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Antimicrobial Agents and Chemotherapy, March 2001, p. 883-892, Vol. 45, No. 3
Earle A. Chiles Research Institute,
Providence Portland Medical Center and the Department of Medicine,
Oregon Health Sciences University, Portland, Oregon
Received 7 March 2000/Returned for modification 27 July
2000/Accepted 19 December 2000
The phenotypic resistance of selected organisms to ciprofloxacin,
levofloxacin, and trovafloxacin was defined as a MIC of The clinical use of fluorinated
4-quinolones continues to increase. They now account for roughly 11%
of antimicrobial prescriptions worldwide (22). Despite
widespread use over 10 or more years, selection of resistant clones has
been modest. Clinically significant resistance to ciprofloxacin has
occurred for Staphylococcus aureus (especially
methicillin-resistant S. aureus [MRSA]), Neisseria gonorrhoeae, Pseudomonas aeruginosa, and
Acinetobacter baumanii (1, 3, 12, 19).
Surprisingly, resistance of Enterobacteriaceae has been
modest. Recent reports of the increasing resistance of Escherichia coli, Campylobacter jejuni, and
Salmonella species raise the concern of the potential spread
of selected resistant mutants (2, 9, 10, 21, 23).
Microbial resistance to fluoroquinolones results from either mutations
in topoisomerase II (DNA gyrase), topoisomerase IV, and/or activation
of drug efflux pumps. Selection of resistant organisms evolves from the
interplay of gene mutation frequency, the number and type of mutations
necessary to express phenotypic resistance, drug potency, concentration
of the test drug, and other factors (5, 11). Mutation and
selection pressure create the potential for survival advantage and
spread of resistant clones.
Assessment of the phenotypic expression of the genotypic changes has
largely been based on changes in the MIC. Studies of fluoroquinolone-selected genetic changes indicate that phenotypic change is often the result of multiple sequential changes in the genome
of the organism (16). Our intent was to study the dynamics of phenotypic resistance over time.
There is a variable but generally low frequency (<1 × 10 We studied the propensity of clinical isolates of S. aureus,
E. coli, Klebsiella pneumoniae,
Enterobacter cloacae, Serratia marcescens, and
P. aeruginosa to develop phenotypic resistance to
ciprofloxacin, levofloxacin, and trovafloxacin after single and
sequential drug exposures.
Bacterial strains.
Consecutive clinical isolates were
collected, including 13 methicillin-susceptible S. aureus
(MSSA) and 15 MRSA isolates; 20 isolates each of E. coli,
K. pneumoniae, and P. aeruginosa; 16 isolates of
S. marcescens; and 19 isolates of E. cloacae.
In vitro susceptibility testing.
Fluoroquinolone in vitro
susceptibility was determined by a standard agar dilution method using
Mueller-Hinton agar and an inoculum of 104 CFU per spot
(15). For testing of S. aureus, 2% sodium
chloride was added to the agar. Laboratory standard powders of
ciprofloxacin were obtained from the Bayer Company, levofloxacin was
obtained from the R. W. Johnson Pharmaceutical Research Institute
(Raritan, N.J.), and trovafloxacin was obtained from Pfizer Inc.
(Groton, Conn.).
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.883-892.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Phenotypic Resistance of Staphylococcus aureus,
Selected Enterobacteriaceae, and Pseudomonas
aeruginosa after Single and Multiple In Vitro Exposures to
Ciprofloxacin, Levofloxacin, and Trovafloxacin
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
4 µg/ml.
