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Antibiotic Resistance in Prevotella Species Isolated from Patients with Cystic fibrosis

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Antibiotic Resistance in Prevotella Species Isolated from Patients with Cystic fibrosis J Antimicrob Chemother 2013; 68: 2369–2374 doi:10.1093/jac/dkt191 Advance Access publication 21 May 2013 Antibiotic resistance in Prevotella species isolated from patients with cystic fibrosis Laura J. Sherrard1,2, Kathryn A. Graham1,2, Stef J. McGrath1,2, Leanne McIlreavey1,2, Joseph Hatch3,4, Marianne S. Muhlebach3, Matthew C. Wolfgang3,4, Deirdre F. Gilpin1,2, J. Stuart Elborn1,5, Thamarai Schneiders5 and Michael M. Tunney1,2* 1CF & Airways Microbiology Group, Queen’s University Belfast, Belfast, UK; 2School of Pharmacy, Queen’s University Belfast, Belfast, UK; 3Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5Centre for Infection & Immunity, School of Medicine, Dentistry & Biomedical Science, Queen’s University Belfast, Belfast, UK *Corresponding author. School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. Tel: +44-(0)28-90972087; Fax: +44-(0)28-90247794; E-mail: [email protected] Received 13 March 2013; returned 29 March 2013; revised 11 April 2013; accepted 12 April 2013 Objectives: To compare the antimicrobial susceptibility of Prevotella spp. isolated from cystic fibrosis (CF) and non- CFpatientsand analyse the impact of antibiotic prescribing in the preceding yearon resistance amongstCFisolates. Methods: The susceptibility of 80 CF Prevotella isolates to 12 antibiotics was compared with that of 50 Prevotella isolates from invasive infections in people who did not have CF and 27 Prevotella isolates from healthy controls. Results: All isolates were susceptible to chloramphenicol, meropenem and piperacillin/tazobactam, with only four isolates resistant to metronidazole. However, resistance to amoxicillin, ceftazidime and tetracycline was apparent in all groups. Significant differences in clindamycin resistance (UK CF, 56%; UK invasive, 10%) and co-amoxiclav non-susceptibility (UK CF, 32%; UK invasive, 12%) were observed between UK CF and UK invasive isolates. The like- lihood of non-susceptibility to clindamycin and co-amoxiclav in UK CF isolates was 5.5-fold and 2.5-fold higher relative to that in UK invasive isolates, respectively. Azithromycin MICs were also significantly higher for CF isolates (P,0.001), which was associated with current prescription of azithromycin. More than 50% of clinical isolates tested in this study were b-lactamase positive. Conclusions: This study profiles antibiotic susceptibility in Prevotella spp. in CFand demonstrates that meropenem, piperacillin/tazobactam, chloramphenicol and metronidazole are likely to be the most effective antibiotics if treat- ment is indicated. Keywords: anaerobic bacteria, antimicrobial susceptibility, b-lactamase production Introduction members of the oral flora in patientswith CF, non-CF bronchiectasis and chronic obstructive pulmonary disease (COPD).9 Prevotella spp. are obligate anaerobic bacteria and common Exposure of other members of the CF microbiota, such as members of the healthy microbiota at various body sites, including Prevotella spp., to antibiotics used in the treatment of CF pulmon- 1,2 the oral cavity and the respiratory tract. Recently, Prevotella spp. ary infection may also increase their resistance to antimicrobials. have been detected as part of diverse polymicrobial communities Therefore, in this study, we determined the antimicrobial suscepti- 3 – 8 in respiratory samples from cystic fibrosis (CF) patients. bility of a large number of clinical Prevotella isolates cultured from Although their precise role in CF lung disease is not yet clear, they patients with CF and those without CF and analysed the impact of may be clinically significant pathogens and contribute to infection antibiotic prescribing on resistance amongst CF isolates. Of the 12 and inflammation in the CF lung. antibiotics selected, 9 (amoxicillin, co-amoxiclav, azithromycin, Antibiotics are employed extensively to treat CF pulmonary in- ceftazidime, chloramphenicol, clindamycin, doxycycline, merope- fection and several studies have examined the effect of persistent nem and piperacillin/tazobactam) are used in the treatment of antibiotic use on bacterial resistance. For example, long-term CF lung infection and have putative activity against anaerobes. macrolide exposure has been shown to significantly increase One antibiotic (tobramycin) is used to treat CF lung infection, macrolide resistance amongst both respiratory pathogens and but has no putative anaerobic activity, and two antibiotics # The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected] 2369 Sherrard et al. (metronidazole