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Antimicrobial Agents and Chemotherapy, May 1998, p. 1269-1273, Vol. 42, No. 5
Department of Pathology, Hershey Medical
Center, Hershey, Pennsylvania 17033,1 and
Department of Pathology, Case Western Reserve University,
Cleveland, Ohio 441062
Received 17 November 1997/Returned for modification 18 February
1998/Accepted 12 March 1998
Activities of clinafloxacin, ciprofloxacin, levofloxacin,
sparfloxacin, trovafloxacin, piperacillin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, ceftazidime, and imipenem against 354 ciprofloxacin-susceptible and -intermediate-resistant organisms were
tested by agar dilution. Clinafloxacin yielded the lowest quinolone
MICs ( Antimicrobial resistance has
developed in most classes of gram-positive and -negative
bacteria. Therefore, there is a need for a compound which can be
used empirically for single-drug therapy of serious systemic
infections such as nosocomial pneumonia, especially in
the immunocompromised host (23).
Clinafloxacin (CI-960, PD 127391) is a broad-spectrum quinolone active
against a broad array of gram-positive and -negative bacteria
(5-8, 12, 13, 15-17, 19, 20). This study further characterized the in vitro activity of clinafloxacin compared to those
of ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, piperacillin, piperacillin-tazobactam,
trimethoprim-sulfamethoxazole, ceftazidime, and imipenem against
354 gram-positive and -negative bacteria with both low and elevated
ciprofloxacin MICs.
Organisms (Table
1) were
clinical isolates selected such that as many species possible had
strains with ciprofloxacin MICs in both the susceptible (
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Comparative Activities of Clinafloxacin against
Gram-Positive and -Negative Bacteria
ABSTRACT
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0.5 µg/ml against ciprofloxacin-susceptible organisms and
16.0 µg/ml against ciprofloxacin-intermediate-resistant organisms) compared to those of levofloxacin, trovafloxacin, and sparfloxacin. Ceftazidime, piperacillin alone or combined with tazobactam,
trimethoprim-sulfamethoxazole, and imipenem usually yielded higher
MICs against ciprofloxacin-resistant strains.
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1.0 µg/ml)
and resistant (
2.0 µg/ml) categories (18). In order to
obtain significant numbers of ciprofloxacin-resistant members of the
family Enterobacteriaceae, many sources were required (see
Acknowledgments), as these strains are uncommon.
TABLE 1.
Results of MIC testing of 354 ciprofloxacin-susceptible
and -resistant strains
Standard agar dilution MICs (18) were performed by using
cation-adjusted Mueller-Hinton agar with the addition of 5% sheep blood for Streptococcus pneumoniae. For this study,
organisms with MICs of 1.0 µg/ml were called ciprofloxacin
susceptible and those with MICs of 2.0 µg/ml were called
intermediate resistant.
Clinafloxacin gave the lowest quinolone MICs for all organisms (Table
1). For ciprofloxacin-susceptible strains, clinafloxacin MICs were
all 0.5 µg/ml compared to MICs of 2.0 µg/ml for levofloxacin, sparfloxacin, and trovafloxacin (Table 1). High MICs against piperacillin alone or combined with tazobactam,
trimethoprim-sulfamethoxazole, and ceftazidime were seen especially in
Chryseobacterium meningosepticum, Myroides
odoratus, and some members of the Enterobacteriaceae. Among ciprofloxacin-susceptible strains, imipenem resistance (MICs 16.0 µg/ml) (18) occurred most commonly in C. meningosepticum and M. odoratus. Imipenem resistance in
ciprofloxacin-susceptible strains was found only in Burkholderia
cepacia, C. meningosepticum, M. odoratus,
methicillin-resistant staphylococci, and Enterococcus faecium (Table 1).
MICs of all compounds tested were higher in ciprofloxacin-resistant
strains with the exception of imipenem against acinetobacters (Table
1). Of gram-negative rods, Stenotrophomonas
maltophilia yielded the lowest clinafloxacin MICs (90%
susceptible at 1.0 µg/ml). Among ciprofloxacin-resistant
members of the Enterobacteriaceae, 83% of
Citrobacter, Serratia, and Providencia
strains were clinafloxacin susceptible. Levofloxacin, sparfloxacin, and
trovafloxacin yielded MICs which were several twofold increments higher
than those of clinafloxacin against ciprofloxacin-resistant
gram-negative rods. Of 15 ciprofloxacin-resistant staphylococci tested,
14 were also methicillin resistant: clinafloxacin and trovafloxacin
were the only quinolones with low MICs (MIC50s of 1.0 and
2.0 µg/ml, respectively) against these strains. All four
quinolones tested gave low MICs against
penicillin-susceptible and -resistant pneumococci.
Among 13 ciprofloxacin-resistant Enterococcus faecalis
strains (3 vancomycin-resistant strains) clinafloxacin MICs were
8.0 µg/ml. Against E. faecium, clinafloxacin MICs
were much lower (0.25 µg/ml) against the two
ciprofloxacin-susceptible, vancomycin-susceptible strains than
against ciprofloxacin-resistant strains, 10 of which were also
vancomycin resistant (MICs 16.0 µg/ml). Although
clinafloxacin had the lowest MICs against ciprofloxacin-resistant
enterococci, most MICs were in the resistant range.
