Antimicrobial Agents and Chemotherapy, October 2000, p. 2740-2746, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Department of Pathology (Clinical Microbiology), Hershey Medical Center, Hershey, Pennsylvania 17033,1 and Department of Pathology (Clinical Microbiology), Case Western Reserve University, Cleveland, Ohio 441062
Received 11 February 2000/Returned for modification 4 June 2000/Accepted 11 July 2000
Ability of daily sequential subcultures in subinhibitory
concentrations of clinafloxacin, ciprofloxacin, and trovafloxacin to
select resistant mutants was studied in 10 pneumococci (ciprofloxacin MICs, 1 to 4 µg/ml, and clinafloxacin and trovafloxacin MICs, 0.06 to
0.125 µg/ml [n = 9]; ciprofloxacin,
clinafloxacin, and trovafloxacin MICs, 32, 0.5, and 2 µg/ml,
respectively [n = 1]). Subculturing was done
50 times, or until MICs increased fourfold or more. Mutants for which
MICs were fourfold (or more) higher than those for parent strains were
selected in five strains by clinafloxacin, in six strains by
trovafloxacin, and nine strains by ciprofloxacin. Sequence analysis of
type II topoisomerase showed that most mutants had mutations in ParC at
Ser79 or Asp83 and in GyrA at Ser81, while a few mutants had mutations
in ParE or GyrB. In the presence of reserpine, the MICs of
ciprofloxacin and clinafloxacin for most mutants were lower (four to
eight times lower), but for none of the mutants were trovafloxacin MICs
lower, suggesting an efflux mechanism affecting the first two agents but not trovafloxacin. Single-step mutation rates were also determined for eight strains for which the MICs were as follows: 0.06 µg/ml (clinafloxacin), 0.06 to 0.125 µg/ml (trovafloxacin), and 1 µg/ml (ciprofloxacin). Single-step mutation rates with drugs at the MIC were
2.0×10
9 to <1.1×10
11,
5.0×10
4 to 3.6×10
9, and
4.8×10
4 to 6.7×10
9, respectively. For two
strains with clinafloxacin MICs of 0.125 to 0.5 µg/ml trovafloxacin
MICs of 0.125 to 2 µg/ml, ciprofloxacin MICs of 4 to 32 µg/ml
mutation rates with drugs at the MIC were 1.1×10
8
9.6×10
8,
3.3×10
6
6.7×10
8, and
2.3×10
5
2.4×10
7, respectively.
Clinafloxacin was bactericidal at four times the MIC after 24 h
against three parent and nine mutant strains by time-kill study. This
study showed that single and multistep clinafloxacin exposure selected
for resistant mutants less frequently than similar exposures to other
drugs studied.
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