Upregulated Palmitoleate and Oleate Production in Escherichia coli Promotes Gentamicin Resistance.

Metabolic reprogramming mediates antibiotic efficacy. However, metabolic adaptation of microbes evolving from antibiotic sensitivity to resistance remains undefined. Therefore, untargeted metabolomics was conducted to unveil relevant metabolic reprogramming and potential intervention targets involved in gentamicin resistance. In total, 61 metabolites and 52 metabolic pathways were significantly altered in gentamicin-resistant E. coli. Notably, the metabolic reprogramming was characterized by decreases in most metabolites involved in carbohydrate and amino acid metabolism, and accumulation of building blocks for nucleotide synthesis in gentamicin-resistant E. coli. Meanwhile, fatty acid metabolism and glycerolipid metabolism were also significantly altered in gentamicin-resistant E. coli. Additionally, glycerol, glycerol-3-phosphate, palmitoleate, and oleate were separately defined as the potential biomarkers for identifying gentamicin resistance in E. coli. Moreover, palmitoleate and oleate could attenuate or even abolished killing effects of gentamicin on E. coli, and separately increased the minimum inhibitory concentration of gentamicin against E. coli by 2 and 4 times. Furthermore, palmitoleate and oleate separately decreased intracellular gentamicin contents, and abolished gentamicin-induced accumulation of reactive oxygen species, indicating involvement of gentamicin metabolism and redox homeostasis in palmitoleate/oleate-promoted gentamicin resistance in E. coli. This study identifies the metabolic reprogramming, potential biomarkers and intervention targets related to gentamicin resistance in bacteria.

Therapeutic potential of salidroside in preserving rat cochlea organ of corti from gentamicin-induced injury through modulation of NRF2 signaling and GSK3ß/NF-κB pathway.

Salidroside (SAL) is a phenol glycoside compound found in plants of the Rhodiola genus which has natural antioxidant and free radical scavenging properties. SAL are able to protect against manganese-induced ototoxicity. However, the molecular mechanism by which SAL reduces levels of reactive oxygen species (ROS) is unclear. Here, we established an in vitro gentamicin (GM) ototoxicity model to observe the protective effect of SAL on GM-induced hair cells (HC) damage. Cochlear explants of postnatal day 4 rats were obtained and randomly divided into six groups: two model groups (treatment with 0.2 mM or 0.4 mM GM for 24 h); two 400 µmol/L SAL-pretreated groups pretreatment with SAL for 3 h followed by GM treatment (0.2 mM or 0.4 mM) for 24 h; 400 µmol/L SAL group (treatment with SAL for 24 h); control group (normal cultured cochlear explants). The protective effects of SAL on GM-induced HC damage, and on mRNA and protein levels of antioxidant enzymes were observed. HC loss occurred after 24 h of GM treatment. Pretreatment with SAL significantly reduced GM-induced OHC loss. In cochlear tissues, mRNA and protein levels of NRF2 and HO-1 were enhanced in the GM alone group compared with the SAL pretreatment GM treatment group. SAL may protect against GM-induced ototoxicity by regulating the antioxidant defense system of cochlear tissues; SAL can activate NRF2/HO-1 signaling, inhibit NF-κB activation, activate AKT, and increase inhibitory phosphorylation of GSK3ß to decrease GSK3 activity, all of which exert antioxidant effects.

Dosificación de gentamicina en pacientes graves con insuficiência renal aguda: evaluación de una fórmula basada en los niveles de creatinina plasmática / Gentamicin dosage in critical patients with acute renal insufficiency: evaluation of a formula based on plasma creatinine levels

Se estudiaron 40 pacientes con diferentes niveles de creatinina plasmática en los que se determinó la concentración de gentamicina sérica basal (método enzimoinmunoensayo), con el objeto de evaluar la fórmula de ajuste: creatininemia (mg/dl) x 8 = h entre dosis. En 7 de 8 pacientes con creatininemias superiores a 2,5mg/dl, las concentraciones basales de la droga alcanzaron niveles tóxicos (más de 2micrograma/ml, en tanto que sólo 1 de 32 pacientes con creatininemias inferiores a la citada supero dicha nivel. Se estableció la relación entre los niveles de creatinina plasmática y la concentración sérica de gentamicina basal: y=0,17+0,77x; r=0,89; p<0,001. Estos hallazgos se confirman por la existencia de una relación de poder entre la T1/2 de la droga y la creatininemia con mayor pendiente que la citada en otras publicaciones. La comparación entre la T1/2 estimada (creatininemia en mg/dl x 4) y la T1/2 medida, evidencia que por encima de las 6h existe una subvaloración de esta última, por lo que el intervalo entre dosis calculado por la fórmula de ajuste evaluada resulta demasiado breve. No aconsejamos la utilización de la fórmula referida en pacientes con creatininemias superiores a 2,5mg/dl

Avaliaçäo da concentraçäo inibitória mínima da ceftriaxona e de aminoglicosídeos em enterobactérias em condiçöes aeróbicas e anaeróbicas / Evaluation of minimal inhibitory concentration of ceftriaxone and aminoglycosides against enterobacteria under aerobic and anaerobic conditions

Alguns trabalhos têm demonstrado que os aminoglicosídeos apresentam uma reduçäo in vitro de sua atividade frente às enterobactérias e ao S. aureus em meios anaeróbicos. O objetivo do estudo foi o de comprovar a atividade da ceftriaxona, netilmicina e gentamicina em 30 cepas de enterobactérias isoladas de infecçöes intra e extra-hospitalares, em condiçöes de anaerobiose e aerobiose. O método para a determinaçäo da MIC foi o da diluiçäo. Os resultados demonstram que a netilmicina e gentamicina perdem (em algumas cepas) a sua atividade em condiçöes de anaerobiose, o mesmo näo ocorrendo com a ceftriaxona. Esses achados sugerem que a ceftriaxona deve ser o antibiótico de eleiçäo, nas infecçöes causadas por enterobactérias onde se suspeite de baixos níveis de oxigênio