Breakpoints for Predicting Pseudomonas aeruginosa Susceptibility to Inhaled Tobramycin in Cystic Fibrosis Patients: Use of High-Range Etest Strips

Abstract

Inhaled administration of tobramycin assures high concentrations in cystic fibrotic lungs, improving the therapeutic ratio over that of parenteral tobramycin levels, particularly against Pseudomonas aeruginosa. Conventional Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards) breakpoints only consider parenteral levels and do not take into account these high antimicrobial concentrations. The Spanish Antibiogram Committee (The MENSURA Group) has tentatively defined specific breakpoint values for inhaled tobramycin when testing P. aeruginosa isolates from cystic fibrosis (CF) patients (susceptible, <64 g/ml; resistant, >128 g/ml). The antimicrobial susceptibilities of 206 prospectively collected CF P. aeruginosa isolates were determined by the reference agar dilution method. For tobramycin, the performance of high range tobramycin Etest strips (AB Biodisk, Solna, Sweden) and conventional tobramycin disks were assessed with the same collection. Applying MENSURA proposed breakpoints, 95.1% of the strains were categorized as susceptible to tobramycin, either using agar dilution or Etest high-range strips (99% categorical agreement between both methods). With CLSI breakpoints, susceptibility rates decreased to 79.1 and 81.1% for agar dilution and Etest strips, respectively (83.5% categorical agreement). Minor, major, and very major errors for Etest strips (CLSI criteria) were 13.6, 1.2, and 14.8%, respectively. Upon applying the new proposed criteria for inhaled tobramycin, only one major and one very major error were observed with Etest strips. Whenever inhaled tobramycin is considered for therapy, we suggest that P. aeruginosa strains from CF patients categorized as intermediate or resistant to tobramycin according to the CLSI criteria should be retested with high-range Etest strips and recategorized using MENSURA interpretive criteria. CLSI breakpoints should still be followed when intravenous tobramycin is used in CF patients, particularly during the course of exacerbations.

Is there value in susceptibility testing ofPseudomonas aeruginosacausing chronic infection in patients with cystic fibrosis?

“…With increasing use of aerosolized therapy, laboratories must be able to provide susceptibility results for both tobramycin and colistin at both aerosol-and serum-achievable levels. Failure to do this may result in reports of false tobramycin resistance in as many as 15% of isolates, resulting in reluctance on the part of some physicians to use this valuable therapeutic approach [20]. Early in the disease course, when the nonmucoid P. aeruginosa is recovered, suggesting a planktonic mode of growth, traditional agar-based methods may predict resistance adequately.…”

“…P. aeruginosa CF isolates can be susceptible at aerosolized-achievable tobramycin levels while resistant to serum ones [20]. In CF patients receiving aerosolized tobramycin for the treatment of P. aeruginosa, dilution-based methods, including E-tests but not disk diffusion, can give a MIC value that can be used to predict resistance to this therapeutic approach [20]. Agar-based susceptibility methods for colistin are problematic because this agent diffuses poorly in agar owing to its size and charge.…”

Antimicrobial susceptibility of Pseudomonas aeruginosa before and after initiation of inhaled tobramycin in Bulgaria

“…Maybe due to the lack of a strict standard policy of care for CF patients in Bulgaria, the isolates of this study, before TOBI introduction, were much more susceptible respectively: piperacillin -20.9, 29.7 and 48.2 %; ceftazidime -14.6, 39.6 and 49.9 %; tobramycin -13.1, 10.1 and 22.2 %; gentamicin -33.0, 47.0 and 52.4 %; ciprofloxacin -28.6, 29.7 and 37.4% [6][7][8]. After the initiation of inhalation regimens with TOBI the susceptibility of P. aeruginosa became much lower compared to the susceptibility reported from Spain and Germany regarding aminoglycosides, cephalosporins and fluoroquinolones (at less than 60% susceptibility for all of the three classes) and much higher regarding carbapenems (over 75% susceptibility) as in USA [5].…”

“…Unfortunately, some colistin-resistant CF isolates of P. aeruginosa have been found lately in Spain [7], UK [6] and Denmark [12]. However, as colistin is not covered by NHI and its high price is making it almost unaffordable for over 90% of CF patients in Bulgaria, it is possible that such colistin-resistant strains are not to be seen in the near future in Bulgaria.…”

“…The difference in susceptibility before and after TOBI introduction in Bulgaria is a worrisome problem, not only because there is no other available approved inhalable antimicrobial therapy for CF patients right now, but also because recent studies in the literature report an increasing colistin-resistance [6,7,12,14]. At the moment, due to the 100% susceptibility to colistin, we use this antimicrobial as the last line of defence.…”