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The American Journal of Case Reports Feb 2024BACKGROUND Candida prosthetic valve endocarditis is a rare disease that is increasing in incidence with the rising rates of fungemia and increased use of intracardiac...
BACKGROUND Candida prosthetic valve endocarditis is a rare disease that is increasing in incidence with the rising rates of fungemia and increased use of intracardiac devices. Chronic antifungal prophylaxis is used after primary treatment to prevent recurrence, but the optimal duration of prophylaxis is currently unknown. This case report is of a woman with a history of mitral valve replacement due to Candida endocarditis presenting 2 years later with prosthetic valve and native aortic valve Candida albicans endocarditis. CASE REPORT A 32-year-old woman with a history of intravenous drug abuse, Staphylococcus and Candida endocarditis, and 2 mitral valve replacements 2 years ago on long-term oral fluconazole presented with fevers, weight loss, and dyspnea. She had stopped taking her oral antifungals prior to presentation. She was found to have vegetations on her prosthetic mitral valve and on her native aortic valve. She was started on ceftriaxone, vancomycin, and micafungin, and blood cultures grew C. albicans. She also developed a C. albicans metatarsal abscess and a splenic infarct. She underwent redo mitral valve replacement and aortic valve debridement successfully and was continued on intravenous micafungin for 8 weeks. CONCLUSIONS This case highlights the association between prosthetic valve endocarditis, intravenous drug abuse, and opportunistic fungal infections. Lifelong oral fluconazole can be considered for all patients with C. albicans prosthetic valve endocarditis, especially in the setting of the presence of other risk factors, such as intravenous drug abuse, as demonstrated in our case. Further studies are needed to determine differences in outcomes.
Topics: Female; Humans; Adult; Candida albicans; Fluconazole; Micafungin; Endocarditis, Bacterial; Substance Abuse, Intravenous; Heart Valve Prosthesis; Endocarditis; Candidiasis; Heart Valve Diseases
PubMed: 38297824
DOI: 10.12659/AJCR.942399 -
Journal of Fungi (Basel, Switzerland) Jan 2024is a recently emerged human fungal pathogen that has posed a significant threat to public health. Since its first identification in 2009, this fungus has caused...
is a recently emerged human fungal pathogen that has posed a significant threat to public health. Since its first identification in 2009, this fungus has caused nosocomial infections in over 47 countries across all inhabited continents. As of May 2023, the whole-genome sequences of over 4000 strains have been reported and a diversity of mutations, including in genes known to be associated with drug resistance in other human fungal pathogens, have been described. Among them, 387 strains contained antifungal-susceptibility information for which different methods might be used depending on the drugs and/or investigators. In most reports on so far, the number of strains analyzed was very small, from one to a few dozen, and the statistical significance of the relationships between these genetic variants and their antifungal susceptibilities could not be assessed. In this study, we conducted genome-wide association studies on individual clades based on previously published isolates to investigate the statistical association between genomic variants and susceptibility differences to nine antifungal drugs belonging to four major drug categories: 5-fluorocytosine, amphotericin B, fluconazole, voriconazole, itraconazole, posaconazole, anidulafungin, caspofungin, and micafungin. Due to the small sample sizes for Clades II, V, and VI, this study only assessed Clades I, III, and IV. Our analyses revealed 15 single nucleotide polymorphisms (SNPs) in Clade I (10 in coding and 5 in noncoding regions), 24 SNPs in Clade III (11 in coding and 13 in noncoding regions), and 13 SNPs in clade IV (10 in coding and 3 in noncoding regions) as statistically significantly associated with susceptibility differences to one or more of the nine antifungal drugs. While four SNPs in genes encoding lanosterol 14-α-demethylase ) and the catalytic subunit of 1,3-beta-D-glucan synthase () were shared between clades, including the experimentally confirmed Ser639Phe/Pro missense substitutions in for echinocandin resistance, most of the identified SNPs were clade specific, consistent with their recent independent origins. Interestingly, the majority of the antifungal resistance-associated SNPs were novel, and in genes and intergenic regions that have never been reported before as associated with antifungal resistance. While targeted study is needed to confirm the role of each novel SNP, the diverse mechanisms of drug resistance in revealed here indicate both challenges for infection control and opportunities for the development of novel antifungal drugs against this and other human fungal pathogens.
PubMed: 38276031
DOI: 10.3390/jof10010086 -
PloS One 2024To examine spatial effects in neonatal care, we conducted a retrospective cohort study to investigate the geographical distribution of antimicrobial exposure among very...
OBJECTIVES
To examine spatial effects in neonatal care, we conducted a retrospective cohort study to investigate the geographical distribution of antimicrobial exposure among very preterm and very low birth weight infants in Japan.
