Bacterial resistance to quinolones is primarily due to target modification, active efflux via membrane -located pumps, and outer membrane porin loss. Sitafloxacin acts on both DNA gyrase and topoisomerase Ⅳ to inhibit bacterial growth. Therefore, high-level resistance to sitafloxacin will not develop unless mutation emerges in both DNA gyrase and topoisomerase Ⅳ. The modification of any one target, DNA gyrase or topoisomerase Ⅳ, will not affect sitafloxacin susceptibility significantly. Ciprofloxacin works primarily by inhibiting the DNA gyrase of gram-negative organisms, and the topoisomerase of gram-positive organisms. Levofloxacin mainly inhibits bacterial DNA gyrase.
It is reported [10] that nearly 70% of E. coli isolates and about 50% of K. pneumoniae isolates are resistant to ciprofloxacin. We found in this study that sitafloxacin inhibited all (100%) the ciprofloxacin-susceptible E. coli and K. pneumoniae strains, 62% of the ciprofloxacin-resistant E. coli and 36.8% of the ciprofloxacin-resistant K. pneumoniae strains. Majority of the non-ESBL-producing E. coli (90.6%) and K. pneumoniae (92.6%) strains were susceptible to sitafloxacin, while relatively lower percentage of ESBL-producing E. coli (70.2%) and K. pneumoniae (51.2%) were susceptible to sitafloxacin.
Sitafloxacin is very active against gram-negative organisms. In a large scale pharmacodynamic study of sitafloxacin [11], the MIC range was ≤ 0.008-4 mg/L for E. coli (MIC50/90: ≤ 0.008/1 mg/L). In the present study, sitafloxacin also displayed potent activity against ciprofloxacin-resistant or ESBL-producing E. coli (MIC50/90: 1/4 and 1/2 mg/L, respectively; MIC range: ≤ 0.25-16 mg/L), but slightly higher MIC values because these are specified resistant strains. Sitafloxacin was also highly active against ciprofloxacin-susceptible or non-ESBL-producing K. pneumoniae (MIC50/90: ≤0.03/0.06 and ≤ 0.03/0.5 mg/L), and active against ciprofloxacin-resistant or ESBL-producing K. pneumoniae (MIC50/90: 2/16 and 1/16 mg/L). Other authors reported that for 445 strains of K. pneumoniae, sitafloxacin resulted in MIC range of ≤ 0.008-8 mg/L (MIC50/90: 0.015/0.12 mg/L). Our MIC50/90 values are relative higher, but MIC range remains the same.
Sitafloxacin is highly active against ciprofloxacin-resistant E. coli and K. pneumoniae. The underlying mechanism may be due to the fact that ciprofloxacin mainly acts on DNA gyrase, while sitafloxacin can inhibit both DNA gyrase and topoisomerase Ⅳ. Even in case of QRDR mutation, sitafloxacin still has good inhibitory effect. Therefore, sitafloxacin remains powerful in inhibiting ciprofloxacin-resistant Enterobacterales strains. Sitafloxacin was much more active than cephalosporins against ciprofloxacin-susceptible E. coli. Sitafloxacin performed much better than other quinolones and cephalosporins, comparable to cefoperazone-sulbactam, and inferior to meropenem and amikacin in the activity against ciprofloxacin-resistant E. coli strains. Sitafloxacin was better than other quinolones, and slightly weaker than third and fourth generation cephalosporins, cefoperazone-sulbactam, meropenem and amikacin in the activity against non-ESBL-producing E. coli.
For ESBL-producing E. coli strains, sitafloxacin had activity much higher other quinolones, slightly better than cefoperazone-sulbactam, but lower than meropenem and amikacin. For ciprofloxacin-susceptible or non-ESBL-producing K. pneumoniae, sitafloxacin was as highly active as most of the comparators; but for ciprofloxacin-resistant strains, sitafloxacin performed much better than other quinolones and cephalosporins, comparable to cefoperazone-sulbactam, and inferior to meropenem and amikacin. Sitafloxacin was not as good as meropenem and amikacin but was apparently better than other comparators in the activity against ESBL-producing K. pneumoniae strains.
Bacterial resistance surveillance network [10] reported that 16.7% of P. aeruginosa and 68.8% of A. baumannii strains were resistant to ciprofloxacin. In the present study, the prevalence of sitafloxacin-resistant P. aeruginosa was 23.9%, higher than the prevalence of ciprofloxacin-resistant P. aeruginosa. The prevalence of sitafloxacin-resistant A. baumannii was 40.2%, lower than the prevalence of ciprofloxacin-resistant A. baumannii. Sitafloxacin was comparable to nemonoxacin and meropenem, slightly better than other quinolones and ceftazidime, and poorer than amikacin in the activity against P. aeruginosa. Sitafloxacin inhibited about 40% of the A. baumannii strains, similar to any of the comparators.
