The emergence of acquired metallo-β-lactamases (MBLs) of the IMP and the VIM types among Gram-negative bacilli is increasing and becoming a life-threatening therapeutic problem. These enzymes are active against most β-lactams including carbapenems and extended-spectrum cephalosporins except the monobactam aztreonam. Moreover, most of the clinical isolates harbouring such enzymes are also often resistant to other antibiotics such as aminoglycosides and fluoroquinolones. Therefore, antibiotic therapy for treating infections arising from MBL-producing strains constitutes a real therapeutic problem. MBLs belonging to the VIM family have been reported in European,1–4 Asian5 and American countries6 among strains of Pseudomonas aeruginosa, but also among strains of members of the family Enterobacteriaceae. blaVIM genes are often carried by mobile gene cassettes inserted into class 1 integrons chromosomally or plasmid located.2,3,7 P. aeruginosa RZ01 strain was recovered from an HIV-positive 46-year-old man, coming from Saudi Arabia who had been hospitalized for an abdominal mass due to a Cryptococcus neoformans voluminous abscess treated with amphotericin B and fluconazole and surgery. Empirical antibiotherapy combining ceftriaxone (2 g/day) and trimethoprim/sulfamethoxazole (80/400 mg/day) was also administered at the same time. One week after the surgical procedure, and 10 days of urinary tract catheter, the patient developed a prostatitis and his condition worsened. P. aeruginosa RZ01 was isolated from urine and was resistant to most anti-pseudomonal β-lactams, including ticarcillin, piperacillin, ceftazidime, cefepime and imipenem, but was moderately susceptible to aztreonam. The isolate was also resistant to most other available antibiotics such as aminoglycosides and fluoroquinolones, except to colimycin and fosfomycin. MICs of β-lactams, determined by Etest and interpreted as recommended (AB Biodisk), were as follows: ticarcillin, 1024 mg/L; piperacillin, >1024 mg/L; ceftazidime, 64 mg/L; imipenem, >32 mg/L; meropenem, 24 mg/L; and aztreonam, 8 mg/L. By an agar dilution technique, the MIC of imipenem was found to be 256 mg/L. A synergy was found between imipenem or ceftazidime and EDTA-containing discs indicating that P. aeruginosa RZ01 produced an MBL. Repeated attempts to transfer ceftazidime or imipenem resistance by conjugation by filter mating to P. aeruginosa or Escherichia coli recipients were unsuccessful. Analysis of the plasmid content of the strain P. aeruginosa RZ01 did not reveal the presence of plasmid DNA and electroporation experiments failed. We used two sets of primers previously reported enabling the detection of class Bβ-lactamases genes.8 PCR experiments followed by sequencing revealed the presence of the carbapenemase VIM-2. The precise genetic environment of blaVIM-2 was not precisely determined except that using primers VIM-2A and 3′CS,3 we were able to amplify 2.7 kb suggesting that this class one integron possesses other antibiotic resistance gene cassettes. Furthermore, we also demonstrated by PCR that blaVIM-2 was the first gene located downstream of inti1 suggesting that the molecular organization of this integron differs from that previously described in P. aeruginosa harbouring blaVIM-2.4,7 In vitro studies of antibiotic associations revealed that the combination of aztreonam plus fosfomycin was synergic and was the most effective of all associations tested. Antibiotherapy combining fosfomycin (12 g/day) and aztreonam (6 g/day) was initiated and continued for 21 days, the patient recovered and all subsequent urine cultures were sterile. The use of high doses of aztreonam was previously suggested to be the most appropriate antibiotherapy for infection due to VIM-2-producing P. aeruginosa in a rat model of pneumonia.9 This supports these results and suggests that the combination of aztreonam and fosfomycin is a potential combination regimen effective against MBL-producing Gram-negative bacteria. However, this report also strengthens the fact that detection of MBL production among Gram-negative bacilli is crucial for the optimal treatment of patients and to control the spread of resistance. It also confirms that VIM-2 is by far the most common VIM-type β-lactamase.7 This isolate was the first and unique P. aeruginosa harbouring this resistance phenotype in our hospital. Moreover, even if this prostatitis corresponded to a nosocomial infection acquired in our hospital, we could not exclude the fact that this patient coming from Saudi Arabia was previously colonized with this strain which was selected by extended-spectrum cephalosporins. To our knowledge, this observation could therefore constitute the first report of the dissemination of VIM-MBL in the Middle East.7 We thank Alain Philippon for excellent advice, Patrice Nordmann for critical reading of the manuscript, and Laurent Poirel, Annick Billouët and Jean-Marie Adam for technical assistance. This work was supported by Université René Descartes Paris 5 and la Fondation pour la Recherche Médicale. 1Service de Bactériologie, Groupe Hospitalier Cochin-Saint Vincent de Paul, Assistance Publique Hôpitaux de Paris, Faculté de Médecine René Descartes Université Paris 5, 27 rue du Faubourg Saint Jacques, 75679 Paris Cedex 14, France; 2Service de Médecine Interne, Groupe Hospitalier Cochin-Saint Vincent de Paul, Assistance Publique Hôpitaux de Paris, Faculté de Médecine René Descartes Université Paris 5, Paris, France
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Guérin et al. (2005) studied this question.