Comparison of simulated candidemia detection during prophylactic antifungal therapy.

BACKGROUND: We investigated the neutralization performance of various automated blood culture systems for antifungal agents with regard to the most commonly isolated Candida species. METHODS: In this study, we evaluated the time to detection (TTD) of simulated candidemia for 6 Candida spp. (C. albicans, C. auris, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis) in 3 automated blood culture systems (BACTEC™ FX, BACT/ALERT® 3D, and BACT/ALERT® VIRTUO®), with or without trough and peak levels of eight antifungal agents (amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole, micafungin, posaconazole, and voriconazole). RESULTS: Caspofungin and micafungin significantly prolonged the TTDs for most of the tested strains in the 3 blood culture instruments, especially at peak concentrations. CONCLUSION: Peak concentrations of caspofungin and micafungin influence the performance of blood culture detection systems. Therefore, one should be careful about the possibility of prolonged TTDs for candidemia when using the abovementioned antifungal agents.

Pharmacokinetic/Pharmacodynamic Target Attainment of Different Antifungal Agents in De-escalation Treatment in Critically Ill Patients: a Step toward Dose Optimization Using Monte Carlo Simulation.

Differences in pharmacokinetics/pharmacodynamics (PK/PD) target attainment are rarely considered when antifungals are switched in critically ill patients. This study intends to explore whether the antifungal de-escalation treatment strategy and the new intermittent dosing strategy of echinocandins in critically ill patients are able to achieve the corresponding PK/PD targets. The published population PK models of antifungals in critically ill patients and a public data set from the MIMIC-III database (n = 662) were employed to evaluate PK/PD target attainment of different dosing regimens of antifungals. Cumulative fraction of response (CFR) was calculated for each dosing regimen. Most guideline-recommended dosing regimens of fluconazole and voriconazole could achieve target exposure as de-escalation treatment in critically ill patients. For initial echinocandin treatment, achievement of the target exposure decreased as body weight increased, and the intermittent dosing strategy had a slightly higher CFR value in most simulations compared to conventional dosing strategy. For Candida albicans and Candida glabrata infection, caspofungin at the lowest dose achieved a CFR of >90%, while micafungin or anidulafungin required almost the highest doses simulated in this study to achieve the same effect. None of the echinocandins other than 150 mg every 24 h (q24h) or 200 mg q48h of caspofungin achieved the target CFR for Candida parapsilosis infection. These findings support the guideline-recommended dose of triazoles for antifungal de-escalation treatment and confirm the insufficient dosage of echinocandins in critically ill patients, indicating that a dosing regimen based on body weight or intermittent dosing of echinocandins may be required.

Caspofungin resistance in Candida albicans: genetic factors and synergistic compounds for combination therapies.

Caspofungin and other echinocandins have been used for the treatment of human infections by the opportunistic yeast pathogen, Candida albicans. There has been an increase in infections by non-albicans Candida species such as Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida krusei, and Candida auris in clinical or hospital settings. This is problematic to public health due to the increasing prevalence of echinocandin resistant species/strains. This review will present a summary on various studies that investigated the inhibitory action of caspofungin on 1,3-ß-D-glucan synthesis, on cell wall structure, and biofilm formation of C. albicans. It will highlight some of the issues linked to caspofungin resistance or reduced caspofungin sensitivity in various Candida species and the potential benefits of antimicrobial peptides and other compounds in synergy with caspofungin.

The antifungal activity of caspofungin in combination with antifungals or non-antifungals against Candida species in vitro and in clinical therapy.

