Selection of resistance by piperacillin during Pseudomonas aeruginosa endocarditis

The mechanisms responsible for emergence of resistance during antimicrobial therapy were investigated in isolates obtained from a patient suffering from Pseudomonas aeruginosa endocarditis. The strain was first isolated from blood cultures obtained upon admission of the patient. It was sensitive to piperacillin, ticarcillin and tobramycin. Piperacillin-tobramycin therapy was therefore instituted and led to a rapid improvement of the patient's condition. Unfortunately, the patient subsequently became febrile again and blood cultures continued to yield P. aeruginosa. However, the organism isolated was now resistant to piperacillin and other penicillins tested. Cell-free extracts of the pre- and post-therapy isolates were analyzed for their β-lactamase activity. The susceptible pre-therapy strain did not produce significant levels of β-lactamase. In contrast, the post-therapy strain produced high levels of the enzyme. Induction experiments indicated that the production of β-lactamase was constitutive in the post-therapy isolate. Thus, piperacillin therapy has led to the selection of resistant mutants which produced high levels of β-lactamase constitutively. This was associated with relapse of the infection and therapeutic failure.