Journal of Antimicrobial Chemotherapy (2000) 46, 11-15
© 2000 The British Society for Antimicrobial Chemotherapy
Comparative in vitro potency of gemifloxacin against European respiratory tract pathogens isolated in the Alexander Project
Institute of Microbiology, University of Genoa Medical School, Largo Rosanna Benzi 10, 16132 Genoa, Italy
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Abstract |
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European isolates collected in 1998 for the Alexander Project were tested for their susceptibility to ciprofloxacin, ofloxacin and a novel fluoroquinolone, gemifloxacin, which has a spectrum of activity including common and atypical respiratory pathogens. MIC90s of gemifloxacin for Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were 0.03, 0.06 and 0.015 mg/L, respectively. On the basis of MIC90s, gemifloxacin was the most potent antimicrobial tested against S. pneumoniae and M. catarrhalis. Against H. influenzae, gemifloxacin was one tube dilution more potent than ofloxacin and one tube dilution less potent than ciprofloxacin. As resistance to currently available antimicrobial agents increases, gemifloxacin offers potential as a promising new agent for the treatment of respiratory tract infection.
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are common pathogens in community-acquired respiratory tract infections (RTIs), such as community-acquired pneumonia, acute exacerbation of chronic obstructive airways disease, otitis media and sinusitis. Atypical pathogens, including Mycoplasma pneumoniae, Legionella pneumophila and Chlamydia pneumoniae, are responsible for a proportion of community-acquired RTIs.1–3
Gemifloxacin (SB-265805; (R,S)-7-(3-aminomethyl-4-syn-methoxyimino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid methanesulphonate) is a novel, broad-spectrum, fluoronaphthyridone antimicrobial agent. Its acts primarily by inhibiting DNA gyrase and topoisomerase II. Gemifloxacin has excellent activity against both Gram-negative and Gram-positive organisms that cause RTIs, including potent antibacterial activity against streptococcal and staphylococcal species. It is also active against the atypical pathogens, legionella, chlamydia and mycoplasma. We have determined the comparative in vitro potency of gemifloxacin, ofloxacin and ciprofloxacin against RTI pathogens collected as part of the Alexander Project during 1998, and compared the results obtained with those previously reported in the literature.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Bacterial isolates and susceptibility tests
The pathogens studied were collected previously from European centres as part of the Alexander Project. They comprised: 1752 S. pneumoniae isolates, 1890 H. influenzae isolates and 371 M. catarrhalis isolates. Details of the criteria for collection of the bacterial isolates, transportation, storage, re-identification and the microbroth dilution susceptibility testing methods have been described previously.4,5
Gemifloxacin was obtained from SmithKline Beecham, Harlow, UK, ciprofloxacin from Bayer AG, Wuppertal, Germany and ofloxacin from Hoechst Marion Roussel, Romainville, France. All three compounds were supplied in a preprepared Sensititre microtitre plate (Trek Diagnostics, East Grinstead, UK). They were tested at concentrations of 0.008–16 mg/L.
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Results |
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The MIC50 of gemifloxacin was 0.015 mg/L for the 1752 S. pneumoniae European Alexander Project isolates, and 0.03 mg/L for isolates from the UK, Germany, Italy, Belgium, Poland and the Czech Republic (Table I
). The MIC90 was 0.03 mg/L for isolates from all individual centres. Gemifloxacin was 32–64 times more potent than ciprofloxacin or ofloxacin (Figure 1). No isolate was resistant to gemifloxacin (tentative breakpoint 
0.5 mg/L),6 although some isolates had elevated MICs of ciprofloxacin (eight had an MIC of 8 mg/L and four an MIC of 
16 mg/L) and ofloxacin (MIC 16 mg/L, n = 8).
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) and ciprofloxacin (
) against Streptococcus pneumoniae (n = 1752) isolated from European centres participating in the Alexander Project in 1998.For the 1890 H. influenzae isolates, the modal MIC of gemifloxacin was 0.008 mg/L, the lowest concentration tested. The overall MIC50 was 0.015 mg/L, with a value of 0.008 mg/L in Italy, Belgium, Greece, Poland and the Czech Republic, and 0.03 mg/L in France (Table II
). The overall MIC90 was 0.06 mg/L, with a value of 0.03 mg/L in Eire and Germany, and 0.015 mg/L in Italy, Belgium, Greece and the Czech Republic. Gemifloxacin was more potent than ofloxacin and as potent or more potent than ciprofloxacin (Figure 2). More importantly, no isolate of H. influenzae was resistant to gemifloxacin (assuming a breakpoint identical to that of ciprofloxacin (0.5 mg/L), although two isolates from France had MICs of 0.5 mg/L.
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For the 371 isolates of M. catarrhalis collected from seven centres in Europe in 1998, the MIC90 of gemifloxacin was 0.015 mg/L, compared with 0.06 mg/L of ciprofloxacin and 0.125 mg/L of ofloxacin (Table III
, Figure 3). Mode MICs were 0.008, 0.03 and 0.125 mg/L, respectively. These results were irrespective of ß-lactamase production. Two isolates had elevated MICs of ciprofloxacin (one 2 mg/L and the other 0.5 mg/L) and ofloxacin (2 mg/L), one each from The Netherlands and Poland.
