Sir, Respiratory colonization with XDR bacteria is common in patients with cystic fibrosis (CF). Combination antibiotic therapy is a standard of care for respiratory exacerbations due to Pseudomonas and Burkholderia species in CF, but constructing efficacious regimens for which already XDR bacteria have in vitro susceptibility to both antibiotics is challenging. We read with interest, therefore, the recent report of Jayol et al.,1 describing in vitro data, and the clinical experiences of Shaw et al.2 in treating New Delhi MBL (NDM)-producing Klebsiella pneumoniae infections using a combination of ceftazidime/avibactam and aztreonam. Marshall et al.3 also previously reported impressive in vitro activity of this combination in aztreonam-, ceftazidime- and ceftazidime/avibactam-resistant isolates of Escherichia coli, Enterobacter cloacae, Providencia rettgeri and Morganella morganii. Based on a PubMed literature search using the keywords ‘ceftazidime/avibactam’ and ‘cystic fibrosis’ (26 January 2018), there are, as yet, no published reports that we could identify of the successful clinical use of ceftazidime/avibactam as monotherapy or combination therapy in cystic fibrosis. Here we report the favourable response to ceftazidime/avibactam, used in combination with aztreonam, in a patient with CF and an XDR Burkholderia multivorans infection. A young adult patient with ΔF508-homozygous CF, chronic airflow limitation, pancreatic insufficiency and frequent respiratory exacerbations presented with increasing shortness of breath and cough productive of green sputum severe enough for hospital admission. Prior sputa had shown chronic colonization for >10 years with B. multivorans (genovar II) as the predominant pathogen (cultured from all 10 sputum specimens over the prior 12 months), with Pseudomonas aeruginosa identified in 50% of specimens. The B. multivorans had previously been susceptible to ceftazidime, but had been resistant to aztreonam in the 6 years prior to presentation, although it had been shown to be susceptible prior to that. Sputum culture on admission to hospital produced a heavy growth of B. multivorans resistant to amikacin, aztreonam, ceftazidime, chloramphenicol, ciprofloxacin, colistin, gentamicin, meropenem, piperacillin/tazobactam and tobramycin. Scanty growths of P. aeruginosa (susceptible to ceftazidime and aztreonam) and Candida albicans were also identified. For the B. multivorans, the MIC of ceftazidime/avibactam was determined to be 2.0 mg/L by MIC test strip. Intravenous ceftazidime/avibactam at 2 g q8h plus aztreonam at 2 g q8h were commenced. The patient made rapid clinical improvement and suffered no adverse effects. After 2 weeks of therapy, the patient’s FEV1 (forced expiratory volume in 1 s) improved from a baseline of 0.9 to 1.24 L (39% of predicted), achieving the best spirometric values for 3 years; in the 5 months since treatment the patient has not been readmitted to hospital. We report the successful use of ceftazidime/avibactam, combined with aztreonam, in a CF patient with XDR B. multivorans infection. Papp-Wallace et al.4 demonstrated that avibactam counteracts the effect of the class A carbapenemase PenA commonly produced by B. multivorans and thought to be an important mechanism of resistance to β-lactams. We hypothesize that this was the most likely mechanism of resistance to ceftazidime in our patient, although other mechanisms may have been relevant. Additionally, avibactam may also have increased the isolate’s susceptibility to aztreonam, given the previous susceptibility, as demonstrated by Everaert and Coenye5,in vitro for some bacteria of the Burkholderia cepacia complex. The action at different PBPs may also have been advantageous; ceftazidime has been shown to have affinity for PBP1a in Burkholderia cenocepacia and PBP1a and PBP3 in P. aeruginosa, and aztreonam has affinity for PBP3 in P. aeruginosa.6–8 Avibactam also binds to PBP2 in E. coli.9 It is also possible that, if overexpressed, two antibiotics acting at the same PBP may lead to saturation when monotherapy does not.8 We fully acknowledge that the clinical response may have been due to ceftazidime/avibactam alone, but we rejected monotherapy because of concern about further resistance, as had already occurred in this patient. A subsequent B. multivorans isolate, ascertained 5 months after the above episode, had an MIC of ceftazidime/avibactam of 3 mg/L (by MIC test strip), but was resistant to the other agents mentioned above. Urgent clinical research to inform the selection of antibiotic regimens that maximize clinical efficacy while minimizing resistance in XDR bacteria is required. Funding This report was written as part of our routine work. Transparency declarations None to declare. References 1 Jayol A , Nordmann P , Poirel L et al. Ceftazidime/avibactam alone or in combination with aztreonam against colistin-resistant and carbapenemase-producing Klebsiella pneumoniae . J Antimicrob Chemother 2018 ; 73 : 542 – 4 . Google Scholar CrossRef Search ADS PubMed 2 Shaw E , Rombauts A , Tubau F et al. Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection . J Antimicrob Chemother 2018 ; 73 : 1104 – 6 . Google Scholar CrossRef Search ADS PubMed 3 Marshall S , Hujer AM , Rojas LJ et al. Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae? Antimicrob Agents Chemother 2017 ; 61 : e02243 - 16 . Google Scholar CrossRef Search ADS PubMed 4 Papp-Wallace KM , Becka SA , Zeiser ET et al. Overcoming an extremely drug resistant (XDR) pathogen: avibactam restores susceptibility to ceftazidime for Burkholderia cepacia complex isolates from cystic fibrosis patients . ACS Infect Dis 2017 ; 3 : 502 – 11 . Google Scholar CrossRef Search ADS PubMed 5 Everaert A , Coenye T. Effect of β-lactamase inhibitors on in vitro activity of β-lactam antibiotics against Burkholderia cepacia complex species . Antimicrob Resist Infect Control 2016 ; 5 : 44 . Google Scholar CrossRef Search ADS PubMed 6 Specht KM , Sheetz KH , Alexander CM et al. Expression and characterization of penicillin-binding proteins in Burkholderia cenocepacia . Curr Microbiol 2010 ; 60 : 274 – 9 . Google Scholar CrossRef Search ADS PubMed 7 Moyá B , Beceiro A , Cabot G et al. Pan-β-lactam resistance development in Pseudomonas aeruginosa clinical strains: molecular mechanisms, penicillin-binding protein profiles, and binding affinities . Antimicrob Agents Chemother 2012 ; 56 : 4771 – 8 . Google Scholar CrossRef Search ADS PubMed 8 Liao X , Hancock RE. Susceptibility to β-lactam antibiotics of Pseudomonas aeruginosa overproducing penicillin-binding protein 3 . Antimicrob Agents Chemother 1997 ; 41 : 1158 – 61 . Google Scholar PubMed 9 King AM , King DT , French S et al. Structural and kinetic characterization of diazabicyclooctanes as dual inhibitors of both serine-β-lactamases and penicillin-binding proteins . ACS Chem Biol 2016 ; 11 : 864 – 8 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: firstname.lastname@example.org. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Journal of Antimicrobial Chemotherapy – Oxford University Press
Published: Apr 17, 2018
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