Treatment Of Invasive Candida Infections Research Articles

Structural and Functional Alterations Caused by Aureobasidin A in Clinical Resistant Strains of Candida spp.

Candida species are one of the most concerning causative agents of fungal infections in humans. The treatment of invasive Candida infections is based on the use of fluconazole, but the emergence of resistant isolates has been an increasing concern which has led to the study of alternative drugs with antifungal activity. Sphingolipids have been considered a promising target due to their roles in fungal growth and virulence. Inhibitors of the sphingolipid biosynthetic pathway have been described to display antifungal properties, such as myriocin and aureobasidin A, which are active against resistant Candida isolates. In the present study, aureobasidin A did not display antibiofilm activity nor synergism with amphotericin B, but its combination with fluconazole was effective against Candida biofilms and protected the host in an in vivo infection model. Alterations in treated cells revealed increased oxidative stress, reduced mitochondrial membrane potential and chitin content, as well as altered morphology, enhanced DNA leakage and a greater susceptibility to sodium dodecyl sulphate (SDS). In addition, it seems to inhibit the efflux pump CaCdr2p. All these data contribute to elucidating the role of aureobasidin A on fungal cells, especially evidencing its promising use in clinical resistant isolates of Candida species.

Biofilm Formation in Medically Important Candida Species.

Worldwide, the number of infections caused by biofilm-forming fungal pathogens is very high. In human medicine, there is an increasing proportion of immunocompromised patients with prolonged hospitalization, and patients with long-term inserted drains, cannulas, catheters, tubes, or other artificial devices, that exhibit a predisposition for colonization by biofilm-forming yeasts. A high percentage of mortality is due to candidemia caused by medically important Candida species. Species of major clinical significance include C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, C. krusei, and C. auris. The association of these pathogenic species in the biofilm structure is a serious therapeutic problem. Candida cells growing in the form of a biofilm are able to resist persistent therapy thanks to a combination of their protective mechanisms and their ability to disseminate to other parts of the body, thus representing a threat from the perspective of a permanent source of infection. The elucidation of the key mechanisms of biofilm formation is essential to progress in the understanding and treatment of invasive Candida infections.

Predictors for Prolonged Hospital Stay Solely to Complete Intravenous Antifungal Treatment in Patients with Candidemia: Results from the ECMM Candida III Multinational European Observational Cohort Study

BackgroundTo date, azoles represent the only viable option for oral treatment of invasive Candida infections, while rates of azole resistance among non-albicans Candida spp. continue to increase. The objective of this sub-analysis of the European multicenter observational cohort study Candida III was to describe demographical and clinical characteristics of the cohort requiring prolonged hospitalization solely to complete intravenous (iv) antifungal treatment (AF Tx).MethodsEach participating hospital (number of eligible hospitals per country determined by population size) included the first ~ 10 blood culture proven adult candidemia cases occurring consecutively after July 1st, 2018, and treating physicians answered the question on whether hospital stay was prolonged only for completion of intravenous antifungal therapy. Descriptive analyses as well as binary logistic regression was used to assess for predictors of prolonged hospitalization solely to complete iv AF Tx.FindingsHospital stay was prolonged solely for the completion of iv AF Tx in 16% (100/621) of candidemia cases by a median of 16 days (IQR 8 – 28). In the multivariable model, initial echinocandin treatment was a positive predictor for prolonged hospitalization to complete iv AF Tx (aOR 2.87, 95% CI 1.55 – 5.32, p < 0.001), while (i) neutropenia, (ii) intensive care unit admission, (iii) catheter related candidemia, (iv) total parenteral nutrition, and (v) C. parapsilosis as causative pathogen were found to be negative predictors (aOR 0.22 – 0.45; p < 0.03).InterpretationHospital stays were prolonged due to need of iv AF Tx in 16% of patients with candidemia. Those patients were more likely to receive echinocandins as initial treatment and were less severely ill and less likely infected with C. parapsilosis.

Aneuploidy enables cross-tolerance to unrelated antifungal drugs in Candida parapsilosis.

