In vitro activity of biofilm inhibitors in combination with antibacterial drugs against extensively drug-resistant Acinetobacter baumannii

Abstract Acinetobacter baumannii is a common pathogen of nosocomial infection, and its ability to form biofilms further contributes to its virulence and multidrug resistance, posing a great threat to global public health. In this study, we investigated the inhibitory effects of five biofilm inhibitors (BFIs) (zinc lactate, stannous fluoride, furanone, azithromycin, and rifampicin) on biofilm formation of nine extensively drug-resistant A. baumannii (XDRAB), and assessed the synergistic antibacterial effects of these BFIs when combined with one of four conventional anti-A. baumannii antibiotics (imipenem, meropenem, tigecycline, and polymyxin B). Each of the five BFIs tested was found to be able to significantly inhibit biofilm formation of all the clinical isolates tested under sub-minimal inhibitory concentrations. Then, we observed synergistic effects (in 22%, 56% and 11% of the isolates) and additive effects (56%, 44% and 44%) when zinc lactate, stannous fluoride and furanone were combined with tigecycline, respectively. When zinc lactate and stannous fluoride were each used with a carbapenem (imipenem or meropenem), in 33% and 56–67% of the isolates, they showed synergistic and additive effects, respectively. Additivity in > 50% of the isolates was detected when rifampicin was combined with imipenem, meropenem, tigecycline, or polymyxin B; and a 100% additivity was noted with azithromycin-polymyxin B combination. However, antagonism and indifference were noted for polymyxin B in its combination with zinc lactate and stannous fluoride, respectively. In conclusion, five BFIs in combination with four antibacterial drugs showed different degrees of in vitro synergistic and additive antibacterial effects against XDRAB.

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In VitroAntibiotic Synergy in Extensively Drug-ResistantAcinetobacter baumannii: the Effect of Testing by Time-Kill, Checkerboard, and Etest Methods

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00850-10 ◽

2010 ◽

Vol 55 (1) ◽

pp. 436-438 ◽

Cited By ~ 26

Author(s):

Thean Yen Tan ◽

Tze Peng Lim ◽

Winnie Hui Ling Lee ◽

Suranthran Sasikala ◽

Li Yang Hsu ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Polymyxin B ◽

Drug Resistant ◽

Extensively Drug Resistant ◽

Resistant Strains ◽

Time Kill

ABSTRACTThis study examined thein vitroeffects of polymyxin B, tigecycline, and rifampin combinations on 16 isolates of extensively drug-resistantAcinetobacter baumannii, including four polymyxin-resistant strains.In vitrosynergy was demonstrated in 19 (40%) of a possible 48 isolate-antibiotic combinations by time-kill methods, 8 (17%) by checkerboard methods, and only 1 (2%) by Etest methods. There was only slight agreement between Etest and checkerboard methods and no agreement between results obtained by other methods.

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In-vitro efficacy of polymyxin B with rifampin, colistin and doxycycline against extensively drug resistant Acinetobacter baumannii

African Journal of Microbiology Research ◽

10.5897/ajmr2013.6168 ◽

2014 ◽

Vol 8 (4) ◽

pp. 341-347

Author(s):

Hannan, Fizza Khalid Abdul ◽

Usman Arshad Muhammad

Keyword(s):

Acinetobacter Baumannii ◽

Polymyxin B ◽

Drug Resistant ◽

Extensively Drug Resistant

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Correlation of Checkerboard Synergy Testing with Time-Kill Analysis and Clinical Outcomes of Extensively Drug-Resistant Acinetobacter baumannii Respiratory Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00981-16 ◽

2016 ◽

Vol 60 (11) ◽

pp. 6892-6895 ◽

Cited By ~ 12

Author(s):

Derek N. Bremmer ◽

Karri A. Bauer ◽

Stephanie M. Pouch ◽

Keelie Thomas ◽

Debra Smith ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Clinical Outcomes ◽

Clinical Utility ◽

Respiratory Infections ◽

Drug Resistant ◽

Content Type ◽

Extensively Drug Resistant ◽

Time Kill ◽

Synergy Testing

ABSTRACTWe tested 76 extensively drug-resistant (XDR)Acinetobacter baumanniiisolates by the checkerboard method using only wells containing serum-achievable concentrations (SACs) of drugs. Checkerboard results were correlated by time-kill assay and clinical outcomes. Minocycline-colistin was the best combinationin vitro, as it inhibited growth in one or more SAC wells in all isolates. Patients who received a combination that inhibited growth in one or more SAC wells demonstrated better microbiological clearance than those who did not (88% versus 30%;P= 0.025). The checkerboard platform may have clinical utility for XDRA. baumanniiinfections.

