Establishing Antimicrobial Susceptibility Testing Methods and Clinical Breakpoints for Inhaled Antibiotic Therapy

Abstract

Inhaled antibiotics are a common and valuable therapy for patients suffering from chronic lung infection, with this particularly well demonstrated for patients with cystic fibrosis. However, in vitro tests to predict patient response to inhaled antibiotic therapy are currently lacking. There are indications that antimicrobial susceptibility testing (AST) may have a role in guidance of therapy, but which tests would correlate best still needs to be researched in clinical studies or animal models. Applying the principles of European Committee on Antimicrobial Susceptibility Testing methodology, the analysis of relevant and reliable data correlating different AST tests to patients' outcomes may yield clinical breakpoints for susceptibility, but these data are currently unavailable. At present, we believe that it is unlikely that standard determination of minimum inhibitory concentration will prove the best predictor.

Keywords: antimicrobial resistance; bronchiectasis; chronic pulmonary infection; cystic fibrosis; inhaled antibiotics; susceptibility breakpoints.

Figure 1.

A, Wild-type and I (susceptible with increased exposure) category coincide; no category for S (susceptible at standard dose) is defined. Strains with minimum inhibitory concentrations (MICs) above the wild-type range are defined as R (resistant). Based on aggregated data from 32 276 observations in the European Committee on Antimicrobial Susceptibility Testing (EUCAST) database (https://mic.eucast.org/search/). B, Activity of meropenem beyond the wild-type distribution is likely with higher exposure. The wild-type category coincides with S (susceptible with standard dose). A non-wild-type I category (susceptible with increased exposure) is defined. Based on aggregated data from 57 615 observations in the EUCAST database (https://mic.eucast.org/search/).

Figure 2.

A, Data were obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) database (https://mic.eucast.org/search/, accessed 2 December 2020). B, Data were adapted from Ekkelenkamp et al [28]. Epidemiological cutoff (ECOFF), as determined in non–cystic fibrosis (CF) isolates = 2 mg/L; Susceptible with standard dose (S) ≤2 mg/L; Resistant (R) >2 mg/L. Comparison of A and B shows how the distribution of the minimum inhibitory concentrations (MICs) has been skewed toward higher MICs for the Pseudomonas aeruginosa strains of persons with CF, likely due to adaptation of these strains to antibiotic exposure; in B, it is therefore not possible to establish a clear ECOFF.

Figure 3.

Comparison of the minimum inhibitory concentration (MIC), minimum biofilm inhibitory concentration (MBIC), and minimum biofilm eradication concentration (MBEC) for 53 Pseudomonas aeruginosa strains isolated from persons with cystic fibrosis. A, The relation between MIC, MBIC, and MBEC varies between the different inhaled antibiotics; for tobramycin, the relative difference between these values is smaller than for colistin and aztreonam. B, Superimposed strains are represented by darker shades or lines. This figure shows that the differences between antimicrobial susceptibility testing parameters are isolate-specific; 1 isolate may have both a higher MIC and a lower MBEC than another isolate. Both figures were originally published by Díez-Aguilar et al [43].