Candida parapsilosis is an emerging major human fungal pathogen. Echinocandins are first-line antifungal drugs for the treatment of invasive Candida infections. In clinical isolates, tolerance to echinocandins in Candida species is mostly due to point mutations of FKS genes, which encode the target protein of echinocandins. However, here, we found chromosome 5 trisomy was the major mechanism of adaptation to the echinocandin drug caspofungin, and FKS mutations were rare events. Chromosome 5 trisomy conferred tolerance to echinocandin drugs caspofungin and micafungin and cross-tolerance to 5-flucytosine, another class of antifungal drugs. The inherent instability of aneuploidy caused unstable drug tolerance. Tolerance to echinocandins might be due to increased copy number and expression of CHS7, which encodes chitin synthase. Although copy number of chitinase genes CHT3 and CHT4 was also increased to the trisomic level, the expression was buffered to the disomic level. Tolerance to 5-flucytosine might be due to the decreased expression of FUR1. Therefore, the pleiotropic effect of aneuploidy on antifungal tolerance was due to the simultaneous regulation of genes on the aneuploid chromosome and genes on euploid chromosomes. In summary, aneuploidy provides a rapid and reversible mechanism of drug tolerance and cross-tolerance in C. parapsilosis.

Rezafungin and invasive candida infections: a new game changing antifungal?

Invasive candidiasis is a hospital-acquired infection with a high associated mortality.1 The antifungal drug armamentarium to manage patients with invasive candida infections is quite small and restricted to three drug families: the polyenes, the azoles, and the echinocandins. The Infectious Diseases Society of America and European Society for Clinical Microbiology Diseases international guidelines both support the use of echinocandins as first-line drugs for the treatment of invasive candida infections.

Optimisation of fluconazole therapy for the treatment of invasive candidiasis in preterm infants

IntroductionFluconazole is an important antifungal in the prevention and treatment of invasive Candida infections in neonates, even though its use in preterm infants is still off-label. Here, we performed a...

Delineation of the Direct Contribution of Candida auris ERG11 Mutations to Clinical Triazole Resistance.

ABSTRACTResistance to fluconazole is one of clinical characteristics most frequently challenging the treatment of invasive Candida auris infections, and is observed among >90% of all characterized clinical isolates. In this work, the native C. auris ERG11 allele in a previously characterized fluconazole-susceptible clinical isolate was replaced with the ERG11 alleles from three highly fluconazole-resistant clinical isolates (MIC ≥256 mg/L), encoding the amino acid substitutions VF125AL, Y132F, and K143R, using Cas9-ribonucleoprotein (RNP) mediated transformation system. Reciprocally, the ERG11WT allele from the same fluconazole-susceptible clinical isolate, lacking any resistance-associated mutation, was introduced into a previously characterized fluconazole-resistant clinical isolate, replacing the native ERG11K143R allele, using the same methods. The resulting collection of strains was subjected to comprehensive triazole susceptibility testing, and the direct impact each of these clinically-derived ERG11 mutations on triazole MIC was determined. Introduction of each of the three mutant ERG11 alleles was observed to increase fluconazole and voriconazole MIC by 8- to 16-fold. The MIC for the other clinically available triazoles were not significantly impacted by any ERG11 mutation. In the fluconazole-resistant clinical isolate background, correction of the K143R encoding mutation led to a similar 16-fold decrease in fluconazole MIC, and 8-fold decrease in voriconazole MIC, while the MIC of other triazoles were minimally changed. Taken together, these findings demonstrate that mutations in C. auris ERG11 significantly contribute to fluconazole and voriconazole resistance, but alone cannot explain the substantially elevated MIC observed among clinical isolates of C. auris.IMPORTANCE Candida auris is an emerging multidrug-resistant and health care-associated pathogen of urgent clinical concern. The triazoles are the most widely prescribed antifungal agents worldwide and are commonly utilized for the treatment of invasive Candida infections. Greater than 90% of all C. auris clinical isolates are observed to be resistant to fluconazole, and nearly all fluconazole-resistant isolates of C. auris are found to have one of three mutations (encoding VF125AL, Y132F, or K143R) in the gene encoding the target of the triazoles, ERG11. However, the direct contribution of these mutations in ERG11 to fluconazole resistance and the impact these mutations may have the susceptibility of the other triazoles remains unknown. The present study seeks to address this knowledge gap and potentially inform the future application the triazole antifungals for the treatment of infections caused by C. auris.

