-
Medicine Sep 2023Streptococcal toxic shock syndrome (STSS) rapidly leads to refractory shock and multiple organ failure. The mortality rate among patients with STSS is 40%; however, most... (Review)
Review
RATIONALE
Streptococcal toxic shock syndrome (STSS) rapidly leads to refractory shock and multiple organ failure. The mortality rate among patients with STSS is 40%; however, most deaths occur within a few days of onset. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) may help avoid acute death in adult patients with STSS. However, the effectiveness of VA-ECMO is unclear. In this study, we report a case of group B STSS, which was successfully treated with VA-ECMO despite cardiopulmonary arrest (CPA) owing to rapidly progressive refractory shock.
PATIENT CONCERNS
A 60-year-old woman was hospitalized because of diarrhea and electrolyte abnormalities owing to chemoradiation therapy for rectal cancer. A sudden deterioration of her condition led to CPA. Conventional cardiopulmonary resuscitation was immediately performed but was ineffective. Therefore, VA-ECMO was initiated. Contrast-enhanced computed tomography revealed duodenal perforation. Hence, septic shock owing to peritonitis was diagnosed, and emergency surgery was performed under VA-ECMO. However, the patient had progressive multiple organ failure and required organ support therapy in the intensive care unit (ICU).
DIAGNOSES
On day 2 in the ICU, blood and ascites fluid culture tests revealed beta-hemolytic streptococci, and the patient was finally diagnosed as having STSS caused by Streptococcus agalactiae.
INTERVENTIONS
Clindamycin was added to meropenem, vancomycin, and micafungin, which had been administered since the sudden deterioration. In addition, VA-ECMO, mechanical ventilation, blood purification therapy, and treatment for disseminated intravascular coagulation were continued.
OUTCOMES
Thereafter, hemodynamics improved rapidly, and the patient was weaned off VA-ECMO on day 5 of ICU admission. She was transferred to a general ward on day 22 in the ICU.
LESSONS
In patients with fatal STSS and rapid progressive refractory shock or CPA, VA-ECMO may help to avoid acute death and improve prognosis by ameliorating tissue oxygenation and providing extra time to treat invasive streptococcal infection.
Topics: Humans; Adult; Female; Middle Aged; Shock, Septic; Extracorporeal Membrane Oxygenation; Multiple Organ Failure; Streptococcal Infections; Clindamycin
PubMed: 37713845
DOI: 10.1097/MD.0000000000034680 -
The Medical Letter on Drugs and... Jun 2024
Topics: Humans; Antifungal Agents; Candidiasis, Invasive; Echinocandins
PubMed: 38905526
DOI: 10.58347/tml.2024.1705d -
Clinical Microbiology and Infection :... Dec 2023Antifungal susceptibility testing is mostly conducted on blood-cultured Candida spp isolates. Because the intra-abdominal cavity has been highlighted as a hidden...
OBJECTIVES
Antifungal susceptibility testing is mostly conducted on blood-cultured Candida spp isolates. Because the intra-abdominal cavity has been highlighted as a hidden echinocandin-resistant C. glabrata reservoir, we assessed whether testing sequential isolates from a given patient might increase the chances of detecting antifungal resistance.
METHODS
Intra-abdominal initial and sequential isolates from the same species from patients included in the CANDIdaemia in MADrid study (January 2019 to June 2022) were studied. We assessed antifungal susceptibility to amphotericin B, azoles, anidulafungin, micafungin, and ibrexafungerp using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology and molecularly characterized resistant isolates.
RESULTS
We collected 308 isolates (C. albicans [n = 179/308; 58.1%], C. glabrata [n = 101/308; 32.8%], C. tropicalis [n = 17/308; 5.5%], and C. parapsilosis [n = 11/308; 3.6%]) from 112 patients distributed as incident (n = 125/308) and sequential (n = 183/308). Per patient resistance rates of fluconazole (13.4% [15/112] vs. 8% [9/112]); 5.4% proportions difference (95% CI, -2.7% to 13.5%, p 0.09) and echinocandins (8.9% [10/112] vs. 1.8% [2/112]); 7.1% proportions difference (95% CI; 1.2-12.9%; p 0.01) were higher when considering all available isolates than only incident isolates. Resistance was detected in 18 of 112 patients and would have been overlooked in 11 of 18 (61.1%) patients if only incident isolates had been studied. Of the patients who harboured fluconazole or echinocandin-resistant isolates, 14 of 15 and 8 of 10 had received or were receiving fluconazole or echinocandins, respectively.
DISCUSSION
Testing sequential Candida isolates from intra-abdominal samples is required to detect antifungal resistance, particularly to echinocandins, in patients whose incident isolates turned out to be susceptible. Furthermore, patients with echinocandin-resistant infections had frequently used echinocandins and had common secondary resistance acquisition.