The dynamics of resistance were studied after single and sequential
drug exposures: clinical isolates of methicillin-susceptible and
methicillin-resistant Staphylococcus aureus (MSSA and
MRSA), Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae, Serratia marcescens, and
Pseudomonas aeruginosa were utilized. After a single 48-h
exposure of a large inoculum to four times the initial MIC for the
organism, the frequency of selection of resistant mutants of MSSA was
greater for trovafloxacin than levofloxacin (P = 0.008); for E. cloacae, the frequency was highest for
ciprofloxacin and lowest for levofloxacin and trovafloxacin; for
S. marcescens, the frequency was highest for trovafloxacin
and lowest for ciprofloxacin (P = 0.003). The results
of serial passage experiments were analyzed both by the Kaplan-Meier
product-limited method as well as by analysis of variance of mean
inhibitory values. By both methods, MSSA and MRSA expressed mutants
resistant to ciprofloxacin after fewer passages than were required for
either levofloxacin or trovafloxacin. For the aerobic gram-negative
bacilli, two general patterns emerged. Mutants resistant to
trovafloxacin appeared sooner and reached higher mean MICs than did
mutants resistant to levofloxacin or ciprofloxacin. Mutants resistant
to ciprofloxacin appeared later and reached mean MICs lower than the
MICs of the other two drugs studied. Even though individual strain
variation occurred, the mean MICs were reproduced when the serial
passage experiment was repeated using an identical panel of E. coli isolates. In summary, the dynamic selection of
fluoroquinolone-resistant bacteria can be demonstrated in experiments
that employ serial passage of bacteria in vitro.
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
9) of resistant organisms when a test organism is
incubated in a concentration of fluoroquinolone that is four times the
baseline MIC (6). Earlier studies have demonstrated
increasing levels of resistance when test organisms are serially
passaged in incrementally increasing concentrations of fluoroquinolone
(7, 13; M. E. Evans and W. E. Titlow, Letter,
Antimicrob. Agents Chemother. 42:727, 1998). We postulated that
differences exist among the fluoroquinolones with respect to the number
of sequential passages necessary to develop potentially clinically
significant levels of drug resistance.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
4 µg/ml; resistance to levofloxacin is defined as a MIC of 8 µg/ml (15). At
present, there are no NCCLS-approved breakpoints for trovafloxacin
versus staphylococci and enteric bacteria. In evaluating the results of
the serial passage experiments, a MIC of 4 µg/ml was selected as an
end point upon which to base statistical evaluation. The selection of a
MIC of 4 µg/ml was arbitrary. We believe that a MIC of 4 µg/ml,
for the quinolones under study, would have potential clinical
relevance. The selection of 4 µg/ml was based primarily on peak
drug concentrations in serum and on recognition that peak trovafloxacin
levels and peak levofloxacin levels are usually lower and higher than 4 µg/ml, respectively.
Frequency of selection of resistant strains after single exposure. Test bacteria were grown overnight in antibiotic-free Mueller-Hinton broth. Inocula of 108 to 1010 CFU were plated on Mueller-Hinton agar containing four times the MIC of the test drugs. The plates were incubated for 48 h. The number of resistant colonies was counted on plates with between 1 and 1,000 visible colonies. Quantitation of each inoculum was done in triplicate. The frequency of resistant isolates selected by each fluoroquinolone was calculated by dividing the number of colonies growing after 48 h by the mean starting inoculum.
One to twenty resistant colonies were selected, and the agar dilution MIC was determined to document the magnitude of resistance.Selection of resistant strains by serial passage. Bacteria were grown overnight in antibiotic-free Mueller-Hinton broth to 107 CFU/ml using a McFarland standard. The inoculum was verified by serial plate dilution. An inoculum of 1 µl containing 104 CFU in log-phase growth was plated in a single spot on a series of Mueller-Hinton agar plates containing increasing twofold concentrations of ciprofloxacin, levofloxacin, or trovafloxacin extending from below to above the baseline measured MIC.
After 48 h of incubation at 35°C, bacterial growth on the plates with the highest drug concentration showing growth was collected, regrown in antibiotic-free broth, and reinoculated onto sets of agar plates with increasing twofold-higher concentrations of fluoroquinolone. Each sequential 48-h incubation was repeated for 10 serial passages. The upper limit of quantitation of resistance was 256 µg/ml. To evaluate reproducibility of results, the serial passage was performed twice using a second collection of 15 isolates of E. coli.Statistical evaluation. All statistical analysis was performed using the SPSS statistical package, version 9.0 (Chicago, Ill.).