Reply to Van Daele et al., "Fluconazole Underexposure in Critically Ill Patients: a Matter of Using the Right Targets?"

We thank Van Daele et al (1) for their interest in our study investigating the pharmacokinetics in critically ill patients with aim to optimize fluconazole dosing for the prevention and treatment of invasive candida infections (2).….

Quantification of anidulafungin and micafungin in human body fluids by high performance-liquid chromatography with UV-detection

The echinocandins anidulafungin (ANID) and micafungin (MICA) are recommended for treatment of invasive Candida infections. As target-site concentrations of antimicrobial agents are crucial for eradication of pathogens, we established and validated high-performance liquid chromatography-UV detection (HPLC-UV) assays for quantification of ANID and MICA in human plasma, ascites fluid, pleural effusion, and in cerebrospinal fluid (CSF). Sample pre-purification was performed by protein precipitation with acetonitrile followed by solid phase extraction. For both assays, intra- and interday precision, and accuracy fulfilled the requirements for bioanalytical methods issued by the European Medicine Agency (EMA). The lower limit of quantification was 0.01 mg/L for both drugs. At 25 °C, ANID and MICA concentrations declined by up to 70% within 24 h. Concentrations remained stable over 24 h at 4 °C and over four weeks at −80 °C. In conclusion, the developed methods are fit for the assessment of target-site pharmacokinetics of ANID and MICA in clinical studies.

Efficacy of humanized single large doses of caspofungin on the lethality and fungal tissue burden in a deeply neutropenic murine model against Candida albicans and Candida dubliniensis.

BackgroundEchinocandins are the first-line therapy for treatment of invasive Candida infections, but the mortality rate remains high, calling for novel strategies. Giving single larger echinocandin doses infrequently is an alternative regimen. Our aim was to test this novel approach in a neutropenic murine model.Materials and methodsWe compared the in vivo efficacy of single 10 and 40 mg/kg of caspofungin (2.5× and 10× the normal humanized dose) to that of the same cumulative doses of daily 2 and 8 mg/kg doses for 5 days against 2 each of wild-type C. albicans and C. dubliniensis as well as echinocandin resistant C. albicans. As a comparator, we tested daily 1 mg/kg amphotericin B.ResultsIn lethality experiments, all caspofungin and amphotericin B regimens improved survival against wild-type C. albicans and C. dubliniensis clinical isolates (P<0.0001) and decreased the mean fungal kidney burdens of both species compared to controls. However, fungal kidney burden decreases were not always statistically significant, especially with single 10 or 40 mg/kg caspofungin doses. Amphotericin B was the least active drug against wild-type C. albicans. Against echinocandin-resistant strains, monodose 40 mg/kg caspofungin and 1 mg/kg of daily amphotericin B were effective in lethality experiments. Although, significant kidney CFU decreases were never found, except for amphotericin B against one of the isolates (p<0.05 at day 3 and p<0.001 at day 6).ConclusionSingle 40 mg/kg caspofungin and 1 mg/kg amphotericin B proved to be effective in the lethality experiments against wild-type and echinocandin-resistant C. albicans and wild-type C. dubliniensis. This was not always shown regarding fungal tissue burdens. Single caspofungin doses used in mice in this study are attainable in humans as well, suggesting a potential place of this dosing strategy not only in prevention but also in curative treatment of evolved invasive Candida infections.

