Testing the mutant selection window hypothesis with meropenem: In vitro model study with OXA-48-producing Klebsiella pneumoniae

Abstract

OXA-48 carbapenemases are frequently expressed by Klebsiella pneumoniae clinical isolates; they decrease the effectiveness of carbapenem therapy, particularly with meropenem. Among these isolates, meropenem-susceptible carbapenemase-producers may show decreased meropenem effectiveness. However, the probability of the emergence of resistance in susceptible carbapenemase-producing isolates and its dependence on specific K. pneumoniae meropenem MICs is not completely known. It is also not completely clear what resistance patterns will be exhibited by these bacteria exposed to meropenem, if they would follow the patterns of non-beta-lactamase-producing bacteria and other than beta-lactams antibiotics. These issues might be clarified if patterns of meropenem resistance related to the mutant selection window (MSW) hypothesis. To test the applicability of the MSW hypothesis to meropenem, OXA-48-carbapenemase-producing K. pneumoniae clinical isolates with MICs in a 64-fold range (from susceptible to resistant) were exposed to meropenem in a hollow-fiber infection model; epithelial lining fluid meropenem pharmacokinetics were simulated following administration of 2 grams every 8 hours in a 3-hour infusion. Strong bell-shaped relationships between the meropenem daily dose infused to the model as related to the specific isolate MIC and both the antimicrobial effect and the emergence of resistance were observed. The applicability of the MSW hypothesis to meropenem and carbapenemase producing K. pneumoniae was confirmed. Low meropenem efficacy indicates very careful prescribing of meropenem to treat K. pneumoniae infections when the causative isolate is confirmed as an OXA-48-carbapenemase producer.

Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing Klebsiella pneumoniae and the Inoculum Effect

“…As reported in numerous studies, MIC-based PK/PD parameters such as AUC/MIC and T >MIC have been used successfully to establish "exposure-resistance" relationships for antibiotics of different classes [17][18][19][20][21][22][23]. Such a relationship for beta-lactamase producing K. pneumoniae exposed to meropenem (DOSE/MIC with MICs determined at SI) has been described by our laboratory [24]. It is possible that combining data for mono and combined treatments in the current study poses some difficulties.…”

“…The operational procedure used in the PD experiments was as described elsewhere [24]. Each experiment was performed at least in duplicate.…”

Comparative Meropenem Pharmacodynamics and Emergence of Resistance against Carbapenem-Susceptible Non-Carbapenemase-Producing and Carbapenemase-Producing Enterobacterales: A Pharmacodynamic Study in a Hollow-Fiber Infection Model

“…To quantify the meropenem total antimicrobial effect, an integral parameter, determined as the area between the control growth and time-kill curves (ABBC) [11], was calculated. The interrelation of ABBC with the antibacterial effect is direct: the greater the effect, the higher the ABBC.…”

“…The interrelation of ABBC with the antibacterial effect is direct: the greater the effect, the higher the ABBC. Time courses of bacterial counts resistant to meropenem (for each meropenem resistance level, from 2× to 16× MIC) in pharmacodynamic experiments were characterized by the area under the bacterial mutant concentration-time curve (AUBC M ) [11] determined from the beginning of treatment to 120 h. The interrelation of AUBC M with the emergence of resistance is direct: the greater the resistant cells growth, the higher the AUBC M .…”

“…As far as we know, the studies aimed at these issues are lacking. Previously, our group conducted a pharmacodynamic study in a hollow-fiber infection model (HFIM) with meropenem and carbapenemase-producing K. pneumoniae strains with a wide range of meropenem susceptibility, including strains with MICs below the 2 mg/L breakpoint [11]. As a result, these susceptible strains displayed intensive regrowth and decreased meropenem susceptibility during meropenem exposure, despite simulating the maximal dose of 2 g over a 3 h infusion.…”