In VitroResistance Development to Nemonoxacin inStreptococcus pneumoniae: A Unique Profile for a Novel Nonfluorinated Quinolone

Abstract

Selection of resistant strains in Streptococcus pneumoniae was studied in vitro with nemonoxacin, a novel nonfluorinated quinolone (NFQ), in comparison with quinolone benchmarks, ciprofloxacin, garenoxacin, and gatifloxacin. In stepwise resistance selection studies, a 256-fold loss of potency was observed after three to four steps of exposure to ciprofloxacin or garenoxacin. In contrast, the loss of potency was limited to eightfold after three steps of exposure to nemonoxacin and repeated attempts to isolate highly resistant organisms after four steps of exposure yielded isolates that could not be subcultured in liquid medium. The quinolone resistance-determining regions of the target genes, parC, parE, gyrA, and gyrB, were analyzed through DNA sequencing. Known mutations, especially in the hotspots of parC and gyrA, were selected with exposure to garenoxacin, ciprofloxacin, and gatifloxacin. In contrast, mutations selected with nemonoxacin were limited to GyrA, GyrB, and ParE, sparing ParC, which is known as a key driver of resistance in clinical isolates of S. pneumoniae. This observation is consistent with previous data using other NFQs, which showed no loss of potency due to ParC mutations in clinical isolates. This apparently unique feature of nemonoxacin is potentially attributable to the structural uniqueness of the NFQs, distinguishing them from the fluoroquinolones that are commonly prescribed for infections by S. pneumoniae.

Structural Characterization of the Millennial Antibacterial (Fluoro)Quinolones—Shaping the Fifth Generation

“…These results suggest that besifloxacin is less affected by target enzymes mutations than earlier FQNs [ 258 ]. The same conclusion was presented by Roychoudhury et al, following in vitro study with nemonoxacin on resistant Streptococcus pneumoniae [ 259 ].…”

<p>Efficacy and Safety of Nemonoxacin in Outpatients with Community-Acquired Pneumonia</p>

“…14 Its site of action differs from that of fluoroquinolones, and no cross-resistance has been observed. 15,16 For outpatients, it is difficult to obtain drug sensitivity results of an infection in a timely and accurate manner, and nearly half of patients are exposed to antibiotics before this information is available. In our investigation, 77 (23.82%) patients stated clearly that they used antibiotics before consultation, the most common being macrolides (49.35%), β-lactams (42.86%), and quinolones (5.19%).…”

“…14 Its site of action differs from that of fluoroquinolones, and no cross-resistance has been observed. 15 , 16…”

Pharmacotherapy of Lower Respiratory Tract Infections in Elderly—Focused on Antibiotics

“…4) Dosing regimen: In a systemic review and meta-analysis of RCTs demonstrated that compared with 500 mg levofloxacin, nemonoxacin (500 mg or 750 mg) was more safe in cardiac conduction as measured by ECG QTc prolongation (Chang et al, 2019). In addition, a single-dose escalation (nemonoxacin 25–1,250 mg) study shows that there were no clinically significant changes in corrected QT in healthy Chinese volunteers (Luke et al, 2010), but the 750 mg dosage had a significantly higher risk of adverse effects than the 500 mg dosage, so the nemonoxacin 500 mg regimen may be adequate for the treatment of CAP (Roychoudhury et al, 2016). The oral dosage of nemonoxacin is 500 mg once daily while it is 100 mg twice daily for levofloxacin, making nemonoxacin a potential therapy for the elderly with LRTIs.…”