Sitafloxacin was much more active than ampicillin and comparable to other comparators (inhibited > 90% of the strains) against H. influenzae. Sitafloxacin was comparable to ceftriaxone in the activity against H. parainfluenzae (MIC50/90: 0.125/0.5 and ≤ 0.06/0.25 mg/L, respectively), and superior to other comparators. Sitafloxacin was highly active against M. catarrhalis, similar to most of the comparators.
According to the bacterial resistance surveillance network [10], about 50% of MRSA and 15% of MSSA strains were resistant to levofloxacin. In the present study, sitafloxacin inhibited 82.8% of MRSA and 100% of MSSA strains, 97.5% of MRCNS and 100% of MSCNS strains. Our MIC range of sitafloxacin for MRSA was ≤ 0.03-8 mg/L, higher than other reports (≤ 0.008–0.03 mg/L) for S. aureus. Our MIC ranges of sitafloxacin for MSSA, MRCNS, and MSCNS are also higher than reported [12]. Sitafloxacin was superior to or apparently better than ciprofloxacin, levofloxacin, and moxifloxacin, but similar to nemonoxacin in the activity against Staphylococcus spp. including methicillin-susceptible and -resistant strains. Sitafloxacin was slightly poorer than vancomycin in the activity of against MRSA, but comparable to vancomycin and obviously better than erythromycin in the activity against MSSA, MSCNS, and MRCNS.
Sitafloxacin was active against vancomycin-susceptible E. faecalis (MIC50/90: 0.25/2 mg/L), but showed poor activity against E. faecium (including vancomycin-susceptible and -resistant strains) with MIC50 range of 2–4 mg/L and MIC90 range of 8–16 mg/L. An overseas study on the in vitro activity of sitafloxacin [13] reported that the MIC90 of sitafloxacin was 2 mg/L for E. faecalis, which is consistent with our result. Sitafloxacin was apparently better than ciprofloxacin, similar to other fluoroquinolones, and poorer than ampicillin and vancomycin in the activity against vancomycin-susceptible E. faecalis. Sitafloxacin was weaker than vancomycin in the activity against vancomycin-susceptible E. faecium, but comparable to other comparators against vancomycin-resistant E. faecium.
A study on the activity of sitafloxacin against 1531 clinical isolates found that the MIC range of sitafloxacin was ≤ 0.008–0.25 mg/L (MIC50/90: 0.03/0.06 mg/L) for PSSP strains, ≤ 0.015–0.25 mg/L (MIC50/90: 0.03/0.06 mg/L) for PISP strains, and MIC50/90 values of 0.03/0.06 mg/L for PRSP strains [14]. The corresponding results of sitafloxacin in our study were ≤ 0.03–0.125 mg/L (MIC50/90: 0.125/0.125 mg/L) for PSSP, 0.06–0.125 mg/L (MIC50/90: 0.125/0.125 mg/L) for PISP, and ≤ 0.06-2 mg/L (MIC50/90: 0.125/0.125 mg/L) for PRSP, all higher than the above report [14]. Sitafloxacin inhibited 98.2% of the PRSP strains and 100% of the PSSP and PISP strains. Sitafloxacin was superior to ciprofloxacin and erythromycin and similar to other comparators in the activity against PSSP and PISP, and superior to ceftriaxone in the activity against PRSP.
A study on anaerobes [15] reported that sitafloxacin was active against anaerobes (MIC range: 0.06-16 mg/L, MIC50/90: 0.5/2 mg/L). We also found that sitafloxacin was highly active against B. fragilis (MIC50/90: 0.06/2 mg/L), and active against Peptostreptococcus and Prevotella spp. (MIC50/90: 0.125/4 and 0.125/8 mg/L, respectively). Our MIC50/90 values are relatively higher than the above report. It is also reported that reduced susceptibility to other fluoroquinolones is found in Bacteroides spp., e.g., about 30% of the strains are resistant to moxifloxacin, higher than the resistance rate to ciprofloxacin and levofloxacin.
Sitafloxacin was highly active against M. pneumoniae (MIC range: ≤ 0.03 mg/L; MIC50/90: ≤ 0.03/≤ 0.03 mg/L). It was superior to erythromycin and azithromycin and comparable to other comparators in the activity against M. pneumoniae.
In summary, a large number of clinical strains are tested for the susceptibility to sitafloxacin. However, the number of isolates for any one bacterial species is still not sufficient to completely reflect sitafloxacin activity against the common clinical isolates. Furthermore, increased MIC values of sitafloxacin are found for some bacteria. This highlights the necessity to implement subsequent in vitro activity studies and put in place surveillance program to monitor the changing pattern of sitafloxacin susceptibility in clinical settings.