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Discussion |
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The increased incidence of antimicrobial resistance among strains of S. pneumoniae, H. influenzae and M. catarrhalis isolated from community-acquired RTIs is a growing concern. Against a background of reduced susceptibility to currently available antimicrobial agents (ß-lactams, macrolides and tetracyclines), the fluoroquinolones continue to demonstrate good potency. Several of the new fluoroquinolones are worthy of particular note, including gemifloxacin, gatifloxacin and moxifloxacin. All these agents are, potentially, important additions to the choices available to clinicians for empirical treatment of RTI. In order to optimize empirical therapeutic choice and to influence prescription habits in a manner that might slow the further development of resistance, it is not only desirable, but essential, to survey individual isolates locally, nationally and worldwide.7,8
The Alexander Project is a continuing, multicentre, international study that generates accurate data on the incidence of resistance in the major pathogens causing RTI.4 It has recorded marked increases in antibiotic resistance since 1992 and this situation continues in many countries in 1998. The prevalence of both intermediate (MIC 0.12–1 mg/L) and resistant (MIC 2 mg/L) penicillin phenotypes of S. pneumoniae has soared.4,5,9 Resistance to macrolides, the principal alternative to ß-lactams for the treatment of lower RTIs involving S. pneumoniae, has also increased. In many countries, macrolide-resistance rates now exceed penicillin-resistance rates.10–12 More worryingly, perhaps, resistance to this class of compounds has increased not only among penicillin-resistant pneumococci but also among penicillin-susceptible strains.
As a consequence, there is an urgent need for alternative antimicrobial agents to treat infections caused by S. pneumoniae. Earlier fluoroquinolones had generally poor activity against this organism, precluding their use for empirical treatment of RTI. However, with the development of new fluoroquinolones characterized by enhanced activity against pneumococci and more favourable pharmacokinetics, the debate has been reopened.
Fluoroquinolone-resistant pneumococci (ciprofloxacin and ofloxacin MICs 16 mg/L) were found only rarely during the period of the study (1992–1998), although an increase was noted between 1996 (0/2160 isolates) and 1997 (10/2036 isolates). Importantly, when clinical susceptibility is defined on the basis of NCCLS breakpoints for ofloxacin (susceptibility, 2 mg/L; intermediate resistance, 4 mg/L; resistance, 8 mg/L),13 there is no obvious association between reduced susceptibility to quinolones (intermediate plus resistant isolates) and penicillin resistance, although multiresistant clones may exist. This supports the use of the new fluoroquinolones as substitutes for ß-lactams.
A number of other studies have examined the comparative in vitro activity of gemifloxacin against S. pneumoniae. For strains susceptible to ß-lactams and fluoroquinolones, gemifloxacin was the most potent agent tested, with typical MIC90s of 0.03–0.06 mg/L,14–19 compared with 0.03 mg/L in the present study. Where tested, gemifloxacin was more potent than moxifloxacin, grepafloxacin, trovafloxacin, sparfloxacin, clinafloxacin and levofloxacin. Similarly, gemifloxacin has been shown to be the most bactericidal fluoroquinolone tested against fluoroquinolone-susceptible or -resistant isolates of S. pneumoniae when compared with ciprofloxacin, grepafloxacin, moxifloxacin, levofloxacin and trovafloxacin.20
There are several potential mechanisms of resistance to fluoroquinolones in S. pneumoniae, involving, primarily, mutations in topoisomerase IV and DNA gyrase.21,22 There are two other classes of mutations, one involving the pmrA gene (efflux pump) and another selected preferentially by sparfloxacin, that may also involve permeability but does not produce cross-resistance to ethidium bromide.23 It is encouraging that one recent study has shown gemifloxacin activity to be only slightly affected by efflux-mediated fluoroquinolone resistance in either isogenic strains or clinical isolates of S. pneumoniae.23
At present, any shift in quinolone MICs is likely to result from a single mutation in topoisomerase IV, as this is the target for ciprofloxacin, the most extensively used quinolone. Newer quinolones that either target DNA gyrase or have two targets would be preferable therapeutic options in the future.
Fluoroquinolones show good activity against H. influenzae: against Alexander Project isolates and in all studies reviewed,15–17,24 gemifloxacin was highly active against H. influenzae, having similar potency to ciprofloxacin. Other studies have shown that, for Haemophilus parainfluenzae, the in vitro potency of gemifloxacin is also similar to that of ciprofloxacin. Typical MIC90s were 0.008 mg/L for H. influenzae and 0.03 mg/L for H. parainfluenzae.15–17,24 In each study, gemifloxacin was one of the most potent fluoroquinolones tested against H. influenzae and H. parainfluenzae.
Resistance to ß-lactams in M. catarrhalis is associated with ß-lactamase production. Since first recognized in the late 1970s, ß-lactamase-producing strains have increased and now account for >80% of clinical isolates.25–27 The Alexander Project data confirm the importance of this resistance mechanism with overall prevalence rates for ß-lactamase production ranging from 75.7% in 1992 to 92.2% in 1998.4,5 Gemifloxacin was highly active against this pathogen, irrespective of ß-lactamase production by the isolates, having an MIC90 of 0.008 mg/L.
In other studies, gemifloxacin has also demonstrated excellent in vitro activity against Streptococcus pyogenes, methicillin-susceptible staphylococci, atypical respiratory pathogens and the pathogens causing acute sinusitis.9
In conclusion, the need for new and effective compounds for the treatment of RTIs has never been more urgent, and gemifloxacin, a new fluoroquinolone that is highly active against the key respiratory pathogens, including strains exhibiting ciprofloxacin resistance and atypical bacteria, could be a suitable therapeutic option. The results of the first clinical studies are awaited eagerly.
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Notes |
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* Corresponding author. Tel: +39-010-3537646 or 502136; Fax: +39-010-504837; E-mail: schitogc{at}aleph.it
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References |
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