Comparative in vitro activity of moxifloxacin against Gram-positive clinical isolates

J. A. A. Hoogkamp-Korstanje* and J. Roelofs-Willemse

Department of Medical Microbiology, University Hospital St Radboud, University of Nijmegen, Geert Grooteplein 24, 6500 HB Nijmegen, The Netherlands


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The in vitro activity of moxifloxacin was compared with that of 15 antibacterial agents against 513 Gram-positive microorganisms. The MIC90 (mg/L) of moxifloxacin was 0.06 for quinolone-susceptible Staphylococcus aureus and Staphylococcus epidermidis, 0.12 for Streptococcus pyogenes and Streptococcus agalactiae; 0.25 for Streptococcus pneumoniae, Streptococcus mitis, Streptococcus bovis, Streptococcus anginosus and Actinomyces pyogenes; 0.5 for Streptococcus sanguis and Listeria monocytogenes, 2 for Corynebacterium jekeium and Bifidobacterium bivius. Over 50% of Enterococcus faecalis, Enterococcus faecium, quinolone-resistant staphylococci, Nocardia steroides and Clostridium difficile were susceptible to 2 mg/L moxifloxacin. Moxifloxacin and trovafloxacin demonstrated comparably high activity towards Gram-positive cocci; moxifloxacin and clinafloxacin were most active against Gram-positive bacilli.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Improved in vitro activity against Gram-positive bacteria occurs with several of the newer quinolones. Among these are sparfloxacin, trovafloxacin and moxifloxacin, the extended-spectrum activity of which looks most promising.1,2,3 We compared the in vitro activity of moxifloxacin with that of other antibiotics used for infections caused by Gram-positive organisms, in which resistance towards penicillins, glycopeptides and macrolides is increasing worldwide.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The strains used were Gram-positive cocci (396 bloodstream isolates) and Gram-positive bacilli (117 clinical isolates of various origin) of patients hospitalized in the University Hospital St Radboud, The Netherlands. Control strains were Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212.

MICs were determined in duplicate by broth microdilution with IsoSensitest Broth (Oxoid CM 491, Haarlem, The Netherlands) supplemented with 2% lysed horse blood for fastidious microorganisms. The inoculum was prepared by the direct colony suspension method: colonies grown overnight on Columbia agar with 5% sheep blood were suspended in sterile saline up to a concentration of McFarland 0.5 turbidity standard. After dilution the final inoculum was 4 x 105 cfu/mL.

The antimicrobial agents tested against Gram-positive cocci were: moxifloxacin, ciprofloxacin, sparfloxacin, trovafloxacin, lomefloxacin, levofloxacin, vancomycin, teicoplanin, erythromycin, clarithromycin, imipenem, meropenem and penicillin (for pneumococci and streptococci). For Gram-positive bacilli the trays contained moxifloxacin, sparfloxacin, trovafloxacin, clinafloxacin, erythromycin, clarithromycin, clindamycin, co-amoxiclav, imipenem and meropenem. For Gram-positive anaerobic bacilli metronidazole was also tested. The antibacterial agents were obtained from the original manufacturers and stock solutions were prepared following the manufacturer's instructions.

Concentrations ranged from 0.008 to 32 mg/L for all drugs except for penicillin (0.008–128 mg/L). The trays were incubated at 37°C and examined for growth after 24 h. The breakpoints defined by the National Committee for Clinical Laboratory Standards4 were used; when breakpoints were unknown, breakpoints for comparable drugs or comparable microorganisms were taken.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The comparative activities of the strains are given in the Table.Go


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Table. MIC50, MIC90, range and percentage susceptibility of 397 bloodstream isolates of Gram-positive cocci and 117 clinical isolates of Gram-positive bacilli
 
Pneumococci

Against pneumococci, including 12 strains either moderately susceptible or resistant to penicillin, moxifloxacin and trovafloxacin were about eight times as active as ciprofloxacin and levofloxacin and 32 times as active as lomefloxacin. At the breakpoint of 2 mg/L, moxifloxacin, trovafloxacin and sparfloxacin were equally active.

All strains were inhibited by the macrolides, vancomycin and carbapenems at concentrations <1 mg/L, with teicoplanin the most active glycopeptide and imipenem the most active carbapenem. Imipenem showed higher activity than penicillin itself. At the breakpoints all strains were suscept-ible to the glycopeptides, macrolides, carbapenems and the quinolones except lomefloxacin.

