Abstract
Activities of clinafloxacin, ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, piperacillin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, ceftazidime, and imipenem against 354 ciprofloxacin-susceptible and -intermediate-resistant organisms were tested by agar dilution. Clinafloxacin yielded the lowest quinolone MICs (≤0.5 μg/ml against ciprofloxacin-susceptible organisms and ≤16.0 μg/ml against ciprofloxacin-intermediate-resistant organisms) compared to those of levofloxacin, trovafloxacin, and sparfloxacin. Ceftazidime, piperacillin alone or combined with tazobactam, trimethoprim-sulfamethoxazole, and imipenem usually yielded higher MICs against ciprofloxacin-resistant strains.
Antimicrobial resistance has developed in most classes of gram-positive and -negative bacteria. Therefore, there is a need for a compound which can be used empirically for single-drug therapy of serious systemic infections such as nosocomial pneumonia, especially in the immunocompromised host (23).
Clinafloxacin (CI-960, PD 127391) is a broad-spectrum quinolone active against a broad array of gram-positive and -negative bacteria (5–8, 12, 13, 15–17, 19, 20). This study further characterized the in vitro activity of clinafloxacin compared to those of ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, piperacillin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, ceftazidime, and imipenem against 354 gram-positive and -negative bacteria with both low and elevated ciprofloxacin MICs.
Organisms (Table 1) were clinical isolates selected such that as many species possible had strains with ciprofloxacin MICs in both the susceptible (≤1.0 μg/ml) and resistant (≥2.0 μg/ml) categories (18). In order to obtain significant numbers of ciprofloxacin-resistant members of the family Enterobacteriaceae, many sources were required (see Acknowledgments), as these strains are uncommon.
TABLE 1.
Results of MIC testing of 354 ciprofloxacin-susceptible and -resistant strains
| Organism (no. of strains)a and antimicrobial agent | MIC (μg/ml)b for strains
|
|||||
|---|---|---|---|---|---|---|
| Ciprofloxacin susceptible (≤1.0 μg/ml)
|
Ciprofloxacin resistant (≥2.0 μg/ml)
|
|||||
| Range | 50% | 90% | Range | 50% | 90% | |
| Pseudomonas aeruginosa (10/10) | ||||||
| Clinafloxacin | 0.06–0.125 | 0.125 | 0.125 | 1.0–8.0 | 2.0 | 4.0 |
| Ciprofloxacin | 0.06–0.25 | 0.25 | 0.25 | 4.0–32.0 | 8.0 | 32.0 |
