scholarly journals 1601. Evaluation of Synergy with β-Lactams Plus Aztreonam Against Pseudomonas aeruginosa (PSA)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S584-S584
Author(s):  
J Nicholas O’Donnell ◽  
Donia Alnasser ◽  
Brittney L Maring ◽  
Thomas Lodise
Keyword(s):  
Inhibitory Concentration ◽  
Medical Center ◽  
Single Agent ◽  
Resistance Mechanisms ◽  
Individual Agent ◽  
Area Of Interest ◽  
Active Individual ◽  
Time Kill ◽  
Combination Regimens ◽  
Synergistic Combinations

Abstract Background Combination therapy is often employed in the treatment of PSA infections. Agents commonly used in combination with β-lactams include aminoglycosides, polymyxins, and fluoroquinolones but are limited by resistance and toxicity concerns. The use of dual β-lactam therapy is an emerging area of interest for the treatment of patients with resistant Gram-negative pathogens. This study evaluated synergy between β-lactam agents and aztreonam (ATM) against PSA isolates with varying degrees of susceptibility. Methods 4 PSA clinical isolates were collected from Albany Medical Center; 1 ATCC isolate was used (Table 1). Synergy with cefepime (FEP), meropenem (MER), and ceftazidime (CAZ), each in combination with ATM, was assessed using fractional inhibitory concentration index determined by checkerboard method. Synergistic combinations were tested in 24-hour time-kill, utilizing minimum and steady-state physiological concentrations (Cmin and Css). Tested bacteria were grown to late log phase, diluted to 1 × 106 cfu/mL and incubated at 37°C for 24 hours. Samples were drawn at 0, 2, 4, 6 and 24 hours. Synergy in time-kill was defined as ≥ 2 log10 cfu/mL kill greater than the most active individual agent at 24 hours. Results In checkerboard studies, combinations with ATM resulted in 80% synergy with FEP and 60% synergy with MER or CAZ combinations. ATM/MER and ATM/CAZ time-kill experiments resulted in indifference for most organisms and concentrations tested. For both single and combination regimens, initial killing was observed but varying degrees of regrowth occurred by 24 hours. The only strain with no regrowth at 24 hours was AMC-PSA2 (bactericidal activity and no regrowth at 24 hours observed for MER Cmin MER Css, and MER+ATM Css). Against AMC-PSA2, CAZ+ATM at Cmin was synergistic with limited regrowth observed. Conclusion Against PSA, tested β-lactam combinations with ATM resulted in lack of synergy in time-kill experiments, despite checkerboard results. Due to the extent of regrowth observed with nearly all single agent and combination regimens, testing of alternative combinations, including those that evade common resistance mechanisms such as efflux pumps or β-lactamases, and studies of dynamic concentrations are warranted. Disclosures All authors: No reported disclosures.

Evaluation of the in vitro interaction of fosfomycin and meropenem against metallo-β-lactamase–producing Pseudomonas aeruginosa using Etest and time-kill assay

2020 ◽  
pp. jim-2020-001573
Author(s):  
Sanjida Jahan ◽  
Heather Davis ◽  
Deborah S Ashcraft ◽  
George A Pankey
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Time Kill ◽  
In Vitro Interaction ◽  
Antimicrobial Combinations

Pseudomonas aeruginosa is a nosocomial pathogen containing various resistance mechanisms. Among them, metallo-β-lactamase (MBL)–producing Pseudomonas are difficult to treat. Fosfomycin is an older antibiotic that has recently seen increased usage due to its activity against a broad spectrum of multidrug-resistant organisms. Our aim was to evaluate the combination of fosfomycin and meropenem against 20 MBL-producing P. aeruginosa (100% meropenem-resistant and 20% fosfomycin-resistant) using both an Etest minimal inhibitory concentration (MIC): MIC method and time-kill assay. MICs for fosfomycin and meropenem were determined by Etest and by broth microdilution method for the latter. The combination demonstrated synergy by Etest in 3/20 (15%) isolates and 5/20 (25%) isolates by time-kill assay. Results from the Etest method and time-kill assay were in agreement for 14/20 (70%) of isolates. No antagonism was found. Comparing both methods, Etest MIC: MIC method may be useful to rapidly evaluate other antimicrobial combinations.

scholarly journals Synergistic Antibacterial and Antibiofilm Activity of the MreB Inhibitor A22 Hydrochloride in Combination with Conventional Antibiotics against Pseudomonas aeruginosa and Escherichia coli Clinical Isolates

