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1.
Antimicrob Agents Chemother ; 67(7): e0037923, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37310234

RESUMO

We conducted in vitro antimicrobial susceptibility testing of 267 Achromobacter isolates for 16 antibiotics from 2017 to 2022. The highest susceptibility was found for piperacillin-tazobactam (70%) and ceftazidime-avibactam (62%). Between 30% and 49% of strains were susceptible to tigecycline, ceftazidime, and meropenem. We applied species-specific Achromobacter xylosoxidans breakpoints for piperacillin-tazobactam, meropenem, and trimethoprim-sulfamethoxazole and EUCAST pharmacokinetic/pharmacodynamic (PK/PD) breakpoints for the others. A. xylosoxidans was the most frequently isolated species, followed by Achromobacter insuavis and Achromobacter ruhlandii.


Assuntos
Achromobacter , Fibrose Cística , Humanos , Meropeném , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Achromobacter/genética , Piperacilina/farmacologia , Tazobactam/farmacologia
2.
Med Mycol ; 61(11)2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37960934

RESUMO

Mycetoma is a neglected tropical disease commonly caused by the fungus Madurella mycetomatis. Standard treatment consists of extensive treatment with itraconazole in combination with surgical excision of the infected tissue, but has a low success rate. To improve treatment outcomes, novel treatment strategies are needed. Here, we determined the potential of manogepix, a novel antifungal agent that targets the GPI-anchor biosynthesis pathway by inhibition of the GWT1 enzyme. Manogepix was evaluated by determining the minimal inhibitory concentrations (MICs) according to the CLSI-based in vitro susceptibility assay for 22 M. mycetomatis strains and by in silico protein comparison of the target protein. The synergy between manogepix and itraconazole was determined using a checkerboard assay. The efficacy of clinically relevant dosages was assessed in an in vivo grain model in Galleria mellonella larvae. MICs for manogepix ranged from <0.008 to >8 mg/l and 16/22 M. mycetomatis strains had an MIC ≥4 mg/ml. Differences in MICs were not related to differences observed in the GWT1 protein sequence. For 70% of the tested isolates, synergism was found between manogepix and itraconazole in vitro. In vivo, enhanced survival was not observed upon admission of 8.6 mg/kg manogepix, nor in combination treatment with 5.7 mg/kg itraconazole. MICs of manogepix were high, but the in vitro antifungal activity of itraconazole was enhanced in combination therapy. However, no efficacy of manogepix was found in an in vivo grain model using clinically relevant dosages. Therefore, the therapeutic potential of manogepix in mycetoma caused by M. mycetomatis seems limited.


Treatment of Madurella mycetomatis-caused mycetoma consists of extensive exposure to antifungals and surgery. To improve therapy, we evaluated manogepix, a novel antifungal agent, as a therapeutic option against M. mycetomatis. Our findings suggest limited therapeutic potential for manogepix.


Assuntos
Madurella , Micetoma , Animais , Itraconazol/farmacologia , Itraconazol/uso terapêutico , Micetoma/tratamento farmacológico , Micetoma/microbiologia , Micetoma/veterinária , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico
3.
Mycoses ; 66(3): 242-248, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36435987

RESUMO

BACKGROUND: Treatment options against infections caused by rare but emerging moulds may be limited by their reduced susceptibility or resistance to clinically available antifungals. The investigational antifungal olorofim, which targets the biosynthesis of pyrimidines within fungi, has activity against different species of filamentous fungi, including Aspergillus and Scedosporium/Lomentospora prolificans isolates that are resistant to available antifungals. OBJECTIVE: We evaluated the in vitro activity of olorofim against 160 isolates within the genera Microascus/Scopulariopsis, Penicillium, Talaromyces and the Rasamsonia argillacea species complex. METHODS: One hundred sixty clinical isolates that had previously been identified to the species level by DNA sequence analysis were included. Antifungal susceptibility testing was performed by CLSI M38 broth microdilution for olorofim, amphotericin B, caspofungin, posaconazole and voriconazole. RESULTS: Olorofim demonstrated in vitro activity against each of the genera tested. Overall, olorofim MICs ranged from ≤0.008 to 0.5 mg/L against all isolates tested, with MIC90 and modal MIC values ranging from ≤0.008 to 0.25 mg/L and ≤0.008 to 0.03 mg/L, respectively. This activity was also maintained against individual isolates that had reduced susceptibility to or in vitro resistance against amphotericin B, posaconazole and/or voriconazole. CONCLUSIONS: The investigational agent olorofim demonstrated good in vitro activity against clinical isolates of emerging mould pathogens, including those with reduced susceptibility or resistance to clinically available antifungals. Further studies are warranted to determine how well this in vitro activity translates into in vivo efficacy against infections caused by these fungi.


