Emergence of quinolone resistance among clinical isolates of methicillin-resistant Staphylococcus aureus in Ontario, Canada

Lamp

et al. 1992

CI-960 is a new fluoroquinolone with enhanced in vitro activity against gram-positive pathogens. The efficacy of the drug was compared with that of vancomycin by using the rabbit model of nafcillin-and ciprofloxacinsusceptible and -resistant Staphylococcus aureus endocarditis. Animals received intravenous therapy with CI-960, 20 mg/kg of body weight every 8 h, or vancomycin, 17.5 mg/kg every 6 h, for 4 days. In a comparison with the effects on untreated controls, both antimicrobial agents effectively cleared bacteremia and significantly reduced bacterial counts in vegetations and tissues of animals infected with any of the test strains. In some cases, the efficacy of CI-960 was superior to that of vancomycin. The therapeutic activity of CI-960 was reduced, but still very good, against ciprofioxacin-resistant strains. One rabbit infected with such a strain and treated with CI-960 was found to harbor a small number of vegetation-associated organisms resistant to the drug at fivefold its original MIC; this was associated with a microbiological, but not a clinical, failure of therapy. We conclude that CI-960 is as effective as vancomycin is in this model ofa serious systemic S. aureus infection, including that caused by strains resistant to ciprofloxacin. Increases in CI-960 MICs may develop during therapy of infections caused by strains highly resistant to ciprofloxacin, but they appear unlikely to occur in ciprofloxacin-susceptible strains.CI-960 (AM-1091, PD 127391) is a new fluoroquinolone that has enhanced activity against gram-positive pathogens, including nafcillin-susceptible and -resistant strains of Staphylococcus aureus (1, 10). Because of the increased potency of this compound compared with those of older fluoroquinolones, it may retain clinically relevant activity against strains of S. aureus that are resistant to such drugs (e.g., ciprofloxacin) (3). In order to examine this possibility, to assess the general in vivo activity of CI-960 against S. aureus, and to determine the frequency at which resistance to the drug develops during therapy, we used the rabbit model of endocarditis and nafcillin-susceptible and -resistant, ciprofloxacin-susceptible and -resistant strains of S. aureus as test organisms. Alternative therapeutic options for serious staphylococcal infections are needed, especially in light of recent reports of clinically relevant glycopeptide resistance in Staphylococcus haemolyticus and S. aureus (8,13). Additionally, if CI-960 is shown to maintain useful activity against strains of S. aureus resistant to ciprofloxacin, intravenous or oral therapy of serious infections caused by such organisms might be feasible. Currently, the rather high incidence of fluoroquinolone resistance among methicillin-resistant strains of S. aureus at many institutions worldwide eliminates this therapeutic option (4,11,12,15). MATERUILS AND METHODSOrganisms. The nafcillin-susceptible and -resistant, ciprofloxacin-susceptible strains of S. aureus used (SA-1199 and MRSA-494, respectively) were isolated from the bl...

Section: Materuils and Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

CI-960, a new fluoroquinolone, for therapy of experimental ciprofloxacin-susceptible and -resistant Staphylococcus aureus endocarditis

Lamp

et al. 1992

“…Therapeutic options for infections caused by this organism can be quite limited, especially when methicillin-resistant strains are involved. The fluoroquinolones held much promise as useful agents for the treatment of infections caused by multidrug-resistant strains of S. aureus, but shortly after their introduction into clinical use, high-level resistance became widespread among methicillinresistant strains (5,18,21). This occurrence virtually eliminated the utility of these drugs as useful alternatives for the therapy of presumptive S. aureus infections in which methicillin-resistant strains might be involved.…”

mentioning

confidence: 99%

Inducible NorA-mediated multidrug resistance in Staphylococcus aureus

1995

239

191

The NorA protein of Staphylococcus aureus mediates the active efflux of hydrophilic fluoroquinolones from the cell, conferring low-level resistance upon the organism. This protein also is capable of transporting additional structurally diverse compounds, indicating that it has a broad substrate specificity. Increased transcription of the norA gene, leading to a greater quantity of the NorA protein within the cytoplasmic membrane, is felt to be the mechanism by which strains possessing such changes resist fluoroquinolones. S. aureus SA-1199 and its in vivo-selected derivative SA-1199B are fluoroquinolone-susceptible and -resistant isolates, respectively; SA-1199B resists hydrophilic fluoroquinolones via a NorA-mediated mechanism in a constitutive manner. SA-1199-3 is an in vitro-produced derivative of SA-1199 in which NorA-mediated multidrug resistance is expressed inducibly. Compared with organisms exposed to subinhibitory concentrations of a NorA substrate for the first time, preexposure of SA-1199-3 to such a compound followed by growth in the presence of that substrate results in the elimination of a 2-to 6-h period of organism killing that occurs prior to the onset of logarithmic growth. The uptake of radiolabeled fluoroquinolone is markedly reduced by preexposure of SA-1199-3 to NorA substrates; such prior exposure also results in a dramatic increase in RNA transcripts that hybridize with a norA probe. Preexposure of SA-1199 and SA-1199B to such substrates results in small increases or no increases in these transcripts. No sequence differences between SA-1199 and SA-1199-3 within the norA gene or flanking DNA were found. It appears likely that the regulation of norA in SA-1199-3, which may be effected by one or more genetic loci outside the norA region of the chromosome, differs from that of SA-1199 and SA-1199B.

“…Development of the fluoroquinolone class of antimicrobial agents advanced the possibility of an effective option for the therapy of serious infections caused by multiresistant strains of S. aureus, even by the oral route of administration. Unfortunately, shortly after introduction of these agents into clinical use the emergence of fluoroquinolone-resistant S. aureus was noted, especially among methicillin-resistant strains (6,23,27). The mechanisms by which S. aureus develops resistance to fluoroquinolones has been the subject of intensive research, and these investigations have defined at least three ways by which resistance to these agents is accomplished.…”

mentioning

confidence: 99%

Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus

Ruble

1993

397

354

Transport processes are used by all organisms to obtain essential nutrients and to expel wastes and other potentially harmful substances from cells. Such processes are important means by which resistance to selected antimicrobial agents in bacteria is achieved. The recently described Staphylococcus aureus norA gene encodes a membrane-associated protein that mediates active efflux of fluoroquinolones from cells. SA-1199B is a fluoroquinolone-resistant strain of S. aureus from which we cloned an allele of norA (norA1199). Similar to that of norA, the protein product of norA1199 preferentially mediates efflux of hydrophilic fluoroquinolones in both S. aureus and an Escherichia coli host, a process driven by the proton motive force. Determination of the nucleotide sequence of norA1199 revealed an encoded 388-amino-acid hydrophobic polypeptide 95% homologous with the norA-encoded protein. Significant homology with other proteins involved in transport processes also exists, but especially with tetracycline efflux proteins and with the Bacillus subtilis Bmr protein that mediates active efflux of structurally unrelated compounds, including fluoroquinolones. In S. aureus, the norA1199-encoded protein also appears to function as a multidrug efflux transporter. Southern hybridization studies indicated that norA1199 (or an allele of it) is a naturally occurring S. aureus gene and that related sequences are present in the S. epidermidis genome. The nucleotide sequence of the wild-type allele of norA1199, cloned from the fluoroquinolone-susceptible parent strain of SA-1199B, did not differ from that of norA1199 throughout the coding region. Northern (RNA) and Southern hybridization studies showed that increased transcription, and not gene amplification, of norA1199 is the basis for fluoroquinolone resistance in SA-1199B.