Effect of Fluoroquinolones and Macrolides on Eradication and Resistance of Haemophilus influenzae in Chronic Obstructive Pulmonary Disease

Abstract

Little is known about the effect of antibiotics on eradication of carriage and development of resistance in Haemophilus influenzae in individuals with chronic obstructive pulmonary disease (COPD). Our goals were to assess antibiotic susceptibilities, prevalence of resistance genes, and development of resistance in H. influenzae and to evaluate the effect of macrolide and fluoroquinolone administration on H. influenzae eradication. Data were from a 15-year longitudinal study of COPD. Genome sequence data were used to determine genotype and identify resistance genes. MICs of antibiotics were determined by reference broth microdilution. Generalized linear mixed models were used to evaluate associations between antibiotic use and H. influenzae eradication. We examined 267 H. influenzae isolates from 77 individuals. All newly acquired H. influenzae isolates were susceptible to azithromycin. Five of 27 (19%) strains developed 4-fold increases in azithromycin MICs and reached or exceeded the susceptibility breakpoint (≤4 μg/ml) during exposure. H. influenzae isolates were uniformly susceptible to ciprofloxacin, levofloxacin, and moxifloxacin (MIC90s of 0.015, 0.015, and 0.06, respectively); there were no mutations in quinolone resistance-determining regions. Fluoroquinolone administration was associated with increased H. influenzae eradication compared to macrolides (odds ratio [OR], 16.67; 95% confidence interval [CI], 2.67 to 104.09). There was no difference in H. influenzae eradication when comparing macrolide administration to no antibiotic (OR, 1.89; 95% CI, 0.43 to 8.30). Fluoroquinolones are effective in eradicating H. influenzae in individuals with COPD. Macrolides are ineffective in eradicating H. influenzae, and their use in COPD patients may lead to decreased macrolide susceptibility and resistance.

FIG 1

Confirmed eradication of a newly acquired H. influenzae strain at 6 weeks. Graph showing the relationship between antibiotic administration within 5 days of the first visit when a newly acquired H. influenzae strain was identified (n = 153 strains) and eradication within 6 weeks of the first visit. Antibiotic categories were as follows: none (n = 86); “other” (n = 30), including cephalosporins, penicillins, sulfa drugs, and all others; fluoroquinolones (n = 28); and macrolides (n = 9). Bars indicate the proportion of strains in each antibiotic category where the strain was eradicated (dark gray) or was not eradicated (light gray) within 6 weeks of the first visit. Numbers of samples in each category are shown above bars. We eliminated from analysis 14 strains that we could not confirm as recent-acquisition isolates; 11 were present at the first study clinic visit, and two were isolated from participants with more than three missing visits prior to strain isolation. One additional strain was eliminated because the participant did not have a follow-up visit.