Assuntos
Ascomicetos , Penicillium , Scopulariopsis , Talaromyces , Humanos , Antifúngicos/farmacologia , Voriconazol/farmacologia , Anfotericina B/farmacologia , Di-Hidro-Orotato Desidrogenase , Pirimidinas/farmacologia , Testes de Sensibilidade Microbiana
4.
Lett Appl Microbiol ; 76(1)2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36688756

RESUMO

This study evaluated in-vitro action of a new molecule, the polypyrrole nanoparticles (Ppy-NP), against Pythium insidiosum isolates using M38-A2/CLSI; the minimal inhibitory (MIC) and minimal oomicidal (MOC) concentrations were also determined. Additionally, changes in the hyphae wall of P. insidiosum CBS 575.85 treated with Ppy-NP were evaluated by scanning electron microscopy (SEM). The MIC100 and MOC for all isolates ranged from 8 to 32 µg mL-1, and the MIC90 and MIC50 were 16 µg mL-1. The SEM showed structural damage to the hyphae of P. insidisoum treated with Ppy-NP, as hyphae surfaces with less turgidity were found, thereby showing scaling and ruptures compared to the control (untreated hyphae). Our findings highlighted the anti-P. insidiosum properties of Ppy-NP proved to be a promising candidate for research using pythiosis experimental models.


Assuntos
Nanopartículas , Pythium , Polímeros , Pirróis
5.
Eur J Clin Microbiol Infect Dis ; 41(1): 163-167, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34529167

RESUMO

We describe a case of recurrent catheter-related blood stream infections (BSI) with Staphylococcus aureus, in which the first isolate tested susceptible to penicillin, while subsequent isolates were resistant. Phenotypic susceptibility correlated with the absence/presence of the blaZ gene. The in vitro stability of penicillin resistance was investigated by subculturing single colonies. In two out of five colonies, phenotypical resistance was lost after a single subculture, which correlated with loss of the blaZ gene. This in vitro phenomenon probably resulted in a very major error in the microbiology report of the first BSI, where penicillin had been recommended as treatment.


Assuntos
Antibacterianos/farmacologia , Bacteriemia/microbiologia , Proteínas de Bactérias/genética , Infecções Relacionadas a Cateter/microbiologia , Penicilinas/farmacologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , beta-Lactamases/genética , Bacteriemia/tratamento farmacológico , Proteínas de Bactérias/metabolismo , Sangue/microbiologia , Infecções Relacionadas a Cateter/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Resistência às Penicilinas , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/enzimologia , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , beta-Lactamases/metabolismo
6.
Mycoses ; 65(6): 650-655, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35398930