STUDY DESIGN
We utilized a nationwide claims database in Japan to extract prescriptions of injectable antimicrobials for 41,423 very preterm and very low birth weight infants admitted within the first two days of life from April 2010 to March 2021. We identified frequently prescribed antimicrobials, revealed early neonatal exposure and neonatal exposure to each antimicrobial agent by 47 prefectures in Japan, and evaluated their spatial autocorrelation using global and local Moran's I statistics. We then scrutinized regional disparities in antimicrobial drug prescriptions.
RESULTS
The top 10 antimicrobials prescribed to very preterm and very low birth weight infants in Japan were ampicillin, amikacin, gentamicin, cefotaxime, fluconazole, ampicillin combination, micafungin, cefmetazole, cefazolin, and vancomycin. We identified northern cold spots for fluconazole exposure and southern hot spots for ampicillin, amikacin, gentamicin, and cefmetazole exposure. Geographical heterogeneity in the selection of antibacterial and antimycotic agents was observed.
CONCLUSION
Our study revealed the geographical distribution of antimicrobial exposure among very preterm and very low birth weight infants in Japan, thus disclosing its spatial effects. Further research addressing the spatial effects of neonatal care is needed to understand how drug exposure affects the outcomes of preterm infants.
Topics: Infant; Infant, Newborn; Humans; Infant, Extremely Premature; Retrospective Studies; Amikacin; Japan; Cefmetazole; Fluconazole; Erythropoietin; Infant, Very Low Birth Weight; Anti-Infective Agents; Ampicillin; Gentamicins
PubMed: 38271353
DOI: 10.1371/journal.pone.0295528 -
MSphere Jan 2024The protein phosphatase calcineurin is vital for the virulence of the opportunistic fungal pathogen . The host-induced stresses that activate calcineurin signaling are...
The protein phosphatase calcineurin is vital for the virulence of the opportunistic fungal pathogen . The host-induced stresses that activate calcineurin signaling are unknown, as are the targets of calcineurin relevant to virulence. To potentially shed light on these processes, millions of transposon insertion mutants throughout the genome of were profiled for fitness defects in the presence of FK506, a specific inhibitor of calcineurin. Eighty-seven specific gene deficiencies depended on calcineurin signaling for full viability both in wild-type and null strains lacking pleiotropic drug resistance. Three genes involved in cell wall biosynthesis (, , ) possess co-essential paralogs whose expression depended on calcineurin and Crz1 in response to micafungin, a clinical antifungal that interferes with cell wall biogenesis. Interestingly, 80% of the FK506-sensitive mutants were deficient in different aspects of vesicular trafficking, such as endocytosis, exocytosis, sorting, and biogenesis of secretory proteins in the endoplasmic reticulum (ER). In response to the experimental antifungal manogepix that blocks GPI-anchor biosynthesis in the ER, calcineurin signaling increased and strongly prevented cell death independent of Crz1, one of its major targets. Comparisons between manogepix, micafungin, and the ER-stressing tunicamycin reveal a correlation between the degree of calcineurin signaling and the degree of cell survival. These findings suggest that calcineurin plays major roles in mitigating stresses of vesicular trafficking. Such stresses may arise during host infection and in response to antifungal therapies.IMPORTANCECalcineurin plays critical roles in the virulence of most pathogenic fungi. This study sheds light on those roles in the opportunistic pathogen using a genome-wide analysis . The findings could lead to antifungal developments that also avoid immunosuppression.
Topics: Antifungal Agents; Candida glabrata; Micafungin; Candidiasis; Calcineurin; Tacrolimus; Fungal Proteins; Aminopyridines; Isoxazoles
PubMed: 38171022
DOI: 10.1128/msphere.00554-23 -
Antimicrobial Agents and Chemotherapy Nov 2023We previously conducted a multicenter surveillance study on epidemiology and antifungal resistance in Madrid (CANDIMAD study; 2019-2021), detecting an increase in...
