Comparison of methodologies for synergism testing of drug combinations against resistant strains of Pseudomonas aeruginosa.

1996 ◽  
Vol 40 (3) ◽  
pp. 677-683 ◽  
Author(s):  
D M Cappelletty ◽  
M J Rybak
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Isolate ◽  
Inhibitory Concentration ◽  
Laboratory Strain ◽  
Fractional Inhibitory Concentration ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Drug Concentrations ◽  
Concentration Indices

The purpose of this study was to determine if synergism was maintained for various combinations of beta-lactams with an aminoglycoside against four clinical strains and one laboratory strain of Pseudomonas aeruginosa which were resistant, according to the MICs, to the beta-lactams and/or aminoglycoside. The results from both the checkerboard and killing curve methodologies were compared. The laboratory strain (ATCC 27853) was manipulated in vitro by serial passage onto agar containing increasing concentrations of each antibiotic to select for resistance. One clinical isolate (R61) was also serially passed to raise the MIC of piperacillin from 128 to 1,024 micrograms/ml. The fractional inhibitory concentration indices for all isolates indicated indifference for all combination therapies, with values ranging from 0.6 to 3. In contrast, killing curve results for all isolates demonstrated synergism with drug concentrations at either one-fourth or one-half the MIC for each organism. The MIC of piperacillin for the laboratory-manipulated clinical isolate R61 was 1,024 micrograms/ml, and synergism was still observed with concentrations of one-half the MIC of piperacillin and amikacin. For clinical isolate R166, which was beta-lactam and tobramycin resistant, synergism continued to be demonstrated with concentrations of tobramycin (1/16 MIC) in combination with piperacillin and cefepime at 1/2 the MIC. The results of this study indicate that against P. aeruginosa, synergism is observed in spite of resistance to beta-lactams and/or aminoglycosides. Synergism appears to be maintained even at very high MICs (piperacillin, 1,024 micrograms/ml; tobramycin, 128 micrograms/ml) with drug concentrations within achievable therapeutic ranges. With current definitions of synergism there was a complete lack of correlation between the results obtained by the checkerboard and killing curve methodologies, with the fractional inhibitory concentration indices showing indifference and killing curves resulting in synergism. The methodologies and definitions of synergism or antagonism are variable and not standardized and should be reevaluated.

scholarly journals Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening

2018 ◽  
Author(s):  
María Pilar Arenaz Callao ◽  
Rubén González del Río ◽  
Ainhoa Lucía Quintana ◽  
Charles J. Thompson ◽  
Alfonso Mendoza-Losana ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Amoxicillin Clavulanate ◽  
Low Toxicity ◽  
Potential Use ◽  
Ulcer Treatment

ABSTRACTThe potential use of clinically approved beta-lactams for Buruli ulcer (BU) treatment was investigated with representative classes analyzed in vitro for activity against Mycobacterium ulcerans. Beta-lactams tested were effective alone and displayed a strong synergistic profile in combination with antibiotics currently used to treat BU, i.e. rifampicin and clarithromycin; this activity was further potentiated in the presence of the beta-lactamase inhibitor clavulanate. In addition, quadruple combinations of rifampicin, clarithromycin, clavulanate and beta-lactams resulted in multiplicative reductions in their minimal inhibitory concentration (MIC) values. The MIC of amoxicillin against a panel of clinical isolates decreased more than 200-fold within this quadruple combination. Amoxicillin/clavulanate formulations are readily available with clinical pedigree, low toxicity, and orally and pediatric available; thus, supporting its potential inclusion as a new anti-BU drug in current combination therapies.

scholarly journals In Vitro Activity of the Ultra-Broad-Spectrum Beta-lactamase Inhibitor QPX7728 in Combination with Multiple Beta-Lactam Antibiotics against Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Olga Lomovskaya ◽  
Debora Rubio-Aparicio ◽  
Kirk Nelson ◽  
Dongxu Sun ◽  
Ruslan Tsivkovski ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Resistance Mechanisms ◽  
Clinical Isolates ◽  
Beta Lactamase ◽  
In Vitro Activity ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Beta Lactamases ◽  
Lactamase Inhibitor