and tetracycline) have putative anaerobic activity, isolates had high MICs of tobramycin (≥64 mg/L). Resistance to but are not routinely used to treat CF lung infection. azithromycin was evident among the UK CF, UK invasive and US CF isolates (MIC90 .256 mg/L), but was less apparent in the UK healthy control isolates (MIC90 3 mg/L). All isolates tested were Methods susceptible to meropenem, piperacillin/tazobactam and chloram- Bacterial isolates and prior antibiotic use phenicol, with resistance to metronidazole (3%) rare. The clinical Prevotella isolates (n¼157) used in this study were split into four groups: (i) 57 isolates cultured from 25 adult (≥18 years) UK CF patients Comparison of antimicrobial susceptibility between UK CF, attending the CF clinic, Belfast, UK [cultured from sputum (n¼53) and invasive and healthy control isolates plaque (n¼4)]; (ii) 23 isolates cultured from 15 paediatric (,18 years) US CF patients attending the CF clinic, University of North Carolina, Chapel Comparison of the MICs for UK isolates (Table 1) showed significant Hill, NC, USA [cultured from bronchoalveolar lavage fluid (n¼14) and differences for ceftazidime (P¼0.035), clindamycin (P,0.001), sputum (n¼9)]; (iii) 50 isolates from invasive infections, including cultures co-amoxiclav (P,0.001), meropenem (P¼0.001), azithromycin from blood, abscesses and ulcers, from 50 UK non-CF patients, kindly pro- (P,0.001), chloramphenicol (P¼0.014) and doxycycline vided by Dr Valerie Hall (Anaerobe Reference Laboratory, Cardiff, UK); and (P¼0.020), with no differences evident for the remaining five anti- ≥ (iv) 27 isolates from 15 adult ( 18 years) UK healthy control subjects (cul- biotics. Post hoc tests revealed that CF isolates had significantly tured from induced sputum). Information on intravenous and oral antibio- higher MICs of clindamycin (P,0.001) and azithromycin tics prescribed in the year preceding culture of UK and US CF isolates was (P,0.001) compared with invasive and healthy control isolates. collected from patient hospital notes where available (Tables S1 and S2, Although there was no difference in either co-amoxiclav or doxy- available as Supplementary data at JAC Online). Quality assurance testing was performed using Bacteroides fragilis ATCC 25285, Pseudomonas cycline MICs between the CF and invasive isolates, both these aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213 and Strepto- groups had significantly higher MICs of co-amoxiclav (CF, coccus pneumoniae ATCC 49619. P,0.001; invasive, P¼0.012) and doxycycline (CF, P¼0.027; inva- sive, P¼0.03) compared with healthy control isolates. For antibiotics with breakpoints approved by the CLSI, we deter- Antimicrobial susceptibility testing and b-lactamase mined the risk of antimicrobial non-susceptibility in UK CF isolates production relative to invasive isolates (Table 2). Significant differences in clin- The antimicrobial susceptibility of isolates was determined by Etest (AB damycin (P,0.001) and co-amoxiclav (P¼0.037) resistance were Biodisk, Hampshire, UK) in accordance with the manufacturer’s instruc- observed. The likelihood of non-susceptibility to clindamycin and tions. MICs were categorized as indicating resistance, intermediate resist- co-amoxiclavin CFisolateswas 5.5-fold and 2.5-fold higher relative ance or susceptibility according to the MIC breakpoints for anaerobes to that in invasive isolates, respectively. defined by the CLSI (Table 1). b-Lactamase production was determined using a nitrocefin assay as described previously.10 Current azithromycin prescription and antibiotic resistance in CF isolates Data analysis To investigate whether increased resistance to azithromycin was The susceptibility (MIC) of UK isolates in the three groups (CF, invasive and associated with current prescription of the antibiotic, isolates healthy control) to each antibiotic was compared using the Kruskal– ¼ Wallis test, with post hoc tests performed using the Mann–Whitney test were grouped [current prescription isolates (n 30) versus no with Bonferroni adjustment applied. The UK and US CF isolates were current prescription isolates (n¼32)], with current prescription grouped according to patient prescription of azithromycin (current prescrip- clearly associated with significantly higher azithromycin MICs tion versus no current prescription) and azithromycin MICs compared using (P¼0.005; Figure 1). Furthermore, isolatesfrom CFpatientsnot cur- the Mann–Whitney test. Spearman’s rank correlation coefficient was used rently prescribed azithromycin (n¼32) had significantly higher to measure the strength of the linear association between azithromycin azithromycin MICs (P¼0.011) compared with isolates (n¼17) MICs and clindamycin
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