Evaluation of the Synergistic Effect of a Combination of Seven Antimicrobials Against a Broad-Spectrum Drug- Resistant Strain of Acinetobacter baumannii
Keywords:
Drug combinations, Synergy, Colistin, Minocycline, Antimicrobial cationic peptidesAbstract
To solve the difficulty in determining the appropriate treatment regimen for patients infected with extensively drug-resistant Acinetobacter baumannii (XDRAB), it is necessary to develop various strategies to increase the therapeutic effect of antimicrobial agents. The purpose of this study was to select the treatment combination showing the greatest antimicrobial effect among seven candidate antimicrobial substances. Seven strains of XDRAB were used in this study. The composition of the treatment consisted of colistin as the base and one of the seven antimicrobial substances, doripenem, minocycline, tigecycline, linezolid, fusidic acid, vancomycin, or alyteserin E4K peptide. The interaction between the drugs in each combination was evaluated by measuring the synergy rates using time-kill analysis. The synergy rates of the seven combinations tested in the time-kill assay in this study were as follows, in descending order from the combination with the highest synergy rate: colistin + minocycline (57.1%), colistin + alyteserin E4K (50.0%), colistin + tigecycline (42.9%), colistin + vancomycin (28.6%), colistin + doripenem (14.3%), colistin + fusidic acid (14.3%), and colistin + linezolid (0%). None of the combinations showed antagonism. The three combinations showing bactericidal activity and the rates of their bactericidal activity were the colistin + alyteserin E4K combination (33.3%), colistin + minocycline (14.3%), and colistin + vancomycin (14.3%). The colistin + minocycline and colistin + alyteserin E4K treatment combinations, which showed high synergy rates, can be considered promising candidates for future in vivo experiments evaluating combination therapies.
References
Conlon JM, Mechkarska M, Arafat K, et al., 2012, Analogues of the Frog Skin Peptide Alyteserin-2a with Enhanced Antimicrobial Activities against Gram-Negative Bacteria. J Pept Sci, 2012(18): 270–275.
Conlon JM, Sonnevend A, Pál T, et al., 2012, Efficacy of Six Frog Skin-Derived Antimicrobial Peptides Against Colistin-Resistant Strains of the Acinetobacter baumannii Group. Int J Antimicrob Agents, 2012(39): 317–320.
Feizabadi MM, Fathollahzadeh B, Taherikalani M, et al., 2008, Antimicrobial Susceptibility Patterns and Distribution of blaOXA Genes Among Acinetobacter spp. Isolated from Patients at Tehran Hospitals. Jpn J Infect Dis, 2008(61): 274–278.
Higgins PG, Wisplinghoff H, Krut O, et al., 2007, A PCR-Based Method to Differentiate Between Acinetobacter baumannii and Acinetobacter Genomic Species 13TU. Clin Microbiol Infect, 2007(13): 1199–1201.
Magiorakos AP, Srinivasan A, Carey RB, et al., 2012, Multidrug Resistant, Extensively Drug-Resistant and Pandrug-Resistant Bacteria: an International Expert Proposal for Interim Standard Definitions for Acquired Resistance. Clin Microbiol Infect, 2012(18): 268–281.
Phee LM, Betts JW, Bharathan B, et al., 2015, Colistin and Fusidic Acid, a Novel Potent Synergistic Combination for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections. Antimicrob Agents Chemother, 2015(59): 4544–4550.
Oleksiuk LM, Nguyen MH, Press EG, et al., 2014, In Vitro Responses of Acinetobacter baumannii to Two-and Three-Drug Combinations Following Exposure to Colistin and Doripenem. Antimicrob Agents Chemother, 2014(58): 1195–1199.
Mao J, Li T, Zhang N, et al., 2021, Dose Optimization of Combined Linezolid and Fosfomycin Against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model. Microbiol Spectr, 2021(9): e00871–21.
Colton B, McConeghy KW, Schreckenberger PC, et al., 2016, I.V. Minocycline Revisited for Infections Caused by Multidrug-Resistant Organisms. Am J Health Syst Pharm, 2016(73): 279–285.
Zhanel GG, Baudry PJ, Tailor F, et al., 2009, Determination of the Pharmacodynamic Activity of Clinically Achievable Tigecycline Serum Concentrations Against Clinical Isolates of Escherichia coli with Extended-Spectrum β-lactamases, Amp C β-lactamases and Reduced Susceptibility to Carbapenems Using an In Vitro Model. J Antimicrob Chemother, 2009(64): 824–828.