Differences in mutation frequency among drugs in the single incubation experiments were assessed using two-way analysis of variance on the logarithmic transformation of mutation frequency. Bonferroni's correction was used to adjust for multiple comparisons between drugs. Data from the serial passage experiments were analyzed by two methods. First, the cumulative risk of an isolate reaching a MIC of4 µg/ml
was assessed using Kaplan-Meier (KM) product-limit estimates. This end
point was selected as the concentration of most clinical import. The
log rank test, with Bonferroni's correction, was used for comparisons.
KM end-point-free plots were used for graphical comparison.
KM analysis of the increasing drug concentrations compatible with
bacterial growth considers only the first passage through the 4-µg/ml
end point and ignores the information beyond that step. As an adjunct
to the KM analysis, differences between drugs using all 10 steps
(passages) were analyzed by two methods. After logarithmic
transformation, the slopes of the inhibitory concentrations between
drugs, determined from the interaction term between drug and serial
passage step, were compared using analysis of variance. Bonferroni's
correction was used for the pairwise comparisons.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Single-incubation mutation frequencies. (i) MIC90.
The baseline and postincubation MIC90s for the seven
bacterial strains are shown in Table 1.
With the exception of trovafloxacin versus MSSA, all the test organisms
exhibited a 16- to 32-fold increase in the MIC90.
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(ii) Mutation frequencies. No statistically significant differences in the frequency of detection of resistant mutants to ciprofloxacin, levofloxacin, or trovafloxacin occurred after a single incubation of MRSA, E. coli, K. pneumoniae, or P. aeruginosa in a concentration of test drug that was four times the baseline MIC (data not shown).
Significant differences in the frequency of detection of resistant mutants of MSSA, E. cloacae, and S. marcescens are shown in Table 2. For MSSA, trovafloxacin showed a statistically significant greater frequency of resistant mutants than did levofloxacin. For E. cloacae, the highest frequency of resistant mutants occurred after incubation with ciprofloxacin; differences between ciprofloxacin, levofloxacin, and trovafloxacin were statistically significant. For S. marcescens a higher frequency of resistant mutants occurred for levofloxacin and trovafloxacin than for ciprofloxacin.
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Serial passage experiments. (i) Pre- and
post-MIC90s.
After 10 serial passages, the
MIC90s increased 16- to 1,024-fold for each of the seven
bacterial species versus the three test drugs (Table
3). Low postpassage MIC90s
observed with trovafloxacin versus MSSA, MRSA, and E. coli
still represent 16- to 400-fold increases from baseline values.
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(ii) KM curves.
KM analysis plots of the percentage of
isolates remaining susceptible to 4-µg/ml concentrations or less of
test fluoroquinolone at each sequential in vitro passage showed that
for E. coli, there were no statistically significant
differences between the test drugs in the rate of accumulation of
resistant mutants. Statistically significant differences between the
three test drugs were observed for the other six organisms tested (Fig.
1).
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), levofloxacin (Levo)(
),
or trovafloxacin (Trova)(
). The data are presented
as KM product-limit estimates with a MIC of 4 µg/ml
significantly faster for ciprofloxacin than for the other two test
quinolones. The KM analysis obscures the gradual increase in
trovofloxacin phenotypic resistance due to the low baseline trovafloxacin MICs. For the other aerobic gram-negative bacilli tested,
two general observations are noteworthy. First, the appearance of
resistant phenotypes was faster with trovafloxacin, and second, phenotypes resistant to ciprofloxacin occurred more slowly than phenotypes resistant to the other test drugs. Note that for K. pneumoniae and E. cloacae strains, the rate of
accumulation of isolates with a drug MIC of 4 µg/ml was slower for
levofloxacin and ciprofloxacin than for trovafloxacin. For S. marcescens, the rate of accumulation of mutants with a
drug MIC of 4 µg/ml was again fastest for trovafloxacin and
slowest for ciprofloxacin. For P. aeruginosa, the
rate of accumulation of mutants with a drug MIC of 4 µg/ml was
fastest for levofloxacin and slowest for ciprofloxacin.
Because the KM method of analysis excludes MIC data after test strains
reached a MIC of 4 µg/ml and failed to consider differences through
the 10 incubation cycles, data were also evaluated by regression analysis.
(iii) Regression analysis.