Topics: Humans; Antifungal Agents; Candida; Fluconazole; Echinocandins; Amphotericin B; Candida albicans; Candida parapsilosis; Candida tropicalis; Candida glabrata; Microbial Sensitivity Tests; Drug Resistance, Fungal
PubMed: 37640239
DOI: 10.1016/j.cmi.2023.08.021 -
European Journal of Medicinal Chemistry Nov 2023Neddylation is a protein modification process similar to ubiquitination, carried out through a series of activating (E1), conjugating (E2), and ligating (E3) enzymes....
Neddylation is a protein modification process similar to ubiquitination, carried out through a series of activating (E1), conjugating (E2), and ligating (E3) enzymes. This process has been found to be overactive in various cancers, leading to increased oncogenic activities. Ubiquitin-conjugating enzyme 2 M (UBE2M) is one of two neddylation enzymes that play a vital role in this pathway. Studies have shown that targeting UBE2M in cancer treatment is crucial, as it regulates many molecular mechanisms like DNA damage, apoptosis, and cell proliferation. However, developing small molecule inhibitors against UBE2M remains challenging due to the lack of suitable druggable pockets. We have discovered that Micafungin, an antifungal agent that inhibits the production of 1,3-β-D-glucan in fungal cell walls, acts as a neddylation inhibitor that targets UBE2M. Biochemical studies reveal that Micafungin obstructs neddylation and stabilizes UBE2M. In cellular experiments, the drug was found to interact with UBE2M, prevent neddylation, accumulate cullin ring ligases (CRLs) substrates, reduce cell survival and migration, and induce DNA damage in gastric cancer cells. This research uncovers a new anti-cancer mechanism for Micafungin, paving the way for the development of a novel class of neddylation inhibitors that target UBE2M.
Topics: Antifungal Agents; Apoptosis; Cell Nucleus; Cell Proliferation; Micafungin; Neoplasms; Ubiquitin-Conjugating Enzymes
PubMed: 37651876
DOI: 10.1016/j.ejmech.2023.115732 -
Indian Journal of Medical Microbiology 2023The purpose of this study was to determine the activity of fluconazole, voriconazole, posaconazole, amphotericin B, micafungin and caspofungin against Candida blood...
PURPOSE
The purpose of this study was to determine the activity of fluconazole, voriconazole, posaconazole, amphotericin B, micafungin and caspofungin against Candida blood stream isolates and to investigate the molecular mechanisms of azole resistance in fluconazole resistant isolates.
METHODS
The in vitro susceptibilities of Candida isolates to fluconazole, voriconazole, posaconazole, amphotericin B, micafungin and caspofungin were tested by E-test ERG11, CDR1, CDR2 and MDR1 genes expression of fluconazole resistant, fluconazole (S-DD) and fluconazole intermediate resistant isolates were investigated by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR).
RESULTS
C. albicans (41%) was the most frequently isolated fungal species from blood stream infections followed by C. parapsilosis (22%). All C. albicans isolates except one and all C. tropicalis isolates were found to be susceptible to fluconazole. Overall, 21% of C. glabrata isolates were resistant to fluconazole. None of the Candida isolates were found to be resistant to caspofungin except 2 C. glabrata isolates. Overexpression of ERG11 and CDR1 genes were detected in all fluconazole S-DD and fluconazole resistant C. glabrata isolates, while CDR2 overexpression was observed in 91% fluconazole S-DD and 67 of % fluconazole resistant C.glabrata isolates. The overexpression of MDR1, ERG11 and CDR1 genes were found 100%, 80% and 80%, respectively, in fluconazole resistant C. parapsilosis isolates.
CONCLUSION
Most of the Candida isolates were susceptible to posaconazole and caspofungin. Our data also highlighted that overexpression of efflux pump genes major cause of azole resistance.
