Evaluation of the Synergistic Activity of Antibacterial and Antifungal Drugs against Candida auris using an Inkjet Printer-Assisted Method

2021 ◽  
Author(s):  
Thea Brennan-Krohn ◽  
Liam Friar ◽  
Sarah Ditelberg ◽  
James E. Kirby
Keyword(s):  
Amphotericin B ◽  
Antibacterial Agents ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Antifungal Drugs ◽  
Synergistic Activity ◽  
Candida Auris ◽  
Healthcare Settings ◽  
Inkjet Printer ◽  
Antibacterial And Antifungal

Candida auris is an emerging multidrug-resistant fungal pathogen that spreads readily in healthcare settings and has caused numerous hospital outbreaks. Very few treatment options exist for C. auris infections. We evaluated the activity of all two-drug combinations of three antifungal agents (amphotericin B, caspofungin, and voriconazole) and two antibacterial agents (minocycline and rifampin) against a collection of 10 C. auris isolates using an automated, inkjet printer-assisted checkerboard array method. Three antibacterial-antifungal combinations (amphotericin B plus rifampin, amphotericin B plus minocycline, and caspofungin plus minocycline) demonstrated synergistic activity by checkerboard array against ≥90% of strains with fractional inhibitory concentration index (FICI) values of 0.094 to 0.5. The two amphotericin B-containing combinations were also synergistic using the time-kill synergy testing method, with up to a 4.99 log 10 decrease in surviving yeast compared to either agent alone. Our results suggest that combinations of antifungal and antibacterial agents may provide a promising avenue for treatment of this multidrug-resistant pathogen.

scholarly journals Synergistic Activity of Minocycline and Rifampin in Combination with Antifungal Drugs against Candida auris

2021 ◽  
Author(s):  
Thea Brennan-Krohn ◽  
Liam Friar ◽  
Sarah Ditelberg ◽  
James E. Kirby
Keyword(s):  
Amphotericin B ◽  
Antibacterial Agents ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Antifungal Drugs ◽  
Synergistic Activity ◽  
Candida Auris ◽  
Healthcare Settings ◽  
Time Kill ◽  
Synergy Testing

ABSTRACTCandida auris is an emerging multidrug-resistant fungal pathogen that spreads readily in healthcare settings and has caused numerous hospital outbreaks. Very few treatment options exist for C. auris infections. We evaluated the activity of all two-drug combinations of three antifungal agents (amphotericin B, caspofungin, and voriconazole) and two antibacterial agents (minocycline and rifampin) against a collection of 10 C. auris isolates using an automated, inkjet printer-assisted checkerboard array method. Three antibacterial-antifungal combinations (amphotericin B plus rifampin, amphotericin B plus minocycline, and caspofungin plus minocycline) demonstrated synergistic activity by checkerboard array against ≥90% of strains. The two amphotericin B-containing combinations were also synergistic using the time-kill synergy testing method. Our results suggest that combinations of antifungal and antibacterial agents may provide a promising avenue for treatment of this multidrug-resistant pathogen.

scholarly journals In Vitro Interactions of Echinocandins with Triazoles Against Multidrug-Resistant Candida auris

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S82-S82
Author(s):  
Hamid Badalii
Keyword(s):  
Amphotericin B ◽  
Antifungal Susceptibility ◽  
Multidrug Resistant ◽  
In Vivo Studies ◽  
Synergistic Activity ◽  
Candida Auris ◽  
Unsuccessful Treatment ◽  
In Vitro Interactions

Abstract Background Blood stream infections due to Candida auris are related to a high mortality rate and treatment failure attributed to resistance to fluconazole, voriconazole, amphotericin B, and caspofungin. Thus, the precise identification of agents and in vitro antifungal susceptibility testing is highly recommended. Novel therapeutic strategies, such as combination therapy, are essential for increasing the efficacy and reducing the toxicity of antifungal agents. Therefore, we investigated the in vitro combination of micafungin plus voriconazole against multidrug-resistant C. auris isolated from cases of candidemia. Methods The in vitro interactions between echinocandins and azoles were determined against ten multidrug-resistant Candida auris strains by using a microdilution checkerboard technique. Results Results revealed that MICs range for voriconazole and micafungin were 0.5–8 and 0.25–8 mg/l, respectively. The checkerboard analysis revealed that the combination of micafungin with voriconazole exhibited synergistic activity against all 10 multidrug-resistant C. auris isolates (FICI range: 0.15–0.5). Overall, no antagonistic effects were observed in this experiments. Conclusion In vitro studies have previously suggested that among azoles isavuconazole and posaconazole are more active drugs against C. auris. In addition, the majority of isolates reported are resistant to fluconazole. Remarkably, unsuccessful treatment of C. auris infections with fluconazole, voriconazole, amphotericin B, caspofungin, and anidulafungin has been already on record. Here in we demonstrates that interaction between micafungin with voriconazole exhibited synergistic activity against multidrug-resistant C. auris isolates. It seems that lower concentrations of drugs cause fewer side-effects and improve the treatment outcomes. However, in vivo studies with suitable animal models of C. auris infection is highly recommended. Disclosures All authors: No reported disclosures.

