Successful Treatment of Bacteremia Due to NDM-1-Producing Morganella morganii with Aztreonam and Ceftazidime-Avibactam Combination in a Pediatric Patient with Hematologic Malignancy

LETTER

The worldwide spread of multiresistant bacteria, especially carbapenemase-producing Enterobacteriaceae, can lead to situations for which no antibiotic therapy option is available. The novel combination ceftazidime-avibactam (CZA) has a broad antibacterial spectrum that led to an increase in its use, notably for immunosuppressed patients treated with anticancer chemotherapy (1), and is associated with a decreased mortality rate in treated patients (2). It demonstrates excellent in vitro activity against bacteria producing Ambler class A, C, and D β-lactamases, including extended-spectrum β-lactamases (ESBLs), cephalosporinases, and carbapenemases, such as KPC-type and OXA-48-like carbapenemases (3), but not against those producing class B metallo-β-lactamases (MBLs), such as New Delhi metallo-beta-lactamase (NDM). Conversely, aztreonam (ATM), a monocyclic β-lactam antibiotic, is hydrolyzed by some extended-spectrum class A and C β-lactamases but not by MBLs (4). Recently, in vitro studies suggested a synergistic effect of ATM combined with CZA (ATM-CZA) on multidrug-resistant Enterobacteriaceae MBL producers (5), but this combination is unfortunately not yet commercialized.

Herein, we report the first successful treatment with ATM-CZA of a pediatric patient with bacteremia due to a Morganella morganii isolate harboring NDM-1 and cephalosporinases.

A 3-year-old girl, treated for a relapse 2 years after the diagnosis of a lymphoblastic acute leukemia (LAL), with severe aplasia and grade 4 mucositis, presented with two successive bacteremias 8 days apart. The first episode was associated with a CTX-M-15-producing K. pneumoniae strain, which was treated with imipenem, and the second episode was associated with a multidrug-resistant NDM-1-producing M. morganii strain. For M. morganii, MICs were determined as previously described (6) by the Etest method (AB bioMérieux, France) on Mueller-Hinton agar (MH) and were as follows: for CZA, >256 mg/liter; for meropenem, 3 mg/liter; for imipenem, >32 mg/liter; for ATM, 4 mg/liter); and for the combination ATM-CZA, 0.016 mg/liter. The patient was treated for 10 days with ATM-CZA (100 mg/kg of body weight/day for ATM and 150 mg/kg/day for CZA), enabling a recovery from the infectious episode, with no relapse within the subsequent 6 months.

β-Lactam resistance genes found by whole-genome sequencing (Illumina) were bla_NDM-1, bla_CMY-4, bla_DHA-5-like, bla_OXA-1, and bla_TEM-1B (a total of 79 contigs were obtained, with a mean coverage of 84× and an N₅₀ of 206,462) (7, 8).

To our knowledge, this study is the first to report the use and success of the ATM-CZA combination in the treatment of NDM-1-producing M. morganii bacteremia in a pediatric patient. The in vitro synergy of ATM-CZA that we observed is explained by the inhibition of the cephalosporinases by avibactam, enabling the activity of aztreonam against the M. morganii organism while allowing ATM to remain stable against the MBL. Shaw et al. recently reported their experience of combining ATM-CZA to treat adults during an outbreak of Klebsiella pneumoniae producing NDM-1, OXA-48, and CTX-M-15 with clinical success in 60% of cases (n = 10) (9). Similarly, Davido et al. reported 2 cases (infected with K. pneumoniae producing OXA-48 and NDM-1 and K. pneumoniae producing NDM-1 and AmpC) efficiently treated after they demonstrated an in vitro synergy (10).

Here we show the clinical efficacy of the aztreonam-ceftazidime–avibactam combination in a pediatric infection due to a multidrug-resistant NDM-1-producing M. morganii strain, supporting the current development of aztreonam-avibactam to treat MBL-producing Enterobacteriaceae.

The oral consent of the child's legal guardians was obtained, as this case is a part of a study approved by the regional Ethics Committee of Robert Debré Hospital, Paris, France (no. 2134141v0).

Data availability.

The draft nucleotide sequences have been deposited in GenBank under the accession number RMBV00000000.