Antimicrobial Susceptibility Testing for Glucose-Nonfermenting Gram-Negative Bacteria: the Tip of the Iceberg

LETTER

We read with great pleasure the recently published manuscript by Caverly and colleagues who studied the in vitro activities of four β-lactam–β-lactamase inhibitors (BL-BLIs), including ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, and piperacillin-tazobactam, against 420 isolates of the following glucose-nonfermenting Gram-negative bacteria: Burkholderia spp., Achromobacter spp., Stenotrophomonas maltophilia, and Pandoraea spp. (1). The authors used the reference antimicrobial susceptibility test method and interpretive criteria for results established by the Clinical and Laboratory Standards Institute (CLSI) for the BL-BLIs against Pseudomonas aeruginosa. Meropenem-vaborbactam had the greatest activity against Burkholderia spp. and Achromobacter spp. among the four tested antibiotics. However, the activity of the four BL-BLIs against Stenotrophomonas maltophilia and Pandoraea spp. was minimal, with ranges of 11% to 40% and 0% to 5%, respectively (1).

The CLSI and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) define guidelines to interpret antimicrobial resistance in the United States and Europe, respectively, and set antimicrobial MIC breakpoints based on clinical, microbiological, pharmacodynamic, and pharmacokinetic profiles of the antimicrobials for particular pathogens (2, 3). The CLSI has established breakpoints for the Burkholderia cepacia complex (Bcc) and S. maltophilia for a limited number of antimicrobials, including ceftazidime, minocycline, levofloxacin, trimethoprim-sulfamethoxazole, chloramphenicol, and ticarcillin-clavulanate in addition to meropenem exclusively for S. maltophilia and cefiderocol for Bcc only (2, 4). The susceptibility testing for Achromobacter spp., Pandoraea spp., and Burkholderia gladioli established by the CLSI is defined by MIC breakpoints for other non-Enterobacteriaceae, which include Pseudomonas spp. (not P. aeruginosa) and other glucose nonfermenters, excluding Acinetobacter spp., Bcc, Burkholderia mallei, Burkholderia pseudomallei, and S. maltophilia, which have separate breakpoints set by CLSI for each (2). Yet, there are not CLSI breakpoints for the four BL-BLIs against the glucose-nonfermenting bacteria except for P. aeruginosa (2). One caveat is that CLSI has established meropenem-vaborbactam MIC breakpoints for Enterobacteriaceae only (interpreted as susceptible if MIC is ≤4/8 μg/ml, intermediate if 8/8 μg/ml, and resistant if ≥16/8 μg/ml), but there is not an MIC breakpoint for the glucose nonfermenters, including P. aeruginosa (2). On the other hand, EUCAST has established P. aeruginosa MIC breakpoints for meropenem-vaborbactam that are interpreted differently (susceptible if MIC is ≤8/8 μg/ml and resistant if >8/8 μg/ml) (3). Trimethoprim-sulfamethoxazole is the only antibiotic with defined MIC breakpoints for S. maltophilia by EUCAST (3). Due to the broad MIC distribution of the Bcc group for the relevant antibiotics, EUCAST recommends against in vitro susceptibility testing for Bcc. Similarly, there are not MIC breakpoints by EUCAST for Achromobacter spp. and Pandorea spp. (3). In the setting of a lack of standardized susceptibility testing for several antibiotics against the glucose nonfermenters, predicting the in vitro activity of antibiotics based on CLSI breakpoints established for P. aeruginosa could be justified only in specific circumstances where the observed MIC falls several dilutions away from the susceptibility range. However, interpreting MICs included within one to two dilutions from the susceptibility range established for another pathogen should be taken with “a grain of salt.”

Despite the Generating Antibiotic Incentives Now (GAIN) Act passed in 2012 as a section of the FDA Safety and Innovation Act to endorse the development of new antibiotics and antimicrobial resistance tests (5, 6) and the 21st Century Cures Act signed in 2016 to accelerate drug and medical device development (7), additional actions and incentives are crucial to facilitate pharmacokinetic-pharmacodynamic and clinical studies for novel antimicrobials that are required to set up interpretative breakpoints that guide antimicrobial therapy and improve patient outcomes (6).

In conclusion, there is an urgent need to develop standardized antimicrobial susceptibility testing for the glucose-nonfermenting Gram-negative bacteria and harmonize the CLSI and EUCAST standards in the era of rapid emergence of multidrug-resistant and difficult-to-treat infections.

Ed. Note: The authors of the published article did not feel that a response was necessary.