Caz-hi, an Extended-Spectrum TEM β-Lactamase (TEM-61), Is Derived from Caz-lo (TEM-11) by In Vivo Selection

Ceftazidime was introduced into our hospital during the second half of 1987. It was aimed especially for use in the intensive care unit to treat infections with gram-negative bacilli with diminished sensitivity for cefuroxime, at that time the first-line β-lactam antibiotic for serious infections. At that time Escherichia coli and Klebsiella sp. isolates were susceptible to ceftazidime. An increase in cefuroxime-resistant isolates was noted, resulting in an increase in the use of ceftazidime. A few months later ceftazidime-resistant E. coli and Klebsiella pneumoniae were isolated. It could be shown that these isolates harbored different plasmid-mediated extended-spectrum β-lactamases (ESBLs), at that time a rare phenomenon (7). The phenotypic characteristics of the isolates and the β-lactamases were reported (10), and the epidemiology is summarized in Fig. 1. From a patient treated with ceftazidime, and in whom the first K. pneumoniae producing an ESBL, called “Caz-lo” (Isoelectric focusing point [pl], 5.6), was observed, 10 days later a more resistant K. pneumoniae, of the same serotype, with an identical arbitrarily primed PCR profile and with a “Caz-hi” enzyme, was isolated. This was indicative of Caz-hi being an in vivo-selected mutant of Caz-lo. Starting from the Caz-lo K. pneumoniae, in vitro selection with ceftazidime resulted in a strain that produced an ESBL with the Caz-hi phenotype. This reinforced the hypothesis of in vivo selection, initially based on epidemiological data only.Fig. 1.Epidemiology of ESBLs. M, mutation of enzyme; T, transfer of plasmid to another serotype or another species; ?, period of apparent disappearance of the enzyme. Months are abbreviated at the top.