scholarly journals Candida auris and Carbapenemase-Producing Organism Prevalence in an Extended Stay Pediatric Hospital, Chicago, Illinois, 2019

2020 ◽  
Vol 41 (S1) ◽  
pp. s145-s146
Author(s):  
Kelly Walblay ◽  
Tristan McPherson ◽  
Elissa Roop ◽  
David Soglin ◽  
Ann Valley ◽  
...  
Keyword(s):  
The United States ◽  
Multidrug Resistant ◽  
Pediatric Hospital ◽  
Mechanical Ventilators ◽  
Candida Auris ◽  
Term Care ◽  
Healthcare Settings ◽  
High Acuity ◽  
Gastrostomy Tubes

Background:Candida auris and carbapenemase-producing organisms (CPO) are multidrug-resistant organisms that can colonize people for prolonged periods and can cause invasive infections and spread in healthcare settings, particularly in high-acuity long-term care facilities. Point-prevalence surveys (PPSs) conducted in long-term acute-care hospitals in the Chicago region identified median prevalence of colonization to be 31% for C. auris and 24% for CPO. Prevalence of C. auris colonization has not been described in pediatric populations in the United States, and limited data exist on CPO colonization in children outside intensive care units. The Chicago Department of Public Health (CDPH) conducted a PPS to assess C. auris and CPO colonization in a pediatric hospital serving high-acuity patients with extended lengths of stay (LOS). Methods: CDPH conducted a PPS in August 2019 in a pediatric hospital with extended LOS to screen for C. auris and CPO colonization. Medical devices (ie, gastrostomy tubes, tracheostomies, mechanical ventilators, and central venous catheters [CVC]) and LOS were documented. Screening specimens consisted of composite bilateral axillae and groin swabs for C. auris and rectal swabs for CPO testing. The Wisconsin State Laboratory of Hygiene tested all specimens. Real-time polymerase chain reaction (PCR) assays were used to detect C. auris DNA and carbapenemase genes: blaKPC, blaNDM, blaVIM, blaOXA-48, and blaIMP (Xpert Carba-R Assay, Cepheid, Sunnyvale, CA). All axillae and groin swabs were processed by PCR and culture to identify C. auris. For CPO, culture was only performed on PCR-positive specimens. Results: Of the 29 patients hospitalized, 26 (90%) had gastrostomy tubes, 24 (83%) had tracheostomies, 20 (69%) required mechanical ventilation, and 3 (10%) had CVCs. Also, 25 (86%) were screened for C. auris and CPO; 4 (14%) lacked parental consent and were not swabbed. Two rectal specimens were unsatisfactory, producing invalid CPO test results. Median LOS was 35 days (range, 1–300 days). No patients were positive for C. auris. From CPO screening, blaOXA-48 was detected in 1 patient sample, yielding a CPO prevalence of 3.4% (1 of 29). No organism was recovered from the blaOXA-48 positive specimen. Conclusions: This is the first documented screening of C. auris colonization in a pediatric hospital with extended LOS. Despite a high prevalence of C. auris and CPOs in adult healthcare settings of similar acuity in the region, C. auris was not identified and CPOs were rare at this pediatric facility. Additional evaluations in pediatric hospitals should be conducted to further understand C. auris and CPO prevalence in this population.Funding: NoneDisclosures: None

scholarly journals 1579. Multidrug-Resistant Candida auris Isolates From New York Hospitals and Healthcare Facilities Are Susceptible to Antifungal Combinations

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S576-S577
Author(s):  
Brittany O’Brien ◽  
Sudha Chaturvedi ◽  
Vishnu Chaturvedi
Keyword(s):  
New York ◽  
Diagnostic System ◽  
Multidrug Resistant ◽  
Drug Combinations ◽  
Antifungal Drugs ◽  
Drug Resistant ◽  
Candida Auris ◽  
Current Case ◽  
Healthcare Facilities ◽  
Broth Microdilution Method