Streptococci

Moxifloxacin and trovafloxacin were two to four times as active as sparfloxacin, eight times as active as ciprofloxacin and levofloxacin, and 32 times as active as lomefloxacin against Streptococcus mitis, Streptococcus sanguis, Streptococcus bovis and Streptococcus anginosus.

Teicoplanin was at least four times as active as vancomycin against all streptococci; imipenem exhibited lower MICs than meropenem and penicillin towards all streptococci. At the breakpoints all strains were inhibited by the glycopeptides and carbapenems.

Macrolides were variably active against the streptococci. Both erythromycin and clarithromycin were highly active against S. sanguis and S. anginosus; their MICs for S. bovis were consistently higher, and we found about 20% of S. mitis to be resistant to the macrolides.

Moxifloxacin and trovafloxacin were twice as active as sparfloxacin against Streptococcus pyogenes and Streptococcus agalactiae, four to eight times as active as ciprofloxacin and levofloxacin and 32 times as active as lomefloxacin. The glycopeptides, macrolides and carbapenems also showed high activity.

Enterococci

Ciprofloxacin-susceptible Enterococcus faecalis showed four-fold lower MICs of moxifloxacin, sparfloxacin and trovafloxacin; ciprofloxacin- and levofloxacin-resistant E. faecalis were also resistant to moxifloxacin, sparfloxacin and trovafloxacin. Sixty per cent of E. faecalis were suscept-ible to all quinolones except lomefloxacin. The activity of the fluoroquinolones against gentamicin-resistant E. faecalis was equally poor. Moxifloxacin and sparfloxacin inhibited 52% and 60%, respectively, of Enterococcus faecium at <2 mg/L. Teicoplanin and vancomycin were the most active compounds against these strains.

Staphylococci

Against ciprofloxacin-susceptible S. aureus and Staphylo-coccus epidermidis moxifloxacin, trovafloxacin and sparfloxacin were eight to 16 times more active than ciprofloxacin, levofloxacin and lomefloxacin. Ciprofloxacin-resistant S. aureus (all MRSA strains) and S. epidermidis exhibited higher MICs of moxifloxacin, sparfloxacin and trovafloxacin, but cross resistance was not complete. Four ciprofloxacin-resistant MRSA strains were resistant to the carbapenems, two also to vancomycin. Combined resistance with macrolides was found in five MRSA strains for ciprofloxacin and sparfloxacin, one strain for trovafloxacin and none for moxifloxacin. Quinolone resistance was, in general, not linked with resistance against glycopeptides, macrolides or carbapenems.

Moxifloxacin was the most active quinolone against Staphylococcus haemolyticus; 76% of strains were suscept-ible. Vancomycin was the most active glycopeptide; imipenem the most active carbapenem.

Gram-positive bacilli

Trovafloxacin was the most active agent against Listeria monocytogenes, followed by clinafloxacin, moxifloxacin and sparfloxacin. At the breakpoints, all strains were susceptible to all drugs tested.

Clinafloxacin and moxifloxacin inhibited over 90% of Corynebacterium jekeium strains. Only two strains were inhibited by carbapenems; none of the strains was suscept-ible to the other drugs. Clinafloxacin was the most active compound against Nocardia asteroides; 50% were also inhibited by moxifloxacin. All strains of Actinomyces pyogenes were highly susceptible to all quinolones. Trovafloxacin, clinafloxacin and moxifloxacin showed high activity against Clostridium difficile and Bifidobacterium bivius strains.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Moxifloxacin and trovafloxacin exhibited superior activity against Gram-positive bacteria compared with sparfloxacin, ciprofloxacin, levofloxacin and lomefloxacin. An important feature is their activity against pneumococci, irrespective of penicillin susceptibility.5,6,7 They may therefore be welcome drugs in countries with a substantial level of penicillin-resistant pneumococci. Their high activity against S. mitis, S. sanguis, S. bovis and S. anginosus was another significant finding, leading to new possibilities for the treatment of serious infections, like endocarditis, deep abscesses, etc. Replacing long-term parenteral therapy with ß-lactams, vancomycin and aminoglycosides, by oral monotherapy with quinolones would be an attractive option.

