if a positive score or rule is used to guide the start of antifungal therapy, many patients may be treated unnecessarily. Candida biomarkers display higher positive predictive values; however, they lack sensitivity and are thus not able to identify all cases of invasive candidiasis. The (1→3)-β-D-glucan (BG) assay, a panfungal antigen test, is recommended as a complementary tool for the diagnosis of invasive mycoses in high-risk hemato-oncological patients. Its role in the more heterogeneous ICU population remains to be defined. More efficient clinical selection strategies combined with performant laboratory tools are needed in order to treat the right patients at the right time by keeping costs of screening and therapy as low as possible. The new approach proposed by Posteraro and colleagues in the previous issue of Critical Care meets these requirements. A single positive BG value in medical patients admitted to the ICU with sepsis and expected to stay for more than 5 days preceded the documentation of candidemia by 1 to 3 days with an unprecedented diagnostic accuracy. Applying this one-point fungal screening on a selected subset of ICU patients with an estimated 15 to 20% risk of developing candidemia is an appealing and potentially cost-effective approach. If confirmed by multicenter investigations, and extended to surgical patients at high risk of invasive candidiasis after abdominal surgery, this Bayesian-based risk stratification approach aimed at maximizing clinical efficiency by minimizing health care resource utilization may substantially simplify the management of critically ill patients at risk of invasive candidiasis.

Prediction of the Clinical Outcome in Invasive Candidiasis Patients Based on Molecular Fingerprints of Five Anti-Candida Antibodies in Serum

Better prognostic predictors for invasive candidiasis (IC) are needed to tailor and individualize therapeutic decision-making and minimize its high morbidity and mortality. We investigated whether molecular profiling of IgG-antibody response to the whole soluble Candida proteome could reveal a prognostic signature that may serve to devise a clinical-outcome prediction model for IC and contribute to known IC prognostic factors. By serological proteome analysis and data-mining procedures, serum 31-IgG antibody-reactivity patterns were examined in 45 IC patients randomly split into training and test sets. Within the training cohort, unsupervised two-way hierarchical clustering and principal-component analyses segregated IC patients into two antibody-reactivity subgroups with distinct prognoses that were unbiased by traditional IC prognostic factors and other patients-related variables. Supervised discriminant analysis with leave-one-out cross-validation identified a five-IgG antibody-reactivity signature as the most simplified and accurate IC clinical-outcome predictor, from which an IC prognosis score (ICPS) was derived. Its robustness was confirmed in the test set. Multivariate logistic-regression and receiver-operating-characteristic curve analyses demonstrated that the ICPS was able to accurately discriminate IC patients at high risk for death from those at low risk and outperformed conventional IC prognostic factors. Further validation of the five-IgG antibody-reactivity signature on a multiplexed immunoassay supported the serological proteome analysis results. The five IgG antibodies incorporated in the ICPS made biologic sense and were associated either with good-prognosis and protective patterns (those to Met6p, Hsp90p, and Pgk1p, putative Candida virulence factors and antiapoptotic mediators) or with poor-prognosis and risk patterns (those to Ssb1p and Gap1p/Tdh3p, potential Candida proapoptotic mediators). We conclude that the ICPS, with additional refinement in future larger prospective cohorts, could be applicable to reliably predict patient clinical-outcome for individualized therapy of IC. Our data further provide insights into molecular mechanisms that may influence clinical outcome in IC and uncover potential targets for vaccine design and immunotherapy against IC.