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Anastasia Kotzialampou ◽  
Efthymia Protonotariou ◽  
Lemonia Skoura ◽  
Afroditi Sivropoulou
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Inhibitory Concentration ◽  
Human Cells ◽  
Laser Scanning Microscopy ◽  
Clinical Isolates ◽  
Antibiofilm Activity ◽  
Conventional Antibiotics ◽  
Time Kill ◽  
Synergistic Combinations

In the era of antibiotic resistance, the bacterial cytoskeletal protein MreB is presented as a potential target for the development of novel antimicrobials. Combined treatments of clinical antibiotics with anti-MreB compounds may be promising candidates in combating the resistance crisis, but also in preserving the potency of many conventional drugs. This study aimed to evaluate the synergistic antibacterial and antibiofilm activities of the MreB inhibitor A22 hydrochloride in combination with various antibiotics. The minimum inhibitory concentration (MIC) values of the individual compounds were determined by the broth microdilution method against 66 clinical isolates of Gram-negative bacteria. Synergy was assessed by the checkerboard assay. The fractional inhibitory concentration index was calculated for each of the A22-antibiotic combination. Bactericidal activity of the combinations was evaluated by time-kill curve assays. The antibiofilm activity of the most synergistic combinations was determined by crystal violet stain, methyl thiazol tetrazolium assay, and confocal laser scanning microscopy analysis. The combined cytotoxic and hemolytic activity was also evaluated toward human cells. According to our results, Pseudomonas aeruginosa and Escherichia coli isolates were resistant to conventional antibiotics to varying degrees. A22 inhibited the bacterial growth in a dose-dependent manner with MIC values ranging between 2 and 64 μg/mL. In combination studies, synergism occurred most frequently with A22-ceftazidime and A22-meropemen against Pseudomonas aeruginosa and A22-cefoxitin and A22-azithromycin against Escherichia coli. No antagonism was observed. In time-kill studies, synergism was observed with all expected combinations. Synergistic combinations even at the lowest tested concentrations were able to inhibit biofilm formation and eradicate mature biofilms in both strains. Cytotoxic and hemolytic effects of the same combinations toward human cells were not observed. The findings of the present study support previous research regarding the use of MreB as a novel antibiotic target. The obtained data expand the existing knowledge about the antimicrobial and antibiofilm activity of the A22 inhibitor, and they indicate that A22 can serve as a leading compound for studying potential synergism between MreB inhibitors and antibiotics in the future.

scholarly journals 1542. The Evaluation of the In Vitro Synergy of Colistin in Combination with Meropenem and Tigecycline against 50 Multi-Drug-resistant Acinetobacter baumannii strains

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S562-S563
Author(s):  
Jacinda Abdul-Mutakabbir ◽  
Juwom Yim ◽  
Logan Nguyen ◽  
Razieh Kebriaei ◽  
Kyle Stamper ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Bactericidal Activity ◽  
Single Agent ◽  
Resistance Mechanisms ◽  
Drug Resistant ◽  
Initial Inoculum ◽  
Log Reduction ◽  
Carbapenem Resistant ◽  
Time Kill

Abstract Background Acinetobacter baumannii possess inherent and acquired antibiotic resistance mechanisms that have rendered most antibiotics, including carbapenems, inactive. Colistin (COL) has risen as salvage therapy against these organisms due to its retained activity against A. baumannii. However, COL monotherapy is often met with suboptimal outcomes. Recently, combination therapy with COL and meropenem (MEM) or tigecycline (TGC) has been shown to be effective in eradicating multi-drug-resistant A. baumannii infections. The objective of this study was to further evaluate the efficacy of COL in combination with MEM or TGC against 50 multi-drug-resistant A. baumannii strains. Methods Fifty carbapenem-resistant A. baumannii strains were evaluated using combination minimum inhibitory concentration (MIC) testing and time-kill analysis (TKA). Single-drug MIC testing was performed for each strain by broth microdilution. Combination MIC testing was performed for COL+MEM and COL+TGC. Each strain was evaluated via 24-hour TKA to assess the synergistic capabilities of COL+MEM, and COL+TGC. Synergy was defined as a ≥ 2-log reduction CFU/mL in either combination from the most active single agent, while bactericidal activity was defined as a ≥ 3-log reduction CFU/mL of either combination from the initial inoculum. Results All 50 strains were resistant to MEM and TGC with MICs ≥ 64 µg/mL and ≥ 4 µg/mL respectively; while 3 strains were resistant to COL, MICs ≥ 2 µg/mL. MEM and TGC MIC values were reduced as much as 128-fold (median 2-fold) and 32-fold (median 2-fold),, respectively, in the presence of subinhibitory COL. COL MIC values were reduced as much as 512-fold (median 4-fold) from baseline in the presence of subinhibitory MEM, and as high as 16-fold (median 2-fold) in the presence of TGC. In TKAs, COL+MEM was synergistic in 45/50 (90%) strains and bactericidal against 43/50 (86%) strains. COL+TGC TKAs revealed synergy in 32/50 (64%) strains, and bactericidal activity against 28/50 (56%) strains. Conclusion The combinations of COL+MEM and COL+TGC demonstrate promise in combating highly resistant A. baumannii. Further research is mandated to explore other combinations that are capable of eradicating multi-drug-resistant A. baumannii. Disclosures All authors: No reported disclosures.