QPX7728 is an ultra-broad-spectrum beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases. QPX7728 enhances the potency of multiple beta-lactams in beta-lactamase producing Enterobacterales and Acinetobacter spp. In this study we evaluated the in vitro activity of QPX7728 (8 μg/ml) combined with multiple beta-lactams against clinical isolates of Pseudomonas aeruginosa with varying beta-lactam resistance mechanisms. Seven-hundred-ninety clinical isolates were included in this study; 500 isolates, termed a “representative panel”, were selected to be representative the MIC distribution of meropenem (MEM), ceftazidime-avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ) resistance for clinical isolates according to 2017 SENTRY surveillance data (representative panel). An additional 290 selected isolates (“challenge panel”), that were either non-susceptible to MEM or were resistant to TOL-TAZ or CAZ-AVI were also tested; 61 strains carried metallo beta-lactamases (MBLs), 211 strains were defective in the carbapenem porin OprD and 185 strains had the MexAB-OprM efflux pump overproduced based on a phenotypic test. Against the representative panel, susceptibility for all QPX7728/beta-lactam combinations was >90%. For the challenge panel, QPX-ceftolozane (TOL) was the most active combination (78.6% susceptible) followed by equipotent QPX-piperacillin (PIP) and QPX-cefepime (FEP), restoring susceptibility in 70.3% of strains (CLSI breakpoints for the beta-lactam compound alone). For MBL-negative strains, QPX-TOL and QPX-FEP restored the MIC values to susceptibility rates in ∼90% and ∼80% of strains, respectively, vs 68-70% for QPX-MEM and QPX-PIP and 63-65% for TOL-TAZ and CAZ-AVI. For MBL-positive strains, QPX-PIP restored the MIC to susceptibility values for ∼70% of strains vs 2-40% for other combinations. Increased efflux and impaired OprD had varying effect on QPX7728 combination depending on the partner beta-lactam tested. QPX7728 enhanced the potency of multiple beta-lactams against P. aeruginosa, with varying results according to the beta-lactamase production and other intrinsic resistance mechanisms.

In vitro synergistic activities of tobramycin and selected beta-lactams against 75 gram-negative clinical isolates.

1997 ◽  
Vol 41 (11) ◽  
pp. 2586-2588 ◽  
Author(s):  
R C Owens ◽  
M A Banevicius ◽  
D P Nicolau ◽  
C H Nightingale ◽  
R Quintiliani
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Enterobacter Cloacae ◽  
Clinical Isolates ◽  
Synergistic Activity ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Acinetobacter Baumanii ◽  
Gram Negative ◽  
Combination Regimens

The microdilution checkerboard technique was utilized to distinguish synergistic activity between tobramycin and four beta-lactams: piperacillin-tazobactam, ticarcillin-clavulanate, ceftazidime, and ceftriaxone. Beta-lactam-aminoglycoside combinations were tested against 75 clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumanii, Citrobacterfreundii, Serratia marcescens, and Enterobacter cloacae. Despite in vitro susceptibilities, all isolates demonstrated either synergism or indifference; no antagonism was observed. Against pathogenic gram-negative nosocomial isolates, a greater percentage of synergy was consistently observed with combination regimens containing tobramycin and piperacillin-tazobactam or ticarcillin-clavulanate than with the cephalosporin-containing regimens.

scholarly journals Synergy of Nitric Oxide and Azoles againstCandida Species In Vitro

1998 ◽  
Vol 42 (9) ◽  
pp. 2342-2346 ◽  
Author(s):  
Gail E. McElhaney-Feser ◽  
Robert E. Raulli ◽  
Ronald L. Cihlar
Keyword(s):  
Nitric Oxide ◽  
Candida Albicans ◽  
Half Life ◽  
Inhibitory Concentration ◽  
Therapeutic Strategies ◽  
Fractional Inhibitory Concentration ◽  
Concentration Indices

ABSTRACT The candidacidal activity of nitric oxide (NO) as delivered by a class of compounds termed diazeniumdiolates has been investigated. Diazeniumdiolates are stable agents capable of releasing NO in a biologically usable form at a predicted rate, and three such compounds were examined for activity. One compound, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), proved to be most suitable for examining NO activity due to its relatively long half-life (20 h) and because of limited candidacidal activity of the uncomplexed DETA nucleophile. DETA-NO was active against six species of Candida for which the MICs necessary to inhibit 50% growth (MIC50s) ranged from 0.25 to 1.0 mg/ml. C. parapsilosis and C. kruseiwere the most susceptible to the compound. In addition to a determination of NO effects alone, the complex was utilized to investigate the synergistic potential of released NO in combination with ketoconazole, fluconazole, and miconazole. Activity was investigated in vitro against representative strains of Candida albicans, C. krusei, C. parapsilosis,C. tropicalis, C. glabrata, and C. dubliniensis. Determination of MIC50, MIC80 and MICs indicated that DETA-NO inhibits all strains tested, with strains of C. parapsilosis and C. krusei being consistently the most sensitive. The combination of DETA-NO with each azole was synergistic against all strains tested as measured by fractional inhibitory concentration indices that ranged from 0.1222 to 0.4583. The data suggest that DETA-NO or compounds with similar properties may be useful in the development of new therapeutic strategies for treatment of Candida infections.