INTRODUCTION: Candida species have been regarded as global health threats due to their ability to cause invasive infections. It is challenging to treat Candida bloodstream infections, which are associated with high mortality levels. Monotherapy with antifungals is sometimes not effective against severe Candida infections, and combination therapy is needed in clinical practice. AREAS COVERED: This review was undertaken based on data from a PubMed search for English language reports published before March 2021 by using the terms 'caspofungin,' 'Candida species,' 'combination therapy,' 'antifungal effect,' and 'novel antifungal agent.' EXPERT OPINION: Combination therapy is an empirical strategy for treating refractory Candida infections. Caspofungin has been recommended to treat candidaemia. Caspofungin in combination therapy has some applications, while the efficacy of combination therapy in the treatment of refractory Candida infections needs more study, such as randomized controlled trials. In addition, novel compounds or drugs with potential antifungal activities have been examined, and some of them exhibit synergistic interactions with caspofungin. Thus, the antifungal activity of caspofungin in combination with antifungals or non-antifungals against Candida species in vitro and in clinical therapy is summarized.

Successful fluconazole combined with caspofungin treatment of candida bloodstream infection in preterm infant: A case report.

RATIONALE: Candida bloodstream infection continues to be a significant cause of mortality in premature infants. Amphotericin B has been recommended as the primary treatment; however, its use is limited due to drug-induced nephrotoxicity and amphotericin B-resistant candidemia. PATIENT CONCERNS: The gestational age was 29 (+6) weeks, and birth weight was 1760 g. DIAGNOSIS: The infant was diagnosed with Candida parapsilosis bloodstream infection. INTERVENTIONS: Fluconazole, 12 mg/kg/day, combined with caspofungin (loading dose 3 mg/kg, at a maintenance dose of 2 mg/kg every 24 h) therapy was administered to premature infant with Candida bloodstream infection. When fluconazole or caspofungin was used to treat Candida bloodstream infection in preterm infants, the blood cultures of the infant remained positive for Candida parapsilosis. OUTCOMES: All persistent candidemia resolved on fluconazole combined with caspofungin therapy. There were no adverse effects, hepatotoxicity, nephrotoxicity, anemia, or thrombocytopenia. LESSONS: Fluconazole combined with caspofungin successfully treated Candida bloodstream infection in premature infants at 29 + 6 weeks' gestational age, but large-scale clinical trials are required.

Caspofungin resistance in clinical Aspergillus flavus isolates.

INTRODUCTION AND AIMS: The present study was conducted to determine the candidate genes involved in caspofungin (CAS) resistance in clinical isolates of Aspergillus flavus (A. flavus). MATERIALS AND METHODS: The antifungal susceptibility assay of the CAS was performed on 14 clinical isolates of A. flavus using the CLSI-M-38-A2 broth micro-dilution protocol. Since CAS had various potencies, the minimum effective concentration (MEC) of anidulafungin (AND) was also evaluated in the present study. The FKS1 gene sequencing was conducted to assess whether mutations occurred in the whole FKS1 gene as well as hot spot regions of the FKS1 gene of the two resistant isolates. A complementary DNA-amplified fragment length polymorphism (CDNA-AFLP) method was performed to investigate differential gene expression between the two resistant and two sensitive clinical isolates in the presence of CAS. Furthermore, quantitative real-time PCR (QRT-PCR) was utilized to determine the relative expression levels of the identified genes. RESULTS: No mutations were observed in the whole FKS1 gene hot spot regions of the FKS1 genes in the resistant isolates. A subset of two genes with known biological functions and four genes with unknown biological functions were identified in the CAS-resistant isolates using the CDNA-AFLP. The QRT-PCR revealed the down-regulation of the P-type ATPase and ubiquinone biosynthesis methyltransferase COQ5 in the CAS-resistant isolates, compared to the susceptible isolates. CONCLUSION: The findings showed that P-type ATPase and ubiquinone biosynthesis methyltransferase COQ5 might be involved in the CAS-resistance A. flavus clinical isolates. Moreover, a subset of genes was differentially expressed to enhance fungi survival in CAS exposure. Further studies are recommended to highlight the gene overexpression and knock-out experiments in A. flavus or surrogate organisms to confirm that these mentioned genes confer the CAS resistant A. flavus.