MICs of piperacillin alone or combined with tazobactam, trimethoprim-sulfamethoxazole, and ceftazidime for ciprofloxacin-resistant strains were higher than those in ciprofloxacin-susceptible strains. Imipenem was active against all ciprofloxacin-resistant strains tested except Pseudomonas aeruginosa, S. maltophilia, B. cepacia, Chryseobacterium and Myroides spp., methicillin-resistant staphylococci, and enterococci.
Our results show that clinafloxacin had the lowest overall MICs of
compounds tested against all organisms (including
ciprofloxacin-resistant strains). Levofloxacin, trovafloxacin,
and sparfloxacin also had low MICs (although higher than those of
clinafloxacin) against most common organisms. These results confirm
findings in previous studies (6-10, 12, 13, 15-17, 20).
Although clinafloxacin MICs (along with those of other quinolones
tested) rose with those of ciprofloxacin, clinafloxacin MICs were still
severalfold lower than those of other quinolones. With a provisional
clinafloxacin-susceptible breakpoint of 1.0 µg/ml (9),
all ciprofloxacin-susceptible strains and 63% of
ciprofloxacin-resistant strains tested were clinafloxacin susceptible.
Activities of other quinolone and nonquinolone compounds reflect
previous findings. Trovafloxacin, sparfloxacin, ciprofloxacin, and
levofloxacin yielded low MICs against most species of
Enterobacteriaceae. However, gram-negative nonfermenters
were generally more resistant to quinolones: of these strains,
P. aeruginosa, S. maltophilia and some
Chryseobacterium and Myroides spp. had the lowest
quinolone MICs. All quinolones had bimodal MIC distributions against
Acinetobacter spp., with strains either susceptible
(MICs 1 µg/ml) or very resistant (MICs 8 µg/ml)
(1, 11, 19, 21, 23).
Clinafloxacin was very active against methicillin-susceptible staphylococci, with MICs a few dilutions lower than those of other quinolones. Clinafloxacin was less active against methicillin-resistant strains, especially those which were also ciprofloxacin resistant. Clinafloxacin and trovafloxacin MICs were several dilutions lower than those of other quinolones against these organisms. Previous workers have described either the same phenomenon or similar clinafloxacin MICs in methicillin-susceptible and -resistant strains (7-10, 12, 13, 15-17, 20). Cohen and coworkers have reported strains of methicillin-resistant S. aureus exhibiting clinafloxacin and ciprofloxacin MICs of 1.0 and 128.0 µg/ml, respectively (6). Antipneumococcal activity of quinolones reflected previous findings, with clinafloxacin showing the lowest MICs (7-13, 15-17, 19, 21). Although clinafloxacin MICs against enterococci were higher than those reported by some workers, others have reported MICs similar to ours (7-10, 13, 15-17, 20).
Ceftazidime was very active against most members of the Enterobacteriaceae and some strains of P. aeruginosa but less active against other gram-negative nonfermenters. Imipenem was very active against members of the Enterobacteriaceae, but high-level resistance was found in most nonfermenter groups (especially S. maltophilia). Methicillin-resistant staphylococci were also imipenem resistant. Trimethoprim-sulfamethoxazole and piperacillin alone or combined with tazobactam were most active against ciprofloxacin-susceptible strains (2, 3, 14).
Against a panel of fluoroquinolone-resistant organisms and at a
quinolone breakpoint of 1.0 µg/ml (9, 18), Cormican and
Jones (9) have reported that clinafloxacin inhibited 65% of
strains compared to 30 to 38% for other quinolones. Shapiro and
coworkers (22) have found clinafloxacin to be effective in
treatment of neutropenic mice with acute systemic infections caused by
gram-positive and -negative organisms. In a murine subcutaneous S. aureus abscess model, Cohen and coworkers (5)
have shown clinafloxacin to be up to 19-fold more protective than
ciprofloxacin.
Bron and coworkers (4) have reported a maximum concentration of clinafloxacin in plasma of 2.5 µg/ml, following oral administration of a single 200-mg dose to human volunteers. Because intravenous administration of this compound is also under development, higher levels in serum are expected, further enlarging its spectrum. In view of these pharmacokinetic data and the MICs presented here and pending the results of human toxicologic studies, clinafloxacin shows promise in treatment of nosocomial pneumonia and other serious systemic infections, especially in the immunocompromised host. Clinical studies are in progress to test these hypotheses.
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ACKNOWLEDGMENTS |
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This study was supported by a grant from Parke-Davis Pharmaceutical Research, Ann Arbor, Mich.
We thank J. Liñares (Barcelona, Spain), R. Fass (Columbus, Ohio), V. La Bombardi (New York, N.Y.), and W. Brown (Detroit, Mich.) for provision of some strains.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-5113. Fax: (717) 531-7953. E-mail: pappelbaum{at}psghs.edu.
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Antimicrobial Agents and Chemotherapy, May 1998, p. 1269-1273, Vol. 42, No. 5
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