RESUMO

INTRODUCTION: Eumycetoma is a subcutaneous mutilating disease that can be caused by many different fungi. Current treatment consists of prolonged itraconazole administration in combination with surgery. In many centres, due to their slow growth rate, the treatment for eumycetoma is often started before the causative agent is identified. This harbours the risk that the causative fungus is not susceptible to the given empirical therapy. In the open-source drug program MycetOS, ravuconazole and luliconazole were promising antifungal agents that were able to inhibit the growth of Madurella mycetomatis, the most common causative agent of mycetoma. However, it is currently not known whether these drugs inhibit the growth of other eumycetoma causative agents. MATERIALS AND METHODS: Here, we determined the in vitro activity of luliconazole, lanoconazole and ravuconazole against commonly encountered eumycetoma causative agents. MICs were determined for lanoconazole, luliconazole and ravuconazole against 37 fungal isolates which included Madurella species, Falciformispora senegalensis, Medicopsis romeroi and Trematosphaeria grisea and compared to those of itraconazole. RESULTS: Ravuconazole, luliconazole and lanoconazole showed high activity against all eumycetoma causative agents tested with median minimal inhibitory concentrations (MICs) ranging from 0.008-2 µg/ml, 0.001-0.064 µg/ml and 0.001-0.064 µg/ml, respectively. Even Ma. fahalii and Me. romeroi, which are not inhibited in growth by itraconazole at a concentration of 4 µg/ml, were inhibited by these azoles. CONCLUSION: The commonly encountered eumycetoma causative agents are inhibited by lanoconazole, luliconazole and ravuconazole. These drugs are promising candidates for further evaluation as potential treatment for eumycetoma.


Assuntos
Madurella , Micetoma , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Humanos , Imidazóis , Itraconazol/farmacologia , Itraconazol/uso terapêutico , Micetoma/tratamento farmacológico , Micetoma/microbiologia , Tiazóis , Triazóis
7.
Int J Mol Sci ; 23(24)2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36555687

RESUMO

Candida tropicalis is an emerging pathogen with a high mortality rate due to its virulence factors, including biofilm formation, that has important repercussions on the public health system. The ability of C. tropicalis to form biofilms, which are potentially more resistant to antifungal drugs and the consequent increasing antimicrobial resistance, highlights an urgent need for the development of novel antifungal. The present study analyzed the antibiofilm capacity of the arylamidine T-2307 on two strains of Candida tropicalis. Antimicrobial activity and time-killing assays were performed to evaluate the anticandidal effects of T-2307, the antibiofilm ability on biomass inhibition and eradication was evaluated by the crystal violet (CV) method. Furthermore, in Galleria mellonella infected larvae an increased survival after pre-and post- treatment with T-2307 was observed. The MTT test was used to determine the viability of immortalized human prostate epithelial cells (PNT1A) after exposure to different concentrations of T-2307. Levels of interleukin IL-4, IL-8, IL-10 were quantified after Candida infection of PNT1A cells and treatment. Active doses of T-2307 did not affect the viability of PNT1A cells, and drug concentrations of 0.005 or 0.01 µg mL-1 inhibited the secretion of inflammatory cytokines. Taken together, these results provide new information on T-2307, indicating this drug as a new and promising alternative therapeutic option for the treatment of Candida infections.


Assuntos
Antifúngicos , Candidíase , Masculino , Animais , Humanos , Antifúngicos/farmacologia , Candida tropicalis/fisiologia , Amidinas/farmacologia , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Biofilmes , Testes de Sensibilidade Microbiana
8.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(4): 696-700, 2022 Jul.
Artigo em Zh | MEDLINE | ID: mdl-35871743

RESUMO

Objective: To investigate the source of Klebsiella pneumoniae (KP) isolated in a hospital in the past decade and the in vitro drug susceptibility, and to provide clinical references for the treatment of KP-associated infection. Methods: The detection rate, the sources of the specimens, and in vitro susceptibility to antimicrobial agents of KP isolated from clinical specimens in a hospital between January 2012 and December 2021 were retrospectively analyzed. Resistance rate of the extended-spectrum ß-lactamases-producing isolates vs. that of the non-enzyme-producing ones, and the resistance rate of imipenem-resistant strains vs. that of imipenem-susceptible ones were compared and analyzed. Carbapenase inhibitor enhancement test was used to identify the types of the carbapenemases. Results: In total, 34 573 strains of KP were isolated from 1 684 668 clinical specimens, accounting for 14.6% of bacterial isolates. There were 16 888 non-repeated strains of KP. The main specimen sources of the isolates were sputum (10 274/16 888, 60.8%), blood (1 913/16 888, 11.3%) and urine (1 876/16 888, 11.1%). The proportion of extended-spectrum ß-lactamases-producing isolates increased from 29.6% (409/1 382) in 2012 to 38.9% (967/2 487) in 2021, and the resistance rate to antimicrobial agents was higher than that of non-enzyme-producing ones ( P<0.05). The proportion of imipenem-resistant strains increased from 3.2% (44/1 382) in 2012 to 23.4% (583/2 487) in 2021, and the resistance rate to antimicrobial agents was higher than that of imipenem-susceptible strains ( P<0.05). Serine carbapenase-producing strains accounted for 91.1% (920/1010). Conclusion: The resistance to antimicrobial agents of KP strains isolated from clinical specimens increased. It is necessary to monitor the in vitro drug susceptibility and the type of the carbapenemases of the isolates in order to provide guidance for the clinical usage of antibiotics.