We previously conducted a multicenter surveillance study on epidemiology and antifungal resistance in Madrid (CANDIMAD study; 2019-2021), detecting an increase in fluconazole-resistant . We here present data on isolates collected in 2022. Furthermore, we report the epidemiology and antifungal resistance trends during the entire period, including an analysis per ward of admission. spp. incident isolates from blood cultures and intra-abdominal samples from patients cared for at 16 hospitals in Madrid, Spain, were tested with the EUCAST E.Def 7.3.2 method against amphotericin B, azoles, micafungin, anidulafungin, and ibrexafungerp and were molecularly characterized. In 2022, we collected 766 sp. isolates (686 patients; blood cultures, 48.8%). was the most common species found, and was undetected. No resistance to amphotericin B was found. Overall, resistance to echinocandins was low (0.7%), whereas fluconazole resistance was 12.0%, being higher in blood cultures (16.0%) mainly due to fluconazole-resistant clones harboring the Y132F-R398I ERG11p substitutions. Ibrexafungerp showed activity against the isolates tested. Whereas was the dominant species in most hospital wards, we observed increasing proportions in blood. During the entire period, echinocandin resistance rates remained steadily low, while fluconazole resistance increased in blood from 6.8% (2019) to 16% (2022), mainly due to fluconazole-resistant (2.6% in 2019 to 36.6% in 2022). Up to 7 out of 16 hospitals were affected by fluconazole-resistant . In conclusion, rampant clonal spreading of fluconazole-resistant genotypes is taking place in Madrid.
Topics: Humans; Fluconazole; Candida; Antifungal Agents; Amphotericin B; Candida parapsilosis; Traction; Echinocandins; Candida albicans; Drug Resistance, Fungal; Microbial Sensitivity Tests
PubMed: 38092562
DOI: 10.1128/aac.00986-23 -
Arthroplasty Today Dec 2023Fungal periprosthetic joint infections are one of the most intractable orthopedic disorders. Continuous local antibiotic perfusion allows direct administration of the...
Fungal periprosthetic joint infections are one of the most intractable orthopedic disorders. Continuous local antibiotic perfusion allows direct administration of the antifungal agent micafungin into the local infection area at biofilm-disruptive concentrations, while controlling the dead space in addition to conventional treatment. Although the appropriate use of continuous local antibiotic perfusion requires familiarity with the characteristics of local antibiotic perfusion, it is a versatile treatment modality that can improve the clinical outcomes of fungal periprosthetic joint infection in combination with conventional treatment methods.
PubMed: 38023642
DOI: 10.1016/j.artd.2023.101245 -
Pharmaceuticals (Basel, Switzerland) Oct 2023Systemic antifungal agents are essential for high-risk patients undergoing immunosuppressive therapy or cancer chemotherapy because of the rapid increase in...
Systemic antifungal agents are essential for high-risk patients undergoing immunosuppressive therapy or cancer chemotherapy because of the rapid increase in opportunistic fungal infections. Therapeutic drug monitoring is crucial to ensuring the efficacy and safety of antifungal agents owing to their pharmacokinetic variability. In the present study, we developed and validated a quantitative method for the simultaneous detection of seven commonly used antifungal drugs (amphotericin B, isavuconazole, voriconazole, fluconazole, posaconazole, caspofungin, and micafungin) using liquid chromatography-tandem mass spectrometry. Methanol (containing 0.1% formic acid) was used for protein precipitation and only 50 μL of serum was required for the analysis. Chromatographic separation was conducted using a Waters Acquity UPLC C8 column, and one stable isotope-labeled agent and two analogs were used as internal standards. The calibration curves ranged from 0.1 to 50 μg/mL for all agents, and the correlation coefficient (R) for all calibration curves was above 0.9835. The intra-day precision (1.2-11.2%), inter-day precision (2.4-13.2%), and mean bias values (-10.9 to 13.6%) were within an acceptable range of ±15%. Successful implementation of the developed method in clinical practice would facilitate the effective monitoring of these antifungal agents.
PubMed: 38004403
DOI: 10.3390/ph16111537 -
The Journal of Antimicrobial... Jan 2024Pharmacokinetic/pharmacodynamic (PK/PD) targets of echinocandins failed to support current clinical breakpoints of Candida parapsilosis as the PTA is low for susceptible...
BACKGROUND
Pharmacokinetic/pharmacodynamic (PK/PD) targets of echinocandins failed to support current clinical breakpoints of Candida parapsilosis as the PTA is low for susceptible isolates despite the good clinical efficacy of echinocandins against these infections. We therefore investigated the effect of micafungin against C. parapsilosis using an in vitro PK/PD in the presence of 10% human serum.
METHODS
Three susceptible (MIC = 0.5-2 mg/L) and one resistant (MIC > 8 mg/L) C. parapsilosis sensu stricto isolates were tested at two different inocula (104 and 103 cfu/mL) simulating micafungin human exposures in RPMI and in RPMI + 10% pooled human serum. The exposure-effect relationship tAUC0-24/MIC was described and different PK/PD targets were determined in order to calculate the PTA for the standard 100 mg IV q24h dose.
