Emergence of IMP-4 metallo-β-lactamase in a clinical isolate from Australia

Sir, Carbapenems are important therapeutic agents for the treatment of multiresistant Gram-negative bacteria. Of the β-lactams, they have the broadest spectrum and greatest stability to β-lactamases. However, the clinical utility of these antimicrobials is under threat with the emergence of acquired carbapenemases, particularly Ambler class B metallo-β-lactamases, now reported in Asia,1 Europe2 and North America.3 These enzymes (IMP- or VIM-types) often confer high-level resistance to all β-lactams except aztreonam and are not inhibited by clavulanic acid, tazobactam or sulbactam.2 The blaIMP-4 gene, coding the IMP-4 enzyme, has recently been described in Acinetobacter spp. isolates from Hong Kong1 and a Citrobacter youngae isolate from the People's Republic of China.4 Of particular importance, these blaIMP-4 genes were identified on class 1 integrons residing on mobile plasmids,5 indicating the ability for horizontal transfer between species. To date, metallo-β-lactamases have not been reported in Australia. In January 2004, a 17-year-old female was admitted to our intensive care unit with disseminated Burkitt's lymphoma requiring urgent chemotherapy. Neutropenic fevers developed requiring multiple antibiotics, including meropenem. Sixteen days after starting meropenem, the patient developed septic shock with refractory hypotension. Blood cultures were taken and empirical ciprofloxacin and teicoplanin were added to meropenem. Unfortunately the patient died within 12 h from overwhelming sepsis. Two days later a carbapenem-resistant Pseudomonas aeruginosa was isolated from blood culture. The isolate was susceptible only to colistin, and was resistant to gentamicin, tobramycin, amikacin, ceftazidime, piperacillin/tazobactam, ticarcillin/clavulanate and ciprofloxacin. The MICs of both imipenem and meropenem were >32 mg/L (Etest, AB Biodisk Solna, Sweden). The ion chelator, EDTA, inhibited imipenemase activity and the double-disc synergy test using imipenem and EDTA was also positive, indicating a metallo-β-lactamase. PCR amplification was positive using primers specific for blaIMP-type genes.6 Nucleotide sequencing confirmed the presence of the blaIMP-4 gene. This is the first report of a clinical isolate with a metallo-β-lactamase in Australia. To our knowledge, it also the first blaIMP-4 gene to be found outside Asia and in P. aeruginosa. Of relevance, we have noted an increase in carbapenem use in our institution, resulting from a multiresistant Acinetobacter spp. outbreak. This has led to ongoing selective pressure for carbapenem-resistant Gram-negative organisms. The recognition of this enzyme in Australia is a worrying development, with clearly devastating consequences when associated with serious infection. Of major concern, is the ability of metallo-β-lactamases to be transferred on mobile genetic elements, suggesting a need for vigilant monitoring of all resistant Gram-negative organisms. Implementation of strict infection control practices and the cautious and prudent use of carbapenems are critical for the future of this invaluable antimicrobial agent. 1Infectious Diseases and Microbiology Unit, The Alfred Hospital, Melbourne, 3181; 2Microbiology and Infectious Diseases Department, Women's and Children's Hospital, Adelaide, Australia