Candida Glabrata Infections Research Articles

Biofilm formation is a risk factor for mortality in patients with Candida albicans bloodstream infection—Scotland, 2012–2013

Bloodstream infections caused by Candida species remain a significant cause of morbidity and mortality in hospitalized patients. Biofilm formation by Candida species is an important virulence factor for disease pathogenesis. A prospective analysis of patients with Candida bloodstream infection (n = 217) in Scotland (2012–2013) was performed to assess the risk factors associated with patient mortality, in particular the impact of biofilm formation. Candida bloodstream isolates (n = 280) and clinical records for 157 patients were collected through 11 different health boards across Scotland. Biofilm formation by clinical isolates was assessed in vitro with standard biomass assays. The role of biofilm phenotype on treatment efficacy was also evaluated in vitro by treating preformed biofilms with fixed concentrations of different classes of antifungal. Available mortality data for 134 patients showed that the 30-day candidaemia case mortality rate was 41%, with predisposing factors including patient age and catheter removal. Multivariate Cox regression survival analysis for 42 patients showed a significantly higher mortality rate for Candida albicans infection than for Candida glabrata infection. Biofilm-forming ability was significantly associated with C. albicans mortality (34 patients). Finally, in vitro antifungal sensitivity testing showed that low biofilm formers and high biofilm formers were differentially affected by azoles and echinocandins, but not by polyenes. This study provides further evidence that the biofilm phenotype represents a significant clinical entity, and that isolates with this phenotype differentially respond to antifungal therapy in vitro. Collectively, these findings show that greater clinical understanding is required with respect to Candida biofilm infections, and the implications of isolate heterogeneity.

New Eugenol Glucoside-based Derivative Shows Fungistatic and Fungicidal Activity against Opportunistic Candida glabrata.

A new series of glucosides modified in their saccharide units were synthesized, evaluated against Candida sp., and compared to prototype 1, an eugenol tetracetyl glucoside previously synthesized and shown to be active against Candida glabrata. Among the new glucosides, benzyl derivative 5 was the most promising, showing fungistatic activity at IC50 18.1 μm against Candida glabrata (threefold higher than fluconazole) and fungicidal activity with a low IC90 value of 36.2 μm. Moreover, the cytotoxic activity of compound 5 (CC50 : 580.9 μm), tested in peripheral blood mononuclear cells, suggests its potential as an agent to treat Candida glabrata infections, with a selectivity index of 32. The new eugenol glucoside 5 may be considered as a novel structural pattern in the development of new anti-Candida drugs.

Contribution of the Slt2-regulated transcription factors to echinocandin tolerance in Candida glabrata.

Echinocandin-class antifungals, including micafungin, are considered as the first-line treatment for Candida glabrata infections. However, recent epidemiological surveys have revealed an increasing number of C.glabrata isolates exhibiting decreased echinocandin susceptibilities. The Slt2 mitogen-activated protein kinase pathway is important for maintenance of cell wall integrity in fungi. Rlm1 and Swi4-Swi6 cell cycle box binding factor (SBF) are transcription factors downstream of Slt2. While Slt2 and Rlm1 play important roles in response to cell wall stresses, such as micafungin exposure, little is known about SBF in C.glabrata. Here, we generated C.glabrata strains lacking or overexpressing SWI4 and SWI6 and evaluated their susceptibilities to micafungin. Micafungin tolerance considerably decreased in the ∆swi4 strain, whereas it increased in the strains overexpressing SWI4. On the other hand, deletion of SWI6 slightly impaired micafungin tolerance, but overexpression of SWI6 had no effect. These results suggest that, although Swi4 and Swi6 form a protein complex, Swi4 is involved in micafungin tolerance more predominantly than Swi6 in C.glabrata. Furthermore, the overexpression of RLM1 induced increased micafungin tolerance in the wild-type background but not in the ∆swi4 and ∆swi6 strains, suggesting that Rlm1 and SBF function interdependently in response to micafungin exposure.

Candida glabrata and pre-term premature rupture of membrane complicating in vitro pregnancy: case report and confirmation of mother to neonate transmission

We report a case of Candida glabrata infection in an in vitro fertilization-assisted pregnancy complicated by pre-term pre-labor rupture of the membranes. We found C. glabrata in gastric fluid, amniotic fluid and maternal vaginal swab. Neonatal and maternal isolates showed indistinguishable molecular patterns analyzed by fingerprint DNA multilocus. Strong consideration should be given to perform a screening test C. glabrata. Multiple treatments, even in pregnancy, should be considered in women who have positive cultures results.

