In vitro effect of ceftazidime concentration and duration of exposure on eradication and resistance development of Klebsiella Pneumoniae

Abstract

K. pneumoniae producing extended- spectrum-beta-lactamase (ESBL) organisms confer resistance to ceftazidime caused important clinical problems from serious infections. The present study aimed to evaluate the effect of ceftazidime concentration and duration of exposure on eradication and resistance development by 3 strains of ESBL producing K. pneumoniae which included highly susceptible strain (KN246:MIC=0.125 microgram/ml), moderately susceptible strain (KN012:MIC=0.5 microgram/ml), and less susceptible strain (KN280:MIC=2 microgram/ml). In the study on the effect of concentration on eradication, 1MIC-8MIC and serum drug level following administer therapeutic dose: 1 g q 8 hr IV (Cmax, Caverage, and Cmin = 70, 35, and 4 microgram/ml) were used. The study on the effect of duration of exposure on the bacterial eradication when the organisms exposed to ceftazidime 4 half-life (8hr) were performed. The results from time kill study demonstrated that the highly susceptible strain (KN246) required concentration at 4MIC and Cmin and exposed to ceftazidime 4 half-life (8hr) to exhibit bactericidal property. For moderately susceptible strain (KN012) and less susceptible strain (KN280), concentration at 8MIC and Cmin exhibited bacteriostatic property whereas Cmax and Caverage had bactericidal property. Furthermore, when duration of exposure more than 2 and 1 half-life (4 and 2 hr), decreasing concentration did not have bactericidal property for moderately susceptible strain (KN012) and less susceptible strain (KN280), respectively. Regarding to study resistance development by daily passage method, results demonstrated that resistance occurred in less susceptible strain (KN280) faster than moderately susceptible strain (KN012) and highly susceptible strain (KN246). Resistance occured when organisms exposed to ceftazidime at day 9, 18, and 24, respectively. From double disk method, resistance mechanisms of these 3 strains were ESBL production. Additionally, when less susceptible strain (KN280) exposed to Cmax at the beginning and decreased concentration at every half-life which simulated pharmacokinetic achievable drug level, organisms was eradicated at the fifth dose. Less susceptible strain (KN280) had range of mutant selection window broader than moderately susceptible strain (KN012) and highly susceptible strain (KN246). When considered mutant prevention concentration and ceftazidime concentration during treatment time, the results demonstrated that the therapeutic dose could eradicate and prevent selection of resistant mutants only for highly susceptible strain (KN246). Whereas, moderately susceptible strain (KN012) required high dosage regimen. For less susceptible strain (KN280), both therapeutic dose and high dosage regimen did not appropriate therefore, combination therapy with aminoglycoside or fluoroquinolone or used more potent drugs such as carbapenem or {490}-lactam-beta-lactamase inhibitor combination would be considered. The results obtained suggest that the concentration and duration of exposure of ceflazidime are appropriate for clinical application.