Assuntos
Infecções por Klebsiella , Klebsiella pneumoniae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Proteínas de Bactérias , Hospitais , Humanos , Imipenem/farmacologia , Imipenem/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , beta-Lactamases
9.
Artigo em Inglês | MEDLINE | ID: mdl-33318015

RESUMO

We present an in vitro susceptibility assay for Madurella mycetomatis hyphae using resazurin for endpoint reading. Using this assay, reproducible MICs were obtained for amphotericin B, itraconazole, voriconazole, posaconazole, terbinafine, and micafungin. Results were comparable with those of a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt (XTT)-based susceptibility assay. The lowest MICs were obtained for itraconazole and posaconazole (MIC50, 0.016 µg/ml) followed by voriconazole (MIC50, 0.063 µg/ml). Amphotericin B, micafungin, and terbinafine appeared much less effective.


Assuntos
Madurella , Antifúngicos/farmacologia , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Oxazinas , Voriconazol/farmacologia , Xantenos
10.
Artigo em Inglês | MEDLINE | ID: mdl-33753333

RESUMO

Candida auris is an emerging pathogen that has rapidly spread to many countries on multiple continents. Invasive infections caused by this species are associated with significant mortality, and treatment options are limited due to antifungal resistance. Ibrexafungerp is the first-in-class member of the triterpenoids, which inhibit the production of (1,3)-ß-d-glucan and can be administered orally. We evaluated the in vitro activity and in vivo efficacy of ibrexafungerp against C. auris Antifungal susceptibility was tested by broth microdilution against 54 C. auris isolates. Neutropenic mice were intravenously infected with a clinical isolate, and a 7-day treatment course was begun 24 h postinoculation with vehicle control, ibrexafungerp (20, 30, and 40 mg/kg orally twice daily), fluconazole (20 mg/kg orally once daily), or caspofungin (10 mg/kg intraperitoneally once daily). Fungal burden was assessed by colony counts in the kidneys on day 8 and on day 21 or as mice became moribund in the survival arm. Ibrexafungerp demonstrated consistent activity, with MICs ranging between 0.25 and 2 µg/ml against all isolates. Marked improvements in survival were observed in mice treated with the higher doses of ibrexafungerp and caspofungin. Similarly, reductions in kidney fungal burden were also observed in these groups. No improvements in survival or reductions in fungal burden were observed with fluconazole, consistent with the in vitro resistance of the isolate used to establish infection to this azole. These results demonstrate that ibrexafungerp is effective in vivo against C. auris even when the start of therapy is delayed.


Assuntos
Candidíase Invasiva , Fluconazol , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Candidíase Invasiva/tratamento farmacológico , Fluconazol/farmacologia , Glicosídeos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Teóricos , Triterpenos
11.
Med Mycol ; 60(1)2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34791380

