Molecular characterization of fluoroquinolone resistance in invasive clinical isolates of Streptococcus pneumoniae susceptible to delafloxacin

TL;DR

The study shows that delafloxacin remains effective against many Streptococcus pneumoniae strains resistant to other fluoroquinolones like levofloxacin.

Contribution

The study identifies specific mutations in S. pneumoniae that confer resistance to delafloxacin and demonstrates its efficacy against levofloxacin-resistant isolates.

Findings

Delafloxacin MICs remained low in isolates with low-level resistance to levofloxacin, with only 8.3% showing mutations in gyrA.

High-level levofloxacin-resistant isolates showed multiple mutations in QRDRs, but 76% remained susceptible to delafloxacin.

Delafloxacin resistance was observed in 24% of high-level levofloxacin-resistant isolates with two to four mutations in QRDRs.

Abstract

Delafloxacin is a dual-targeting fluoroquinolone against topoisomerase IV and DNA gyrase that could decrease resistance selection by diminishing the likelihood of multiple mutational events in both enzymes.

To determine the activity of delafloxacin against invasive Streptococcus pneumoniae isolates resistant to levofloxacin (LEV-R), compare delafloxacin MICs for LEV-R isolates with those of susceptible strains, and analyse mutations in QRDRs.

A total of 130 S. pneumoniae isolates (2014–20) were studied. The isolates were distributed according to levofloxacin MICs: high-level LEV-R (n = 46; MIC > 32 mg/L), low-level LEV-R (n = 36; MIC range 3–12 mg/L) and susceptible (LEV-S; n = 48; MIC ≤2 mg/L). We considered delafloxacin-resistant to be MIC ≥ 0.12 mg/L (EUCAST epidemiological cut-off). MICs were determined by gradient diffusion (control strain S. pneumoniae ATCC 49619). All isolates were subjected to PCR and sequencing of parC, parE, gyrA and gyrB genes.

All LEV-S isolates showed delafloxacin MICs of ≤0.008 mg/L, and did not show mutations in QRDRs. Isolates with levofloxacin MICs of 3–12 mg/L showed delafloxacin MICs of <0.12 mg/L, with 3 (8.3%) presenting mutations in gyrA, and 11 (30.6%) in parC previously related to resistance. Isolates with levofloxacin MICs of >32 mg/L showed two to four mutations in QRDRs and 11 (24%) were delafloxacin resistant, presenting at least two mutations in gyrAS81F/L/V + parCS79F; four accumulated three mutations, and two showed four mutations in QRDRs.

Among LEV-R pneumococci, 71 (87%) were susceptible to delafloxacin, indicating that it maintains its activity despite the presence of mutations in gyrA + parC that lead to high-level resistance to levofloxacin.

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