Natural products targeting the synthesis of ß(1,3)-D-glucan and chitin of the fungal cell wall. Existing drugs and recent findings.

BACKGROUND: During the last three decades systemic fungal infections associated to immunosuppressive therapies have become a serious healthcare problem. Clinical development of new antifungals is an urgent requirement. Since fungal but not mammalian cells are encased in a carbohydrate-containing cell wall, which is required for the growth and viability of fungi, the inhibition of cell wall synthesizing machinery, such as ß(1,3)-D-glucan synthases (GS) and chitin synthases (CS) that catalyze the synthesis of ß(1-3)-D-glucan and chitin, respectively, represent an ideal mode of action of antifungal agents. Although the echinocandins anidulafungin, caspofungin and micafungin are clinically well-established GS inhibitors for the treatment of invasive fungal infections, much effort must still be made to identify inhibitors of other enzymes and processes involved in the synthesis of the fungal cell wall. PURPOSE: Since natural products (NPs) have been the source of several antifungals in clinical use and also have provided important scaffolds for the development of semisynthetic analogues, this review was devoted to investigate the advances made to date in the discovery of NPs from plants that showed capacity of inhibiting cell wall synthesis targets. The chemical characterization, specific target, discovery process, along with the stage of development are provided here. METHODS: An extensive systematic search for NPs against the cell wall was performed considering all the articles published until the end of 2020 through the following scientific databases: NCBI PubMed, Scopus and Google Scholar and using the combination of the terms "natural antifungals" and "plant extracts" with "fungal cell wall". RESULTS: The first part of this review introduces the state of the art of the structure and biosynthesis of the fungal cell wall and considers exclusively those naturally produced GS antifungals that have given rise to both existing semisynthetic approved drugs and those derivatives currently in clinical trials. According to their chemical structure, natural GS inhibitors can be classified as 1) cyclic lipopeptides, 2) glycolipids and 3) acidic terpenoids. We also included nikkomycins and polyoxins, NPs that inhibit the CS, which have traditionally been considered good candidates for antifungal drug development but have finally been discarded after enduring unsuccessful clinical trials. Finally, the review focuses in the most recent findings about the growing field of plant-derived molecules and extracts that exhibit activity against the fungal cell wall. Thus, this search yielded sixteen articles, nine of which deal with pure compounds and seven with plant extracts or fractions with proven activity against the fungal cell wall. Regarding the mechanism of action, seven (44%) produced GS inhibition while five (31%) inhibited CS. Some of them (56%) interfered with other components of the cell wall. Most of the analyzed articles refer to tests carried out in vitro and therefore are in early stages of development. CONCLUSION: This report delivers an overview about both existing natural antifungals targeting GS and CS activities and their mechanisms of action. It also presents recent discoveries on natural products that may be used as starting points for the development of potential selective and non-toxic antifungal drugs.

Comparative Pharmacodynamics of Echinocandins against Aspergillus fumigatus Using an In Vitro Pharmacokinetic/Pharmacodynamic Model That Correlates with Clinical Response to Caspofungin Therapy: Is There a Place for Dose Optimization?