| Levofloxacin | 0.25–1.0 | 0.5 | 1.0 | 8.0–>32.0 | 16.0 | 32.0 |
| Sparfloxacin | 0.25–1.0 | 1.0 | 1.0 | 8.0–>32.0 | 16.0 | >32.0 |
| Trovafloxacin | 0.25–0.5 | 0.5 | 0.5 | 4.0–>32.0 | 16.0 | >32.0 |
| Piperacillin | 4.0–8.0 | 4.0 | 8.0 | 2.0–>128.0 | 128.0 | >128.0 |
| Piperacillin-tazobactam | 4.0 | 4.0 | 4.0 | 2.0–>128.0 | 128.0 | >128.0 |
| Trimethoprim-sulfamethoxazole | 8.0–16.0 | 8.0 | 16.0 | 1.0–>16.0 | 16.0 | >16.0 |
| Ceftazidime | 1.0–2.0 | 2.0 | 2.0 | 1.0–>128.0 | >128.0 | >128.0 |
| Imipenem | 1.0–2.0 | 1.0 | 2.0 | 0.25–128.0 | 16.0 | 32.0 |
| Stenotrophomonas maltophilia (0/10) | ||||||
| Clinafloxacin | 0.5–2.0 | 1.0 | 1.0 | |||
| Ciprofloxacin | 4.0–16.0 | 16.0 | 16.0 | |||
| Levofloxacin | 2.0–8.0 | 4.0 | 4.0 | |||
| Sparfloxacin | 0.5–4.0 | 2.0 | 4.0 | |||
| Trovafloxacin | 1.0–4.0 | 2.0 | 4.0 | |||
| Piperacillin | 16.0–>128.0 | 128.0 | >128.0 | |||
| Piperacillin-tazobactam | 16.0–>128.0 | 128.0 | >128.0 | |||
| Trimethoprim-sulfamethoxazole | 4.0–>16.0 | 16.0 | >16.0 | |||
| Ceftazidime | 4.0–>128.0 | 16.0 | 128.0 | |||
| Imipenem | >128.0 | >128.0 | >128.0 | |||
| Acinetobacter spp. (10/10) | ||||||
| Clinafloxacin | ≤0.008–0.125 | 0.06 | 0.125 | 0.125–8.0 | 4.0 | 4.0 |
| Ciprofloxacin | 0.125–1.0 | 0.25 | 0.5 | 4.0–>32.0 | >32.0 | >32.0 |
| Levofloxacin | 0.03–0.5 | 0.25 | 0.5 | 1.0–16.0 | 16.0 | 16.0 |
| Sparfloxacin | ≤0.008–0.125 | 0.06 | 0.06 | 0.25–16.0 | 8.0 | 16.0 |
| Trovafloxacin | ≤0.008–0.06 | 0.03 | 0.06 | 0.25–16.0 | 8.0 | 16.0 |
| Piperacillin | 1.0–64.0 | 8.0 | 16.0 | 1.0–>128.0 | 32.0 | >128.0 |
| Piperacillin-tazobactam | ≤0.06–16.0 | ≤0.06 | 4.0 | ≤0.06–>128.0 | 32.0 | >128.0 |
| Trimethoprim-sulfamethoxazole | 0.125–1.0 | 0.25 | 0.5 | 1.0–>16.0 | 8.0 | 16.0 |
| Ceftazidime | 2.0–64.0 | 4.0 | 8.0 | 1.0–>128.0 | 32.0 | >128.0 |
| Imipenem | 0.06–0.5 | 0.25 | 0.5 | 0.25–1.0 | 0.5 | 1.0 |
| Burkholderia cepacia (2/12) | ||||||
| Clinafloxacin | 0.25–0.5 | 0.25 | 1.0–4.0 | 2.0 | 4.0 | |
| Ciprofloxacin | 1.0 | 1.0 | 2.0–32.0 | 8.0 | 16.0 | |
| Levofloxacin | 2.0 | 2.0 | 4.0–16.0 | 8.0 | 16.0 | |
| Sparfloxacin | 0.5–1.0 | 0.5 | 2.0–16.0 | 8.0 | 16.0 | |
| Trovafloxacin | 1.0 | 1.0 | 2.0–16.0 | 8.0 | 16.0 | |
| Piperacillin | 4.0 | 4.0 | 4.0–64.0 | 32.0 | 64.0 | |
| Piperacillin-tazobactam | 1.0–2.0 | 1.0 | 2.0–64.0 | 32.0 | 64.0 | |
| Trimethoprim-sulfamethoxazole | 1.0–2.0 | 1.0 | 1.0–16.0 | 4.0 | 16.0 | |
