Eradication ofBurkholderia cepaciacomplex in cystic fibrosis patients with inhalation of amiloride and tobramycin combined with oral cotrimoxazole

Abstract

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Burkholderia cepacia complex in cystic fibrosis: critical gaps in diagnosis and therapy

“…Among the Bcc species usually identified in cultures of respiratory secretions of people with CF are B. cenocepacia , Burkholderia stabilis , Burkholderia multivorans ( B. multivorans ), and Burkholderia vietnamensis [ 1 , 7 ], the latter considered the species most susceptible to aminoglycosides [ 7 ]. Unfortunately, 85–97% of lung infections caused by Bcc in this population worldwide are by B. cenocepacia and B. multivorans [ 1 , 20 , 40 , 41 ], which are recognized as the most virulent species of this complex [ 7 , 21 ], 94% and 50% of the respective infections being chronic despite the aggressive antibiotic therapies applied [ 42–45 ].…”

“…Antibiotic therapy is essential in the clinical management of CF patients infected by Bcc [ 20 ] since timely eradication can prevent the rapid decline of lung function and improve quality of life [ 41 ]. Studies in the Cochrane database of systematic reviews have recognized that therapy for Bcc lung infections in people with CF is a significant challenge [ 42 , 58 , 59 ], due to factors as diverse as the natural multi-antimicrobial resistance of Bcc species [ 1 , 2 , 40 ], their intrinsic resistance to disinfectants and antiseptics [ 16 ], their strong ability to develop resistance to other antimicrobial agents [ 1 , 3 , 20 ], including those of last option [ 60 ], the high variability in the expression of virulence factors in each strain [ 45 ], their ability to survive intracellularly in lung epithelial cells and macrophages [ 21 , 45 ], and the establishment of biofilms [ 7 ].…”

“…The scarcity of clinical studies has led to antibiotic therapies being chosen primarily because of the imprecise results of antibiograms [ 7 , 19 , 20 ], the experience of the treating specialist [ 7 ], or the findings of the few case series and case reports [ 41 ], while the duration of therapy is commonly based on the clinical and microbiological response visualized [ 50 ]. Empirically, aggressive treatments with different combinations of antibiotics have been suggested [ 5 , 41 , 42 , 58–60 ], complemented by different routes of administration, such as nebulized application [ 5 , 41 , 60 ] or inhalation [ 41 , 42 , 58 ], since this route of administration permits a concentration up to 100 times higher than that of the antimicrobial agent [ 58 ], coupled with the possibility of being administered in conjunction with oral and intravenous antibiotics, which would hypothetically delay or prevent the establishment of chronic infections [ 41 , 42 ].…”

“…Reports on the application of different treatment regimens have shown that inhaled administration of TM is insufficient to suppress pulmonary infection by Bcc in patients with CF 7 . Therefore, its synergy with other compounds has been explored, such as amiloride or verapamil, compounds that have demonstrated in vitro the ability to inhibit efflux pumps [ 7 ] and block sodium channels [ 41 ], which have managed to increase the antimicrobial activity of TM [ 7 , 41 ]. The clinical results of these combined treatments have shown effectiveness in most cases [ 7 , 41 , 63 ].…”

“…Therefore, its synergy with other compounds has been explored, such as amiloride or verapamil, compounds that have demonstrated in vitro the ability to inhibit efflux pumps [ 7 ] and block sodium channels [ 41 ], which have managed to increase the antimicrobial activity of TM [ 7 , 41 ]. The clinical results of these combined treatments have shown effectiveness in most cases [ 7 , 41 , 63 ]. However, infections caused by B. dolosa [ 7 ] and B. cenocepacia [ 63 ] have exhibited notorious difficulties [ 7 , 63 ].…”