Colistin became the critical treatment option for multidrug-resistant Gram-negative bacteria (GNB); however, resistance to colistin is increasingly being reported among clinical isolates. New therapy strategies should be considered nowadays. The aim of this study was to investigate the in vitro activity of a novel β-lactam/β-lactamases inhibitor ceftazidime-avibactam (CZA) alone and in combination with amikacin against colistin-resistant Gram-negative pathogens.
Results:
Among all the colistin-resistant GNB strains, 30.4% (21/69) were resistant to CZA, which was similar to the resistance rate of 25.4% (35/138) in colistin-susceptible strains (p > 0.05), displaying a relatively lower resistance rate compared with other antimicrobial agents (except amikacin). A majority of CZA-resistant GNB isolates (33/56) produced NDM carbapenemase. The fractional inhibitory concentration index method revealed synergistic (47.6%, 10/21) or additive (52.4%, 11/21) effects of CZA in combination with amikacin against colistin- and CZA-resistant GNB isolates, wherein the synergistic activity was found against all tested Klebsiella pneumoniae isolates (four) and Pseudomonas aeruginosa isolates (two). The time-killing curve assay verified the synergistic activity of CZA and amikacin in K. pneumoniae (FK2778) and P. aeruginosa (TL2294). The susceptible breakpoint index values showed that CZA in combination with amikacin reduced the MIC to less than the susceptibility breakpoint among 71.4% (15/21) of all tested strains.
Conclusion:
CZA may be a new alternative for colistin-resistant Gram-negative infections and pending clinical studies combining CZA with amikacin should be considered against these pathogens, particularly for K. pneumoniae and P. aeruginosa.
Get full access to this article
View all access options for this article.
References
1.
LuepkeK.H., and J.F. 3rd Mohr. 2017. The antibiotic pipeline: reviving research and development and speeding drugs to market. Expert Rev. Anti. Infect. Ther. 15:425–433.
2.
FalagasM.E., MavroudisA.D, and VardakasK.Z.. 2016. The antibiotic pipeline for multi-drug resistant Gram negative bacteria: what can we expect? Expert Rev. Anti. Infect. Ther. 14:747–763.
3.
MacVane, S.H. 2017. Antimicrobial resistance in the intensive care unit: a focus on gram-negative bacterial infections. J. Intensive Care Med. 32:25–37.
4.
DomalaonR., IdowuT., ZhanelG.G, and SchweizerF.. 2018. Antibiotic hybrids: the next generation of agents and adjuvants against gram-negative pathogens? Clin. Microbiol. Rev. 31:e00077-17.
5.
KoulentiD., SongA., EllingboeA., Abdul-AzizM.H, HarrisP., GaveyE., and LipmanJ.. 2019. Infections by multidrug-resistant Gram-negative Bacteria: what's new in our arsenal and what's in the pipeline? Int. J. Antimicrob. Agents. 53:211–224.
6.
FalagasM.E., and KasiakouS.K.. 2005. Colistin: the revival of polymyxins for the management of multidrug-resistant Gram-negative bacterial infections. Clin. Infect. Dis. 40:1333–1341.
7.
PerezF., El ChakhtouraN.G, YasminM., and BonomoR.A.. 2019. Polymyxins: to combine or not to combine? Antibiotics (Basel). 8:38.
8.
ZhangY., WangX., LiX., DongL., HuX., NieT., LuY., LuX., PangJ., LiG., YangX., LiC., and YouX.. 2019. Synergistic Effect of Colistin Combined with PFK-158 against Colistin-Resistant Enterobacteriaceae. Antimicrob. Agents Chemother. 63:e00271-19.
9.
CannatelliA., PrincipatoS., ColavecchioO.L, PallecchiL., and RossoliniG.M.. 2018. Synergistic activity of colistin in combination with resveratrol against colistin-resistant gram-negative pathogens. Front. Microbiol. 9:1808.
10.
NastroM., RodriguezC.H, MongeR., ZintgraffJ., NeiraL., RebolloM., VayC., and FamigliettiA.. 2014. Activity of the colistin-rifampicin combination against colistin-resistant, carbapenemase-producing Gram-negative bacteria. J. Chemother. 26:211–216.
11.
BaronS.A., and RolainJ.M.. 2018. Efflux pump inhibitor CCCP to rescue colistin susceptibility in mcr-1 plasmid-mediated colistin-resistant strains and Gram-negative bacteria. J. Antimicrob. Chemother. 73:1862–1871.
12.
PetrosilloN., TagliettiF., and GranataG.. 2019. Treatment Options for Colistin Resistant Klebsiella pneumoniae: present and Future. J Clin Med. 8:934.
13.
WongD., and van DuinD.. 2017. Novel Beta-Lactamase Inhibitors: unlocking their potential in therapy. Drugs. 77:615–628.
14.
van DuinD., LokJ.J, EarleyM., CoberE., RichterS.S, PerezF., SalataR.A, KalayjianR.C, WatkinsR.R, DoiY., KayeK.S, JrV.G. Fowler, PatersonD.L, BonomoR.A, EvansS., and Antibacterial Resistance LeadershipG.. 2018. Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Clin. Infect. Dis. 66:163–171.
15.