| Ceftazidime | 2.0 | 2.0 | 2.0–8.0 | 4.0 | 8.0 | |
| Imipenem | 2.0–8.0 | 2.0 | 4.0–>128.0 | 16.0 | 128.0 | |
| Chryseobacterium and Myroides spp. (7/15)c | ||||||
| Clinafloxacin | 0.03–0.25 | 0.125 | 0.125–4.0 | 0.5 | 4.0 | |
| Ciprofloxacin | 0.125–1.0 | 1.0 | 2.0–>32.0 | 2.0 | >32.0 | |
| Levofloxacin | 0.25–1.0 | 0.5 | 0.5–32.0 | 2.0 | 16.0 | |
| Sparfloxacin | 0.06–0.25 | 0.125 | 0.06–8.0 | 0.5 | 4.0 | |
| Trovafloxacin | 0.06–0.125 | 0.06 | 0.06–4.0 | 0.25 | 4.0 | |
| Piperacillin | 4.0–64.0 | 16.0 | 16.0–128.0 | 32.0 | 64.0 | |
| Piperacillin-tazobactam | 4.0–64.0 | 16.0 | 0.5–128.0 | 16.0 | 64.0 | |
| Trimethoprim-sulfamethoxazole | 0.25–>16.0 | >16.0 | 4.0–>16.0 | 16.0 | >16.0 | |
| Ceftazidime | 4.0–>128.0 | 128.0 | 32.0–>128.0 | 128.0 | >128.0 | |
| Imipenem | 0.25–32.0 | 4.0 | 4.0–64.0 | 16.0 | 32.0 | |
| Escherichia coli (10/10) | ||||||
| Clinafloxacin | ≤0.008–0.016 | ≤0.008 | 0.016 | 0.25–8.0 | 1.0 | 4.0 |
| Ciprofloxacin | 0.016–0.03 | 0.016 | 0.016 | 2.0–>32.0 | 32.0 | >32.0 |
| Levofloxacin | 0.03–0.06 | 0.03 | 0.06 | 2.0–>32.0 | 16.0 | >32.0 |
| Sparfloxacin | 0.016–0.03 | 0.03 | 0.03 | 2.0–>32.0 | 16.0 | >32.0 |
| Trovafloxacin | 0.016–0.03 | 0.03 | 0.03 | 2.0–>32.0 | 16.0 | >32.0 |
| Piperacillin | 1.0–>128.0 | 2.0 | 64.0 | 1.0–>128.0 | 16.0 | >128.0 |
| Piperacillin-tazobactam | 1.0–2.0 | 2.0 | 2.0 | 1.0–16.0 | 4.0 | 16.0 |
| Trimethoprim-sulfamethoxazole | 0.125–>16.0 | 0.5 | >16.0 | 0.25–>16.0 | 4.0 | >16.0 |
| Ceftazidime | 0.25 | 0.25 | 0.25 | 0.125–128.0 | 0.25 | 64.0 |
| Imipenem | 0.125–0.25 | 0.125 | 0.25 | 0.06–0.5 | 0.125 | 0.25 |
| Klebsiella spp. (10/10)d | ||||||
| Clinafloxacin | 0.016–0.06 | 0.016 | 0.03 | 1.0–8.0 | 1.0 | 8.0 |
| Ciprofloxacin | 0.016–0.125 | 0.03 | 0.06 | 4.0–>32.0 | 8.0 | >32.0 |
| Levofloxacin | 0.06–0.5 | 0.06 | 0.125 | 4.0–>32.0 | 16.0 | 32.0 |
| Sparfloxacin | 0.03–0.5 | 0.06 | 0.125 | 4.0–>32.0 | 8.0 | >32.0 |
| Trovafloxacin | 0.06–0.5 | 0.06 | 0.25 | 2.0–>32.0 | 8.0 | >32.0 |
| Piperacillin | 4.0–>128.0 | 8.0 | >128.0 | 4.0–>128.0 | >128.0 | >128.0 |
| Piperacillin-tazobactam | 2.0–>128.0 | 4.0 | 8.0 | 2.0–>128.0 | 4.0 | >128.0 |
| Trimethoprim-sulfamethoxazole | 0.25–>16.0 | 1.0 | >16.0 | 2.0–>16.0 | >16.0 | >16.0 |
| Ceftazidime | ≤0.06–1.0 | 0.25 | 0.5 | 0.25–>128.0 | 1.0 | 128.0 |
| Imipenem | 0.125–0.25 | 0.125 | 0.25 | 0.06–0.25 | 0.125 | 0.25 |
| Enterobacter spp. (16/12)e | ||||||