Echinocandins have been used as primary therapy of invasive aspergillosis (IA), with suboptimal results at standard dosing. Here, we explored the efficacy of dose escalation in a validated in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. Six echinocandin wild-type (WT) and three non-WT A. fumigatus isolates were tested in an in vitro PK/PD model simulating anidulafungin, caspofungin, and micafungin exposures with a free drug maximum concentration (fCmax) of 0.01 to 16 mg/liter and a half-life (t1/2) of 8 to 22 h. The relationship between the area under the dosing interval time-free drug concentration curve (fAUC0-24)/minimum effective concentration (MEC) and % aberrant mycelium formation was analyzed. PK/PD indices associated with 50 to 99.99% maximal activity (EI50 to EI99.99) were correlated with the clinical outcome of a 50-mg/day standard dose of caspofungin. The probability of target attainment (PTA) was calculated for different dosing regimens of each echinocandin via Monte Carlo analysis. A sigmoidal PK/PD relationship was found for WT isolates with EI99 values of 766, 8.8, and 115 fAUC0-24/CLSI MEC for anidulafungin, caspofungin, and micafungin, respectively. No aberrant mycelia were observed for non-WT isolates, irrespective of their MEC and drug exposure. The EI99, EI99.9, and EI99.99 values corresponded to 2-, 3-, and 4-log10 formation of aberrant mycelia and correlated with survival, favorable, and complete response rates to caspofungin primary therapy in patients with IA. A very low PTA (<13%) was found for the standard doses of all echinocandins, whereas a PTA of ≥90% was found with 100 and 150 mg/day of caspofungin and 1,400 mg/day micafungin against WT isolates. For anidulafungin, the PTA for 1,500 mg/day was 10%. Among the three echinocandins, only caspofungin at 2 or 3 times the licensed dosing was associated with a high PTA. Caspofungin dose escalation might deserve clinical validation.

Caspofungin suppresses zymosan-induced cytokine and chemokine release in THP-1 cells: possible involvement of the spleen tyrosine kinase pathway.

Systemic inflammatory response syndrome and sepsis are considered to contribute to hypercytokinemia in both patients with severe infection and immunocompromised condition. Past research has demonstrated that antibiotics and antifungals not only have antimicrobial efficacy but also affect the immune system. We previously examined whether immune cells were modulated by antibiotics such as tetracyclines or macrolides. The modulation of lipopolysaccharide-stimulated cells by those agents was elucidated. However, few reports about the modulation of the immune system by antifungal agents were found. In this study, the production of pro-inflammatory cytokines and chemokines and signaling pathways involved were investigated in zymosan-activated THP-1 cells. The effects were examined using antifungal agents such as echinocandin including caspofungin (CAS) and micafungin. Pro-inflammatory cytokine and chemokine levels were determined using enzyme-linked immunosorbent assay. Protein phosphorylation was evaluated by western blot analysis. CAS significantly decreased zymosan-induced pro-inflammatory cytokine and chemokine release in THP-1 cells. CAS (30 µg/mL) also downregulated tumor necrosis factor alpha levels, as shown by enzyme-linked immunosorbent assay. In western blot analysis, inhibitor of nuclear factor-kappa-B alpha, p38, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and nuclear factor of activated T-cells phosphorylation and activation of caspase-1 and spleen tyrosine kinase (Syk) were downregulated. The major underlying mechanism of pro-inflammatory cytokine and chemokine suppression by CAS is to inhibit activation of Syk and its downstream signaling molecules. Based on the results, it can be concluded that CAS activity possibly involves Syk signaling pathways and has potential to prevent hypercytokinemia in fungal sepsis.

Impact of biofilm production by Candida species and antifungal therapy on mortality of patients with candidemia.

BACKGROUND AND OBJECTIVES: Few studies have investigated the clinical outcomes of patients with candidemia caused by Candida species with different levels of biofilm formation. We aimed to investigate the impact of antifungal therapy on the outcome of candidemia caused by Candida species that were categorised as low biofilm formers (LBFs), moderate biofilm formers (MBFs), and high biofilm formers (HBFs). METHODS: Adults with candidemia caused by LBF and HBF/MBF Candida species that were susceptible to fluconazole and caspofungin were included to investigate the impact of treatment with fluconazole vs an echinocandin on 30-day crude mortality. RESULTS: In total, 215 patients with candidemia received fluconazole and 116 patients received an echinocandin. In multivariate analysis, Pittsburgh bacteremia score ≥ 4 (adjusted odds ratio [AOR] =2.42; 95% confidence interval [CI], 1.32-4.41), malignancy (AOR = 3.45; 95% CI, 1.83-6.51), not removing the central venous catheter within 48 hours of a positive blood culture (AOR = 4.69; 95% CI, 2.61-8.45), and treatment with fluconazole for candidemia due to HBF/MBF Candida spp. (AOR = 2.23; 95% CI, 1.22-4.06) were independent factors associated with 30-day mortality. Of the 165 patients infected by HBF/MBF Candida isolates, those who received azole therapy had a significantly higher sepsis-related mortality rate than those who received echinocandin therapy (44.9% [49/109] vs 26.8% [15/56], P = .03). CONCLUSIONS: There was a trend of an independent association between fluconazole treatment and poor outcomes in the patients infected by HBF/MBF Candida strains.