Antifungal resistance does not necessarily affect Candida glabrata fitness

Although there has been an overall good coverage of Candida glabrata infections by the echinocandins, emergence of antifungal resistance during therapy has been reported. We investigated, by using an invertebrate host model, the fitness of sequential C. glabrata isolates with different echinocandins susceptibility patterns. The studied strains were isolated from a case of recurrent fungemia with a fatal outcome due to C. glabrata that developed cross-resistance to echinocandins during caspofungin therapy. The sequential strains isolated post-therapy showed a S663P mutation in the Fks2p hot spot 1. In vivo study in the invertebrate host Galleria mellonella did not suggest a fitness cost related to the acquired antifungal resistance, the three isolates displayed a similar rate of killing (P = 0·54). We observed a clear correlation between emergence of antifungal resistance and persistence of the causal agent, probably aided by the unchanged fitness and unresponsiveness in vivo to the adopted therapy.

Candida glabrata infection following total hip arthroplasty: A case report.

Candida glabrata infection following total hip arthroplasty is rare and, due to the insufficiency of standardized clinical and evidence-based guidelines, there is no appropriate therapeutic schedule. The present study reports the case of a 44-year-old patient with Candida glabrata infection following a total hip arthroplasty. The patient was successfully treated by administration of intravenous and oral voriconazole without removal of the prosthesis. This case illustrates the significance of postoperative follow-up, clinician experience and the choice of the correct antifungal agent. In this case, we found in the early stage of Candida glabrata infection, we were able to control the infection without surgery through thorough irrigation. This reduces patient suffering and economic burden.

The Pneumocystis Ace2 Transcription Factor Regulates Cell Wall-remodeling Genes and Organism Virulence

Pneumocystis carinii (Pc) β-glucans are major components of the organism cell wall; yet, the regulation of Pc cell wall genesis and remodeling is not well understood. Ace2 transcription factors, which are present in many fungi, regulate glucanases and other enzymes needed for cell wall remodeling. The cloning and heterologous expression of PcAce2 in ace2Δ Saccharomyces cerevisiae demonstrated that PcAce2 can restore the defective glucanase and endochitinase gene expression of the mutant as well as regulate cell wall β-glucan biosynthetic genes. Furthermore, when a reconstructed yeast system was used, PcAce2 activated the transcription of the Pneumocystis gsc1 β-glucan synthetase, confirming the activity of a Pc transcription factor on a native Pneumocystis promoter and gene for the first time. We further observed that Pneumocystis binding to host extracellular matrix proteins and lung epithelial cells induced the phosphorylation (activation) of the PcAce2 transcription factor. Finally, we present a novel method that confirms the role of PcAce2 in modulating organism virulence using ace2Δ Candida glabrata infection in neutropenic mice. Together, these results indicate that the adherence of Pc to lung matrix proteins and epithelial cells leads to the activation of the Ace2 transcription factor, which regulates cell wall degradation and biosynthesis genes that are required for cell wall remodeling.

A severe case of haemodynamic instability during anidulafungin administration

Anidulafugin is an echinocandin used for the treatment of candida infections in non-neutropenic adults. Echinocandins show few drug-drug interactions and are usually well tolerated. We report a case of acute hypotension, bradycardia and haemodynamic instability with consecutive cardiopulmonary resuscitation during anidulafungin administration. A 41-year-old man ICU patient received anidulafungin for a suspected Candida glabrata infection. During the first administration of the drug, he developed acute haemodynamic instability with hypotension and bradycardia. The infusion was discontinued immediately and cardiopulmonary resuscitation was performed successfully. The patient regained haemodynamic stability. To the authors' knowledge, this is the first report of a life-threatening adverse event due to haemodynamic instability during anidulafungin administration. Cardiac toxicity associated with echinocandins has been described. Further studies seem to be mandatory to investigate this potential risk.

Candida-Infektionen im hohen Alter

Candida infections of the skin, mucous membranes as well as of internal organs may be more frequent and more serious in the elderly. There are several biological reasons for this, for example, alterations in the immune system. Whereas Candida albicans remains the major pathogen, there has been a relative increase of Candida glabrata infections. This species is associated with higher mortality. Furthermore, C. glabrata is in general less susceptible to fluconazole, so that this drug does not represent the agent of first choice for the treatment of yeast infections. The choice of the antimycotic agent must take into consideration their inherent side effects and interaction profiles; echinocandins play a particular role in the treatment of yeast infections in the elderly. These drugs have low toxicities, low potential for interactions with co-medications, as well as broad and good activities against yeasts.

