1. J Antimicrob Chemother. 2017 May 1;72(5):1421-1428. doi: 10.1093/jac/dkx001.

Determining β-lactam exposure threshold to suppress resistance development in
Gram-negative bacteria.

Tam VH(1), Chang KT(1), Zhou J(1), Ledesma KR(1), Phe K(1), Gao S(1), Van Bambeke
F(2), Sánchez-Díaz AM(3), Zamorano L(4), Oliver A(4), Cantón R(3).

Author information: 
(1)University of Houston, Houston, TX, USA.
(2)Pharmacologie Cellulaire et Moléculaire & Louvain Drug Research Institute,
Université Catholique de Louvain, Brussels, Belgium.
(3)Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto 
Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
(4)University Hospital Son Espases, Instituto de Investigación Sanitaria de
Palma, Palma de Mallorca, Spain.

Objectives: β-Lactams are commonly used for nosocomial infections and resistance 
to these agents among Gram-negative bacteria is increasing rapidly. Optimized
dosing is expected to reduce the likelihood of resistance development during
antimicrobial therapy, but the target for clinical dose adjustment is not well
established. We examined the likelihood that various dosing exposures would
suppress resistance development in an in vitro hollow-fibre infection model.
Methods: Two strains of Klebsiella pneumoniae and two strains of Pseudomonas
aeruginosa (baseline inocula of ∼10 8  cfu/mL) were examined. Various dosing
exposures of cefepime, ceftazidime and meropenem were simulated in the
hollow-fibre infection model. Serial samples were obtained to ascertain the
pharmacokinetic simulations and viable bacterial burden for up to 120 h. Drug
concentrations were determined by a validated LC-MS/MS assay and the simulated
exposures were expressed as C min /MIC ratios. Resistance development was
detected by quantitative culture on drug-supplemented media plates (at 3× the
corresponding baseline MIC). The C min /MIC breakpoint threshold to prevent
bacterial regrowth was identified by classification and regression tree (CART)
Results: For all strains, the bacterial burden declined initially with the
simulated exposures, but regrowth was observed in 9 out of 31 experiments. CART
analysis revealed that a C min /MIC ratio ≥3.8 was significantly associated with 
regrowth prevention (100% versus 44%, P  = 0.001).
Conclusions: The development of β-lactam resistance during therapy could be
suppressed by an optimized dosing exposure. Validation of the proposed target in 
a well-designed clinical study is warranted.

DOI: 10.1093/jac/dkx001 
PMID: 28158470