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. 2017 May 22:12:1507-1518.
doi: 10.2147/COPD.S135338. eCollection 2017.

Ampicillin resistance in Haemophilus influenzae from COPD patients in the UK

Satyanarayana Maddi  1 , Umme Kolsum  1 , Sarah Jackson  1 , Richard Barraclough  2 , Barbara Maschera  3 , Karen D Simpson  3 , Thierry G Pascal  4 , Serge Durviaux  4 , Edith M Hessel  3 , Dave Singh  1
Affiliations

Ampicillin resistance in Haemophilus influenzae from COPD patients in the UK

Satyanarayana Maddi et al. Int J Chron Obstruct Pulmon Dis. .

Abstract

Background: Haemophilus influenzae is commonly isolated from the airways of COPD patients. Antibiotic treatment may cause the emergence of resistant H. influenzae strains, particularly ampicillin-resistant strains, including β-lactamase-negative ampicillin resistance (BLNAR) strains. Genetic identification using ftsI sequencing is the optimum method for identifying mutations within BLNAR strains. The prevalence of BLNAR in COPD patients during the stable state has not been reported. We investigated the antibiotic resistance patterns of H. influenzae present in the sputum of stable COPD patients, focusing on ampicillin resistance; the prevalence of enzyme and non-enzyme-mediated ampicillin resistance was determined. A subset of patients was followed up longitudinally to study H. influenzae strain switching and antibiotic sensitivity changes.

Patients and methods: Sputum sampling was performed in 61 COPD patients, with 42 samples obtained at baseline; H. influenzae was detected by polymerase chain reaction in 28 samples. In all, 45 patients completed the follow-up for 2 years; 24 H. influenzae isolates were obtained.

Results: Disk diffusion showed the highest antibiotic resistance in the penicillin antibiotic group (eg, 67% for ampicillin) and macrolides (eg, 46% for erythromycin), whereas all isolates were susceptible to quinolones. Of the 16 isolates resistant to ampicillin, 9 (56%) were β-lactamase positive. The β-lactamase-negative isolates were further investigated; none of these fulfilled the phenotypic BLNAR classification criteria of ampicillin minimum inhibitory concentration >1 µg/mL, and only one demonstrated an ftsI mutation. Frequent H. influenzae strain switching was confirmed using multilocus sequence typing and was associated with changes in the antibiotic sensitivity pattern.

Conclusion: We observed an overidentification of ampicillin resistance by disk diffusion. The majority of ampicillin resistance was due to enzyme production. H. influenzae strain changes during the stable state may be associated with a change in antibiotic sensitivity; this has implications for empirical antibiotic prescribing.

Keywords: BLNAR; COPD; MLST; ampicillin resistance.

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Conflict of interest statement

Disclosure BM, KDS, TGP, SD, and EMH are employees of the Glaxo-SmithKline group of companies. BM, KDS, TGP, and EMH hold shares/restricted shares in the GlaxoSmithKline group of companies. DS has received sponsorship to attend international meetings, honoraria for lecturing or attending advisory boards, and research grants from various pharmaceutical companies including Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Merck, NAPP, Novartis, Pfizer, Respivert, Skypharma, Takeda, Teva, Therevance, and Verona. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Detection of bacteria by culture and qPCR (n=37 paired samples). Notes: qPCR: negative is defined if the count was below the limit of detection for each pathogen. Culture: negative is defined as no bacteria detected. No lower limit of detection was applied. Abbreviations: qPCR, quantitative polymerase chain reaction; HI, Haemophilus influenzae; SP, Streptococcus pneumoniae; MC, Moraxella catarrhalis.
Figure 2
Figure 2
Antibiotic sensitivity of H. influenzae isolates from (A) the first stable visit (n=15); and (B) all H. influenzae isolates (n=24). Abbreviation: H. influenzae, Haemophilus influenzae.
Figure 3
Figure 3
Biotype distribution among ampicillin-resistant and ampicillin-sensitive H. influenzae isolates (n=24). Abbreviation: H. influenzae, Haemophilus influenzae.
See this image and copyright information in PMC

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