RESUMO

The incidence of infections caused by uncommon Chaetomiaceae (Chaetomium and related species) in humans has increased in the recent years. The in vitro activity of eight antifungal drugs (amphotericin B, five azoles, two echinocandins) against 42 morphologically identified Chaetomium strains was determined according to the Clinical and Laboratory Standards Institute (CLSI) guideline. The strains were subsequently identified based on sequences of the internal transcribed spacer 1 and 2 including the intervening 5.8S nrDNA region (ITS) and the partial ß tubulin gene (tub2). Chaetomium globosum (n = 24), was the most frequently isolated species, followed by Amesia atrobrunnea (syn. Chaetomium atrobrunnea, n = 6), Dichotomopilus dolichotrichus (syn. Chaetomium dolichotrichum, n = 2) and Acrophialophora jodhpurensis, Chaetomium coarctatum, C. elatum, C. gracile, C. subaffine, C. tarraconense, C. unguicola, Dichotomopilus sp., Dichotomopilus variostiolatus, Ovatospora brasiliensis (all represented by a single strain). The geometric means of the minimum inhibitory concentrations/minimum effective concentrations (MICs/MECs) of the antifungals across all strains were (in increasing order): micafungin 0.12 µg/ml, itraconazole and posaconazole 0.21 µg/ml, amphotericin B 0.25 µg/ml, voriconazole 0.45 µg/ml, isavuconazole 0.54 µg/ml, caspofungin 2.57 µg/ml, and fluconazole 45.25 µg/ml. Micafungin had the lowest geometric mean followed by amphotericin B which had the largest range against tested isolates. All examined C. globosum strains had similar antifungal susceptibility patterns. Fluconazole and caspofungin could not be considered as an option for treatment of infections caused by Chaetomium and chaetomium-like species. LAY SUMMARY: Infections caused by uncommon fungi such as Chaetomium have increased in the recent years. Chaetomium globosum has been reported from onychomycosis and phaeohyphomycosis. This species often induces superficial infections in immunocompetent patients. The taxonomy of Chaetomium spp. has changed dramatically in the last years. Antifungal treatment is a crucial step for managing these kinds of infections. Therefore, the in vitro activity of eight antifungal drugs against Chaetomium strains was determined and ß-tubulin (tub2) sequencing was applied to identify the strains. Chaetomium globosum was the most frequent species in our dataset. Based on the results of susceptibility testing, micafungin had the lowest geometric mean followed by amphotericin B. Fluconazole and caspofungin cannot be considered a proper treatment option for infections caused by Chaetomium and chaetomium-like species.


Assuntos
Antifúngicos/farmacologia , Chaetomium/efeitos dos fármacos , Animais , Humanos , Testes de Sensibilidade Microbiana
12.
Artigo em Inglês | MEDLINE | ID: mdl-34232906

RESUMO

In the present study, the effectiveness of six antimicrobial agents have been tested against 24 borrelia strains isolated from Ixodes ricinus ticks (11 Borrelia lusitaniae, eight Borrelia afzelii, three Borrelia garinii and two Borrelia valaisiana) and one B. lusitaniae strain isolated from human skin. The minimum inhibitory concentration range of antimicrobial agents was as follows: amoxicillin, 0.125-2 mg/L; doxycycline, 0.125-1 mg/L, ceftriaxone, 0.016-0.063 mg/L; cefuroxime, 0.063-1 mg/L; azithromycin, 0.0017-0.11 mg/L; amikacin 32-512 mg/L. Potentially pathogenic B. lusitaniae and B. valaisiana species were more susceptible to amoxicillin and azithromycin than pathogenic B. afzelii and B. garinii (P < 0.05); B. garinii, B. lusitaniae and B. valaisiana were more susceptible to doxycycline than B. afzelii (P < 0.05) while all species showed same susceptibility to ceftriaxone and cefuroxime (P > 0.05). This study is the first report on in vitro susceptibility of isolates from Serbia to antimicrobial agents and the first report on susceptibility of larger number of isolates of potentially pathogenic species B. lusitaniae. We showed that antimicrobial agents in vitro inhibit growth of borrelia strains very effectively, indicating the potential of their equally beneficial use in the treatment of Lyme borreliosis.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31844006

RESUMO

The in vitro and in vivo activity of the arylamidine T-2307 against Candida auris was evaluated. T-2307 demonstrated in vitro activity (MIC ranges ≤ 0.008 to 0.015 µg/ml at 50% inhibition; 0.125 to >4 µg/ml at 100% inhibition). Treatment with T-2307 (3 mg/kg subcutaneous [SC] once daily) also significantly improved survival (70% at 21 days postinfection) and reduced kidney fungal burden (5.06 log10 CFU/g) compared to control (0% survival and 7.09 log10 CFU/g) (P < 0.01).