Abstract Background Candida auris outbreak continues unabated in New York with the current case counts exceeding 300 patients. We used a modification of standard CLSI broth microdilution method (BMD) if two-drug combinations are efficacious against C. auris isolates with high-resistance to fluconazole (FZ, MIC50 >256 mg/L), and variable resistance to other broad-spectrum antifungal drugs. Methods BMD plates were custom-designed and quality controlled by TREK Diagnostic System. The combination tests of 15 drug-resistant C. auris involved microtiter wells with the initial 144 two-drug combinations and their two-fold dilutions (1/2–1/32) to get 864 two-drug combinations finally. We utilized MIC100 endpoints for the drug combination readings as reported earlier for the intra- and inter-laboratory agreements obtained against Candida species and Aspergillus fumigatus (Antimicrob Agents Chemother. 2015. 59:1759–1766). We also tested minimum fungicidal concentrations (MFC). Results We tested all possible 864 two-drug antifungal combinations for nine antifungal drugs in use to yield 12,960 MIC100 readings, and MFC readings for 15 C. auris isolates. Flucytosine (FLC) at 2.0 mg/L potentiated most successful combinations with other drugs. Micafungin (MFG), Anidulafungin (AFG), Caspofungin (CAS) at individual concentrations of 0.25 mg/L combined well with FLC (2.0 mg/L) to yield MIC100 for 14, 13, and 12 of 15 C. auris isolates tested, respectively. MFG/FLC combination was also fungicidal for 4 of 15 isolates. AMB / FLC (0.25/1.0 mg/L) yielded MIC100 for 13 isolates and MFC for three test isolates. Posaconazole (POS), and Isavuconazole (ISA) and Voriconazole (VRC) also combined well with FLC (0.25/2.0 mg/L) to yield MIC100 for 12, 13, and 13 isolates, respectively. POS/FLC combination was fungicidal for three isolates. Conclusion We identified seven two drug-combinations of antifungals efficacious against drug-resistant C. auris strains. The modified BMD combination susceptibility testing could be used by the clinical laboratories to assist providers with the selection of optimal treatment for C. auris candidemia. Disclosures All authors: No reported disclosures.

scholarly journals In Vitro Antifungal Combination of Flucytosine with Amphotericin B, Voriconazole, or Micafungin against Candida auris Shows No Antagonism

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
A. L. Bidaud ◽  
F. Botterel ◽  
A. Chowdhary ◽  
E. Dannaoui
Keyword(s):  
Amphotericin B ◽  
Inhibitory Concentration ◽  
Geometric Mean ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Resistant Mutants ◽  
Hospital Acquired

ABSTRACT Candida auris is an emerging, multidrug-resistant pathogen responsible for invasive hospital-acquired infections. Flucytosine is an effective anti-Candida species drug, but which cannot be used as a monotherapy because of the risk of development of resistant mutants during treatment. It is, therefore, noteworthy to test possible combinations with flucytosine that may have a synergistic interaction. In this study, we determined the in vitro interaction between flucytosine and amphotericin B, micafungin, or voriconazole. These combinations have been tested against 15 C. auris isolates. The MIC ranges (geometric mean [Gmean]) of flucytosine, amphotericin B, micafungin, and voriconazole were 0.125 to 1 μg/ml (0.42 μg/ml), 0.25 to 1 μg/ml (0.66 μg/ml), 0.125 to 0.5 μg/ml (0.3 μg/ml), and 0.03 to 4 μg/ml (1.05 μg/ml), respectively. When tested in combination, indifferent interactions were mostly observed with fractional inhibitory concentration index values from 0.5 to 1, 0.31 to 1.01, and 0.5 to 1.06 for the combinations of flucytosine with amphotericin B, micafungin, and voriconazole, respectively. A synergy was observed for the strain CBS 10913 from Japan. No antagonism was observed for any combination. The combination of flucytosine with amphotericin B or micafungin may be relevant for the treatment of C. auris infections.

scholarly journals Cyathea gigantea (Cyatheaceae) as an antimicrobial agent against multidrug resistant organisms

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Kathakali Nath ◽  
Anupam Das Talukdar ◽  
Mrinal Kanti Bhattacharya ◽  
Deepshikha Bhowmik ◽  
Shiela Chetri ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Antibacterial Property ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Synergistic Activity ◽  
Gram Positive ◽  
Traditional Use ◽  
Gram Negative ◽  
Multidrug Resistant Organisms

