In vitro activity of gemifloxacin (SB 265805; LB20304a) against human mycoplasmas

Peter C. T. Hannana,* and Gary Woodnuttb

a Mycoplasma Experience Ltd, 1 Norbury Road, Reigate RH2 9BY, UK; b SmithKline Beecham Pharmaceuticals, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
The in vitro activity of gemifloxacin, a new broad-spectrum fluoroquinolone, was compared with those of ciprofloxacin, erythromycin, azithromycin and doxycycline against 29 human respiratory or urogenital tract mycoplasmas. Gemifloxacin was highly active against all of the mycoplasma and ureaplasma species tested (MIC range 0.001–0.25 mg/L) and was 5- to 100-fold more active than ciprofloxacin. Doxycycline was less active than gemifloxacin against the mycoplasmas (MIC range 0.01–1 mg/L) but had similar activity against Ureaplasma urealyticum (MIC ranges 0.025–0.25 mg/L and 0.1–0.25 mg/L, respectively). The macrolides, particularly azithromycin, were more active than gemifloxacin against Mycoplasma pneumoniae (MIC range 0.001–0.0025 mg/L) and Mycoplasma genitalium (0.0005–0.001 mg/L) isolates but were less active against Mycoplasma fermentans and U. urealyticum and inactive against Mycoplasma hominis. Gemifloxacin may therefore be useful in the treatment of respiratory, urogenital or systemic mycoplasma infections in humans.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Gemifloxacin (SB 265805; LB20304a) is a new fluoroquinolone demonstrating potent activity against a wide range of Gram-negative and Gram-positive bacteria, in particular Streptococcus pneumoniae (MIC90 0.06 mg/L), Haemophilus influenzae (MIC90 0.08 mg/L) and Moraxella catarrhalis (MIC90 0.015 mg/L).1 Gemifloxacin therefore could be an important agent for the empirical treatment of community infections, particularly those of the respiratory and urogenital tracts. The bactericidal action of this class of compounds2 suggests also that gemifloxacin could be of considerable benefit when treating immunocompromised patients who are prone to developing bacterial, mycoplasmal and fungal infections. This study was undertaken to investigate the in vitro activity of gemifloxacin against clinically relevant mycoplasmas such as Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum, or potentially pathogenic mycoplasmas from cases of non-gonococcal urethritis (Mycoplasma genitalium) or those reputedly isolated from HIV-1-seropositive or AIDS patients (Mycoplasma fermentans, Mycoplasma penetrans or Mycoplasma pirum)3 compared with agents currently recommended for the treatment of mycoplasma infections, erythromycin, azithromycin and doxycycline, as well as a comparator quinolone, ciprofloxacin.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Gemifloxacin was supplied by SmithKline Beecham Pharmaceuticals (Upper Providence, PA, USA). Doxycycline and erythromycin were obtained from Sigma– Aldrich (Poole, UK). Ciprofloxacin and azithromycin were extracted from commercially available materials.

Mycoplasma species

Clinical isolates and/or reference strains including the type strains of M. pneumoniae (ten strains), M. fermentans (five strains, including one AIDS-associated isolate), M. hominis (five strains), the type strains of M. penetrans, GTU 54 (ATCC 55252) isolated from the urine of an AIDS patient, M. pirum HRC 70-159 (NC 11702), M. genitalium (three isolates) and U. urealyticum (four isolates) were used in these studies.

Broth-dilution susceptibility testing

MICs were determined as described previously4 using a broth microdilution method and employing three commercially available broths containing the pH indicator phenol red (Mycoplasma Experience Ltd, Reigate, UK) and 0.1% w/v glucose at pH 7.6 for the glucose-fermenting mycoplasmas (M. pneumoniae, M. fermentans, M. penetrans, M. pirum and M. genitalium), 0.1% w/v arginine at pH 6.8 for M. hominis, or 0.1% w/v urea at pH 6.6 for U. urealyticum isolates. Final dilution ranges varied according to the mycoplasma species under test and the class of antimicrobial under investigation and were chosen with knowledge of the likely MICs.3,5,6 Tests were inoculated with 103–105 colour changing units (ccu) per mL of the appropriate mycoplasma species. The microtitre plates were then sealed and incubated at 36°C. The type strain of each species was included in each test for reference purposes. MICs were recorded when the colour of the growth control wells matched that of end-point controls (pH 6.8 or 7.6 depending on whether the pH shift was to an acid or alkaline reaction) and were defined as the lowest concentrations of antibiotic to show no change in colour.