Like others7,8 we found cross resistance between the older and newer quinolones, resulting in increased MICs of moxifloxacin, sparfloxacin and trovafloxacin for quinolone-resistant S. aureus and S. epidermidis, mostly linked with methicillin resistance. Nevertheless, over 75% of these strains were still susceptible.

Most enterococci tested were isolated from our intensive care units, where enterococcal resistance to ciprofloxacin has risen to 60%. This is also the experience of others.9 Enterococci moderately susceptible to ciprofloxacin were inhibited by 0.5 mg/L of moxifloxacin or trovafloxacin. This represents a considerable improvement of activity. However, ciprofloxacin-resistant strains were also moxifloxacin, sparfloxacin and trovafloxacin resistant. Moxifloxacin inhibited 52% of E. faecium strains at <2 mg/L, equalling the activity of sparfloxacin.

An important finding was the activity of moxifloxacin and clinafloxacin against Gram-positive bacilli. Until now no quinolone has exhibited sufficient activity against these significant and often multiresistant pathogens. Moxifloxacin and clinafloxacin may be options for treating infections by these organisms, in particular C. jekeium and N. asteroides.

In conclusion, moxifloxacin and trovafloxacin were highly active against pneumococci, haemolytic streptococci, staphylococci and L. monocytogenes. Moxifloxacin and clinafloxacin were the most active compounds against C. jekeium, N. asteroides and C. difficile. Moxifloxacin, trovafloxacin and clinafloxacin may be useful drugs for therapy of Gram-positive infections.


    Acknowledgments
 
This study was supported by Bayer AG Division Forschung, Wuppertal, Germany.


    Notes
 
*Corresponding author. Tel: +31-24-36-14-356; Fax: +31-24-35-40-216; E-mail: j.hoogkamp{at}mmb.azn.nl Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Piddock, L. J. (1994). New quinolones and Gram-positive bac-teria. Antimicrobial Agents and Chemotherapy 38, 163–9.[ISI][Medline]

2 . Hoogkamp-Korstanje, J. A. A. (1997). In-vitro activities of ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin, pefloxacin, sparfloxacin and trovafloxacin against Gram-positive and Gram-negative pathogens from respiratory tract infections. Journal of Antimicrobial Chemotherapy 40, 427–31.[Abstract]

3 . Woodcock, J. M., Andrews,J. M., Boswell, F. J., Brenwald, N. P. & Wise, R. (1997). In-vitro activity of BAY 12-8039, a new fluoroquinolone. Antimicrobial Agents and Chemotherapy 41, 101–6.[Abstract]

4 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fourth Edition: M7-A4. NCCLS, Wayne, PA.

5 . Visalli, M. A., Jacobs, M. R. & Appelbaum, P. C. (1996). Activity of CP 99,219 (trovafloxacin) compared with ciprofloxacin, sparfloxacin, clinafloxacin, lomefloxacin and cefuroxime against ten penicillin-susceptible and penicillin-resistant pneumococci by time–kill methodology. Journal of Antimicrobial Chemotherapy 37, 77–84.[Abstract]

6 . Weiss, K., Laverdiere, M. & Restieri, C. (1998). Comparative activity of trovafloxacin and BAY 12-8039 against 452 clinical isoalates of Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy 42, 523–5.[Abstract]

7 . Souli, M., Wennersten, C. B. & Eliopoulos, G. M. (1998). In-vitro activity of BAY 12-8039, a new fluoroquinolone, against species representative of respiratory tract pathogens. International Journal of Antimicrobial Agents 10, 23–30.[ISI][Medline]

8 . Blumberg, H. M., Rimland, D., Carroll, D. J., Terry, P. & Wachsmuth, I. K. (1991). Rapid development of ciprofloxacin resistance in methicillin-susceptible and -resistant Staphylococcus aureus. Journal of Infectious Diseases 163, 1279–85.[ISI][Medline]

9 . Schaberg, D. R., Dillon, W. I., Terpenning, M. S., Robinson, K. A., Bradley, S. & Kauffman, C. A. (1992). Increasing resistance of enterococci to ciprofloxacin. Antimicrobial Agents and Chemotherapy 36, 2533–5.[Abstract]

Received 11 January 1999; returned 29 March 1999; revised 11 June 1999; accepted 11 September 1999