| Clinafloxacin | ≤0.008–0.125 | 0.016 | 0.03 | 0.5–4.0 | 1.0 | 4.0 |
| Ciprofloxacin | ≤0.008–0.25 | 0.016 | 0.125 | 4.0–>32.0 | 8.0 | >32.0 |
| Levofloxacin | 0.03–0.5 | 0.06 | 0.25 | 4.0–>32.0 | 8.0 | 32.0 |
| Sparfloxacin | 0.03–0.5 | 0.03 | 0.5 | 2.0–>32.0 | 8.0 | >32.0 |
| Trovafloxacin | 0.03–0.5 | 0.06 | 0.125 | 4.0–>32.0 | 16.0 | >32.0 |
| Piperacillin | 2.0–>128.0 | 4.0 | 64.0 | 2.0–128.0 | 64.0 | 64.0 |
| Piperacillin-tazobactam | 2.0–64.0 | 4.0 | 32.0 | 2.0–64.0 | 16.0 | 64.0 |
| Trimethoprim-sulfamethoxazole | 0.25–>16.0 | 0.5 | 1.0 | 0.5–>16.0 | 1.0 | >16.0 |
| Ceftazidime | 0.25–64.0 | 0.5 | 64.0 | 0.5–128.0 | 8.0 | 128.0 |
| Imipenem | 0.125–0.5 | 0.25 | 0.5 | 0.125–1.0 | 0.25 | 1.0 |
| Citrobacter spp. (13/7)f | ||||||
| Clinafloxacin | ≤0.008–0.25 | 0.016 | 0.03 | 0.5–2.0 | 1.0 | |
| Ciprofloxacin | ≤0.008–1.0 | 0.016 | 0.125 | 2.0–32.0 | 4.0 | |
| Levofloxacin | 0.03–2.0 | 0.06 | 0.25 | 4.0–16.0 | 8.0 | |
| Sparfloxacin | 0.016–2.0 | 0.06 | 0.25 | 4.0–>32.0 | 16.0 | |
| Trovafloxacin | 0.03–2.0 | 0.06 | 0.5 | 4.0–32.0 | 16.0 | |
| Piperacillin | 2.0–>128.0 | 4.0 | >128.0 | 8.0–>128.0 | >128.0 | |
| Piperacillin-tazobactam | 2.0–16.0 | 2.0 | 8.0 | 8.0–>128.0 | 32.0 | |
| Trimethoprim-sulfamethoxazole | 0.25–>16.0 | 0.5 | >16.0 | 0.125–>16.0 | 4.0 | |
| Ceftazidime | ≤0.006–32.0 | 0.5 | 1.0 | 1.0–>128.0 | 64.0 | |
| Imipenem | 0.125–0.5 | 0.25 | 0.5 | 0.125–0.5 | 0.25 | |
| Serratia spp. (12/12)g | ||||||
| Clinafloxacin | 0.016–0.125 | 0.03 | 0.125 | 0.5–4.0 | 1.0 | 2.0 |
| Ciprofloxacin | 0.03–0.125 | 0.125 | 0.125 | 2.0–>32.0 | 4.0 | 8.0 |
| Levofloxacin | 0.06–0.5 | 0.25 | 0.25 | 2.0–32.0 | 8.0 | 8.0 |
| Sparfloxacin | 0.06–1.0 | 0.25 | 1.0 | 2.0–>32.0 | 8.0 | 16.0 |
| Trovafloxacin | 0.125–1.0 | 0.25 | 1.0 | 4.0–>32.0 | 8.0 | 16.0 |
| Piperacillin | 2.0–>128.0 | 4.0 | 4.0 | 2.0–>128.0 | 8.0 | 128.0 |
| Piperacillin-tazobactam | 2.0–>128.0 | 2.0 | 4.0 | 2.0–>128.0 | 8.0 | 128.0 |
| Trimethoprim-sulfamethoxazole | 0.5–2.0 | 1.0 | 2.0 | 1.0–>16.0 | 8.0 | 16.0 |
| Ceftazidime | 0.25–4.0 | 0.5 | 0.5 | 0.25–2.0 | 0.5 | 1.0 |
| Imipenem | 0.5–4.0 | 1.0 | 1.0 | 0.25–2.0 | 1.0 | 2.0 |
| Morganella and Providencia spp. (10/13)h | ||||||
| Clinafloxacin | 0.016–0.125 | 0.06 | 0.06 | 0.5–8.0 | 1.0 | 2.0 |
| Ciprofloxacin | 0.03–0.25 | 0.06 | 0.125 | 2.0–>32.0 | 8.0 | >32.0 |
| Levofloxacin | 0.125–1.0 | 0.25 | 0.25 | 2.0–>32.0 | 8.0 | 32.0 |
| Sparfloxacin | 0.125–1.0 | 0.25 | 1.0 | 0.5–>32.0 | 16.0 | 16.0 |