Micellization of coenzyme Q by the fungicide caspofungin allows for safe intravenous administration to reach extreme supraphysiological concentrations.

Coenzyme Q10 (CoQ10; also known as ubiquinone) is a vital, redox-active membrane component that functions as obligate electron transporter in the mitochondrial respiratory chain, as cofactor in other enzymatic processes and as antioxidant. CoQ10 supplementation has been widely investigated for treating a variety of acute and chronic conditions in which mitochondrial function or oxidative stress play a role. In addition, it is used as replacement therapy in patients with CoQ deficiency including inborn primary CoQ10 deficiency due to mutations in CoQ10-biosynthetic genes as well as secondary CoQ10 deficiency, which is frequently observed in patients with mitochondrial disease syndrome and in other conditions. However, despite many tests and some promising results, whether CoQ10 treatment is beneficial in any indication has remained inconclusive. Because CoQ10 is highly insoluble, it is only available in oral formulations, despite its very poor oral bioavailability. Using a novel model of CoQ-deficient cells, we screened a library of FDA-approved drugs for an activity that could increase the uptake of exogenous CoQ10 by the cell. We identified the fungicide caspofungin as capable of increasing the aqueous solubility of CoQ10 by several orders of magnitude. Caspofungin is a mild surfactant that solubilizes CoQ10 by forming nano-micelles with unique properties favoring stability and cellular uptake. Intravenous administration of the formulation in mice achieves unprecedented increases in CoQ10 plasma levels and in tissue uptake, with no observable toxicity. As it contains only two safe components (caspofungin and CoQ10), this injectable formulation presents a high potential for clinical safety and efficacy.

Emergence of azole resistant-Aspergillus fumigatus infections during STAT3-deficiency.

Introduction. Signal transducer and activator of transcription 3 (STAT3) deficiency is a rare primary immunodeficiency associated with increased susceptibility to bacterial and fungal infections, notably pulmonary aspergillosis.Aim. We describe the emergence of azole-resistant Aspergillus fumigatus infections in STAT3-deficient patients.Methodology. During a retrospective study of 13 pulmonary aspergillosis cases in STAT3-deficient patients conducted in France, we identified patients infected with azole-resistant A. fumigatus isolates.Results. Two out of the 13 STAT3-deficient patients with aspergillosis had azole-resistant A. fumigatus infection, indicating an unexpectedly high prevalence of resistance. The first patient with STAT3 deficiency presented several flares of allergic bronchopulmonary aspergillosis-like episodes. He was chronically infected with two azole-resistant A. fumigatus isolates (TR34/L98). Despite prolonged antifungal treatment, including caspofungin and amphotericin B, the patient was not able to clear the azole-resistant A. fumigatus. The second patient had chronic cavitary pulmonary aspergillosis (CCPA). The A. fumigatus isolate was initially azole susceptible but harboured three F46Y, M172V and E427K point mutations. Despite prolonged antifungal therapies, lesions worsened and the isolate became resistant to all azoles. Surgery and caspofungin treatments were then required to cure CCPA. Resistance was probably acquired from the environment (TR34/L98) in the first case whereas resistance developed under antifungal treatments in the second case. These infections required long-term antifungal treatments and surgery.Conclusions. The emergence of azole-resistant A. fumigatus infections in STAT3-deficiency dramatically impacts both curative and prophylactic antifungal strategies. Physicians following patients with primary immune-deficiencies should be aware of this emerging problem as it complicates management of the patient.