Effects of echinocandins on cytokine/chemokine production by human monocytes activated by infection with Candida glabrata or by lipopolysaccharide

Serious Candida glabrata infections, which can be difficult to treat, are often treated with echinocandins. We compared in vitro the effects of high and low concentrations of 3 echinocandins (micafungin [MCF], caspofungin [CAS], and anidulafungin [ANF]), voriconazole (VRC), and amphotericin B (AmB), singly and VRC in combination with MCF, CAS, and ANF, on the production of cytokines/chemokines by human monocyte–derived macrophages (MDM). MDM were activated by infection with C. glabrata or lipopolysaccharide (LPS). Luminex multi-analyte microsphere technology was used for cytokine/chemokine analysis. Concentrations of cytokines/chemokines were significantly elevated following activation by infection or LPS. Treatment with high concentrations of echinocandins, singly or in combination with VRC, was most effective in lowering the elevated cytokine/chemokine levels. This effect occurred only with MDM activated by infection with C. glabrata and not with LPS. Treatment with VRC or AmB alone had little or no effect on cytokine/chemokine levels. In severe C. glabrata infection associated with very high concentrations of dysregulated cytokines/chemokines, echinocandins, singly or in combination with VRC, may decrease cytokine/chemokine concentrations and thus may improve host survival.

Fungicidal activity of the human peptide hepcidin 20 alone or in combination with other antifungals against Candida glabrata isolates

Candida glabrata infections are often difficult to eradicate due to the intrinsically low susceptibility to azoles of this species. In addition, C. glabrata has also been shown to be insensitive to several cationic peptides, which have been shown to be promising novel therapeutic candidates for the treatment of fungal infection. In this study, the in vitro fungicidal activity of the human cationic peptide hepcidin 20 (Hep-20) was evaluated against clinical isolates of C. glabrata with different levels of fluconazole susceptibility. Interestingly, all isolates were susceptible to Hep-20 (100–200 μg/ml) at pH 7.4, whereas the fungicidal effect of the peptide was higher (50 μg/ml) at acidic pH values. In addition, an increased antifungal activity was observed for Hep-20 with amphotericin B and a synergistic effect was demonstrated for the Hep-20/fluconazole and Hep-20/caspofungin combinations.

Therapeutic efficacy of posaconazole against Candida glabrata in a murine model of vaginitis

The frequency of mucosal infections caused by Candida glabrata has increased significantly. Candida glabrata infections are often resistant to many azole antifungal agents, especially fluconazole. The purpose of this study was to compare the efficacies of posaconazole (PSC) and fluconazole (FLC) in the treatment of experimental C. glabrata vaginitis caused by isolates with different FLC susceptibilities. A battery of 36 vaginal isolates of C. glabrata was tested against PSC and FLC to determine their in vitro susceptibilities. The 48-h geometric mean MICs for all isolates tested were 0.156 and 4.238 μg ml(-1) for PSC and FLC respectively. Two strains of C. glabrata for which FLC MICs were different were selected for in vivo study. The treatment regimens for the vaginal murine infection model were PSC or FLC at 10 or 20 mg kg(-1) of body weight/day and 20 mg kg(-1) twice a day. Regimens with PSC at 20 mg kg(-1) once or twice a day were effective in reducing the load of both the FLC-susceptible and -resistant isolates of C. glabrata. FLC at 20 mg kg(-1) twice a day was effective in reducing the load of both the isolates of C. glabrata. PSC displayed a more effective in vivo activity than FLC in the treatment of murine C. glabrata vaginitis.

The synthesis and structure–activity relationship of pyridazinones as glucan synthase inhibitors

A structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a β-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection.

Is age a risk factor for Candida glabrata colonisation?

Studies have reported that Candida glabrata infections are more common in older adults. We sought to determine colonisation rates of C. glabrata in the oral cavity and its relationship with age, comorbid illnesses and hospital or extended care facility stay. Samples were obtained from four sites in the oral cavity and from dentures, when available, from 408 subjects from the community (136), hospital (126) or an extended care facility (146). Overall, 219 (53.7%) subjects were colonised with yeast; the predominant species was Candida albicans. Sixty-two patients (15.2%) were colonised with C. glabrata. None of the subjects <40 years was colonised with C. glabrata; in those from the community, only nine persons, all of whom were >60 years, were colonised with C. glabrata. By multivariate analysis, increasing age, dentures and use of psychotropic medications were independently associated with C. glabrata colonisation; residing in the community, rather than hospital or extended care, was strongly protective against colonisation. Candida glabrata colonisation is multifactorial; age, and hospitalisation/extended care stay contribute to colonisation. Dentures are strongly associated with colonisation with any yeast and with C. glabrata. Further study is needed to evaluate the relationship of these findings to increasing C. glabrata infections in older adults.