| Trovafloxacin | 0.125–1.0 | 0.25 | 0.5 | 0.5–>32.0 | 16.0 | 32.0 |
| Piperacillin | 1.0–8.0 | 1.0 | 4.0 | 1.0–>128.0 | 4.0 | 128.0 |
| Piperacillin-tazobactam | 0.5–8.0 | 1.0 | 2.0 | 1.0–64.0 | 4.0 | 16.0 |
| Trimethoprim-sulfamethoxazole | 0.25–>16.0 | 0.5 | >16.0 | 0.25–>16.0 | >16.0 | >16.0 |
| Ceftazidime | 0.125–1.0 | 0.25 | 0.5 | 0.25–>128.0 | 0.5 | 64.0 |
| Imipenem | 1.0–4.0 | 2.0 | 4.0 | 0.5–2.0 | 1.0 | 2.0 |
| Staphylococcus spp. (25/15)i | ||||||
| Clinafloxacin | 0.03–0.125 | 0.03 | 0.06 | 0.06–4.0 | 1.0 | 2.0 |
| Ciprofloxacin | 0.25–1.0 | 0.5 | 1.0 | 2.0–>32.0 | 32.0 | >32.0 |
| Levofloxacin | 0.125–1.0 | 0.25 | 0.5 | 0.25–>32.0 | 8.0 | 32.0 |
| Sparfloxacin | 0.06–0.25 | 0.125 | 0.25 | 0.125–16.0 | 8.0 | 16.0 |
| Trovafloxacin | 0.016–0.125 | 0.06 | 0.06 | 0.06–8.0 | 2.0 | 8.0 |
| Piperacillin | 0.5–>128.0 | 2.0 | 128.0 | 2.0–>128.0 | 128.0 | >128.0 |
| Piperacillin-tazobactam | ≤0.06–64.0 | 1.0 | 8.0 | 1.0–128.0 | 64.0 | 128.0 |
| Trimethoprim-sulfamethoxazole | ≤0.06–>16.0 | 0.125 | 16.0 | ≤0.06–>16.0 | 2.0 | >16.0 |
| Ceftazidime | 4.0–>128.0 | 16.0 | 64.0 | 8.0–>128.0 | >128.0 | >128.0 |
| Imipenem | ≤0.016–64.0 | ≤0.016 | 32.0 | ≤0.016–32.0 | 4.0 | 32.0 |
| Streptococcus pneumoniae (16/44)j | ||||||
| Clinafloxacin | 0.03–0.125 | 0.06 | 0.06 | 0.06–0.25 | 0.125 | 0.25 |
| Ciprofloxacin | 0.5–1.0 | 1.0 | 1.0 | 2.0–8.0 | 2.0 | 4.0 |
| Levofloxacin | 0.5–1.0 | 1.0 | 1.0 | 1.0–2.0 | 2.0 | 2.0 |
| Sparfloxacin | 0.125–0.25 | 0.25 | 0.25 | 0.125–0.5 | 0.5 | 0.5 |
| Trovafloxacin | 0.06–0.125 | 0.06 | 0.125 | 0.06–0.25 | 0.25 | 0.25 |
| Piperacillin | ≤0.06–4.0 | 1.0 | 2.0 | ≤0.06–8.0 | 1.0 | 8.0 |
| Piperacillin-tazobactam | ≤0.06–4.0 | 0.5 | 2.0 | ≤0.06–8.0 | 0.5 | 4.0 |
| Trimethoprim-sulfamethoxazole | 0.125–>16.0 | 2.0 | 8.0 | 0.125–>16.0 | 1.0 | 8.0 |
| Ceftazidime | 0.25–64.0 | 1.0 | 16.0 | 0.125–64.0 | 2.0 | 16.0 |
| Imipenem | ≤0.016–0.25 | ≤0.016 | 0.125 | ≤0.016–0.5 | 0.03 | 0.5 |
| Enterococcus faecalis (0/13)k | ||||||
| Clinafloxacin | 0.25–8.0 | 4.0 | 4.0 | |||
| Ciprofloxacin | 2.0–>32.0 | >32.0 | >32.0 | |||
| Levofloxacin | 2.0–>32.0 | 32.0 | >32.0 | |||
| Sparfloxacin | 1.0–>32.0 | 32.0 | >32.0 | |||
| Trovafloxacin | 0.5–32.0 | 4.0 | 16.0 | |||
| Piperacillin | 2.0–32.0 | 8.0 | 16.0 | |||
| Piperacillin-tazobactam | 1.0–32.0 | 8.0 | 16.0 | |||
| Trimethoprim-sulfamethoxazole | 0.125–>16.0 | 8.0 | >16.0 | |||