Assuntos
Amidinas/uso terapêutico , Antifúngicos/uso terapêutico , Candida/patogenicidade , Candidíase Invasiva/tratamento farmacológico , Animais , Candida/efeitos dos fármacos , Caspofungina/uso terapêutico , Modelos Animais de Doenças , Farmacorresistência Fúngica , Fluconazol/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICR
14.
Mycopathologia ; 185(5): 801-812, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31845178

RESUMO

Pythiosis is an emerging infectious disease caused by the aquatic oomycete Pythium insidiosum, a fungal-like organism. It is believed that P. insidiosum's zoospores, its infected form, play major role in pathogenesis. Vascular and ocular infections are the most common clinical manifestation in humans. It is difficult to establish the diagnosis given its relatively rarity and difficulty to distinguish P. insidiosum from other molds. Delay in diagnosis and treatment has been associated with poor outcomes. High index of suspicion is the key, particularly in thalassemia patients with arterial insufficiency and patients with fungal keratitis/endophthalmitis without improvement on antifungal therapy. Tissue culture and zoospore induction remain gold standard for diagnosis; however, DNA-based method should be performed simultaneously. The combination of radical surgery, antifungal agents, and immunotherapy has been recommended. It was previously believed that surgery with negative surgical margins was the essential to survive in vascular pythiosis; however, it was recently found that patients could have residual disease despite documented negative surgical margins as infected clot may be dislodged to proximal arterial sites prior to surgery. Serum ß-D-glucan (BG) has been used to monitor disease response after treatment initiation in vascular pythiosis. A significant decrease in BG levels within 2 weeks after surgery is indicative of the absence of residual infection. Unfortunately, monitoring tools for ocular pythiosis are not yet available. Itraconazole plus terbinafine have generally been used in P. insidiosum-infected patients; however, antibacterial agents, including azithromycin and linezolid, have also been used with favorable outcomes in ocular disease. Recently, azithromycin or clarithromycin plus doxycyclin were used in two relapsed vascular pythiosis patients with good outcomes.


Assuntos
Pitiose , Pythium , Antibacterianos/uso terapêutico , Antifúngicos/farmacologia , Doenças Transmissíveis Emergentes/diagnóstico , Doenças Transmissíveis Emergentes/terapia , Doenças Transmissíveis Emergentes/transmissão , Combinação de Medicamentos , Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares Fúngicas/terapia , Imunoterapia/métodos , Itraconazol/farmacologia , Oomicetos , Patologia Molecular , Pitiose/diagnóstico , Pitiose/patologia , Pitiose/terapia , Pitiose/transmissão , Pythium/efeitos dos fármacos , Pythium/isolamento & purificação , Testes Sorológicos , Esporos Fúngicos/isolamento & purificação , Terbinafina/farmacologia , Talassemia/complicações , Lesões do Sistema Vascular/diagnóstico , Lesões do Sistema Vascular/microbiologia , Lesões do Sistema Vascular/terapia , beta-Glucanas/sangue
15.
Artigo em Inglês | MEDLINE | ID: mdl-30530603

RESUMO

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.


Assuntos
Inibidores de 14-alfa Desmetilase/uso terapêutico , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase Invasiva/tratamento farmacológico , Piridinas/uso terapêutico , Tetrazóis/uso terapêutico , Animais , Candidíase Invasiva/microbiologia , Caspofungina/uso terapêutico , Modelos Animais de Doenças , Fluconazol/uso terapêutico , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Esterol 14-Desmetilase/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-30478163