The data were analyzed using two
methods. First, the mean log concentration MIC at each incubation step
was plotted for each drug and each group of organisms. The results are
presented in Fig. 2. As in the KM
analysis, rapid identification of mutants of MSSA and MRSA with
phenotypic resistance to ciprofloxacin is evident. The difference
between levofloxacin and trovafloxacin is statistically significant for
MRSA (P < 0.001) but not for MSSA (P = 0.08). The difference between ciprofloxacin and both levofloxacin
and trovafloxacin was statistically significant for both MRSA and MSSA
(P < 0.001).
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(iv) Reproducibility.
Since observed phenotypic changes in
resistance might be the result of random genetic mutations, an
additional 15 consecutive clinical isolates of E. coli were
serially passaged twice and the results were compared with each other,
as well as with those for the first 20 E. coli clinical
isolates described above. In Fig. 4, the
mean MIC is plotted against the result at each serial passage step. In
the first 20 clinical isolates, the log mean MIC was higher for
trovafloxacin and levofloxacin than for ciprofloxacin (P < 0.0001). Similarly, mean ciprofloxacin MICs were lower than those
of levofloxacin or trovafloxacin in the first experiment with the
"new" 15 E. coli strains. The second
experiment with the 15 E. coli strains yielded a similar
relationship of ciprofloxacin to the other two drugs. Although the
levofloxacin and trovafloxacin curves appear farther apart on the
second experiment, there is no statistically significant difference
between trovafloxacin and levofloxacin in either of the two experiments
with the 15 clinical isolates or the experiments with the original 20 isolates. The results with all 35 E. coli strains are
summarized in Fig. 3D. Standard deviations are included and again
indicate the lower mean MICs for ciprofloxacin than for the other two
test drugs, as the mean MIC rises with serial passage.
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DISCUSSION |
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Introduction
Materials and Methods
Results
Discussion
References
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The goal of our experiments was to study changes in the MIC over time under the influence of repeated drug exposure, as might happen clinically to the endogenous flora of the skin, nasopharynx, or gastrointestinal tract. The results indicate the potential for creating fluoroquinolone resistance in the organisms and drugs tested. However, there are differences in the ease of selection of resistant mutants between organisms and between drugs for a specific organism. The rapid emergence of phenotypic resistance of both MSSA and MRSA to ciprofloxacin confirms the work of others and also correlates with the rapid loss of the clinical utility of ciprofloxacin for S. aureus infections (4, 14, 17, 18).
Our results document the ease of emergence of resistance of Enterobacteriaceae, especially that of K. pneumoniae, E. cloacae, and S. marcescens to trovafloxacin. Conversely, these organisms showed a reduced propensity to develop mutants with phenotypic resistance to ciprofloxacin. Despite roughly 16 years of clinical use of fluoroquinolones, resistance of Enterobacteriaceae to ciprofloxacin has remained low worldwide (22). However, the recent reports of increasing resistance of E. coli, C. jejuni, and Salmonella enterica serovar Typhi are noteworthy (9, 21, 23).
For some drug-organism combinations, the mutation frequency after a single 48-h incubation did predict the differences observed after serial passages. The differences between drugs observed after a single incubation with S. marcescens and E. cloacae were repeated and magnified during 10 serial passages. On the other hand, only the difference between trovafloxacin and levofloxacin was statistically significant after one incubation with MSSA, while differences between all three drugs appeared during serial passage. Also noteworthy is the absence of any detectable differences in mutation frequency for the other four organisms when incubated with the three test drugs.
KM survival curve analyses have not typically been applied to in vitro studies of susceptibility of bacteria to antimicrobials. The KM analysis is generally applied to data with dichotomous end points: e.g., life versus death. The strength of applying this type of analysis to our data is the immediate visual impact of differences. A potential weakness is the risk of missing subtle differences as a consequence of ignoring data after the "cutoff" of 4 µg/ml is achieved. For the latter reason, additional regression analysis was performed that evaluated both the mean MIC data and the slopes of the resistance curves over the 10 serial passages. Of interest, in no instance were the data in the KM approach in conflict with the data from the regression analysis of the slope. The weakness of the KM analysis is a lack of appreciation of the degree of elevation of MICs after the predetermined "cutoff" value is reached.
