Antimicrobial activity of BMS 284756, a novel des-fluoro (6) quinolone and seven fluoroquinolones against Streptococcus pneumoniae
Authors: L. Saravolatz, O. Manzor, J. Pawlak, B. Belian
Journal: Clinical Microbiology and Infection (2001)

BMS 284756 is a novel des-fluoro (6) quinolone that demonstrates broad activity against a wide range of clinically important pathogens, including Gram-positive and Gram-negative aerobes and anaerobes [1Takahata M Mitsuyama J Yamashiro Y et al.In vitro and in vivo antimicrobial activities of T-3811ME, a novel des-F(6)-quinolone.Antimicrob Agents Chemother. 1999; 43: 1077-1084PubMed Google Scholar]. Because of the enhanced activity of recently released fluoroquinolones against Gram-positive bacteria along with the increasing prevalence of penicillin nonsusceptible strains of Streptococcus pneumoniae, this study was undertaken to evaluate and compare the in vitro activity of BMS 284756 compared to that of seven other fluoroquinolones. These antibiotics were tested against 199 clinical isolates of S. pneumoniae from a United States regional surveillance study. Strains of S. pneumoniae (n = 199) isolated during 1998–99 from a 10-hospital health care system in south-eastern Michigan were collected from clinical specimens and stored at −70 °C. Only one isolate per patient was included, thus excluding duplication. The isolates were collected from blood (66 patients), respiratory secretions (132 patients) and cerebrospinal fluid (one patient). Break-points used for penicillin susceptibility were divided into three categories according to NCCLS guidelines: penicillin susceptible (PSSP) minimal inhibitory concentration (MIC) ≤0.06 mg/L; intermediate susceptibility (PISP) MIC = 0.12–1.0 mg/L, and penicillin resistant (PRSP) MIC ≥2.0 mg/L [2National Committee for Clinical Laboratory Standards Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 4th edn. Approved Standard M7-A4. NCCLS, Wayne, PA1997Google Scholar]. Antimicrobial agents including standard powders were provided by the manufacturer and included: BMS 284756 (Bristol-Myers Squibb, Princeton, NJ), ciprofloxacin, moxifloxacin (Bayer Corp., West Haven, CT) clinafloxacin, sparfloxacin (Parke Davis, Ann Arbor, MI), grepafloxacin (Glaxo-Wellcome Research, Triangle Park, NC), levofloxacin (Ortho-McNeil, Raritan, NJ), and trovafloxacin (Pfizer, Groton, CT). The powders were used to prepare stock antibiotic dilutions as outlined in the NCCLS standards [2National Committee for Clinical Laboratory Standards Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 4th edn. Approved Standard M7-A4. NCCLS, Wayne, PA1997Google Scholar]. MICs were determined by microdilution broth assay, using cation-adjusted Mueller Hinton broth supplemented with 2–5% lysed horse blood (Cleveland Scientific, Bath, OH, USA). Suspensions were prepared from an 18-h pure culture in saline adjusted to a 0.5 McFarland standard with a final inoculum of 5×105 colony-forming units (CFU)/mL. Microtiter plates were incubated at 35 °C for 20–24 h in ambient air. The standard quality control strain S. pneumoniae ATCC 49619 was included in each run. The determined susceptibility data for each of the antimicrobial agents tested are summarised in Table 1. BMS 284756 demonstrated the greatest in vitro activity with the lowest MIC90. There were no isolates resistant to any of the quinolones except for ciprofloxacin where 10 isolates (5%) were nonsusceptible at a ciprofloxacin concentration of 4 mg/L. For the 10 isolates with ciprofloxacin MICs ≥4 mg/L, the MIC90 for BMS 284756 was identical to the MIC90 for the 199 isolates.Table 1Susceptibility of 199 Streptococcus pneumoniae clinical isolates and pharmacodynamics for the eight fluoroquinolones testedMIC (mg/L)Antimicrobial agentRangeMIC50MIC90BMS 2847560.03–0.130.030.06Moxifloxacin0.03–20.130.13Trovafloxacin0.03–640.130.25Clinafloxacin0.03–0.250.060.13Levofloxacin0.03–640.51.0Grepafloxacin0.03–20.130.25Sparfloxacin0.03–10.250.50Ciprofloxacin0.03–81.02.0MIC, minimal inhibitory concentration Open table in a new tab MIC, minimal inhibitory concentration When evaluating quinolone activity relative to penicillin susceptibility, isolates categorised into groups as PSSP (54), PISP (78) and PRSP (67) showed no difference for BMS 284756 or any of the other fluoroquinolones tested. There have been 10 fluoroquinolones released since ciprofloxacin was introduced in 1987 [3Neu HC The quinolones: prospects.in: Andriole VT The Quinolones. Academic Press Ltd, London1988: 235-254Crossref Google Scholar]. Recently, the newest agents have been advocated for the empiric treatment of respiratory tract infections due to the increase in resistance to penicillin and the need to identify alternative classes of antimicrobial agents with enhanced activity against S. pneumoniae. These agents can also be useful in the treatment of the patient allergic to β-lactam agents. With the advantages already enumerated, pharmaceutical manufacturers have promoted this class of drugs as effective for the treatment of respiratory tract infections due to S. pneumoniae. However, the clinician has been given data limited to each drug alone or compared to only a few fluoroquinolones to assess the relative activity of these agents in order to select the most effective agent. This study determined the potency of a novel des-fluoro (6) quinolone, BMS 284756 and seven other quinolones by determining their MICs for recent isolates of S. pneumoniae. When evaluating potency, the most recently developed fluoroquinolones clearly demonstrate superior activity compared to earlier agents such as, ciprofloxacin and levofloxacin. BMS 284756 is a novel fourth generation fluoroquinolone with excellent activity against S. pneumoniae as seen in this study. BMS 284756 was unaffected by decreased susceptibility to other quinolones, though only 5% of the isolates tested in this study were nonsusceptibile to ciprofloxacin at a concentration of 4 mg/L. A small number of isolates were tested in this study with decreased ciprofloxacin susceptibility and thus any interpretation must be made cautiously. Chen et al. have emphasised the increase in the prevalence of pneumococci with reduced susceptibility to fluoroquinolones in Canada, probably as a result of selective pressure from the increased use of fluoroquinolones [4Chen DK McGreer A Azavedo JC Low DE Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada.N Engl Med J. 1999; 341: 233-239Crossref PubMed Scopus (1023) Google Scholar]. Finally, a balance between efficacy and toxicity must enter into the consideration of selection of any antimicrobial agent. In spite of good in vitro activity, grepafloxacin, sparfloxacin, temafloxacin and trovafloxacin have had toxicities arise that have either severely limited these agents or completely eliminated them from clinical consideration. As shown by previous studies with smaller number of isolates, BMS 284756 demonstrated greater in vitro potency when compared to other fluoroquinolones. This study extends the observations from studies in Japan by including a larger number of isolates as well as comparative agents [1Takahata M Mitsuyama J Yamashiro Y et al.In vitro and in vivo antimicrobial activities of T-3811ME, a novel des-F(6)-quinolone.Antimicrob Agents Chemother. 1999; 43: 1077-1084PubMed Google Scholar]. In summary, whereas all the new fluoroquinolones tested in this study demonstrated enhanced in vitro activity compared to ciprofloxacin and levofloxacin, BMS 284756 demonstrated the greatest in vitro activity. This work was supported by a research grant from Bristol-Myers Squibb Pharmaceutical Company.