First report on echinocandin resistant Polish Candida isolates.

PURPOSE: Candida spp. are ranked as one of the four major causative agents of fungal infections. The number of infections caused by Candida species resistant to fluconazole, which is applied as the first line drug in candidiasis treatment, increases every year. In such cases the application of echinocandin is necessary. Echinocandin susceptibility testing has become a routine laboratory practice in many countries due to the increasing frequency of clinical failures during treatment with these drugs. METHODS: We performed anidulafungin, micafungin and caspofungin susceptibility testing according to the microdilution broth method on 240 Candida isolates collected in Polish hospitals. RESULTS: We identified 12 isolates resistant to all echinocandins within 240 examined isolates. Moreover, 6 of the examined samples were identified as rare Candida species and among them we observed very high echinocandin MIC values. CONCLUSION: Our research proves that in Poland there is a problem of echinocandin resistance. Moreover, we identified two species of Candida which are rare causative agents of human infections, and there was no reported incidence of such infections in Poland until now.

Synergistic effect of nikkomycin Z with caspofungin and micafungin against Candida albicans and Candida parapsilosis biofilms.

Antifungal lock therapy has received significant interest in the last few years because the frequently usage of intravascular devices is associated with an increasing number of catheter-related bloodstream infections caused by Candida species. Antifungal combinations with synergistic interaction can be a good choice for antifungal lock therapy; therefore, interactions were examined between two echinocandins (caspofungin and micafungin) and the chitin synthesis inhibitor nikkomycin Z against Candida albicans and C. parapsilosis biofilms. Susceptibility was evaluated using the XTT-based checkerboard microdilution method, while the nature of interactions was assessed by calculating fractional inhibitory concentration indices and using the Bliss independence model. Mathematic-based evaluations were supplemented with fluorescent LIVE/DEAD viability assay. The results obtained by statistical interaction analyses correlated well with the viability assay. The tested echinocandins with nikkomycin Z caused an extended cell death and the structure of the biofilm was sparse compared to the control, especially for C. albicans. The findings support the simultaneous usage of nikkomycin Z and caspofungin or micafungin in alternative therapies such as the antifungal lock therapy. SIGNIFICANCE AND IMPACT OF THE STUDY: Antifungal lock therapy can be a potential therapeutic approach to eradicate the intraluminal Candida biofilms; however, there is no approved lock strategy against fungal species so far. The results of this study provide valuable evidence that nikkomycin Z acts synergistically in combination with caspofungin or micafungin against biofilms. In addition, this synergy was more pronounced for micafungin combined with nikkomycin Z. Therefore, nikkomycin Z can be considered as a potential agent in antifungal lock therapy especially with micafungin against C. albicans or C. parapsilosis biofilms.

Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis.

The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal agent manogepix (APX001A) inhibits glycosylphosphatidylinositol-anchored protein maturation and has demonstrated activity against numerous pathogenic fungi, including C. auris Our objective was to evaluate the in vivo efficacy of fosmanogepix, the N-phosphonooxymethyl prodrug (APX001), following delayed initiation of therapy in a murine model of C. auris invasive candidiasis. Neutropenic mice were intravenously infected with a fluconazole-resistant clinical isolate of C. auris Twenty-four hours postinoculation, treatment began with vehicle control, fosmanogepix (104 and 130 mg/kg of body weight by intraperitoneal injection three times daily, or intraperitoneal 260 mg/kg twice daily), fluconazole (20 mg/kg by oral gavage once daily), or caspofungin (intraperitoneal 10 mg/kg once daily) and continued for 7 days. Fungal burden was assessed via colony count in the kidneys and brains on day 8 in the fungal burden arm and on day 21 as the mice became moribund in the survival arm. Significant improvements in survival were observed in each group administered fosmanogepix and caspofungin. Similarly, reductions in fungal burden were also observed in both the kidneys and brains of mice treated with the highest dose of fosmanogepix in the fungal burden arm and in each fosmanogepix group and with caspofungin in the survival arm. In contrast, no improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole. These results demonstrate that fosmanogepix is effective in vivo against fluconazole-resistant C. auris even when therapy is delayed.

