Cefamandole therapy in a patient with suppurative thrombophlebitis failed due to selection of a resistant variant of the causative organism Klebsiella pneumoniae. Analysis of the resistance mechanism revealed that in the resistant variant one of the major outer membrane proteins, OmpF, was missing. Resistance of this type has implications for therapy with other antibiotics including non-beta-lactam antibiotics. This report demonstrates the role of outer membrane permeation in the emergence of bacterial resistance during antibiotic therapy.