OBJECTIVE: To compare the kinetics of killing/regrowth of differentially susceptible clinical isolates of Staphylococcus aureus exposed to ABT492 and levofloxacin and to explore their relative abilities to prevent the selection of resistant mutants. METHODS: Three clinical isolates of S. aureus--including two ciprofloxacin-susceptible S. aureus, 201 and 480--and a ciprofloxacin-resistant S. aureus 866, were exposed to clinically achievable ratios of area under the curve (AUC) to MIC in a dynamic model that simulated human pharmacokinetics of ABT492 (400 mg) and levofloxacin (500 mg) as a single dose. In addition, S. aureus 201 was exposed to single and multiple doses of ABT492 and levofloxacin (both once daily for 3 days) over wide ranges of 24 h AUC/MIC (AUC24/MIC) including clinically achievable AUC24/MIC ratios. RESULTS: With each isolate, ABT492 at clinically achievable AUC/MICs produced greater anti-staphylococcal effects than levofloxacin. Areas between the control growth and the time--kill curves (ABBC in single dose simulations and the sum of ABBCs determined after the first, second and third dosing in multiple dose simulations--ABBC(1+2+3)) were higher with ABT492 than levofloxacin. Moreover, at comparable AUC/MICs and AUC24/MICs, the maximal reductions in the starting inoculum of ABT492-exposed S. aureus were more pronounced than with levofloxacin. Loss in susceptibility of S. aureus 201 exposed to ABT492 or levofloxacin depended on the simulated AUC24/MIC. Although the maximal increase in MIC (MICfinal) related to its initial value (MICinitial) was seen at a higher AUC24/MIC ratio of ABT492 (120 h) than levofloxacin (50 h), similar AUC24/MICs (240 and 200 h, respectively) were protective against the selection of resistant S. aureus. These threshold values are readily achievable with 400 mg ABT492 (AUC24/MIC 870 h) but not with 500 mg levofloxacin (AUC24/MIC 70 h). CONCLUSION: Overall, these findings predict greater efficacy of clinically achievable AUC/MIC (or AUC24/MIC) of ABT492 both in terms of the anti-staphylococcal effect and prevention of the selection of resistant mutants.
OBJECTIVE: To compare the kinetics of killing/regrowth of differentially susceptible clinical isolates of Staphylococcus aureus exposed to ABT492 and levofloxacin and to explore their relative abilities to prevent the selection of resistant mutants. METHODS: Three clinical isolates of S. aureus--including two ciprofloxacin-susceptible S. aureus, 201 and 480--and a ciprofloxacin-resistant S. aureus 866, were exposed to clinically achievable ratios of area under the curve (AUC) to MIC in a dynamic model that simulated human pharmacokinetics of ABT492 (400 mg) and levofloxacin (500 mg) as a single dose. In addition, S. aureus 201 was exposed to single and multiple doses of ABT492 and levofloxacin (both once daily for 3 days) over wide ranges of 24 h AUC/MIC (AUC24/MIC) including clinically achievable AUC24/MIC ratios. RESULTS: With each isolate, ABT492 at clinically achievable AUC/MICs produced greater anti-staphylococcal effects than levofloxacin. Areas between the control growth and the time--kill curves (ABBC in single dose simulations and the sum of ABBCs determined after the first, second and third dosing in multiple dose simulations--ABBC(1+2+3)) were higher with ABT492 than levofloxacin. Moreover, at comparable AUC/MICs and AUC24/MICs, the maximal reductions in the starting inoculum of ABT492-exposed S. aureus were more pronounced than with levofloxacin. Loss in susceptibility of S. aureus 201 exposed to ABT492 or levofloxacin depended on the simulated AUC24/MIC. Although the maximal increase in MIC (MICfinal) related to its initial value (MICinitial) was seen at a higher AUC24/MIC ratio of ABT492 (120 h) than levofloxacin (50 h), similar AUC24/MICs (240 and 200 h, respectively) were protective against the selection of resistant S. aureus. These threshold values are readily achievable with 400 mg ABT492 (AUC24/MIC 870 h) but not with 500 mg levofloxacin (AUC24/MIC 70 h). CONCLUSION: Overall, these findings predict greater efficacy of clinically achievable AUC/MIC (or AUC24/MIC) of ABT492 both in terms of the anti-staphylococcal effect and prevention of the selection of resistant mutants.
Authors: Elena N Strukova; Yury A Portnoy; Andrey V Romanov; Mikhail V Edelstein; Stephen H Zinner; Alexander A Firsov Journal: Antimicrob Agents Chemother Date: 2015-12-07 Impact factor: 5.191
Authors: Alexander A Firsov; Irene Y Lubenko; Maria V Smirnova; Elena N Strukova; Stephen H Zinner Journal: Antimicrob Agents Chemother Date: 2008-03-31 Impact factor: 5.191
Authors: Roger D Kouyos; C Jessica E Metcalf; Ruthie Birger; Eili Y Klein; Pia Abel zur Wiesch; Peter Ankomah; Nimalan Arinaminpathy; Tiffany L Bogich; Sebastian Bonhoeffer; Charles Brower; Geoffrey Chi-Johnston; Ted Cohen; Troy Day; Bryan Greenhouse; Silvie Huijben; Joshua Metlay; Nicole Mideo; Laura C Pollitt; Andrew F Read; David L Smith; Claire Standley; Nina Wale; Bryan Grenfell Journal: Proc Biol Sci Date: 2014-11-07 Impact factor: 5.349
Authors: Karl Drlica; Hiroshi Hiasa; Robert Kerns; Muhammad Malik; Arkady Mustaev; Xilin Zhao Journal: Curr Top Med Chem Date: 2009 Impact factor: 3.295