The KM curves require a specific value as an end point. The in vitro
cutoff for fluoroquinolone resistance varies between 2 and 8 µg/ml,
depending on the drug and the organism. Hence we chose a MIC of 4
µg/ml as potentially clinically relevant. "Survival" required
keeping the drug MIC for the isolate at <4 µg/ml. When the KM
approach is used, the results show definite differences between the
test drugs for MSSA, MRSA, and S. marcescens. A
lower or higher "cutoff" would change the shape of the curves but
not the relationship of the drugs to each other.
In general, the three statistical methods employed identified similar differences. The S. marcescens data are the exception. KM curves and plots of the log mean MIC versus serial passage yielded a clear hierarchy of the likelihood of identification of resistant mutants: i.e., more likely with trovafloxacin and least likely with ciprofloxacin. Analysis of the slopes of the resistance curves did not show differences between the three test drugs versus S. marcescens. This is likely due to a greater variability of the drug MICs for S. marcescens than for the other test organisms.
Much of the previously published work in this area has focused on in vitro acquisition of resistance by S. aureus. In investigations of phenotypic resistance that focused on MRSA, Evans and Titlow performed serial incubation studies (7; Evans and Titlow, Letter). They found greater absolute increases in MICs of ciprofloxacin than in MICs of levofloxacin and greater increases in MICs of ciprofloxacin than in MICs of trovafloxacin. Many other studies, focused on the underlying genetic mechanism of resistance, demonstrate that the observed increase in resistance of S. aureus results from stepwise acquisition of at least two genetic mutations (8, 16, 20).
Although the phenotypic resistance data presented cannot compare to the precise delineation of genotypic mechanisms of resistance, analysis of the emergence of resistance of a population of organisms complements genotypic studies by adding the perspective of population dynamics. The serial passage experiments help to delineate differences in emergence of resistance among the organisms and fluoroquinolones tested. When the E. coli serial passage experiment was repeated, the overall results were similar (mean values), but the results for individual isolates were dramatically different. This observation is consistent with an ongoing ever-changing population of genotypes. Nonetheless, the behavior of the population of organisms remains the same with respect to the speed and degree of acquisition of resistant genotypes.
Many questions remain unanswered. How "fit" are the resistant mutants after 10 sequential incubation periods? Is their virulence the same as that of the original susceptible organisms? In the absence of the fluoroquinolone and with continued serial passage in the absence of drug, will the resistant phenotype persist or revert to a more susceptible population of organisms? Lastly, will the changes in in vitro behavior of a population of bacteria repeatedly exposed to a specific fluoroquinolone have any predictive value as to development of clinical resistance?
In summary, the in vitro development of phenotypic resistance was studied in single exposure and serial passage experiments with seven bacterial species and three fluoroquinolones. Determination of the frequency of development of resistant mutants after a single 48-h incubation had a low sensitivity as a predictor of results obtained after serial 48-h incubation periods. Based on the serial passage experiments, MSAA and MRSA phenotypic resistance to ciprofloxacin develops rapidly. For three of the Enterobacteriaceae tested, i.e., K. pneumoniae, E. cloacae, and S. marcescens, phenotypic resistance to trovafloxacin emerged more quickly than resistance to levofloxacin or ciprofloxacin; in contrast, the resistance to ciprofloxacin was slow to emerge. These studies also demonstrate the uniqueness of the interaction between specific bacteria and specific fluoroquinolones; e.g., the results for E. coli were substantively different from those for S. marcescens. For E. coli, repetition of the serial passage experiments yielded similar overall results, even though individual strains displayed marked differences. The results indicate that dynamic studies of acquisition of phenotypic resistance of fluoroquinolones complement studies that determine genetic mechanisms of resistance.
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FOOTNOTES |
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* Corresponding author. Mailing address: Providence Portland Medical Center, 5050 NE Hoyt, Suite 540, Portland, OR 97213. Phone: (503) 215-6258. Fax: (503) 215-6857. E-mail: dagilbert{at}providence.org.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, March 2001, p. 883-892, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.883-892.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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