Recent advances in molecular and non-PCR-based platforms for the rapid diagnosis of invasive candidasis in the ICU

Invasive candidasis (IC) accounts for 15?30% of all nosocomial intensive care unit (ICU) infections. Two-thirds of infections are due to candidemia, a rate 5?10 times higher compared with that in the general hospital population. Crude mortality rates and associated health costs remain high, despite advances in antifungal therapy. Candida albicans remains the most frequently isolated species (45%) although there has been a slow but definite shift towards non-C. albicans species (especially Candida glabrata) infections, which has been attributed to the increased use of fluconazole prophylaxis in some centres. Early antifungal therapy significantly reduces IC-related mortality but is often delayed because ?gold standard? diagnosis by culture and/or histology is insensitive (for example, 50% candidemia cases not detected by blood culture) and slow (at least 48?96 hours required for species detection and identification). This article highlights a number of recent advances in molecular and non-PCR-based technologies that have enabled more rapid diagnosis of IC in the ICU (a recent review provides a comprehensive summary of molecular and serological methods in diagnostic mycology).

Comparison of costs, length of stay, and mortality associated with Candida glabrata and Candida albicans bloodstream infections

We compared costs, length of stay, and mortality between adults with Candida albicans and Candida glabrata bloodstream infections. Early evidence of C glabrata, as defined by a positive culture within 2 days of admission, was associated with higher costs ($56,026 vs $32,810; P = .04) and longer hospital stays (19.7 vs 14.5 days; P = .05) compared with early evidence of C albicans. Mortality was similar between the groups.

Blood Stream Infections by Candida glabrata and Candida krusei: A Single-Center Experience

Background/AimsThe increasing incidence of Candida glabrata and Candida krusei infections is a significant problem because they are generally more resistant to fluconazole. We compared the risk factors associated with C. glabrata and C. krusei fungemia with Candida albicans fungemia and examined the clinical manifestations and prognostic factors associated with candidemia.MethodsWe retrospectively reviewed demographic data, risk factors, clinical manifestations, and outcomes associated with C. glabrata and C. krusei fungemia at a tertiary-care teaching hospital during a 10-years period from 1997 to 2006.ResultsDuring the study period, there were 497 fungemia episodes. C. glabrata fungemia accounted for 23 episodes and C. krusei fungemia accounted for 8. Complete medical records were available for 27 of these episodes and form the basis of this study. Compared to 54 episodes of C. albicans fungemia, renal insufficiency and prior fluconazole prophylaxis were associated with development of C. glabrata or C. krusei fungemia. The overall mortality was 67%. The fungemia-related mortality of C. glabrata and C. krusei was higher than that of C. albicans (52 vs. 26%, p=0.021). Empirical antifungal therapy did not decrease the crude mortality. Multiple logistic regression analysis showed that high APACHE II scores, catheter maintenance, and shock were independently associated with an increased risk of death.ConclusionsRenal insufficiency and prior fluconazole prophylaxis were associated with the development of C. glabrata or C. krusei fungemia. Fungemia-related mortality of C. glabrata or C. krusei was higher than that of C. albicans. Outcomes appeared to be related to catheter removal, APACHE II scores, and shock.

A case of Candida glabrata infection after bipolar hemiarthroplasty for the hip fracture

A case of Candida glabrata infection after bipolar hemiarthroplasty for the hip fracture

Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD+ Precursor Vitamins in Human Nutrition

Although baseline requirements for nicotinamide adenine dinucleotide (NAD+) synthesis can be met either with dietary tryptophan or with less than 20 mg of daily niacin, which consists of nicotinic acid and/or nicotinamide, there is growing evidence that substantially greater rates of NAD+ synthesis may be beneficial to protect against neurological degeneration, Candida glabrata infection, and possibly to enhance reverse cholesterol transport. The distinct and tissue-specific biosynthetic and/or ligand activities of tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD+ precursor, nicotinamide riboside, reviewed herein, are responsible for vitamin-specific effects and side effects. Because current data suggest that nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis, we present prospects for human nicotinamide riboside supplementation and propose areas for future research.

Treatment of a critically ill child with disseminated Candida glabrata with a recombinant human antibody specific for fungal heat shock protein 90 and liposomal amphotericin B, caspofungin, and voriconazole

To report a case of fungal sepsis treated prospectively with liposomal amphotericin, caspofungin, and a novel monoclonal antibody specific for candidal heat shock protein 90 (Mycograb, Neutec Pharma, Manchester, UK). Case report. Pediatric intensive care unit in a tertiary care children's hospital. A 7-yr-old male with a history of global developmental delay, epilepsy, and gastroesophageal reflux, who presented to the emergency department with a transdiaphragmatic herniation of bowel and subsequent Candida glabrata infection. Efungumab 1 mg/kg twice daily for 5 days. C-reactive protein fell from 225 mg/L to 99 mg/L, and physiological monitoring parameters improved when Mycograb was used in conjunction with high-dose antifungals. Mycograb therapy was well tolerated, but further experience with this therapy in children is needed.