scholarly journals Is In Vitro Antibiotic Combination More Effective than Single-Drug Therapy against Anthrax?

2005 ◽  
Vol 49 (4) ◽  
pp. 1323-1325 ◽  
Author(s):  
Abed Athamna ◽  
Muhammad Athamna ◽  
Aburashed Nura ◽  
Eli Shlyakov ◽  
Darrin J. Bast ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Antibacterial Efficacy ◽  
Bacterial Killing ◽  
Single Drug ◽  
Development Of Resistance ◽  
Single Drug Therapy ◽  
Time Kill ◽  
Synergistic Combinations ◽  
Over Time

ABSTRACT Antibiotic combinations are used to enhance antibacterial efficacy and to prevent the development of resistance. We have tested a possible synergistic effect of several antibacterial combinations on Bacillus anthracis. The in vitro activities of antibiotic combinations against two strains of B. anthracis, strain Sterne and the Russian anthrax vaccine strain STi, were tested by the fractional inhibitory concentration (FIC) method, derived from the MICs of the agents in combination, and by measuring the rate of bacterial killing over time by several antibiotic combinations. The FIC results showed that synergism against both B. anthracis strains was observed only with the combination of rifampin and clindamycin. The telithromycin-amoxicillin combination showed synergism against strain Sterne only. All other combinations were either indifferent or antagonistic. The results of the bacterial time-kill study demonstrated indifferent effects for all combinations. These in vitro results demonstrate the difficulties in obtaining synergistic combinations of antibiotics against B. anthracis.

scholarly journals Synergistic Combinations of Antibiotics with Cumin, Oregano and Rosewood Oils as a Strategy to Preserve the Antibiotic Repertoire

2019 ◽  
Vol 5 (4) ◽  
pp. 337-353
Author(s):  
Lucy Owen ◽  
Katie Laird
Keyword(s):  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Resistant Bacteria ◽  
Positive Interactions ◽  
Antibiotic Resistant ◽  
Test Species ◽  
Clinical Sensitivity ◽  
E Coli ◽  
Time Kill ◽  
Synergistic Combinations

Background: Formulations employing synergistic combinations of antibiotics with Essential Oils (EOs) could help preserve the antibiotic repertoire by improving their activity against resistant bacteria. Objective: Antimicrobial interactions between double and triple combinations of EOs, EO components and antibiotics were determined using the checkerboard method. The most active triple combinations were then assessed by a time-kill assay. Methods: Two synergistic EO-antibiotic combinations and eight additive EO-antibiotic combinations reduced the antibiotic minimum inhibitory concentration below clinical sensitivity breakpoints according to the checkerboard method. However, all the tested combinations were additive according to the time-kill assay; while the combinations completely killed S. aureus, E. coli and P. aeruginosa cells in 2 h. At least one EO compound from the combination alone completely killed the cells of test species. Results: Two synergistic EO-antibiotic combinations and eight additive EO-antibiotic combinations reduced the antibiotic minimum inhibitory concentration below clinical sensitivity breakpoints according to the checkerboard method. However, all the tested combinations were additive according to the time-kill assay; while the combinations completely killed S. aureus, E. coli and P. aeruginosa cells in 2 h. At least one EO compound from the combination alone completely killed the cells of test species. Conclusion: Positive interactions support the use of EOs or EO components to enhance antibiotic efficacy against antibiotic resistant bacteria. The EO-antibiotic combinations tested by the time kill assay were indifferent; therefore, the observed antimicrobial activity did not arise from synergistic mechanisms as indicated by the checkerboard method. Investigation of other synergistic combinations identified by the checkerboard method could reveal more promising candidates.