JacquelineC., HowlandK., and ChesnelL.. 2017. In vitro activity of ceftolozane/tazobactam in combination with other classes of antibacterial agents. J. Glob. Antimicrob. Resist. 10:326–329.
16.
DelisG.A., SiarkouV.I, VingopoulouE.I, Koutsoviti-PapadopoulouM., and BatziasG.C.. 2018. Pharmacodynamic interactions of amikacin with selected β-lactams and fluoroquinolones against canine Escherichia coli isolates. Res. Vet. Sci. 117:187–195.
17.
MonogueM.L., and NicolauD.P.. 2018. Antibacterial activity of ceftolozane/tazobactam alone and in combination with other antimicrobial agents against MDR Pseudomonas aeruginosa. J. Antimicrob. Chemother. 73:942–952.
18.
Singkham-InU., and ChatsuwanT.. 2018. In vitro activities of carbapenems in combination with amikacin, colistin, or fosfomycin against carbapenem-resistant Acinetobacter baumannii clinical isolates. Diagn. Microbiol. Infect. Dis. 91:169–174.
19.
AkyüzS., ParlakM., and GüdücüoğluH.. 2020. [In-vitro activity of ceftolozane-tazobactam in combination with various antibiotics against multidrug-resistant Acinetobacter baumannii isolated from intensive care patients]. Mikrobiyol. Bul. 54:154–162.
20.
Clinical and Laboratory Standards Institute. 2018. Performance standards for antimicrobial susceptibility testing, 28th ed. CLSI supplement M100. Clinical and Laboratory Standards Institute, Wayne, PA.
21.
The European Committee on Antimicrobial Susceptibility Testing. 2017. Breakpoint tables for interpretation of MICs and zone diameters, Version 7.1. Available at www.eucast.org.
22.
StokesJ.M., MacNairC.R, IlyasB., FrenchS., CoteJ.P, BouwmanC., FarhaM.A, SieronA.O, WhitfieldC., CoombesB.K, and BrownE.D.. 2017. Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance. Nat. Microbiol. 2:17028.
23.
OjdanaD., GutowskaA., SachaP., MajewskiP., WieczorekP., and TryniszewskaE.. 2019. Activity of Ceftazidime-Avibactam Alone and in Combination with Ertapenem, Fosfomycin, and Tigecycline Against Carbapenemase-Producing Klebsiella pneumoniae. Microb. Drug Resist. 25:1357–1364.
24.
MilneK.E., and GouldI.M.. 2010. Combination testing of multidrug-resistant cystic fibrosis isolates of Pseudomonas aeruginosa: use of a new parameter, the susceptible breakpoint index. J. Antimicrob. Chemother. 65:82–90.
25.
WuT., MeyerK., HarringtonA.T, DanzigerL.H, and WenzlerE.. 2019. In vitro activity of oritavancin alone or in combination against vancomycin-susceptible and -resistant enterococci. J. Antimicrob. Chemother. 74:1300–1305.
26.
LiJ., NationR.L, TurnidgeJ.D, MilneR.W, CoulthardK., RaynerC.R, and PatersonD.L.. 2006. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect. Dis. 6:589–601.
27.
BaronS., HadjadjL., RolainJ.M, and OlaitanA.O.. 2016. Molecular mechanisms of polymyxin resistance: knowns and unknowns. Int. J. Antimicrob. Agents. 48:583–591.
28.
SchillaciD., SpanoV., ParrinoB., CarboneA., MontalbanoA., BarrajaP., DianaP., CirrincioneG., and CascioferroS.. 2017. Pharmaceutical approaches to target antibiotic resistance mechanisms. J. Med. Chem. 60:8268–8297.
29.
LohansC.T., BremJ., and SchofieldC.J.. 2017. New Delhi Metallo-beta-Lactamase 1 catalyzes avibactam and aztreonam hydrolysis. Antimicrob. Agents Chemother. 61:e01224-17.
30.
WangY., WangJ., WangR., and CaiY.. 2019. Resistance to Ceftazidime-Avibactam and Underlying Mechanisms. J. Glob. Antimicrob. Resist. [Epub ahead of print]; DOI:10.1016/j.jgar.2019.12.009.
31.
ZhouM., ChenJ., LiuY., HuY., LiuY., LuJ., ZhangS., YuY., HuangX., YangQ., LiaoK., JinY., HuangW., FengX., YangQ., and XuY.. 2018. In vitro activities of ceftaroline/avibactam, ceftazidime/avibactam, and other comparators against pathogens from various complicated infections in China. Clin. Infect. Dis. 67:S206–S216.
32.
AbbottI.J., SlavinM.A, TurnidgeJ.D, ThurskyK.A, and WorthL.J.. 2011. Stenotrophomonas maltophilia: emerging disease patterns and challenges for treatment. Expert Rev. Anti. Infect. Ther. 9:471–488.
33.
GofmanN., ToK., WhitmanM., and Garcia-MoralesE.. 2018. Successful treatment of ventriculitis caused by Pseudomonas aeruginosa and carbapenem-resistant Klebsiella pneumoniae with i.v. ceftazidime-avibactam and intrathecal amikacin. Am. J. Health Syst. Pharm. 75:953–957.