In vitro synergy of eugenol and methyleugenol with fluconazole against clinical Candida isolates

2010 ◽  
Vol 59 (10) ◽  
pp. 1178-1184 ◽  
Author(s):  
Aijaz Ahmad ◽  
Amber Khan ◽  
Luqman Ahmad Khan ◽  
Nikhat Manzoor
Keyword(s):  
Inhibitory Concentration ◽  
High Sensitivity ◽  
Antagonistic Activity ◽  
Fractional Inhibitory Concentration ◽  
Antifungal Drug Resistance ◽  
Naturally Occurring ◽  
Opportunistic Pathogenic ◽  
Concentration Indices ◽  
Compromised Patients

The species Candida is a group of opportunistic pathogenic commensals in immune-compromised patients. Treatment of Candida infections is becoming increasingly difficult due to antifungal drug resistance, especially with fluconazole (FLC), which is a commonly used azole. In the present study the in vitro antifungal activity of eugenol (EUG) and methyleugenol (MEUG) alone and in combination against 64 FLC-sensitive and 34 FLC-resistant clinical Candida isolates is highlighted. All the strains were susceptible to both the naturally occurring phenyl propanoids. The nature of the interaction was studied from fractional inhibitory concentration indices (FICIs) for both EUG plus FLC, and MEUG plus FLC combinations calculated from chequerboard microdilution assays. FICI values depicted a high synergism of FLC with both compounds, which was greatest with MEUG. FLC-resistant Candida isolates showed high sensitivity to both compounds. No antagonistic activity was seen in the strains tested in the present study. From these results we suggest that EUG and MEUG have great potential as antifungals, and that FLC can be supplemented with EUG and MEUG to treat FLC-resistant Candida infections.

scholarly journals ANTIMICROBIAL ACTIVITY OF THUJA ORIENTALIS IN COMBINATION WITH CIPROFLOXACIN AGAINST PSEUDOMONAS AERUGINOSA

2019 ◽  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Minimum Inhibitory Concentration ◽  
Synergistic Effect ◽  
Concentration Index ◽  
Inhibitory Concentration ◽  
Disc Diffusion ◽  
Fractional Inhibitory Concentration ◽  
Fractional Inhibitory Concentration Index ◽  
Thuja Orientalis

OBJECTIVES: To compare the combined antimicrobial effect of Thuja orientalis and Ciprofloxacin against Pseudomonas aeruginosa in vitro samples. METHODS: In-vitro antibacterial activity of plant-extracts was evaluated alone and in combination with ciprofloxacin against Pseudomonas aeruginosa using disc-diffusion susceptibility assay (Kirby Bauer method) and minimum inhibitory concentration (96 well broth microdilution method) following CLSI guidelines. Pseudomonas aeruginosa clinical strains were collected from Rehman Medical Institute (RMI) and Northwest General Hospital Peshawar, Pakistan and ATCC strains (no.9721) of this bacterium were collected from Agriculture University Peshawar. The organism was tested six times with crude extract and fractionation with different solvents such as n-hexane, chloroform, ethyl acetate and butanol at concentrations of 1, 4, 8, 12, 16, 20, 24, 30 and 36 mg/ml. The mean MIC and FICI (fractional inhibitory concentration index) was obtained to report the synergism. The data were analysed using SPSS version-21. RESULTS: In combination, methanolic crude extract, chloroform and butanol fraction showed synergistic effect at all tested concentrations against Pseudomonas aeruginosa (ATCC 9721 and clinical) except with 1, 4, 16 mg/ml concentrations. Ethyl acetate and aqueous fractions shows indifference and synergistic effect against Pseudomonas aeruginosa (ATCC 9721 and clinical) at different concentrations. The fractional inhibitory concentration index (FICI) ranged from 1.24 to 3.24 against Pseudomonas aeruginosa alone and in combination with ciprofloxacin. CONCLUSION: By disc diffusion method, this study shows synergistic effect against Pseudomonas aeruginosa in combination with ciprofloxacin. However, through minimum inhibitory concentration method, it shows antagonism and indifference but no synergistic effect against different fractions of plant.

