The outer membrane of Gram-negative bacteria serves as barrier to permeation. Transport across this barrier often occurs through channels created by porins. Changes in these porins can account for antibiotic resistance. The combination of a permeability barrier and beta-lactamases in the periplasmic space leads to a situation in which concentrations, at the target, of even third-generation cephalosporins, can be significantly decreased.
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Hiroshi Nikaido (1988) studied this question.