Diagnosis and treatment of invasive Candida infections – a review article

&lt;p&gt;Candida albicans is the most common cause of fungal infections worldwide. Invasive candidiasis comprises candidemia and deep-seated candidiasis. Most yeast invasive infections are endogenous with a high mortality. Pathogenesis of candidiasis depends on avoiding host immune responses, as well as the virulence factors of the fungus enabling colonization and invasion of tissues. Adequate source control and antifungal therapy administered within a short time is critical to get a better prognosis. The emergence of drug resistance and the side effects of currently available antifungals are becoming the major problem in the management of Candida spp. infection.&lt;/p&gt;

Application of granulocyte colony stimulating factor in the treatment of invasive fungal infections in congeni-tal immunodeficiency:Two pediatric cases reports and review of literatures

Objective To discuss the therapeutic significance of granulocyte colony stimulating factor (G-CSF) in the treatment of invasive Candida infections in congenital immunodeficiency, especially in cases with low level of interleukin 17(IL-17). Methods Therapeutic processes of 2 children suffering from invasive Candida infections secondary to congenital immunodeficiency were retrospectively studied, furthermore, the related literatures were also reviewed. Results Whole-exome sequencing revealed CARD9 mutation in the first patient, who suffered from Candida albicans meningoencephalitis, while the other patient revealed STAT1 mutation suffering from recurrent lung abscess caused by Candida albicans, and both of them showed low level of blood IL-17.Routine antifungal drugs were insufficiency, even treatment period had prolonged for several months.But after the G-CSF adjuvant therapy, their symptoms, signs and images recovered.With 5 to 10 months follow-up, no recurrent infections were found. Conclusion Antifungal drugs combined with G-CSF can effectively improve the treatment effect in invasive fungal infections secondary to immunodeficiency.Further more, genetic screening especially whole-exome sequencing can be suggested to find unusual immunodeficiency, which helps more individualized treatment. Key words: Congenital immunodeficiency; Invasive Candida infection; Granulocyte colony stimulating factor; Caspase-associated recruitment domain-containing protein 9; Signal transducers and activators of transcription 1; Interleukin-17

Micafungin: A Review in the Prophylaxis and Treatment of Invasive Candida Infections in Paediatric Patients.

Intravenous micafungin (Mycamine®; Funguard®), an echinocandin, is approved in the EU for the treatment of invasive candidiasis in children (including neonates) and adolescents (<16 years of age) and as prophylaxis against Candida infections in patients undergoing haematopoietic stem cell transplantation (HSCT) or who are expected to have neutropenia for ≥10 days. This narrative review focuses on the use of micafungin in paediatric indications approved in the EU, which may vary from those approved elsewhere in the world. Micafungin has a broad spectrum of in vitro activity against clinically relevant isolates of Candida spp. (including fluconazole-resistant Candida glabrata isolates), a low propensity for emergence of resistant isolates and a convenient once-daily regimen. In paediatric substudies and a small multinational, phase 3 trial in neonates with proven invasive candidiasis, intravenous micafungin was effective and generally well tolerated in the treatment of candidaemia and other types of invasive candidiasis and as prophylaxis against fungal infections in patients undergoing HSCT. Hence, micafungin remains an important option for the prophylaxis and treatment of invasive Candida infections in paediatric and adult patients.

Leberfunktionsstörungen in der Intensivmedizin – Konsequenzen für die Therapie invasiver Candidainfektionen

Liver dysfunction is common among patients on intensive care units (ICU) due to sepsis, chronic liver disease, ischemic hepatitis, drug toxicity and intensive care measures. Critically ill patients with invasive fungal infections should therefore be treated with antifungals that are not metabolized by the liver. This may help to avoid therapeutic complications by drug accumulation, inadequate dosages or drug-drug interactions. Echinocandins are established as the antifungal class of choice in the treatment of invasive Candida infections. Anidulafungin is not hepatically metabolized and may be used without dose adjustments in patients with severe liver dysfunction. It has no known clinically relevant drug interactions. In the primary endpoint of the randomized pivotal trial in patients with candidemia or invasive candidiasis, anidulafungin was statistically superior versus the former standard therapy (fluconazole), with a favourable overall safety profile. More recent study data particularly in ICU patients confirm the efficacy of anidulafungin for these patient groups. Therefore, anidulafungin is an important antifungal treatment option for patients with liver dysfunction.

Treatment of Invasive Candida Infections in the Neonatal Intensive Care Unit

Invasive Candida infections are a leading cause of morbidity and mortality in the neonatal intensive care unit (NICU). Extremely preterm and very low birth weight infants are at the highest risk of infection. There are currently no antifungal agents that have FDA-labeling for the treatment of invasive candidiasis in the neonatal population. Based on the current IDSA guidelines, amphotericin and fluconazole are considered first-line options for neonatal candidiasis. The newer antifungal agents (i.e., echinocandins and voriconazole) are currently considered second-line or salvage therapy; however, evidence supporting their use is emerging. This review focuses on the supporting evidence for the selection of antifungal agents for treatment of invasive Candida infections in the NICU.