RESUMO

As a consequence of emerging numbers of vulvovaginitis cases caused by azole-resistant and biofilm-forming Candida species, fast and efficient treatment of this infection has become challenging. The problem is further exacerbated by the severe side effects of azoles as long-term-use medications in the recurrent form. There is therefore an increasing demand for novel and safely applicable effective antifungal therapeutic strategies. The small, cysteine-rich, and cationic antifungal proteins from filamentous ascomycetes are potential candidates, as they inhibit the growth of several Candida spp. in vitro; however, no information is available about their in vivo antifungal potency against yeasts. In the present study, we investigated the possible therapeutic application of one of their representatives in the treatment of vulvovaginal candidiasis, Neosartorya fischeri antifungal protein 2 (NFAP2). NFAP2 inhibited the growth of a fluconazole (FLC)-resistant Candida albicans strain isolated from a vulvovaginal infection, and it was effective against both planktonic cells and biofilm in vitro We observed that the fungal cell-killing activity of NFAP2 is connected to its pore-forming ability in the cell membrane. NFAP2 did not exert cytotoxic effects on primary human keratinocytes and dermal fibroblasts at the MIC in vitro. In vivo murine vulvovaginitis model experiments showed that NFAP2 significantly decreases the number of FLC-resistant C. albicans cells, and combined application with FLC enhances the efficacy. These results suggest that NFAP2 provides a feasible base for the development of a fundamental new, safely applicable mono- or polytherapeutic topical agent for the treatment of superficial candidiasis.


Assuntos
Antifúngicos/metabolismo , Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/tratamento farmacológico , Neosartorya/metabolismo , Animais , Candidíase Vulvovaginal/microbiologia , Farmacorresistência Fúngica , Feminino , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana
17.
Med Mycol ; 57(4): 523-525, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30929019

RESUMO

We tested 25 isolates of Pythium insidiosum to investigate their susceptibility to antibacterial drugs that act through inhibition of protein synthesis or other mechanisms of action. We observed that tetracycline, erythromycin, linezolid, nitrofurantoin, Synercid (quinupristin and dalfopristin), chloramphenicol, clindamycin, cetrimide, and crystal violet had inhibitory activity against P. insidiosum. Those in vitro results suggest that antibacterials that inhibit protein synthesis should be the primary antimicrobials investigated for the treatment of pythiosis in animals and humans.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Pythium/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Humanos , Pitiose/microbiologia , Pythium/crescimento & desenvolvimento , Pythium/isolamento & purificação
18.
Artigo em Inglês | MEDLINE | ID: mdl-29530856

RESUMO

The objective of this study was to assess the in vitro activity of the novel triazole antifungal drug, efinaconazole, and five comparators (luliconazole, lanoconazole, terbinafine, itraconazole, and fluconazole) against a large collection of Trichophyton interdigitale and Trichophyton rubrum clinical isolates. The geometric mean MICs were the lowest for luliconazole (0.0005 µg/ml), followed by lanoconazole (0.002 µg/ml), efinaconazole (0.007 µg/ml), terbinafine (0.011 µg/ml), itraconazole (0.095 µg/ml), and fluconazole (12.77 µg/ml). It appears that efinaconazole, lanoconazole, and luliconazole are promising candidates for the treatment of dermatophytosis due to T. interdigitale and T. rubrum.


Assuntos
Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Triazóis/farmacologia , Fluconazol/farmacologia , Imidazóis/farmacologia , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Terbinafina/farmacologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-29914964

RESUMO

We tested the in vitro susceptibility of ceftazidime-avibactam and ceftolozane-tazobactam and 13 other antibiotics against 91 Burkholderia cepacia complex (BCC) strains isolated from cystic fibrosis patients since 2012. The highest susceptibility (82%) was found for trimethoprim-sulfamethoxazole. Eighty-one and 63% of all BCC strains were susceptible to ceftazidime-avibactam and ceftolozane-tazobactam, respectively. For temocillin, ceftazidime, piperacillin-tazobactam, and meropenem, at least 50% of the strains were susceptible. B. stabilis seems to be more resistant than other BCC species.


Assuntos
Compostos Azabicíclicos/farmacologia , Complexo Burkholderia cepacia/efeitos dos fármacos , Ceftazidima/farmacologia , Cefalosporinas/farmacologia , Fibrose Cística/microbiologia , Tazobactam/farmacocinética , Antibacterianos/farmacologia , Complexo Burkholderia cepacia/isolamento & purificação , Combinação de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Sulfametoxazol/farmacologia , Tazobactam/farmacologia , Trimetoprima/farmacologia
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