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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, August 2000, p. 2211-2213, Vol. 44, No. 8
Institute of Medical Microbiology, Immunology
and Hygiene, University of Cologne, 50935 Cologne,
Germany,1 and Medical College of
Virginia, Virginia Commonwealth University, Richmond,
Virginia2
Received 16 March 2000/Returned for modification 25 April
2000/Accepted 11 May 2000
In vitro activities of seven fluoroquinolones against 140 clinical
Acinetobacter baumannii isolates representing 138 different strain types were determined. The rank order of activity was
clinafloxacin > gatifloxacin > levofloxacin > trovafloxacin > gemifloxacin = moxifloxacin > ciprofloxacin. The 31 outbreak-related A. baumannii strains
were significantly more resistant than were 109 sporadic strains.
During the past 20 years,
Acinetobacter baumannii has emerged as a significant
nosocomial pathogen (3, 6, 11, 20, 27). These organisms have
a particular propensity for nosocomial cross-transmission, and numerous
outbreaks of infections have been reported (8, 17, 21, 24,
25). The widespread multiresistance of these organisms is a cause
of concern. Aminoglycosides, carbapenems, and fluoroquinolones remain
the mainstay of therapy for serious A. baumannii infections,
although reports of increasing resistance against these agents have
appeared (8, 15, 16, 21, 22, 23).
Recently, several new fluoroquinolones with a greater potency against a
variety of bacterial species have been developed (4). These
agents exert a promising activity against A. baumannii
(1, 13, 26). The present study was conducted to evaluate the
in vitro activity of ciprofloxacin in comparison to those of the novel
fluoroquinolone compounds clinafloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and trovafloxacin against clinically significant A. baumannii isolates that were recovered from
blood cultures, tracheal secretions, wound swabs, and urine.
Acinetobacter species were identified as nonfermentative,
gram-negative, nonmotile, oxidase-negative bacilli. Phenotypic
identification as A. baumannii was performed using the
simplified identification scheme of Bouvet and Grimont (5).
Possible strain relatedness of the organisms was assessed by molecular
typing methods, such as randomly amplified polymorphic DNA (RAPD)
analysis, performed with two different primers (ERIC-2 and M13) using
Ready-To-Go RAPD Analysis Beads (Pharmacia Biotech, Freiburg, Germany)
and/or pulsed-field gel electrophoresis of genomic DNA using the
restriction enzyme ApaI as described previously (9,
18). The organisms were selected on the basis of exhibiting a
unique DNA fingerprint pattern. Usually, only one isolate per patient
was included, as was one isolate per given hospital outbreak. A second
isolate was considered only if the isolate differed in its
ciprofloxacin MIC by three or more twofold dilutions, as was the case
for two isolates. In total, 109 sporadic and 31 outbreak-related
isolates were selected. Included were 47 isolates that were originally
recovered from patients in the Cologne metropolitan area in Germany
between 1 July 1990 and 31 December 1998. Twelve of these strains were
isolated from 10 well-defined hospital outbreaks caused by 10 different
clonal strains. Details of these outbreaks have been described
elsewhere (17, 18, 27). Thirty-five strains were sporadic
isolates from the same geographic area but were epidemiologically
unrelated and represent different strain types (19). Also
included were a number of strains related to well-defined hospital
outbreaks (n = 9), as well as sporadic strains
(n = 13) from various hospitals in Germany and
neighboring European countries, such as Belgium, Denmark, and Great
Britain. In addition, 71 A. baumannii blood culture isolates
recovered from patients throughout the United States between 1 March
1996 and 28 February 1998 were selected. These isolates included 10 outbreak-related strains as well as 61 strains that were
epidemiologically unrelated (28). MICs were determined by
the agar dilution method recommended by the National Committee for
Clinical Laboratory Standards (NCCLS) (12) by using
cation-adjusted Mueller-Hinton agar (DIFCO, Augsburg, Germany). Plates
were inoculated with a Steers replicator with a final inoculum of
approximately 104 CFU per spot and incubated for 18 h
at 37°C. The MIC was defined as the lowest concentration of drug that
prevented visible growth. The following antibiotics were tested at
concentrations ranging from 0.03 to 128 mg/liter: ciprofloxacin (Bayer
AG, Leverkusen, Germany), clinafloxacin (Parke-Davis
Pharmaceuticals, Ann Arbor, Mich.), gatifloxacin (Grünenthal
GmbH, Stolberg, Germany), gemifloxacin (SmithKline Beecham, Munich,
Germany), levofloxacin (Hoechst AG, Frankfurt, Germany), moxifloxacin
(Bayer AG) and trovafloxacin (Pfizer Central Research, Groton, Conn.).
The breakpoints used for ciprofloxacin and levofloxacin were those
recommended by the NCCLS, while the breakpoints chosen for each of the
novel fluoroquinolones were those recommended by the manufacturers
(Table 1). Escherichia coli
ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213, and A. baumannii ATCC 19606 were used as controls.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Comparative Activities of Ciprofloxacin, Clinafloxacin,
Gatifloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin, and
Trovafloxacin against Epidemiologically Defined Acinetobacter
baumannii Strains
ABSTRACT
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TABLE 1.