Innovative Antimykotika zur Therapie invasiver Pilzinfektionen

Invasive fungal infections have gained importance in many areas of clinical medicine and represent a growing diagnostic and therapeutic challenge for clinicians. During the last decade, several new antifungals were introduced into routine therapy: two second-generation triazoles and the new class of echinocandins. These innovative drugs showed convincing efficacy and favorable safety in randomized clinical trials. Consequently, they were integrated in recent therapeutic guidelines, often replacing former standard drugs as first-line options. The echinocandins (anidulafungin, caspofungin, micafungin) primarily have gained a central role in the treatment of invasive Candida infections, while the novel triazoles voriconazole and posaconazole established themselves as the current mainstays in therapy and prophylaxis of invasive fungal infections, particularly aspergillosis, in hemato-oncologic high-risk patients.

Micafungin im Vergleich zu Caspofungin bei der Behandlung von invasiven Candida-Infektionen: Eine Kosteneffektivitätsanalyse für Deutschland

Although echinocandins such as micafungin and caspofungin have been shown to be effective and tolerated in the treatment of candidal infections there has been no appraisal of the cost-effectiveness of both echinocandins in Germany. This study compares the cost-effectiveness of micafungin and caspofungin in the treatment of invasive candida infections in Germany. To this end, a health economic decision model, based on a phase-III double-blind randomised controlled trial and German hospitalisation and primary medication costs, was used. The effectiveness outcome is defined as patients who are successfully treated and alive at the end of the study period and cost-effectiveness is measured as total costs per patient related to effectiveness. To test for robustness, a two-way sensitivity analysis and a probabilistic sensitivity analysis (PSA) were performed and a cost-effectiveness acceptability curve (CEAC) was calculated. The two-way sensitivity analysis renders micafungin more cost-effective than caspofungin in the global population sample in 19 out of 20 scenarios (20 out of 20 scenarios in the European subsample). Average costs in the PSA were €38,793 for micafungin and €40,072 for caspofungin, while effectiveness was 59.61% and 57.52%, respectively. The average cost-effectiveness is €65,271 for micafungin and €69,835 for caspofungin. For the European subsample, the calculated average costs in the PSA are €40,025 for micafungin and €40,082 for caspofungin, while the effectiveness is 63.29% and 53.69%. Micafungin shows an average cost-effectiveness of €64,412, compared to €76,791 for caspofungin. The CEAC shows that the probability for micafungin being more cost-effective than caspofungin ranges between 51.6% (no willingness to pay for additional costs per successfully treated patient) and 67.7% (infinitely high willingness to pay) in the total sample and between 48.8% and 79.5% in the European subsample. According to this study both lower costs and higher effectiveness show micafungin to be more cost-effective than caspofungin for the treatment of systemic candida infections in Germany.

Pharmacotherapy of Candida Infections with Echinocandins

The classic recommended antifungal agents for the treatment of invasive Candida infections were amphotericin B, a lipid formulation of amphotericin B and fluconazole in both neutropenic or nonneutropenic patients as either primary or alternative therapies. Voriconazole has been recommended when additional coverage for filamentous fungi is needed (e.g. neutropenic patients). More recently and based on well designed comparative clinical trials, the three echinocandins, caspofungin, anidulafungin and micafungin have been added as primary or alternative therapies especially for critically ill or neutropenic patients. In general, the echinocandins are most useful when patients have previously been exposed to an azole or are unstable.

Combination therapy with efungumab for the treatment of invasive Candida infections: several illustrative case reports

Efungumab (Mycograb®) is a human recombinant antibody against fungal Hsp90 that, in combination with lipid-associated amphotericin B, has shown efficacy in patients with invasive candidiasis (phase 3 data). Eight compassionate-use case studies of efungumab in combination with antifungal agents in the treatment of invasive Candida infections are presented.