RESULTS
A maximal effect was found at fCmax ≥ 4 mg/L in RPMI and tCmax ≥ 64 mg/L (fCmax = 0.08 mg/L) in the presence of serum for which in vitro PK/PD targets were 50 times lower. Stasis in the presence of serum was found at 272-240 tAUC0-24/MIC, close to the clinical PK/PD target (285 tAUC/MIC), validating the in vitro model. However, the PTA was low for susceptible isolates with EUCAST/CLSI MICs ≤ 2 mg/L. Among the different PK/PD targets investigated, the PK/PD target 28 tAUC/MIC associated with 10% of maximal effect with the low inoculum resulted in PTAs ≥ 95% for susceptible isolates with EUCAST/CLSI MICs ≤ 2 mg/L.
CONCLUSIONS
A new PK/PD target was found for micafungin and C. parapsilosis that supports the current clinical breakpoint. This target could be used for assessing echinocandin efficacy against C. parapsilosis.
Topics: Humans; Micafungin; Candida parapsilosis; Antifungal Agents; Lipopeptides; Candida; Echinocandins; Mitomycin; Microbial Sensitivity Tests
PubMed: 38000088
DOI: 10.1093/jac/dkad360 -
Cells Nov 2023Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic species have evolved intrinsic and... (Review)
Review
Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic species have evolved intrinsic and acquired resistance to a variety of antifungal medications. The primary goal of this literature review is to summarize the molecular mechanisms associated with antifungal resistance in species. Resistance can be conferred via gain-of-function mutations in target pathway genes or their transcriptional regulators. Therefore, an overview of the known gene mutations is presented for the following antifungals: azoles (fluconazole, voriconazole, posaconazole and itraconazole), echinocandins (caspofungin, anidulafungin and micafungin), polyenes (amphotericin B and nystatin) and 5-fluorocytosine (5-FC). The following mutation hot spots were identified: (1) ergosterol biosynthesis pathway mutations (ERG11 and UPC2), resulting in azole resistance; (2) overexpression of the efflux pumps, promoting azole resistance (transcription factor genes: and ; transporter genes: CDR1, CDR2, MDR1, PDR16 and SNQ2); (3) cell wall biosynthesis mutations (FKS1, FKS2 and PDR1), conferring resistance to echinocandins; (4) mutations of nucleic acid synthesis/repair genes (FCY1, FCY2 and FUR1), resulting in 5-FC resistance; and (5) biofilm production, promoting general antifungal resistance. This review also provides a summary of standardized inhibitory breakpoints obtained from international guidelines for prominent species. Notably, , and demonstrate fluconazole resistance.
Topics: Antifungal Agents; Candida; Fluconazole; Echinocandins; Azoles
PubMed: 37998390
DOI: 10.3390/cells12222655 -
BMC Microbiology Nov 2023Candida glabrata is an important cause of invasive candidiasis. Echinocandins are the first-line treatment of invasive candidiasis caused by C. glabrata. The...
BACKGROUND
Candida glabrata is an important cause of invasive candidiasis. Echinocandins are the first-line treatment of invasive candidiasis caused by C. glabrata. The epidemiological echinocandin sensitivity requires long-term surveillance and the understanding about whole genome characteristics of echinocandin non-susceptible isolates was limited.
RESULTS
The present study investigated the echinocandin susceptibility of 1650 C. glabrata clinical isolates in China from August 2014 to July 2019. The in vitro activity of micafungin was significantly better than those of caspofungin and anidulafungin (P < 0.001), assessed by MIC values. Whole genome sequencing was conducted on non-susceptible isolates and geography-matched susceptible isolates. Thirteen isolates (0.79%) were resistant to at least one echinocandin. Six isolates (0.36%) were solely intermediate to caspofungin. Common evolutionary analysis of echinocandin-resistant and echinocandin-intermediate isolates revealed genes related with reduced caspofungin sensitivity, including previously identified sphinganine hydroxylase encoding gene SUR2. Genome-wide association study identified SNPs at subtelometric regions that were associated with echinocandin non-susceptibility. In-host evolution of echinocandin resistance of serial isolates revealed an enrichment for non-synonymous mutations in adhesins genes and loss of subtelometric regions containing adhesin genes.
CONCLUSIONS
The echinocandins are highly active against C. glabrata in China with a resistant rate of 0.79%. Echinocandin non-susceptible isolates carried common evolved genes which are related with reduced caspofungin sensitivity. In-host evolution of C. glabrata accompanied intensive changing of adhesins profile.
Topics: Humans; Echinocandins; Candida glabrata; Caspofungin; Antifungal Agents; Genome-Wide Association Study; Microbial Sensitivity Tests; Candidiasis, Invasive; China; Drug Resistance, Fungal
PubMed: 37974063
DOI: 10.1186/s12866-023-03105-3