PubMed: 37573042
DOI: 10.1016/j.ijmmb.2023.100389 -
Journal of Fungi (Basel, Switzerland) Mar 2024Commercial tests are often employed in clinical microbiology laboratories for antifungal susceptibility testing of filamentous fungi. Method-dependent epidemiological... (Review)
Review
Commercial tests are often employed in clinical microbiology laboratories for antifungal susceptibility testing of filamentous fungi. Method-dependent epidemiological cutoff values (ECVs) have been defined in order to detect non-wild-type (NWT) isolates harboring resistance mechanisms. We reviewed the literature in order to find studies where commercial methods were used to evaluate for in vitro susceptibility of filamentous fungi and assess their ability to detect NWT isolates according to the available ECVs. Data were found for the gradient concentration strips Etest and MIC Test Strips (MTS), broth microdilution Sensititre YeastOne (SYO), Micronaut-AM and the agar dilution VIPcheck assays. Applying itraconazole, voriconazole and posaconazole Etest ECVs for , Etest was able to detect 90.3% (84/93), 61.2% (90/147) and 86% (31/36) of isolates with known mutations, respectively. Moreover, Etest also was able to detect 3/3 mutants using caspofungin ECVs and 2/3 micafungin mutant isolates. Applying the voriconazole and posaconazole SYO ECVs, 57.7% (67/116) and 100% (47/47) of mutants with known substitutions were classified as NWT, respectively. VIPcheck detected 90.3% (159/176), 80.1% (141/176) and 66% (141/176)of mutants via itraconazole, voriconazole and posaconazole, respectively, whereas Micronaut-AM detected 88% (22/25). In conclusion, Etest posaconazole and itraconazole, as well as micafungin and caspofungin ECVs, detected mutants. On the other hand, while the posaconazole SYO ECV was able to detect mutants, similar data were not observed with the SYO voriconazole ECV.
PubMed: 38535222
DOI: 10.3390/jof10030214 -
Pathogens (Basel, Switzerland) Mar 2024(1) Background: Despite being considered a non-pathogenic yeast, recently, a growing occurrence of infections has been noted. There is little knowledge about the drug...
(1) Background: Despite being considered a non-pathogenic yeast, recently, a growing occurrence of infections has been noted. There is little knowledge about the drug susceptibility of this species. Therefore, the objective of this research was to expand it and determine the drug susceptibility profile of a local collection of clinical isolates of this species. (2) Methods: This study contained 55 clinical isolates identified as using the MALDI-TOF method. The susceptibility of was tested to 10 antifungals (amphotericin B, flucytosine, fluconazole, voriconazole, posaconazole, micafungin, anidulafungin, caspofungin, and itraconazole) using MICRONAUT-AT tests and manogepix, a new drug, using the microdilution method according to EUCAST. (3) Results: Overall, most strains were classified as sensitive to amphotericin B and flucytosine (MIC ranges of ≤0.03-1 and ≤0.06-0.125, respectively) and also to echinocandins. However, five isolates expressed high MIC values for all of the tested azoles, indicating cross-resistance. The MIC range for manogepix was 0.001-0.125 mg/L, with an MIC of 0.03 mg/L and an MIC of 0.06 mg/L. (4) Conclusions: The occurrence of resistance to azoles may be a concerning problem and therefore should be investigated further. However, the new antifungal manogepix appears to be an interesting new therapeutic option for treating such infections.
PubMed: 38535591
DOI: 10.3390/pathogens13030248 -
Analytical Chemistry Oct 2023Rapid antifungal susceptibility testing (AFST) is urgently needed in clinics to treat invasive fungal infections with the appropriate antifungal drugs and to slow the...
Rapid antifungal susceptibility testing (AFST) is urgently needed in clinics to treat invasive fungal infections with the appropriate antifungal drugs and to slow the emergence of antifungal resistance. However, current AFST methods are time-consuming (24-48 h) due to the slow growth of fungal cells and the methods not being able to work directly for clinical samples. Here, we demonstrate rapid AFST by measuring the metabolism in single fungal cells using stimulated Raman scattering imaging and deuterium probing. Distinct metabolic responses were observed in to different classes of antifungal drugs: while the metabolism was inhibited by amphotericin B, it was stimulated by azoles (fluconazole and voriconazole) and micafungin. Accordingly, we propose metabolism change as a biomarker for rapid AFST. The results were obtained in 4 h with 100% categorical agreement with the gold standard broth microdilution test. In addition, a protocol was developed for direct AFST from positive blood cultures. This method overcomes the limitation of slow growth in conventional methods and has the potential for the rapid diagnosis of candidemia and other clinical fungal infections.
Topics: Antifungal Agents; Candida; Spectrum Analysis, Raman; Microbial Sensitivity Tests; Fluconazole
PubMed: 37815933
DOI: 10.1021/acs.analchem.3c02243 -
Pediatric Transplantation May 2024Pediatric lung transplant patients are at risk for developing invasive fungal infections post-transplant. No consensus exists on optimal antifungal regimens and...
BACKGROUND
Pediatric lung transplant patients are at risk for developing invasive fungal infections post-transplant. No consensus exists on optimal antifungal regimens and voriconazole, a common first-line agent, has been shown to cause hepatotoxicity. We describe a single-center experience utilizing a novel antifungal regimen of intravenous micafungin and nebulized amphotericin B immediately post-transplant with conversion to an azole at the time of hospital discharge and compare it to a historical cohort of patients who received voriconazole monotherapy throughout their immediate post-operative course.