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Extensively drug-resistant Acinetobacter baumannii in a Thai hospital: a molecular epidemiologic analysis and identification of bactericidal Polymyxin B-based combinations

Antimicrobial Resistance and Infection Control ◽

10.1186/s13756-015-0043-x ◽

2015 ◽

Vol 4 (1) ◽

Cited By ~ 20

Author(s):

Jocelyn Teo ◽

Tze-Peng Lim ◽

Li-Yang Hsu ◽

Thean-Yen Tan ◽

Suranthran Sasikala ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Polymyxin B ◽

Drug Resistant ◽

Extensively Drug Resistant ◽

Epidemiologic Analysis

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In Vitro Antimicrobial Activity of Dermcidin-1L Against Extensively-Drug-Resistant and Pandrug-Resistant Acinetobacter baumannii

Jundishapur Journal of Microbiology ◽

10.5812/jjm.13201 ◽

2017 ◽

Vol 10 (5) ◽

Cited By ~ 1

Author(s):

Zahra Farshadzadeh ◽

Mohammad Hossein Modaresi ◽

Behrouz Taheri ◽

Sara Rahimi ◽

Abbas Bahador

Keyword(s):

Antimicrobial Activity ◽

Acinetobacter Baumannii ◽

Drug Resistant ◽

In Vitro Antimicrobial Activity ◽

Extensively Drug Resistant

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Determining the Development of Persisters in Extensively Drug-Resistant Acinetobacter baumannii upon Exposure to Polymyxin B-Based Antibiotic Combinations Using Flow Cytometry

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01712-19 ◽

2019 ◽

Vol 64 (3) ◽

Cited By ~ 4

Author(s):

Fiona Hui-Sian Wong ◽

Yiying Cai ◽

Hui Leck ◽

Tze-Peng Lim ◽

Jocelyn Qi-Min Teo ◽

...

Keyword(s):

Flow Cytometry ◽

Acinetobacter Baumannii ◽

Polymyxin B ◽

Live Cells ◽

Drug Resistant ◽

Bacterial Cells ◽

Persister Cells ◽

Content Type ◽

Initial Inoculum ◽

Extensively Drug Resistant

ABSTRACT Polymyxin B-based combinations are increasingly prescribed as a last-line option against extensively drug-resistant (XDR) Acinetobacter baumannii. It is unknown if such combinations can result in the development of nondividing persister cells in XDR A. baumannii. We investigated persister development upon exposure of XDR A. baumannii to polymyxin B-based antibiotic combinations using flow cytometry. Time-kill studies (TKSs) were conducted in three nonclonal XDR A. baumannii strains with 5 log10 CFU/ml bacteria against polymyxin B alone and polymyxin B-based two-drug combinations over 24 h. At different time points, samples were obtained and enumerated by viable plating and flow cytometry. Propidium iodide and carboxyfluorescein succinimidyl ester dyes were used to differentiate between live and dead cells and between dividing and nondividing cells, respectively, at the single-cell level, and nondividing live cells were resuscitated and characterized phenotypically. Our results from viable plating showed that polymyxin B plus meropenem and polymyxin B plus rifampin were each bactericidal (>99.9% kill compared to the initial inoculum) against 2/3 XDR A. baumannii strains at 24 h. By flow cytometry, however, none of the combinations were bactericidal against XDR A. baumannii at 24 h. Further analysis using cellular dyes in flow cytometry revealed that upon exposure to polymyxin B-based combinations, XDR A. baumannii entered a viable but nondividing persister state. These bacterial cells reinitiated division upon the removal of antibiotic pressure and did not have a growth deficit compared to the parent strain. We conclude that persister cells develop in XDR A. baumannii upon exposure to polymyxin B-based combinations and that nonplating methods appear to complement viable-plating methods in describing the killing activity of polymyxin B-based combinations against XDR A. baumannii.

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Identification of a bacteria-produced benzisoxazole with antibiotic activity against multi-drug resistant Acinetobacter baumannii

The Journal of Antibiotics ◽

10.1038/s41429-021-00412-7 ◽

2021 ◽

Author(s):

Robert W. Deering ◽

Kristen E. Whalen ◽

Ivan Alvarez ◽

Kathryn Daffinee ◽

Maya Beganovic ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Metabolic Pathways ◽

Pathogenic Bacteria ◽

Antibacterial Agents ◽

De Novo ◽

Drug Resistant ◽

Antibacterial Effects ◽

Naturally Occurring ◽

Molecular Modeling Studies

AbstractThe emergence of multi-drug resistant pathogenic bacteria represents a serious and growing threat to national healthcare systems. Most pressing is an immediate need for the development of novel antibacterial agents to treat Gram-negative multi-drug resistant infections, including the opportunistic, hospital-derived pathogen, Acinetobacter baumannii. Herein we report a naturally occurring 1,2-benzisoxazole with minimum inhibitory concentrations as low as 6.25 μg ml−1 against clinical strains of multi-drug resistant A. baumannii and investigate its possible mechanisms of action. This molecule represents a new chemotype for antibacterial agents against A. baumannii and is easily accessed in two steps via de novo synthesis. In vitro testing of structural analogs suggest that the natural compound may already be optimized for activity against this pathogen. Our results demonstrate that supplementation of 4-hydroxybenzoate in minimal media was able to reverse 1,2-benzisoxazole’s antibacterial effects in A. baumannii. A search of metabolic pathways involving 4-hydroxybenzoate coupled with molecular modeling studies implicates two enzymes, chorismate pyruvate-lyase and 4-hydroxybenzoate octaprenyltransferase, as promising leads for the target of 3,6-dihydroxy-1,2-benzisoxazole.

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