[Mutation window for the "pneumococcus-fluoroquinolone" couple. Contribution of experimental models]

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Context:

• Low-level fluoroquinolone resistance in *Streptococcus pneumoniae* (pneumococci) is uncommon but increasing.
• This resistance, characterized by *parC* mutations, is linked to prior fluoroquinolone exposure and treatment failures.
• A humanized mouse model of pneumococcal pneumonia was employed to study resistance dynamics.

Purpose:

• To investigate the efficacy of fluoroquinolones (ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin) against pneumococci with varying resistance profiles.
• To evaluate the emergence of fluoroquinolone resistance during treatment in a pneumonia model.
• To assess the utility of the mutation prevention concentration (MPC) in predicting treatment outcomes.

Summary:

• In wild-type pneumococcal pneumonia, ciprofloxacin failed due to *parC* mutants; levofloxacin was less effective than gatifloxacin or moxifloxacin.
• For efflux strains, levofloxacin failed without mutants, while gatifloxacin was combined with mutant emergence, and moxifloxacin remained effective.
• Susceptible *parC* strains rapidly developed resistance (*gyrA* mutation) to all tested fluoroquinolones, rendering treatment ineffective.
• Mutation prevention concentration (MPC) measurements correlated with observed resistance patterns, defining a 'mutation window'.

Impact:

• Highlights the risk of therapeutic failure and the emergence of highly resistant pneumococcal strains.
• Stresses the importance of identifying patients with low-level fluoroquinolone-resistant pneumococci.
• Informs clinical decision-making regarding fluoroquinolone use in pneumococcal infections, especially in previously treated patients.