METHODS
This is a retrospective review of patients in the age 0-18 who received a lung transplant from June 2016-May 2021. Data points collected included: demographic data, transplant date and discharge date, Aspergillus colonization, type of lung transplant, hospitalization and level of care information, induction and antifungal medication regimen; AST, ALT, GGT, bilirubin, and direct bilirubin at various timepoints; and respiratory and blood culture results. The two patient groups were compared by assessment of changes in LFTs and culture results.
RESULTS
Forty-two patients were included in the analysis, with 24 patients receiving micafungin and nebulized amphotericin and 18 patients receiving voriconazole. All patients in both groups experienced a post-operative elevation in at least one transaminase or bilirubin. More patients in the micafungin/amphotericin group had resolution of all abnormal LFTs by 1 month post-transplant (p = .036). Additionally, patients in the micafungin/amphotericin group experienced faster normalization of their LFTs compared with the voriconazole group (p < .001). Ten patients in the micafungin/amphotericin group and five patients in the voriconazole group were found to have fungal growth on culture post-transplant, but this difference was not found to be statistically significant (p = .507).
CONCLUSIONS
An antifungal regimen of micafungin and nebulized amphotericin B liposomal may be useful at decreasing the duration of elevated liver enzymes in pediatric patients in the immediate post-lung transplant period when compared with voriconazole monotherapy. Larger prospective studies looking at antifungal regimens in pediatric patients post-lung transplant are warranted.
Topics: Humans; Child; Infant, Newborn; Infant; Child, Preschool; Adolescent; Antifungal Agents; Amphotericin B; Voriconazole; Micafungin; Transplant Recipients; Prospective Studies; Bilirubin; Lung; Chemical and Drug Induced Liver Injury
PubMed: 38616325
DOI: 10.1111/petr.14740 -
European Journal of Medicinal Chemistry Jul 2023A series of spiro-quinazolinone scaffolds were constructed based on the bioactivity of quinazolinone and the inherent feature of spirocycle to design novel chitin...
A series of spiro-quinazolinone scaffolds were constructed based on the bioactivity of quinazolinone and the inherent feature of spirocycle to design novel chitin synthase inhibitors that possess mode of action different from that of the currently used antifungal agents. Among them, the spiro[thiophen-quinazolin]-one derivatives containing α, β-unsaturated carbonyl fragments had shown inhibitory activities against chitin synthase and antifungal activities. The enzymatic experiments showed that among the sixteen compounds, compounds 12d, 12g, 12j, 12l and 12m exhibited inhibitions against chitin synthase with IC values of 116.7 ± 19.6 μM, 106.7 ± 14.2 μM, 102.3 ± 9.6 μM, 122.7 ± 22.2 μM and 136.8 ± 12.4 μM, respectively, which were comparable to that of polyoxin B (IC = 93.5 ± 11.1 μM). The assays of enzymatic Kinetic parameters showed that compound 12g was a non-competitive inhibitor of chitin synthase. The antifungal assays showed that compounds 12d, 12g, 12j, 12l and 12m exhibited a broad-spectrum of antifungal activity against the four strains tested in vitro. In which, compounds 12g and 12j had stronger antifungal activity against four tested strains than that of polyoxin B and similar to that of fluconazole, while compounds 12d, 12l and 12m showed antifungal activity comparable to that of polyoxin B against four tested strains. Meanwhile, compounds 12d, 12g, 12j, 12l and 12m exhibited good antifungal activity against fluconazole-resistant and micafungin-resistant fungi variants with MIC values ranging from 4 to 32 μg/mL while the MIC values of reference drugs were above 256 μg/mL. Furthermore, the results of drug-combination experiments showed that compounds 12d, 12g, 12j, 12l and 12m had synergistic or additive effects with fluconazole or polyoxin B. The results of sorbitol protection experiment and the experiment of antifungal activity against micafungin-resistant fungi further demonstrated that these compounds target chitin synthase. The result of cytotoxicity assay showed that compound 12g had low toxicity toward human lung cancer A549 cells and the ADME analysis in silico displayed that compound 12g possessed promising pharmacokinetic properties. The molecular docking indicated that compound 12g formed multiple hydrogen bond interactions binding to chitin synthase, which might be conductive to increasing the binding affinity and inhibiting the activity of chitin synthase. The above results indicated that the designed compounds were chitin synthase inhibitors with selectivity and broad-spectrum antifungal activity and could be act as the lead compounds against drug-resistant fungi.
Topics: Humans; Antifungal Agents; Structure-Activity Relationship; Chitin Synthase; Enzyme Inhibitors; Quinazolinones; Fluconazole; Micafungin; Chitin; Molecular Docking Simulation; Microbial Sensitivity Tests; Fungi; Drug Design
PubMed: 37141707
DOI: 10.1016/j.ejmech.2023.115388