Species distribution and antifungal drug susceptibilities of yeasts isolated from the blood samples of patients with candidemia.

Candida albicans is the most frequently isolated fungal species in hospital settings worldwide. However, non-albicans Candida species with decreased susceptibility to antifungals have emerged as an important cause of fungemia. The aims of this study were to determine the species distribution of fungi isolated from the blood samples of patients at a Swedish University Hospital and to define the in vitro susceptibilities of these isolates to nine antifungal agents. In total, 233 yeast isolates from 143 patients were included in this study. Antifungal susceptibility testing was performed using broth dilution Sensititre YeastOne panels, which comprised amphotericin B, 5-flucytosine, fluconazole, itraconazole, voriconazole, posaconazole, anidulafungin, micafungin, and caspofungin. The most common species in all age groups was C. albicans (n = 93, 65%), followed by C. glabrata (n = 27, 19%) and C. parapsilosis (n = 15, 10%). C. glabrata was mostly found in elderly individuals, while C. parapsilosis was found mainly in young children (p = 0.008). Antifungal resistance was low in the Candida species, except for reduced susceptibility to fluconazole among C. glabrata strains. C. albicans is the most frequent colonizer of Swedish patients. In general antifungal resistance is uncommon in Candida species. Nevertheless, reduced susceptibilities to fluconazole and echinocandins were found in C. glabrata and C. parapsilosis, respectively.

Therapeutic tools for oral candidiasis: Current and new antifungal drugs.

BACKGROUND: Candidiasis is one of the most common opportunistic oral infections that presents different acute and chronic clinical presentations with diverse diagnostic and therapeutic approaches. The present study carries out a bibliographic review on the therapeutic tools available against oral candidiasis and their usefulness in each clinical situation. MATERIAL AND METHODS: Recent studies on treatment of oral candidiasis were retrieved from PubMed and Cochrane Library. RESULTS: Nystatin and miconazole are the most commonly used topical antifungal drugs. Both antifungal drugs are very effective but need a long time of use to eradicate the infection. The pharmacological presentations of miconazole are more comfortable for patients but this drug may interact with other drugs and this fact should be assessed before use. Other topical alternatives for oral candidiasis, such as amphotericin B or clotrimazole, are not available in many countries. Oral fluconazole is effective in treating oral candidiasis that does not respond to topical treatment. Other systemic treatment alternatives, oral or intravenous, less used are itraconazole, voriconazole or posaconazole. Available novelties include echinocandins (anidulafungin, caspofungin) and isavuconazole. Echinocandins can only be used intravenously. Isavuconazole is available for oral and intravenous use. Other hopeful alternatives are new drugs, such as ibrexafungerp, or the use of antibodies, cytokines and antimicrobial peptides. CONCLUSIONS: Nystatin, miconazole, and fluconazole are very effective for treating oral candidiasis. There are systemic alternatives for treating recalcitrant infections, such as the new triazoles, echinocandins, or lipidic presentations of amphotericin B.

The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris.

Candida auris is an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated in vitro and in vivo against C. auris Susceptibility testing was performed against 100 clinical isolates of C. auris by broth microdilution. Neutropenic mice were infected intravenously with C. auris, and treatment began 24 h postinoculation with a vehicle control, oral VT-1598 (5, 15, and 50 mg/kg of body weight once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstrated in vitro activity against C. auris, with a mode MIC of 0.25 µg/ml and MICs ranging from 0.03 to 8 µg/ml. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival, 15 and >21 days for VT-1598 at 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (reductions of 1.88 to 3.61 log10 CFU/g) compared to the control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to those with the control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by C. auris.