    Results and discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
The comparative activities of gemifloxacin and the other antimicrobials tested are shown in the TableGo. Gemifloxacin was highly active against the mycoplasma and ureaplasma species tested, with an overall range of MIC from 0.001 to 0.25 mg/L, which would be well within the range of expected clinical susceptibility based upon the pharmacokinetics in man at the proposed clinical dose (320 mg od; AUC 9.06 mg•h/L and t1/2 7–8 h).7 Ciprofloxacin was 5- to 100-fold less active than gemifloxacin against the species and isolates tested. Doxycycline was also less active than gemifloxacin against all of the mycoplasma species, but had a similar MIC range against isolates of U. urealyticum (0.025–0.25 mg/L and 0.1–0.25 mg/L, respectively). The macrolides, particularly azithromycin, were more active than gemifloxacin against M. pneumoniae and M. genitalium isolates. Although azithromycin also showed similar activity against the single isolates of M. penetrans and M. pirum tested, gemifloxacin was generally superior in activity against the remaining species. M. hominis isolates, which are intrinsically resistant to 14-membered macrolides such as erythromycin3 and 15-membered macrolides such as azithromycin3 but susceptible to josamycin (16-membered macrolide), were highly susceptible to gemifloxacin (MIC range 0.0025–0.01 mg/L).


View this table:
[in this window]
[in a new window]
 
Table. Comparative MICs of gemifloxacin and four reference compounds against six human mycoplasma species and Ureaplasma urealyticum
 
These results for gemifloxacin are largely consistent with those reported recently for grepafloxacin, ciprofloxacin, erythromycin and doxycycline by Bébéar et al.8 against a similar range of human mycoplasma species and show gemifloxacin to be as active as or slightly more active in vitro than grepafloxacin against certain species (M. hominis, M. fermentans and M. penetrans). They also show gemifloxacin to have in vitro activity similar to or better than that reported recently for certain other new fluoroquinolones, moxifloxacin (BAY 12-8039),9 clinafloxacin10 and sparfloxacin9 against isolates of M. pneumoniae, M. hominis or U. urealyticum.

The potency and breadth of the spectrum of antimycoplasma activity of gemifloxacin shows that, overall, it is superior in vitro to ciprofloxacin and the comparator agents, erythromycin, azithromycin and doxycycline, currently used to treat mycoplasma infections. These data suggest that gemifloxacin may also be useful in the treatment of such infections and that, with its high intrinsic activity against a range of Gram-negative and Gram-positive bacterial pathogens, it could be an important new agent for empirical therapy of respiratory, urogenital or systemic infections in humans.


    Acknowledgments
 
This research was presented at the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, USA, 24–27 September 1998.


    Notes
 
* Corresponding author. Tel: +44-1737-226662; Fax: +44-1737-224751. Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
1 . Boswell, F. J., Andrews, J. M. & Wise, R. (1999). The comparative in-vitro activity of gemifloxacin, a novel fluoroquinolone. (P413). Journal of Antimicrobial Chemotherapy 44, Suppl. A, 132.

2 . Smith, J. T. (1984). Awakening the slumbering potential of the 4-quinolone antibacterials. Pharmaceutical Journal 233, 299–305.

3 . Hannan, P. C. (1998). Comparative susceptibilities of various AIDS-associated and human urogenital tract mycoplasmas and strains of Mycoplasma pneumoniae to 10 classes of antimicrobial agent in vitro. Journal of Medical Microbiology 47, 1115–22.[Abstract]

4 . Hannan, P. C., Windsor, G. D., de Jong, A., Schmeer, N. & Stegemann, M. (1997). Comparative susceptibilities of various animal-pathogenic mycoplasmas to fluoroquinolones. Antimicrobial Agents and Chemotherapy 41, 2037–40.[Abstract]

5 . Waites, K. B., Duffy, L. B., Schmid, T., Crabb, D., Pate, M. S. & Cassell, G. H. (1991). In-vitro susceptibilities of Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum to sparfloxacin and PD 127391. Antimicrobial Agents and Chemotherapy 35, 1181–5.[ISI][Medline]

6 . Hannan, P. C. (1995). Antibiotic susceptibility of Mycoplasma fermentans strains from various sources and the development of resistance to aminoglycosides in vitro. Journal of Medical Microbiology 42, 421–8.[Abstract]

7 . Allen, A., Bygate, E., Teillol-Foo, M., Oliver, S. D., Johnson, M. R. & Ward, C. (1999). Multiple-dose pharmacokinetics and tolerability of gemifloxacin following oral doses to healthy volunteers. (P418). Journal of Antimicrobial Chemotherapy 44, Suppl. A, 133.[Free Full Text]

8 . Bébéar, C. M., Renaudin, H., Schaeverbeke, T., Leblanc, F. & Bébéar, C. (1999). In-vitro activity of grepafloxacin, a new fluoroquinolone, against mycoplasmas. Journal of Antimicrobial Chemotherapy 43, 711–14.[Abstract/Free Full Text]

9 . Bébéar, C. M., Renaudin, H., Boudjadja, A. & Bébéar, C. (1998). In-vitro activity of BAY 12-8039, a new fluoroquinolone, against mycoplasmas. Antimicrobial Agents and Chemotherapy 42, 703–4.[Abstract/Free Full Text]

10 . Cohen, M. A. & Huband, M. D. (1997). In-vitro susceptibilities of Mycoplasma pneumoniae, Mycoplasma hominis, and Ureaplasma urealyticum to clinafloxacin, PD 131628, ciprofloxacin and comparator drugs. Journal of Antimicrobial Chemotherapy 40, 308–9.[Free Full Text]

Received 8 March 1999; returned 6 August 1999; revised 15 September 1999; accepted 2 November 1999