Gordon NC, Png K, Wareham DW, 2010, Potent Synergy and Sustained Bactericidal Activity of a Vancomycin-Colistin Combination Versus Multidrug-Resistant Strains of Acinetobacter baumannii. Antimicrob Agents Chemother, 2010(54): 5316–5322.
Kim UJ, Kim CM, Jang SJ, et al., 2020, Evaluation of Synergistic Effect of Combined Multidrug-Resistant Acinetobacter baumannii Treatment with Linalool and Colistin on to Expand Candidate for Therapeutic Option. Ann Clin Microbiol, 2020(23): 11–20.
Park GC, Choi JA, Jang SJ, et al., 2016, In Vitro Interactions of Antibiotic Combinations of Colistin, Tigecycline, and Doripenem Against Extensively Drug Resistant and Multidrug-resistant Acinetobacter baumannii. Ann Lab Med, 2016(36): 124–130.
Clinical and Laboratory Standards Institute (CLSI), 2018, Performance Standards for Antimicrobial Susceptibility Testing, CLSI document M100, Wayne, PA.
Tan TY, Yong Ng LS, Tan E, et al., 2007, In vitro Effect of Minocycline and Colistin Combinations on Imipenem-Resistant Acinetobacter baumannii Clinical Isolates. J Antimicrob Chemother, 2007(60): 421–423.
March GA, Bratos MA, 2015, A Meta-Analysis of In Vitro Antibiotic Synergy Against Acinetobacter baumannii. J Microbiol Methods, 2015(119): 31–36.
Principe L, D’Arezzo S, Capone A, et al., 2009, In Vitro Activity of Tigecycline in Combination with Various Antimicrobials Against Multidrug Resistant Acinetobacter baumannii. Ann Clin Microbiol Antimicrob, 2009(8): 18.
Peck KR, Kim MJ, Choi JY, et al., 2012, In Vitro Time-Kill Studies of Antimicrobial Agents Against Blood Isolates of Imipenem-Resistant Acinetobacter baumannii, Including Colistin- or Tigecycline-Resistant Isolates. J Med Microbiol, 2012(61): 353-360.
Li J, Yang X, Chen L, et al., 2017, In Vitro Activity of Various Antibiotics in Combination with Tigecycline Against Acinetobacter baumannii: a Systematic Review and Meta-Analysis. Microb Drug Resist, 2017(23): 982–993.
Vidaillac C, Benichou L, Duval RE, 2012, In Vitro Synergy of Colistin Combinations Against Colistin Resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae Isolates. Antimicrob Agents Chemother, 2012(56): 4856–4861.
Pankuch GA, Seifert H, Appelbaum PC, 2010, Activity of Doripenem With and Without Levofloxacin, Amikacin, and Colistin Against Pseudomonas aeruginosa and Acinetobacter baumannii. Diagn Microbiol Infect Dis, 2010(67): 191–197.
Principe L, Capone A, Mazzarelli A, et al., 2013, In Vitro Activity of Doripenem in Combination with Various Antimicrobials Against Multidrug-Resistant Acinetobacter baumannii: Possible Options for the Treatment of Complicated Infection. Microb Drug Resist, 2013(19): 407–414.
Ma XL, Guo YZ, Wu YM, et al., 2020, In Vivo Bactericidal Effect of Colistin Linezolid Combination in a Murine Model of MDR and XDR Acinetobacter baumannii Pneumonia. Sci Rep, 2020(10): 17518.
Oliva A, Garzoli S, De Angelis M, et al., 2019, In Vitro Evaluation of Different Antimicrobial Combinations With and Without Colistin Against Carbapenem-Resistant Acinetobacter baumannii. Molecules, 2019(24): 886.
Zusman O, Avni T, Leibovici L, et al., 2013, Systematic Review and Meta-Analysis of In Vitro Synergy of Polymyxins and Carbapenems. Antimicrob Agents Chemother, 2013(57): 5104–5111.
Liu CB, Shan B, Bai HM, et al., 2015, Hydrophilic/Hydrophobic Characters of Antimicrobial Peptides Derived from Animals and their Effects on Multidrug Resistant Clinical Isolates. Dongwuxue Yanjiu, 2015(36): 41–47.