Abstract Background Rapid emergence of multidrug resistant (MDR) organisms in hospital and community settings often result into treatment failure, thus leading the clinicians with fewer treatment options. Cyathea gigantea, an ethnomedicinally important fern used in cuts and wound infections. So, if this medicinal plant is used in treating the MDR infections then it might bring certain relief in future treatment options. Methods Antibacterial activity of C. gigantea against MDR bacteria was assed using well diffusion and broth microdilution methods to determine the diameters of growth inhibition zones, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Synergistic activity was also determined with the conventional antibiotics by disc diffusion method followed by FIC index of each of the tested antibiotic was calculated. The active extract was then subjected to fractionation by column chromatography and antibacterial activity was done with each of the collected fractions. Results Crude extract of C. gigantea was found to be active against all the tested organisms. The MIC was 200 μg/ml against Gram-positive i.e., Staphylococcus aureus ATCC 25923 and 400 μg/ml against Gram-negative i.e., Escherichia coli ATCC 25922 and Pseudomonas aeruginosa PAO1, while the MBC was 400 μg/ml in case of Gram-positive and 800 μg/ml for Gram-negative. The synergistic activity revealed that the plant extract increased the antibacterial property of the studied antibiotics and the FIC index showed that significant synergistic activity was shown by ciprofloxacin followed by tetracycline, ampicillin and oxacillin. Antibacterial activity with the fractionated extract showed that the FR II, FR III and FR IV were active against both Gram-positive and Gram-negative bacteria, whereas FR I, FR V and FR VI did not show antibacterial property against any of the tested bacteria. Conclusions Extracts of C. gigantea was found active against both selected Gram-positive and Gram-negative organisms and thus offers the scientific basis for the traditional use of the fern. The present study also provides the basis for future study to validate the possible use against multidrug resistant organisms.

scholarly journals Candida duobushaemulonii: An Old But Unreported Pathogen

2020 ◽  
Vol 6 (4) ◽  
pp. 374
Author(s):  
Irene Jurado-Martín ◽  
Cristina Marcos-Arias ◽  
Esther Tamayo ◽  
Andrea Guridi ◽  
Piet W. J. de Groot ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Related Species ◽  
Antifungal Drugs ◽  
Candida Auris ◽  
Closely Related Species ◽  
Identification Methods ◽  
Phenotypic Identification ◽  
Candida Intermedia ◽  
Candida Haemulonii

Candidiasis caused by species of the Candida haemulonii complex (Candida haemulonii and Candida duobushaemulonii) and closely related species, Candida auris and Candida pseudohaemulonii are increasing. These species often show reduced susceptibility to antifungal drugs, such as azoles and amphotericin B or, less frequently, echinocandins. However, conventional phenotypic identification methods are unable to accurately differentiate these species and, therefore, their prevalence may have been underestimated. In this study, 150 isolates that were probably misidentified were reanalyzed using two novel PCR approaches. We found that one isolate previously identified in 1996 as Candida intermedia was C. duobushaemulonii, being one of the oldest isolates of this species described to date. We also found that this isolate had reduced susceptibility to fluconazole, itraconazole, and amphotericin B.

scholarly journals Synergistic Activity of Colistin-Containing Combinations against Colistin-ResistantEnterobacteriaceae

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Thea Brennan-Krohn ◽  
Alejandro Pironti ◽  
James E. Kirby
Keyword(s):  
Treatment Options ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Resistant Strains ◽  
Bacterial Outer Membrane ◽  
Time Kill ◽  
Synergistic Combinations

ABSTRACTResistance to colistin, a polypeptide drug used as an agent of last resort for the treatment of infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, including carbapenem-resistantEnterobacteriaceae(CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We investigated the synergistic activity of colistin in combination with 19 antibiotics against a collection of 20 colistin-resistantEnterobacteriaceaeisolates, 15 of which were also CRE. All combinations were tested against all strains using an inkjet printer-assisted digital dispensing checkerboard array, and the activities of those that demonstrated synergy by this method were evaluated against a single isolate in a time-kill synergy study. Eighteen of 19 combinations demonstrated synergy against two or more isolates, and the 4 most highly synergistic combinations (colistin combined with linezolid, rifampin, azithromycin, and fusidic acid) were synergistic against ≥90% of strains. Sixteen of 18 combinations (88.9%) that were synergistic in the checkerboard array were also synergistic in a time-kill study. Our findings demonstrate that colistin in combination with a range of antibiotics, particularly protein and RNA synthesis inhibitors, exhibits synergy against colistin-resistant strains, suggesting that colistin may exert a subinhibitory permeabilizing effect on the Gram-negative bacterial outer membrane even in isolates that are resistant to it. These findings suggest that colistin combination therapy may have promise as a treatment approach for patients infected with colistin-resistant XDR Gram-negative pathogens.

scholarly journals Assessment of Candida auris Response to Antifungal Drugs Using Time–Kill Assays and an Animal Model