| Ceftazidime | 16.0–>128.0 | >128.0 | >128.0 | |||
| Imipenem | 0.5–16.0 | 2.0 | 4.0 | |||
| Enterococcus faecium (2/18)l | ||||||
| Clinafloxacin | 0.125–0.25 | 0.125 | 0.25–16.0 | 8.0 | 8.0 | |
| Ciprofloxacin | 1.0 | 1.0 | 2.0–>32.0 | >32.0 | >32.0 | |
| Levofloxacin | 2.0 | 2.0 | 4.0–>32.0 | >32.0 | >32.0 | |
| Sparfloxacin | 1.0 | 1.0 | 1.0–>32.0 | 32.0 | >32.0 | |
| Trovafloxacin | 0.5 | 0.5 | 0.5–16.0 | 16.0 | 16.0 | |
| Piperacillin | 8.0–64.0 | 8.0 | 8.0–>128.0 | >128.0 | >128.0 | |
| Piperacillin-tazobactam | 8.0–32.0 | 8.0 | 8.0–>128.0 | >128.0 | >128.0 | |
| Trimethoprim-sulfamethoxazole | 2.0–16.0 | 2.0 | 0.125–>16.0 | 4.0 | >16.0 | |
| Ceftazidime | >128.0 | >128.0 | >128.0 | >128.0 | >128.0 | |
| Imipenem | 2.0–16.0 | 2.0 | 2.0–>128.0 | 128.0 | >128.0 | |
The number of ciprofloxacin-susceptible strains is shown before the slash, and the number of ciprofloxacin-resistant strains is shown after the slash.
50% and 90%, MICs for 50 and 90% of isolates tested, respectively.
The ciprofloxacin-susceptible strains are Chryseobacterium meningosepticum (three strains) and Myroides odoratus (four strains). The ciprofloxacin-resistant strains are C. meningosepticum (seven strains), M. odoratus (seven strains), and Chryseobacterium indologenes or Chryseobacterium gleum (one strain).
The ciprofloxacin-susceptible strains are Klebsiella pneumoniae (five strains) and Klebsiella oxytoca (five strains). The ciprofloxacin-resistant strains are K. pneumoniae (seven strains) and K. oxytoca (three strains).
The ciprofloxacin-susceptible strains are Enterobacter cloacae (eight strains) and Enterobacter aerogenes (eight strains). The ciprofloxacin-resistant strains are E. cloacae (eight strains) and E. aerogenes (four strains).
The ciprofloxacin-susceptible strains are Citrobacter freundii (eight strains) and Citrobacter diversus (five strains). The ciprofloxacin-resistant strains are C. freundii (seven strains).
The ciprofloxacin-susceptible strains are Serratia marcescens (11 strains) and Serratia liquefaciens (1 strain). The ciprofloxacin-resistant strains are S. marcescens (12 strains).
The ciprofloxacin-susceptible strains are Morganella morganii (six strains), Providencia stuartii (three strains), and Providencia rettgeri (one strain). The ciprofloxacin-resistant strains are M. morganii (three strains), P. stuartii (nine strains), and Providencia rettgeri (one strain).
