Efficacy of generic meropenem products in combination with colistin in carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis

P Tattevin (1, 2, 3) , A Dinh (4) , I Ghout (5) , W Mouton (6) , M.-C. Verdier (7, 3) , F Laurent (6) , F Lemaître (7, 3) , L Gatin (4) , A Saleh-Mghir (4) , A.-C. Cremieux (4)

1 Biosit : Biologie - Santé - Innovation Technologique - Structure Fédérative de Recherche en Biologie et Santé de Rennes
2 BRM - ARN régulateurs bactériens et médecine
3 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
4 2I - Infection et inflammation
5 Hôpital Ambroise Paré [AP-HP]
6 HCL - Hospices Civils de Lyon
7 CIC - Centre d'Investigation Clinique [Rennes]

Guidelines for the management of carbapenemase-producing Enterobacterales (CPE) infections recommend a combination of two active agents, including meropenem if the minimum inhibitory concentration (MIC) is ≤8 mg/L. The therapeutic equivalence of meropenem generics has been challenged. We compared the bactericidal activity of meropenem innovator (AstraZeneca) and four generic products (Actavis, Kabi, Mylan and Panpharma), both in vitro and in vivo, in association with colistin. In vitro time-kill studies were performed at 4 × MIC. An experimental model of KPC-producing Klebsiella pneumoniae osteomyelitis was induced in rabbits by tibial injection of a sclerosing agent followed by 2 × 10 CFU of K. pneumoniae KPC-99YC (meropenem MIC = 4 mg/L; colistin MIC = 1 mg/L). At 14 days after inoculation, treatment for 7 days started in seven groups of ≥10 rabbits, including a control group, a colistin group, and one group for each meropenem product (i.e. the innovator and four generics), in combination with colistin. In vitro, meropenem + colistin was bactericidal with no viable bacteria after 6 h, and this effect was similar with all meropenem products. In the osteomyelitis model, there was no significant difference between meropenem generics and the innovator when combined with colistin. Colistin-resistant strains were detected after treatment with colistin + meropenem innovator (n = 3) and generics (n = 3). The efficacy of four meropenem generics did not differ from the innovator in vitro and in an experimental rabbit model of KPC-producing K. pneumoniae osteomyelitis in terms of bactericidal activity and the emergence of resistance.

Mots clés: Carbapenemase; Colistin; Generics; Klebsiella pneumoniae; Meropenem; Osteomyelitis

Domaines: Pharmacologie; Maladies infectieuses; Bactériologie

P Tattevin, A Dinh, I Ghout, W Mouton, M.-C. Verdier, et al.. Efficacy of generic meropenem products in combination with colistin in carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis. International Journal of Antimicrobial Agents, 2020, 56 (5), pp.106152. ⟨10.1016/j.ijantimicag.2020.106152⟩. ⟨hal-02959729⟩