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S73-S73 ◽  
Author(s):  
Ronen Ben-Ami ◽  
Liat Ashkenazi ◽  
Judith Berman ◽  
Nuphar Korolker ◽  
Anna Novikov
Keyword(s):  
Amphotericin B ◽  
Fungicidal Activity ◽  
Antifungal Drugs ◽  
Rank Test ◽  
Infection Model ◽  
Candida Auris ◽  
Fungistatic Activity ◽  
Kill Curve ◽  
Time Kill

Abstract Background Candida auris is an emerging nosocomial pathogen that is resistant to Fluconazole and variably susceptible to other systemic drug classes. Treatment with echinocandins has been recommended based on MICs in the susceptible range, but supporting in vivo data is lacking. Methods We tested the MIC of C. auris strains (n = 12) to fluconazole, voriconazole, posaconazole. anidulafungin, amphotericin B and flucytosine. Representative C. auris strains from Israel and South Africa, and a reference C. albicans strain were analysed using time–kill curve assays. Fungicidal activity was defined as reduction of ≥3 log from baseline CFU/ml. Response to caspofungin treatment was assessed in BALB/c mice immunosuppressed with cyclophosphamide and inoculated with 7 × 107C. auris cells by tail vein injection. Mice were treated from day +1 to day +7 with caspofungin (IP) at doses of 1 or 5 mg/kg and compared with sham-treated controls. Survival was assessed daily. Kaplan-Meier survival analyses were performed and treatment arms were compared using the log-rank test. Results Drug susceptibility results (MIC50 and MIC90) were: fluconazole, 64 and 128 mg/l; voriconazole, 0.5 and 24 mg/l; posaconazole, 0.5 and 27 mg/l; anidulafungin, 0.03 and 0.06 mg/l; amphotericin B, 2 and 8 mg/l; flucytosine, 0.3 and 1 mg/l. Time–kill curve analyses showed log reduction from baseline CFU concentration of −3.0 to −2.8 for fluconazole (MIC ×1), 5.6–6.1 for amphotericin B (MIC ×4) and −0.4 to −0.9 for caspofungin (MIC ×16), consistent with fungicidal activity of amphotericin B and weak fungistatic activity of caspofungin. In the mouse model, survival rate was similar with sham treatment (33%) and treatment with caspofungin 1 mg/kg/day (44%) and 5 mg/kg/day (22%), P = 0.7. Conclusion Despite generally low MIC, caspofungin has only mild fungistatic activity on C. auris and no effect on survival in a mouse infection model. Amphotericin B has fungicidal activity against C. auris. Disclosures All authors: No reported disclosures.

scholarly journals A Cluster of Candida auris Blood Stream Infections in a Tertiary Care Hospital in Oman from 2016 to 2019

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 638 ◽  
Author(s):  
Jalila Mohsin ◽  
Sanjeewani Weerakoon ◽  
Sarah Ahmed ◽  
Ynze Puts ◽  
Zainab Al Balushi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Tertiary Care ◽  
Care Facility ◽  
Antifungal Drugs ◽  
Care Hospital ◽  
Candida Auris ◽  
Maldi Tof ◽  
Healthcare Settings ◽  
Line Therapy ◽  
Rdna Sequencing

(1) Background: Candida auris has been reported as emerging yeast pathogen that can cause invasive bloodstream infections in healthcare settings. It is associated with high mortality rates and resistance to multiple classes of antifungal drugs and is difficult to identify with standard laboratory methods. (2) Methods: We conducted a retrospective review of epidemiological, clinical, and microbiological records for 23 C. auris fungemia cases at the Royal Hospital, a tertiary care facility in Oman, between 2016 and 2018. Demographic data, risk factors associated with mortality, microbiology investigation and treatment regimens are described. Yeasts were identified by MALDI-TOF. (3) Results: We identified 23 patients with C. auris fungemia. All positive samples from patients were confirmed as C. auris using MALDI-TOF, and ITS-rDNA sequencing. Microsatellite genotyping showed that the Omani isolates belong to the South Asian clade I. The majority of patients had multiple underlying illnesses and other risk factors that have been associated with fungemia. All isolates were non-susceptible to fluconazole. Isolates from all patients were sensitive to echinocandins and these were used as first line therapy. (4) Conclusions: Candida auris affects adults and children with a variety of risk factors including central venous catheters and overuse of antibiotics. Infections occur in both immunocompromised and immunocompetent individuals. Mortality was high in this series, and the organism can be transmitted in healthcare settings. Programs for raising awareness in Oman hospitals are warranted. Caspofungin remains 1st line therapy as MICs are still low despite its wide use.

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