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Antimicrobial Agents and Chemotherapy, September 2001, p. 2666-2667, Vol. 45, No. 9
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.9.2666-2667.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
LETTERS TO THE EDITOR
Propensity of Fluoroquinolones with Different Moieties at
Position 8 to Cause Resistance Development in Clinical Isolates
of Streptococcus pneumoniae
 |
LETTER |
In a recent study, we exposed Streptococcus
pneumoniae isolates to subinhibitory concentrations of six
fluoroquinolones (FQs) (1). This subculturing led to
resistance development. None of the FQs, however, was associated with a
clearly lower potential to cause resistance development, measured as an
increase in MIC-doubling dilutions. However, based on the limited data
available, i.e., six isolates, further studies were needed to clarify
whether resistance development is strain dependent or dichotomous due
to differences in the FQ composition.
Thus, we repeatedly exposed 70 clinical S. pneumoniae
strains for 6 days to ciprofloxacin (CIP), gatifloxacin (GAT),
gemifloxacin (GEM), levofloxacin (LEV), and moxifloxacin (MOX)
(1). Mean MICs (in micrograms per milliliter) for the
original isolates were as follows: GEM, 0.017; MOX, 0.091; GAT, 0.175;
LEV, 0.707; CIP, 0.788.
In order to analyze the rate of resistance development, we converted
the MICs for all clinical strains and selected mutant isolates to a log
scale (base 2). Initial values at time zero (original MICs) were
subtracted from MICs on days 1 through 6. The slope of the MIC increase
over the 6-day period was computed by linear regression and compared by
analysis of variance with the Student-Newman-Keuls posthoc test;
differences were considered statistically significant if P
was <0.05. Judging from the squared correlation coefficients
R2 (means ± standard errors: CIP,
0.916 ± 0.007; GAT, 0.754 ± 0.018; GEM, 0.926 ± 0.008; LEV, 0.899 ± 0.009; MOX, 0.755 ± 0.019), the linearity of the individual lines was good, meaning that the regression coefficients were a reasonable measure of the resistance development rate. The relatively low R2 values of GAT and
MOX reflect low slope values rather than lack of linearity.
Nearly identical lines were found for CIP and GEM, both reaching rather
high log2 MIC increases after 6 days (4.6 ± 0.14 and 4.3 ± 0.15 µg/ml), while much lower increases were measured for LEV (2.99 ± 0.14 µg/ml), MOX (2.20 ± 0.11 µg/ml), and
GAT (2.16 ± 0.11 µg/ml). The rates of resistance development
are statistically different between the drugs tested (Fig.
1). These differences, measured on the
log scale, correspond to x-fold increases in the initial
MICs per day: GAT, 1.30-fold; MOX, 1.30-fold; LEV, 1.52-fold; GEM,
1.68-fold; CIP, 1.78-fold. Thus, GAT and MOX, the two FQs with a
methoxy moiety at the C-8 position, displayed the lowest propensity for
causing resistance development.
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FIG. 1.
The rate of resistance development as measured by the
slopes of individual time-dependent increases in MICs of five FQs. The
data are means with standard errors (n = 70 strains). GAT exhibits
the lowest MIC increase, with a mean rate of <0.4 log2
units per day (corresponding to a 1.30-fold increase per day), while
CIP shows the highest mean slope, with >0.8 log2 units per
day (corresponding to a 1.78-fold increase per day).
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|
Our data are supported by reports from the laboratory of Drlica and
coworkers, who showed that GAT was less affected by changes in either
DNA gyrase or topoisomerase IV (2, 5-8). Similar results
were reported by A. Dalhoff for MOX (8th Int. Cong. Infect. Dis.,
poster 47.003, 1998; 37th Annu. Meet. Infect. Dis. Soc. Am., poster
102, 1999; 1st Int. Symp. Resist. Gram-Positive Infect., 2000). Data
reported by other authors demonstrate that the molecular entity
selected for the C-8 position of an FQ can enhance the drug's
antibacterial activity (3, 4). In summary, the clinical relevance of a potentially lower propensity of an FQ with the C-8-methoxy moiety to develop resistance should be analyzed in animal
studies as well as in surveillance studies to investigate FQ MIC
increases for S. pneumoniae in combination with the use of
different FQs.
| |
FOOTNOTES |
*
Phone and fax: 49-2132-72040
E-mail: schmitfj{at}uni-duesseldorf.de
| |
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| | | | |
F.-J. Schmitz*
Mechthild Boos
Susanne Mayer
Institute for Medical Microbiology and Virology
Heinrich-Heine-Universität Düsseldorf
Universitatsstrasse 1, Geb. 22.21
D-40225 Düsseldorf, Germany
|
| | | | |
Dieter Hafner
Harold Jagusch
Institute for Pharmacology and Clinical Pharmacology
Heinrich-Heine-Universität Düsseldorf
Düsseldorf, Germany
|
| | | | |
Jan Verhoef
Ad C. Fluit
University Medical Center Utrecht
Utrecht, The Netherlands
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Antimicrobial Agents and Chemotherapy, September 2001, p. 2666-2667, Vol. 45, No. 9
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.9.2666-2667.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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