The ciprofloxacin-susceptible strains are methicillin-susceptible Staphylococcus aureus (9 strains), methicillin-susceptible coagulase-negative staphylococci (10 strains), methicillin-resistant S. aureus (2 strains), and methicillin-resistant coagulase-negative staphylococci (4 strains). The ciprofloxacin-resistant strains are methicillin-susceptible S. aureus (one strain), methicillin-resistant S. aureus (eight strains), and methicillin-resistant coagulase-negative staphylococci (six strains).
Twenty strains each of penicillin-susceptible, -intermediate-resistant, and -resistant strains.
Three vancomycin-resistant strains.
The two ciprofloxacin-susceptible strains were also vancomycin susceptible. Of the ciprofloxacin-resistant strains, eight were vancomycin susceptible.
Standard agar dilution MICs (18) were performed by using cation-adjusted Mueller-Hinton agar with the addition of 5% sheep blood for Streptococcus pneumoniae. For this study, organisms with MICs of ≤1.0 μg/ml were called ciprofloxacin susceptible and those with MICs of ≥2.0 μg/ml were called intermediate resistant.
Clinafloxacin gave the lowest quinolone MICs for all organisms (Table 1). For ciprofloxacin-susceptible strains, clinafloxacin MICs were all ≤0.5 μg/ml compared to MICs of ≤2.0 μg/ml for levofloxacin, sparfloxacin, and trovafloxacin (Table 1). High MICs against piperacillin alone or combined with tazobactam, trimethoprim-sulfamethoxazole, and ceftazidime were seen especially in Chryseobacterium meningosepticum, Myroides odoratus, and some members of the Enterobacteriaceae. Among ciprofloxacin-susceptible strains, imipenem resistance (MICs ≥ 16.0 μg/ml) (18) occurred most commonly in C. meningosepticum and M. odoratus. Imipenem resistance in ciprofloxacin-susceptible strains was found only in Burkholderia cepacia, C. meningosepticum, M. odoratus, methicillin-resistant staphylococci, and Enterococcus faecium (Table 1).
MICs of all compounds tested were higher in ciprofloxacin-resistant strains with the exception of imipenem against acinetobacters (Table 1). Of gram-negative rods, Stenotrophomonas maltophilia yielded the lowest clinafloxacin MICs (90% susceptible at ≤1.0 μg/ml). Among ciprofloxacin-resistant members of the Enterobacteriaceae, ≥83% of Citrobacter, Serratia, and Providencia strains were clinafloxacin susceptible. Levofloxacin, sparfloxacin, and trovafloxacin yielded MICs which were several twofold increments higher than those of clinafloxacin against ciprofloxacin-resistant gram-negative rods. Of 15 ciprofloxacin-resistant staphylococci tested, 14 were also methicillin resistant: clinafloxacin and trovafloxacin were the only quinolones with low MICs (MIC50s of 1.0 and 2.0 μg/ml, respectively) against these strains. All four quinolones tested gave low MICs against penicillin-susceptible and -resistant pneumococci.
Among 13 ciprofloxacin-resistant Enterococcus faecalis strains (3 vancomycin-resistant strains) clinafloxacin MICs were ≤8.0 μg/ml. Against E. faecium, clinafloxacin MICs were much lower (≤0.25 μg/ml) against the two ciprofloxacin-susceptible, vancomycin-susceptible strains than against ciprofloxacin-resistant strains, 10 of which were also vancomycin resistant (MICs ≥ 16.0 μg/ml). Although clinafloxacin had the lowest MICs against ciprofloxacin-resistant enterococci, most MICs were in the resistant range.
MICs of piperacillin alone or combined with tazobactam, trimethoprim-sulfamethoxazole, and ceftazidime for ciprofloxacin-resistant strains were higher than those in ciprofloxacin-susceptible strains. Imipenem was active against all ciprofloxacin-resistant strains tested except Pseudomonas aeruginosa, S. maltophilia, B. cepacia, Chryseobacterium and Myroides spp., methicillin-resistant staphylococci, and enterococci.