Iranian HIV/AIDS patients with oropharyngeal candidiasis: identification, prevalence and antifungal susceptibility of Candida species.

Oropharyngeal candidiasis is the commonest mucocutaneous infection in HIV-positive individuals. Herein, samples were taken from oral cavities of 150 HIV-infected patients and cultured on Sabouraud-dextrose agar; 89 (59·3%) of 150 patients had positive culture for Candida and presented clinical sign of classical oral candidiasis. Totally, 102 morphologically distinct colonies were isolated from Candida positive cultures and subsequently identified by polymerase chain reaction and sequencing assay, presenting the following frequency: 54 C. albicans (52·9%), 16 C. dubliniensis (15·7%), 12 C. tropicalis (11·8%), 9 C. glabrata (8·8%), 7 C. kefyr (6·9%) and 4 C. africana (3·9%). Additionally, multiple Candida species were co-isolated from 13·5% (12/89) patients. Regarding the antifungal susceptibility test, which was performed by CLSI protocol (M27-A3/M27-S3), all Candida isolates were susceptible to amphotericin B and caspofungin, while some of them were resistant to fluconazole (17·6%; 16 C. albicans, 1 C. dubliniensis and 1 C. glabrata), itraconazole (16·7%; 15 C. albicans, 1 C. dubliniensis and 1 C. tropicalis) and voriconazole (5·9%; 5 C. albicans and 1 C. tropicalis). Collectively, our findings reinforce the urgent necessity to find new therapeutic agents to treat oral candidiasis in HIV-positive patients, especially due to the high incidence of azole-resistant Candida strains and the increased frequency of non-C. albicans species. SIGNIFICANCE AND IMPACT OF THE STUDY: The Candida species recovered from oral cavity of 150 Iranian HIV/AIDS patients and their antifungal susceptibility profiles were reported. Candida albicans was the commonest Candida species, followed by C. dubliniensis, C. tropicalis, C. glabrata, C. kefyr and C. africana. All Candida isolates were susceptible to amphotericin B and caspofungin, while resistance to azoles was detected. The growing drug-resistance profile reported in clinical isolates of C. albicans and non-C. albicans strains is a serious problem in hospitals worldwide. Consequently, the suitable antifungal choice to treat the HIV/AIDS population with oral candidiasis needs to be rethought and new therapeutic options must urgently arise.

Evolution of tigecycline- and colistin-resistant CRKP (carbapenem-resistant Klebsiella pneumoniae) in vivo and its persistence in the GI tract.

Emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains that also exhibit resistance to tigecycline and colistin have become a major clinical concern, as these two agents are the last-resort antibiotics used for treatment of CRKP infections. A leukemia patient infected with CRKP was subjected to follow-up analysis of variation in phenotypic and genotypic characteristics of CRKP strains isolated from various specimens at different stages of treatment over a period of 3 years. Our data showed that (1) carbapenem treatment led to the emergence of CRKP in the gastrointestinal (GI) tract of the patient, which subsequently caused infections at other body sites as well as septicemia; (2) treatment with tigecycline led to the emergence of tigecycline-resistant CRKP, possibly through induction of the expression of a variant tet(A) gene located in a conjugative plasmid; (3) colistin treatment was effective in clearing CRKP from the bloodstream but led to the emergence of mcr-1-positive Enterobacteriaceae strains as well as colistin-resistant CRKP in the GI tract due to inactivation of the mgrB gene; and (4) tigecycline- and colistin-resistant CRKP could persist in the human GI tract for a prolonged period even without antibiotic selection pressure. In conclusion, clinical CRKP strains carrying a conjugative plasmid that harbors the blaKPC-2 and tet(A) variant genes readily evolve into tigecycline- and colistin-resistant CRKP upon treatment with these two antibiotics and persist in the human GI tract.