Amplification of Antimicrobial Resistance in Gut Flora of Patients Treated with Ceftriaxone [PublishAheadOfPrint]

Although antibacterial therapy has an impact on human intestinal flora and emergence of resistant bacteria, its role on amplification of antimicrobial resistance and the quantitative exposure-effect relationship is not clear. An observational prospective study was conducted to determine whether and how ceftriaxone exposure is related to amplification of resistance in non- ICU patients.Serial stool samples from 122 ESBL(+) hospitalized patients were analyzed with quantitative real-time PCR to quantify the resistant gene bla_CTX-M. Drug exposure was calculated for each patient using a population pharmacokinetic model. Multi- and univariate regression and classification regression tree (CART) analysis was used to explore relationships between measures of exposure and amplification of bla_CTX-M genes. Amplification of bla_CTX-M was observed in 0% (0/11) patients with no treatment and 33% (20/61) of patients treated with ceftriaxone. Stepwise regression analysis showed a significant association between amplification of bla_CTX-M and plasma fAUC_0-24, fCmax and the duration of ceftriaxone therapy. Using CART analysis, amplification of bla_CTX-M was observed in 11/16 (69%) of patients treated >14d and in 9/40 (23%) of patients treated ≤14d (p=0.0019). In the latter group, amplification was observed in 5/7 (71%) of patients with fAUC_0-24 ≥222 mg.h/l and in 4/33 (12%) of patients with lower drug exposures (p=0.0033). A similar association was found for fCmax ≥30 mg/l (63% vs. 13%, p=0.0079). A significant association was found between amplification of bla_CTX-M resistance genes and exposure of ceftriaxone. Both duration of treatment and degree of ceftriaxone exposure have a significant impact on of amplification of resistance genes.

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