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. C hronic obstructive pulmonary disease (COPD) affects approximately 24 million people in the United States and is the third leading cause of death worldwide (1, 2). Disease is characterized by intermittent acute exacerbations of COPD (AECOPD) that result in missed work, clinic visits, emergency room visits, hospital admissions, and respiratory failure requiring mechanical ventilation. Approximately half of AECOPD cases are caused by bacterial infection, with nontypeable Haemophilus influenzae being the most common pathogen (3, 4). H. influenzae also colonizes the lower airways of individuals with COPD for extended periods and contributes to inflammation, impaired pulmonary function, and increases in daily respiratory symptoms (3-6).Clinical studies indicate that antibiotic therapy results in accelerated recovery and reduced complications of moderate and severe exacerbations (7,8). Thus, antibiotics, particularly oral macrolides and fluoroquinolones, are commonly prescribed for treatment of AECOPD (4,(8)(9)(10). Several recent clinical trials demonstrated that daily azithromycin results in fewer exacerbations and improved quality of life, and thus, azithromycin is increasingly administered prophylactically to many COPD patients (11)(12)(13).In spite of widespread administration of antibiotics for treatment and prophylaxis of infection in COPD, remarkably little is known about the effect of antibiotics on carriage and eradication of respiratory tract pathogens, particularly H. influenzae. Prior studies suggested that fluoroquinolones were superior to macrolides in eradicating H. influenzae (14-17). However, a significant limitation of these studies is that eradication was assumed if the patient was unable to produce sputum and/or was determined by a single posttreatment sputum culture. This study design misses the possibility of H. influenzae persistence in spite of negative culture, a scenario known to be common in COPD (3). When microbiologic confirmation was obtained, the strains were not genotyped, precluding determination of whether a positive culture represented unsuccessful bacterial eradication or acquisition of a new strain...

The role of acute and chronic respiratory colonization and infections in the pathogenesis of COPD

“…186 A 15-year longitudinal study conducted by Pettigrew et al concluded that fluoroquinolones represent the best choice for eradicating H. influenzae in COPD patients. 184 In their study, none of the bacterial isolates developed resistance to fluoroquinolones. 184 Even though P. aeruginosa is a relatively uncommon cause of COPD exacerbations, its incidence is on the rise and the rapid emergence and spread of MDR (defined by resistance to at least three antibiotic classes) is a serious cause for concern.…”

“…184 In their study, none of the bacterial isolates developed resistance to fluoroquinolones. 184 Even though P. aeruginosa is a relatively uncommon cause of COPD exacerbations, its incidence is on the rise and the rapid emergence and spread of MDR (defined by resistance to at least three antibiotic classes) is a serious cause for concern. A comparative study conducted in Spain has demonstrated that the carriage of MDR P. aeruginosa in COPD patients was associated with increased mortality rates and more recent work in AECOPD reveals a high burden of antibiotic resistance.…”

“…Prolonged use of macrolides for the prophylaxis and treatment of COPD exacerbations has been shown to increase antimicrobial drug resistance in H. influenzae. 184 The commonly used drug azithromycin has a long half-life of around 66 h, which can lead to drug concentrations below the minimum inhibitory concentration for an extended period of time. 185 This prolonged exposure to subinhibitory concentrations of the drug may be one of the reasons behind the increased resistance to macrolides.…”

Azithromycin Pharmacodynamics against Persistent Haemophilus influenzae in Chronic Obstructive Pulmonary Disease

“…The development of azithromycin resistance in H. influenzae presents a major public health challenge. In order to understand the factors driving NTHi resistance to azithro-mycin, we investigated isolates from a 20-year longitudinal study of COPD infection conducted in Buffalo, NY, a unique collection of NTHi sputum isolates with corresponding whole-genome sequences and epidemiologic, clinical, and antibiotic susceptibility data (4,13). From this unique collection, serially obtained NTHi isolates which persisted in COPD patients during treatment with azithromycin were further analyzed for resistance to or elevated MICs of azithromycin.…”

“…From this unique collection, serially obtained NTHi isolates which persisted in COPD patients during treatment with azithromycin were further analyzed for resistance to or elevated MICs of azithromycin. Two strains developed a known macrolide resistance mutation in L22 during persistence in the human airways; in this protein, a switch from glycine to aspartic acid at amino acid 91 (G91D) occurred (13). Thus, the objectives of this study were to (i) compare azithromycin pharmacodynamics (PD) in vitro in the "first" and "last" isolates of two persistent strains of NTHi from COPD patients who received azithromycin and (ii) simulate the human pharmacokinetic (PK) profiles of azithromycin Z-Pak dosing regimens in the hollow-fiber infection model (HFIM) against the strains upon acquisition by the patients to understand the profile and time course of bacterial response and understand the evolution of resistance.…”