To the Editor—Carbapenems, such as imipenem and meropenem, are recom mended as first-line therapy for severe infections caused by cephalosporin-resistant Enterobacteriaceae. The emergence of carbapenem-resistant enterobacteria is therefore worrisome from a public health point of view because (1) the antimicrobial treatment options are very limited and (2) they may represent therapeutic dead ends, as novel treatments against gram-negative bacteria are not expected in the near future.
A 53-year-old male patient had a medical history of tuberculosis, fibromatosis, and chronic renal failure. Because of a peritoneal infection, he underwent abdominal surgery.
Strains of Hafnia alvei (H1), Enterobacter cloacae (E1), and Enterococcus faecalis were isolated from peroperative samples. The patient was treated with piperacillin-tazobactam after surgery, because H1, E1, and the E. faecalis isolates were susceptible. After 1 week, the patient became unstable and underwent surgery. Strains of H. alvei (H2) and E. cloacae (E2), both resistant to cephalosporins and piperacillin-tazobactam; an E. faecalis susceptible to ampicillin; and a methicillin-resistant coagulase-negative Staphylococcus were isolated, and the antibiotic therapy was changed to imipenem, vancomycin, gentamicin, and fluconazole. Twelve days later, a carbapenem-resistant H. alvei (H3) was isolated from a bronchoalveolar lavage sample and the therapy was changed to levofloxacin and gentamicin. Antibiotic resistance phenotypes and minimum inhibitory concentrations of carbapenems are presented in Table 1. Unfortunately, the patient died 2 weeks later with multiple organ failure and acute respiratory distress syndrome.
Evolution of the Minimum Inhibitory Concentrations (MICs) of Carbapenems and Antibiotic Phenotypes under Antibiotic Treatment
H1, H2, and H3, initially identified as H. alvei with use of API 20E strips, were then identified as belonging to the very recent Hafnia paralvei sp nov (formerly known as H. alvei DNA group 2) [1], by partial sequencing of RNA polymerase β-subunit (rpoB) and 16S ribosomal RNA genes. H1, H2, and H3 were indistinguishable by pulsed field gel electrophoresis, as were E1 and E2. Repeated attempts to transfer carbapenem resistance from H3 to Escherichia coli by conjugation were unsuccessful, and no decrease in the minimum inhibitor concentrations of carbapenems was observed when plates supplemented with cloxacillin (for inhibition of cephalosporinase activity) or E-test containing EDTA (for inhibition of metallo-β-lactamases) were used. Analysis of outer-membrane proteins of H1, H2, and H3 by sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed the lack of a major outer-membrane protein of 37 kDa in carbapenem-resistant isolate H3. This protein could correspond to OmpK36, known to play a role in permeability to carbapenems in Enterobacteriacae (Figure 1) [2].
Outer-membrane proteins of carbapenem-susceptible (H1, H2) and -resistant (H3) Hafnia paralvei sp nov. Lane M molecular mass standards; strain H3 is lacking a prominent protein band with an estimated molecular mass of 37 kDa. The sequence of the 10 N-terminal amino acids of this protein were identical to those of OmpK36 of Klebsiella pneumoniae and other members of the family Enterobacteriaceae. This figure appears only in the online version of the journal.
Among the medically important commensal Enterobacteriaceae [3], carbapenem resistance has been so far reported in Citrobacter, Enterobacter, Escherichia, Klebsiella, Morganella, Proteus, and Providencia species [4], but not in Hafnia species. Hafnia species are a cause of intestinal infections, especially in children, and of extraintestinal infections, in particular in adults with chronic underlying disease or previous antibiotic therapy [5].
Ceftazidime resistance has been often reported since 1993 in Hafnia species [6], but no resistance to the carbapenems has been observed. To our knowledge, this is the first report of carbapenem-resistant Hafnia selected in a patient treated with imipenem. This indicates that the threat of carbapenem resistance is now present among all Enterobacteriaceae of medical importance, stressing more than ever the need for new antibiotics and new approaches against pan-resistant bacteria.
Acknowledgments
Financial support. Institut National de la Veille Sanitaire and the French National Reference Center for Antibiotic Resistance.
Potential conflicts of interest. All authors: no conflicts.
References
Present affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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