Document Type : Original Article
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Uludag University, Nilufer, Turkiye
Institute of Health Science, Uludag University, Nilufer, Turkiye
Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Uludag University, Nilufer, Turkiye
Due to the high prevalence of multi-drug resistant bacteria, combination therapy is an efficient choice for treatment of infections caused by highly resistant strains. In this study, the efficacy of ceftiofur plus danofloxacin combination was investigated against resistant Escherichia coli. The interaction between the two drugs was determined by checkerboard tests and time-kill assays. The combination was defined as bactericidal or bacteriostatic based on the minimum bactericidal concentration test results. Mutant prevention concentration test was used to evaluate the resistance tendency suppression potential of the combination. The combination had a synergistic effect against 83.00% of the isolates as verified by the checkerboard and time-kill assays. The combination was defined as bactericidal against all E. coli strains, since minimum bactericidal concentration: minimum inhibitory concentration ratios were below four thresholds and also markedly reduced mutant prevention concentration values of ceftiofur up to 4000-fold compared to its single use. Ceftiofur plus danofloxacin combination inhibited growth of E. coli strains which were resistant to ceftiofur or newer generation of fluoroquinolones. Our results suggest that ceftiofur plus danofloxacin combination has a bactericidal characteristic and can be an important alternative for the treatment of infections caused by resistant E. coli.
- Brooks BD, Brooks AE. Therapeutic strategies to combat antibiotic resistance. Adv Drug Deliv Rev 2014; 78: 14-27.
- Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev 2012; 25(3): 450-470.
- Committee for Veterinary Medicinal Products. Ceftiofur, EMEA/MRL/498/98- FINAL 1999; 1-6.
- European Food Safety Authority. The European Union summary report on antimicrobial resistance in zoonotic and indicator bacteria from humans, animals and food in 2015. doi: 10.2903/j.efsa.2017.4694
- Committee for Veterinary Medicinal Products. Danofloxacin, EMEA/MRL/254/97- FINAL 1997; 1-4.
- Vanni M, Meucci V, Tognetti R, et al. Fluoroquinolone resistance and molecular characterization of gyrA and parC quinolone resistance-determining regions in Escherichia coli isolated from poultry. Poult Sci 2014; 93(4): 856-863.
- European Medicines Agency. Guideline for the demonstration of efficacy for veterinary medicinal products containing antimicrobial substances EMA/CVMP/627/2001-Rev.1, 2016; 4-5 , 18.
- Van Bambeke F, Pagès JM, Lee VJ. Inhibitors of bacterial efflux pumps as adjuvants in antibiotic treatments and diagnostic tools for detection of resistance by efflux. Recent Pat Antiinfect Drug Discov 2006; 1(2): 157-175.
- Cengiz M, Sahinturk P. Assessment of synergistic interactions of danofloxacin and orbifloxacin against quinolone-resistant Escherichia coli isolated from animals by the checkerboard and time-kill methods. J Antibiot 2013; 66: 629-631.
- Lorian V. Antibiotics in laboratory medicine (step-up). 5th Philadelphia, USA: Lippincott Williams & Wilkins 2005; 309.
- Maaland MG, Mo SS, Schwarz S, et al. In vitro assessment of chloramphenicol and florfenicol as second-line antimicrobial agents in dogs. J Vet Pharmacol Ther 2015; 38(5): 443-450.
- Blondeau JM, Zhao X, Hansen G, et al. Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 2001; 45(2): 433-438.
- Drago L, De Vecchi E, Nicola L, et al. In vitro selection of resistance in Pseudomonas aeruginosa and Acinetobacter by levofloxacin and ciprofloxacin alone and in combination with β-lactams and amikacin. J Antimicrob Chemother 2005; 56(2): 353-359.
- Drago L, De Vecchi E, Nicola L, et al. In vitro synergy and selection of resistance by fluoroquinolones plus amikacin or beta-lactams against extended-spectrum beta-lactamase-producing Escherichia coli. J Chemother 2005; 17(1): 46-53.
- Skorup P, Maudsdotter L, Lipcsey M, et al. Beneficial antimicrobial effect of the addition of an amino-glycoside to a β-lactam antibiotic in an coli porcine intensive care severe sepsis model. Plos One 2014; 9(2): e90441. doi:10.1371/journal.pone.0090441
- Al-Hasan MN, Wilson JW, Lahr BD, et al. Betalactam and fluoroquinolone combination antibiotic therapy for bacteremia caused by gram-negative bacilli. Antimicrob Agents Chemother 2009; 53(4): 1386-1394.
- Pankey GA, Ashcraft DS. In vitro synergy of ciprofloxacin and gatifloxacin against ciprofloxacin-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005; 49(7): 2959-2964.
- White RL, Burgess DS, Manduru M, et al. Comparison of three different in vitro methods of detecting synergy: time-kill, checkerboard, and E test. Antimicrob Agents Chemother 1996; 40(8): 1914-1918.
- Drago L, Nicola L, Rodighiero V, et al. Comparative evaluation of synergy of combinations of beta-lactams with fluoroquinolones or a macrolide in Streptococcus pneumoniae. J Antimicrob Chemother 2011; 66(4): 845-849.
- Mayer I, Nagy E. Investigation of the synergic effects of aminoglycoside–fluoroquinolone and third-generation cephalosporin combinations against clinical isolates of Pseudomonas J Antimicrob Chemother 1999; 43(5): 651-657.
- Navas D, Caillon J, Gras-Le Guen C, et al. Comparison of in vivo intrinsic activity of cefepime and imipenem in a Pseudomonas aeruginosa rabbit endocarditis model: effect of combination with tobramycin simulating human serum pharmacokinetics. J Antimicrob Chemother 2004; 54(4): 767-771.
- Levison ME, Levison JH. Pharmacokinetics and pharmacodynamics of antibacterial agents. Infect Dis Clin North Am 2009; 23(4): 791-815.
- Blondeau JM. New concepts in antimicrobial susceptibility testing: the mutant prevention concentration and mutant selection window aproach. Vet Dermatol 2009; 20(5-6): 383-396.
- Marcusson LL, Olofsson SK, Komp Lindgren P, et al. Mutant prevention concentrations of ciprofloxacin for urinary tract infection isolates of Escherichia coli. J Antimicrob Chemother 2005; 55(6): 938-943.
- Credito K, Kosowska-Shick K, McGhee P, et al. Comparative study of the mutant prevention concentrations of moxifloxacin, levofloxacin, and gemifloxacin against Pneumococci. Antimicrob Agents Chemother 2010; 54(2): 673-677.
- Hansen GT, Blondeau JM. Comparison of the minimum inhibitory, mutant prevention and minimum bactericidal concentrations of ciprofloxacin, levofloxacin and garenoxacin against enteric Gram-negative urinary tract infection pathogens. J Chemother 2015; 17(5): 484-492.