In Vitro Susceptibility of Invasive Isolates of Candida spp. to Anidulafungin, Caspofungin, and Micafungin: Six Years of Global Surveillance

The echinocandins are being used increasingly as therapy for invasive candidiasis. Prospective sentinel surveillance for the emergence of in vitro resistance to the echinocandins among invasive Candida sp. isolates is indicated. We determined the in vitro activities of anidulafungin, caspofungin, and micafungin against 5,346 invasive (bloodstream or sterile-site) isolates of Candida spp. collected from over 90 medical centers worldwide from 1 January 2001 to 31 December 2006. We performed susceptibility testing according to the CLSI M27-A2 method and used RPMI 1640 broth, 24-h incubation, and a prominent inhibition endpoint for determination of the MICs. Of 5,346 invasive Candida sp. isolates, species distribution was 54% C. albicans, 14% C. parapsilosis, 14% C. glabrata, 12% C. tropicalis, 3% C. krusei, 1% C. guilliermondii, and 2% other Candida spp. Overall, all three echinocandins were very active against Candida: anidulafungin (MIC50, 0.06 microg/ml; MIC90, 2 microg/ml), caspofungin (MIC50, 0.03 microg/ml; MIC90, 0.25 microg/ml), micafungin (MIC50, 0.015 microg/ml; MIC90, 1 microg/ml). More than 99% of isolates were inhibited by < or = 2 microg/ml of all three agents. Results by species (expressed as the percentages of isolates inhibited by < or = 2 microg/ml of anidulafungin, caspofungin, and micafungin, respectively) were as follows: for C. albicans, 99.6%, 100%, and 100%; for C. parapsilosis, 92.5%, 99.9%, and 100%; for C. glabrata, 99.9%, 99.9%, and 100%; for C. tropicalis, 100%, 99.8%, and 100%; for C. krusei, 100%, 100%, and 100%; and for C. guilliermondii, 90.2%, 95.1%, and 100%. There was no significant change in the activities of the three echinocandins over the 6-year study period and no difference in activity by geographic region. All three echinocandins have excellent in vitro activities against invasive strains of Candida isolated from centers worldwide. Our prospective sentinel surveillance reveals no evidence of emerging echinocandin resistance among invasive clinical isolates of Candida spp.

In Vitro Susceptibilities of Candida spp. to Caspofungin: Four Years of Global Surveillance

Caspofungin is being used increasingly as therapy for invasive candidiasis. Prospective sentinel surveillance for emergence of in vitro resistance to caspofungin among invasive Candida spp. isolates is indicated. We determined the in vitro activity of caspofungin against 8,197 invasive (bloodstream or sterile-site) unique patient isolates of Candida collected from 91 medical centers worldwide from 1 January 2001 to 31 December 2004. We performed antifungal susceptibility testing according to the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) M27-A2 method and used a 24-h prominent inhibition endpoint for determination of the MIC. Of 8,197 invasive Candida spp. isolates, species distribution was as follows: 54% Candida albicans, 14% C. glabrata, 14% C. parapsilosis, 11% C. tropicalis, 3% C. krusei, and 4% other Candida spp. Overall, caspofungin was very active against Candida (MIC50/MIC90, 0.03/0.25 microg/ml; 98.2% were inhibited at a MIC of < or = 0.5 microg/ml and 99.7% were inhibited at a MIC of < or = 1 microg/ml). Results by species (expressed as MIC50/MIC90 and the percentage inhibited at < or = 1 microg/ml) were as follows: C. albicans, 0.03/0.06, 99.9; C. glabrata, 0.03/0.06, 99.9; C. parapsilosis, 0.5/0.5, 99.0; C. tropicalis, 0.03/0.06, 99.7; C. krusei, 0.12/0.5, 99.0; and C. guilliermondii, 0.5/1, 94.4. Of the 25 isolates with caspofungin MICs of >1 microg/ml, 12 isolates were C. parapsilosis, 6 isolates were C. guilliermondii, 2 isolates were C. rugosa, and 1 isolate each was C. albicans, C. glabrata, C. krusei, C. lusitaniae, and C. tropicalis. There was no significant change in caspofungin activity over the 4-year study period. Likewise, there was no difference in activity by geographic region. Caspofungin has excellent in vitro activity against invasive clinical isolates of Candida from centers worldwide. Our prospective sentinel surveillance reveals no evidence of emerging caspofungin resistance among invasive clinical isolates of Candida.