In vitro activities of ciprofloxacin, clinafloxacin,
gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and
trovafloxacin against 140 A. baumannii isolates
The in vitro activities of the different fluoroquinolones against 140 clinical A. baumannii isolates are shown in Table 1. While
all of the novel fluoroquinolones were 4- to 16-fold more active than
ciprofloxacin, the activities of the novel quinolone compounds did not
exhibit major differences. The rank order of activity as determined by
their MICs at which 90% of the isolates tested are inhibited
(MIC90s) was as follows: clinafloxacin > gatifloxacin = levofloxacin > trovafloxacin = gemifloxacin = moxifloxacin > ciprofloxacin. The overall
respective MIC50s and MIC90s were as follows:
ciprofloxacin, 0.5 and 64 mg/liter; clinafloxacin, 0.12 and 4 mg/liter;
gatifloxacin 0.12 and 8 mg/liter; gemifloxacin, 0.12 and 16 mg/liter;
levofloxacin, 0.25 and 8 mg/liter; moxifloxacin, 0.12 and 16 mg/liter;
and trovafloxacin, 0.06 and 16 mg/liter. Although the novel quinolones
were considerably more active than ciprofloxacin in terms of
MIC50s, MIC90s, and geometric mean MICs, there
were only minor differences regarding the percentage of strains
susceptible at the respective breakpoints. For example, among the 38 strains resistant to ciprofloxacin (MIC, 
4 mg/liter), only nine
strains were fully susceptible to clinafloxacin (MIC, 
1 mg/liter).
Most studies reporting data of antimicrobial drug susceptibilities of A. baumannii did not consider the high epidemicity of these bacteria at many institutions. Their results were probably biased by the inclusion of isolates that were obtained from different patients but were nevertheless clonally related (10, 13, 16). It is obvious that the analysis of isolates collected consecutively from hospitalized patients even in multicenter studies with the inclusion of highly resistant epidemic strains tends to overestimate the resistance of these microorganisms to antimicrobial agents. We therefore included only isolates that represent different strain types as shown by molecular typing. This may explain why the percentages of strains susceptible to fluoroquinolones, ranging from 66 to 79% in our study, were considerably higher than in other recent studies (2, 13, 15, 16).
If outbreak-related strains were compared to sporadic strains, A. baumannii outbreak strains were significantly more resistant to
fluoroquinolone agents than sporadic strains. These differences were
highly significant for all the quinolones tested (P 0.0001, data not shown). Whereas susceptibilities to
fluoroquinolones ranged from 76 to 86% among sporadic isolates, only
32 to 55% of outbreak-related A. baumannii strains were
susceptible to the quinolones tested (Table
2). Villers et al. (25)
recently found that previous therapy with a fluoroquinolone was an
independent risk factor for infection with epidemic A. baumannii. It appeared that the selection pressure caused by the
indiscriminate use of fluoroquinolones was responsible for the
persistence and epidemic spread of multidrug-resistant A. baumannii clones for at least 5 years.
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Resistance of A. baumannii to the fluoroquinolones has been attributed to changes in the structure of DNA gyrase or topoisomerase IV which are caused by mutations in the gyrA or parC genes, respectively, which lower the affinity of the drug in the enzyme-DNA complex (7, 14, 23). A second mechanism of resistance has been described with mutations of chromosomally encoded drug influx and efflux systems that determine intracellular drug accumulation (4, 7, 14); these mutations result in either reduced production of outer membrane proteins, which mediate quinolone influx, or stimulation of the cells' efflux system, which leads to active drug expulsion. The basis of the increased activity of the novel quinolones against A. baumannii remains to be determined.
In conclusion, the novel quinolones demonstrated superior activity against A. baumannii compared to ciprofloxacin. Clinafloxacin was the most active agent against sporadic as well as outbreak-related A. baumannii isolates, the latter being significantly more resistant to all agents tested. Our findings demonstrate the need to analyze epidemiologically well-defined A. baumannii isolates and to exclude clonally related strains from hospital outbreaks or from nosocomial cross-transmission between patients. In the light of the limited therapeutic options for the treatment of infections caused by A. baumannii, clinical studies are required to test the relevance of the increased activities of the novel fluoroquinolones against A. baumannii infections.
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ACKNOWLEDGMENTS |
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We thank D. Stefanik for excellent technical assistance and P. Gerner-Smidt (Department of Clinical Microbiology, Statens Seruminstitut, Copenhagen, Denmark) for providing some of the A. baumannii strains investigated in this study.
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FOOTNOTES |
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* Corresponding author. Mailing address: Institute of Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstr. 19-21, 50935 Cologne, Germany. Phone: 0049 221 4783009. Fax: 0049 221 4783067. E-mail: harald.seifert{at}uni-koeln.de.
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