scholarly journals 1597. Ceftolozane-Tazobactam and Meropenem Synergy Testing Against Multi-Drug and Extensively-Drug Resistant Pseudomonas aeruginosa

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S794-S795
Author(s):  
Mary Francine P Chua ◽  
Syeda Sara Nida ◽  
Jerry Lawhorn ◽  
Janak Koirala
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Synergistic Effect ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Additive Effect ◽  
Teaching Hospitals ◽  
Drug Resistant ◽  
Extensively Drug Resistant ◽  
Synergy Testing ◽  
Concentration Indices

Abstract Background Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa (PA) have limited therapeutic options for treatment. Ceftolozane/tazobactam is a newer anti-pseudomonal drug effective against resistant PA infections, however resistance against this drug has now also developed and is increasing. In this study, we explored the combination of ceftolozane/tazobactam (CT) and meropenem (MP) as a possible effective regimen against MDR and XDR PA. Methods We obtained 33 non-duplicate isolates of MDR and XDR PA grown from blood, urine and respiratory samples collected from patients admitted between 2015 and 2019 at our two affiliate teaching hospitals. MDR PA was defined as resistance to 3 or more classes of anti-pseudomonal antibiotics, and XDR PA as resistance to all but two or less classes of anti-pseudomonal antibiotics. Antimicrobial preparations of both MP and CT were made according to manufacturer instructions. Susceptibility testing was performed using the checkerboard method in accordance to CLSI guidelines (CLSI M100, 2017). The ATCC 27853 strain of PA used as control. Synergy, additive effect, indifference and antagonism were defined as FIC (fractional inhibitory concentration) indices of ≤0.5, >0.5 to <1, >1 to <4, and >4, respectively. Results Thirteen (39%) of 33 PA isolates were classified as XDR, while 20 (61%) PA isolates were MDR. All isolates were resistant to MP (MIC50 >32 ug/mL), while only 2 (6%) isolates were susceptible to CT (MIC50 64 ug/mL). A synergistic effect was seen in 9 (27.3%) of PA isolates (FIC index range 0.28 to 0.5)— 2 of which were XDR PA, and 7 were MDR PA. An additive effect was seen in 12 (36.4%), with indifference seen in 12 (36.4%) of isolates. In this study, no antagonism was seen when CT and MP were combined. Conclusion When used in combination, CT and MP can exert a synergistic effect against MDR and XDR PA. Additive effect and indifference can also be seen when both antibiotics were used. Moreover, there was no antagonism seen when both antibiotics were combined. This study shows that the use of CT and MP in combination may be an option against XDR and MDR PA infections. Disclosures All Authors: No reported disclosures

scholarly journals In vitro synergy of isavuconazole in combination with colistin against Candida auris

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick Schwarz ◽  
Anne-Laure Bidaud ◽  
Eric Dannaoui
Keyword(s):  
Response Surface ◽  
Surface Analysis ◽  
Concentration Index ◽  
Inhibitory Concentration ◽  
Response Surface Analysis ◽  
Fractional Inhibitory Concentration ◽  
Candida Auris ◽  
Fractional Inhibitory Concentration Index ◽  
Agar Diffusion

AbstractThe in vitro interactions of isavuconazole with colistin were evaluated against 15 clinical Candida auris isolates by a microdilution checkerboard technique based on the EUCAST reference method for antifungal susceptibility testing and by agar diffusion using isavuconazole gradient concentration strips with or without colistin incorporated RPMI agar. Interpretation of the checkerboard results was done by the fractional inhibitory concentration index and by response surface analysis based on the Bliss model. By checkerboard, combination was synergistic for 93% of the isolates when interpretation of the data was done by fractional inhibitory concentration index, and for 80% of the isolates by response surface analysis interpretation. By agar diffusion test, although all MICs in combination decreased compared to isavuconazole alone, only 13% of the isolates met the definition of synergy. Essential agreement of EUCAST and gradient concentration strip MICs at +/− 2 log2 dilutions was 93.3%. Antagonistic interactions were never observed for any technique or interpretation model used.

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