Our results show that clinafloxacin had the lowest overall MICs of compounds tested against all organisms (including ciprofloxacin-resistant strains). Levofloxacin, trovafloxacin, and sparfloxacin also had low MICs (although higher than those of clinafloxacin) against most common organisms. These results confirm findings in previous studies (6–10, 12, 13, 15–17, 20). Although clinafloxacin MICs (along with those of other quinolones tested) rose with those of ciprofloxacin, clinafloxacin MICs were still severalfold lower than those of other quinolones. With a provisional clinafloxacin-susceptible breakpoint of ≤1.0 μg/ml (9), all ciprofloxacin-susceptible strains and 63% of ciprofloxacin-resistant strains tested were clinafloxacin susceptible.
Activities of other quinolone and nonquinolone compounds reflect previous findings. Trovafloxacin, sparfloxacin, ciprofloxacin, and levofloxacin yielded low MICs against most species of Enterobacteriaceae. However, gram-negative nonfermenters were generally more resistant to quinolones: of these strains, P. aeruginosa, S. maltophilia and some Chryseobacterium and Myroides spp. had the lowest quinolone MICs. All quinolones had bimodal MIC distributions against Acinetobacter spp., with strains either susceptible (MICs ≤ 1 μg/ml) or very resistant (MICs ≥ 8 μg/ml) (1, 11, 19, 21, 23).
Clinafloxacin was very active against methicillin-susceptible staphylococci, with MICs a few dilutions lower than those of other quinolones. Clinafloxacin was less active against methicillin-resistant strains, especially those which were also ciprofloxacin resistant. Clinafloxacin and trovafloxacin MICs were several dilutions lower than those of other quinolones against these organisms. Previous workers have described either the same phenomenon or similar clinafloxacin MICs in methicillin-susceptible and -resistant strains (7–10, 12, 13, 15–17, 20). Cohen and coworkers have reported strains of methicillin-resistant S. aureus exhibiting clinafloxacin and ciprofloxacin MICs of 1.0 and 128.0 μg/ml, respectively (6). Antipneumococcal activity of quinolones reflected previous findings, with clinafloxacin showing the lowest MICs (7–13, 15–17, 19, 21). Although clinafloxacin MICs against enterococci were higher than those reported by some workers, others have reported MICs similar to ours (7–10, 13, 15–17, 20).
Ceftazidime was very active against most members of the Enterobacteriaceae and some strains of P. aeruginosa but less active against other gram-negative nonfermenters. Imipenem was very active against members of the Enterobacteriaceae, but high-level resistance was found in most nonfermenter groups (especially S. maltophilia). Methicillin-resistant staphylococci were also imipenem resistant. Trimethoprim-sulfamethoxazole and piperacillin alone or combined with tazobactam were most active against ciprofloxacin-susceptible strains (2, 3, 14).
Against a panel of fluoroquinolone-resistant organisms and at a quinolone breakpoint of ≤1.0 μg/ml (9, 18), Cormican and Jones (9) have reported that clinafloxacin inhibited 65% of strains compared to 30 to 38% for other quinolones. Shapiro and coworkers (22) have found clinafloxacin to be effective in treatment of neutropenic mice with acute systemic infections caused by gram-positive and -negative organisms. In a murine subcutaneous S. aureus abscess model, Cohen and coworkers (5) have shown clinafloxacin to be up to 19-fold more protective than ciprofloxacin.
Bron and coworkers (4) have reported a maximum concentration of clinafloxacin in plasma of 2.5 μg/ml, following oral administration of a single 200-mg dose to human volunteers. Because intravenous administration of this compound is also under development, higher levels in serum are expected, further enlarging its spectrum. In view of these pharmacokinetic data and the MICs presented here and pending the results of human toxicologic studies, clinafloxacin shows promise in treatment of nosocomial pneumonia and other serious systemic infections, especially in the immunocompromised host. Clinical studies are in progress to test these hypotheses.
Acknowledgments
This study was supported by a grant from Parke-Davis Pharmaceutical Research, Ann Arbor, Mich.
We thank J. Liñares (Barcelona, Spain), R. Fass (Columbus, Ohio), V. La Bombardi (New York, N.Y.), and W. Brown (Detroit, Mich.) for provision of some strains.
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