In vitro and in vivo activity of oxazolidinone candidate OTB-658 against Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Shaochen Guo ◽  
Bin Wang ◽  
Lei Fu ◽  
Xi Chen ◽  
Weiyan Zhang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inhibitory Concentration ◽  
Early Stage ◽  
Drug Resistant ◽  
Lower Minimum Inhibitory Concentration ◽  
Time Kill ◽  
Combination Regimens ◽  
Tuberculosis Activity

In this work, we assess anti-tuberculosis activity of OTB-658 in vitro and in vivo . In vitro , OTB-658 showed bacteriostatic effectiveness with a lower minimum inhibitory concentration than linezolid against Mycobacterium tuberculosis . The minimal bactericidal concentrations and time-kill curves for OTB-658 indicated similar inhibition activity to that of linezolid. OTB-658 entered macrophages to inhibit of M. tuberculosis growth. OTB-658 had a low mutant frequency (10 −8 ), which would prevent drug-resistant mutations from emerging in combination regimens. In vivo , OTB-658 reduced colony-forming unit counts in the lungs and slightly inhibited bacterial growth in the spleen in the early stage and steady state in acute and chronic murine TB models. These results support the preclinical evaluation of OTB-658 and further clinical trials in China.

scholarly journals Characterization of Porin Expression in Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae Identifies Isolates Most Susceptible to the Combination of Colistin and Carbapenems

2013 ◽  
Vol 57 (5) ◽  
pp. 2147-2153 ◽  
Author(s):  
Jae H. Hong ◽  
Cornelius J. Clancy ◽  
Shaoji Cheng ◽  
Ryan K. Shields ◽  
Liang Chen ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Bacterial Killing ◽  
Content Type ◽  
Klebsiella Pneumoniae Carbapenemase ◽  
Effective Combination ◽  
Time Kill ◽  
Combination Regimens

ABSTRACTWe characterized carbapenem resistance mechanisms among 12Klebsiella pneumoniaecarbapenemase (KPC)-producingK. pneumoniae(referred to here as KPCK. pneumoniae) clinical isolates and evaluated their effects on the activity of 2- and 3-drug combinations of colistin, doripenem, and ertapenem. All isolates were resistant to ertapenem and doripenem; 75% (9/12) were resistant to colistin. Isolates belonged to the ST258 clonal group and harboredblaKPC-2,blaSHV-12, andblaTEM-1. As determined by time-kill assays, doripenem (8 μg/ml) and ertapenem (2 μg/ml) were inactive against 92% (11/12) and 100% (12/12) of isolates, respectively. Colistin (2.5 μg/ml) exerted some activity (range, 0.39 to 2.5 log10) against 78% (7/9) of colistin-resistant isolates. Colistin-ertapenem, colistin-doripenem, and colistin-doripenem-ertapenem exhibited synergy against 42% (5/12), 50% (6/12), and 67% (8/12) of isolates, respectively. Expression ofompK35andompK36porins correlated with each other (R2= 0.80). Levels of porin expression did not correlate with colistin-doripenem or colistin-ertapenem synergy. However, synergy with colistin-doripenem-ertapenem was more likely against isolates with high porin expression than those with low expression (100% [8/8] versus 0% [0/4];P= 0.002). Moreover, bactericidal activity (area under the bacterial killing curve) against isolates with high porin expression was greater for colistin-doripenem-ertapenem than colistin-doripenem or colistin-ertapenem (P≤ 0.049). In conclusion, colistin-carbapenem combinations may provide optimal activity against KPCK. pneumoniae, including colistin-resistant isolates. Screening for porin expression may identify isolates that are most likely to respond to a triple combination of colistin-doripenem-ertapenem. In the future, molecular characterization of KPCK. pneumoniaeisolates may be a practical tool for identifying effective combination regimens.

Evaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models

2019 ◽  
Author(s):  
Daniel Sun ◽  
Soumya Poddar ◽  
Roy D. Pan ◽  
Juno Van Valkenburgh ◽  
Ethan Rosser ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Small Cell Lung Carcinoma ◽  
Single Agent ◽  
Resistance Mechanisms ◽  
Tumor Models ◽  
Cell Lung Carcinoma ◽  
Adaptive Resistance ◽  
Cancer Models ◽  
Nanomolar Range

The lead compound, an ⍺-N-heterocyclic carboxaldehyde thiosemicarbazone <b>HCT-13</b>, was highly potent against a panel of pancreatic, small cell lung carcinoma, and prostate cancer models, with IC<sub>90</sub> values in the low-to-mid nanomolar range.<b> </b>We show that the cytotoxicity of <b>HCT-13</b> is copper-dependent, that it acts as a copper ionophore, induces production of reactive oxygen species (ROS), and promotes mitochondrial dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR), were identified as actionable adaptive resistance mechanisms following <b>HCT-13 </b>treatment. Taken together, <b>HCT-13 </b>is potent against solid tumor models and warrants <i>in vivo</i> evaluation against aggressive tumor models, either as a single agent or as part of a combination therapy.

scholarly journals Synergistic Interaction of Methanol Extract fromCanarium odontophyllumMiq. Leaf in Combination with Oxacillin against Methicillin-ResistantStaphylococcus aureus(MRSA) ATCC 33591

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Dayang Fredalina Basri ◽  
Vimashiinee Sandra
Keyword(s):  
Inhibitory Concentration ◽  
Methanol Extract ◽  
Bactericidal Effect ◽  
Acetone Extract ◽  
Pharmacodynamic Interaction ◽  
Antistaphylococcal Activity ◽  
Preliminary Study ◽  
Canarium Odontophyllum ◽  
Time Kill ◽  
Acetone Extracts

Canarium odontophyllum(CO) Miq. has been considered as one of the most sought-after plant species in Sarawak, Malaysia, due to its nutritional and pharmacological benefits. This study aimed to evaluate the pharmacodynamic interaction of crude methanol and acetone extracts from CO leaves in combination with oxacillin, vancomycin, and linezolid, respectively, against MRSA ATCC 33591 as preliminary study has reported its potential antistaphylococcal activity. The broth microdilution assay revealed that both methanol and acetone extracts were bactericidal with Minimum Inhibitory Concentration (MIC) of 312.5 μg/mL and 156.25 μg/mL and Minimum Bactericidal Concentration (MBC) of 625 μg/mL and 312.5 μg/mL, respectively. Fractional Inhibitory Concentration (FIC) indices were obtained via the chequerboard dilution assay where methanol extract-oxacillin, acetone extract-oxacillin, methanol extract-linezolid, and acetone extract-linezolid combinations exhibited synergism (FIC index ≤ 0.5). The synergistic action of the methanol extract-oxacillin combination was verified by time-kill analysis where bactericidal effect was observed at concentration of 1/8 × MIC of both compounds at 9.6 h compared to oxacillin alone. As such, these findings postulated that both extracts exert their anti-MRSA mechanism of action similar to that of vancomycin and provide evidence that the leaves ofC. odontophyllumhave the potential to be developed into antistaphylococcal agents.

MEMBRANE-ACTIVE METHANOLIC CRUDE EXTRACT OF THERMOTOLERANT, Aspergillus fumigatus SSH01 AND ITS MODE OF ACTION AGAINST GRAM-POSITIVE PATHOGENS

2017 ◽  
Vol 80 (1) ◽  
Author(s):  
Mohamad Khairil Radzali ◽  
Akmal Hayat Abdul Karim ◽  
Syahida Ahmad ◽  
Wan Zuhainis Saad
Keyword(s):  
Aspergillus Fumigatus ◽  
Crude Extract ◽  
Inhibitory Concentration ◽  
Minimum Bactericidal Concentration ◽  
Antibacterial Properties ◽  
Bacterial Membrane ◽  
Antibacterial Effects ◽  
Gram Positive ◽  
Bacillus Subtilis Atcc ◽  
Time Kill

This study was undertaken to investigate the antibacterial properties and the mode of actions of crude extract of Aspergillus fumigatus SSH01. Antibacterial properties was observed against Gram-positive pathogens and showed inhibition against Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538, methicillin-resistant S. aureus S547 (MRSA) and Listeria monocytogenes L10 with minimum inhibitory concentration (MIC, 0.097- 12.5 mg/ml) and minimum bactericidal concentration (MBC, 0.195 – 25 mg/ml). No surviving cells were detected after 15 h of treatment with the 2MIC of extracts for time-kill assay. Leakage of cellular contents of the treated test pathogens were identified and increased as the concentrations of the extracts increased. The study of morphological surface has shown the bacterial membrane was disrupted and caused loss of viability. This implies the antibacterial effects of A. fumigatus SSH01 extract may serve as the potential antibiotic. 

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