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Pharmacokinetic/Pharmacodynamic Correlation of Cefquinome Against Experimental Catheter-Associated Biofilm Infection Due to Staphylococcus aureus.

ABSTRACT: Biofilm formations play an important role in Staphylococcus aureus pathogenesis and contribute to antibiotic treatment failures in biofilm-associated infections. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) profiles of cefquinome against an experimental catheter-related biofilm model due to S. aureus, including three clinical isolates and one non-clinical isolate. The minimal inhibitory concentration (MIC), minimal biofilm inhibitory concentration (MBIC), biofilm bactericidal concentration (BBC), minimal biofilm eradication concentration (MBEC) and biofilm prevention concentration (BPC) and in vitro time-kill curves of cefquinome were studied in both planktonic and biofilm cells of study S. aureus strains. The in vivo post-antibiotic effects (PAEs), PK profiles and efficacy of cefquinome were performed in the catheter-related biofilm infection model in murine. A sigmoid E max model was utilized to determine the PK/PD index that best described the dose-response profiles in the model. The MICs and MBICs of cefquinome for the four S. aureus strains were 0.5 and 16 ?g/mL, respectively. The BBCs (32-64 ?g/mL) and MBECs (64-256 ?g/mL) of these study strains were much higher than their corresponding BPC values (1-2 ?g/mL). Cefquinome showed time-dependent killing both on planktonic and biofilm cells, but produced much shorter PAEs in biofilm infections. The best-correlated PK/PD parameters of cefquinome for planktonic and biofilm cells were the duration of time that the free drug level exceeded the MIC (fT > MIC, R (2) = 96.2%) and the MBIC (fT > MBIC, R (2) = 94.7%), respectively. In addition, the AUC24h/MBIC of cefquinome also significantly correlated with the anti-biofilm outcome in this model (R (2) = 93.1%). The values of AUC24h/MBIC for biofilm-static and 1-log10-unit biofilm-cidal activity were 22.8 and 35.6 h; respectively. These results indicate that the PK/PD profiles of cefquinome could be used as valuable guidance for effective dosing regimens treating S. aureus biofilm-related infections.

SUBMITTER: Zhou YF

PROVIDER: S-EPMC4703793 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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[Hypertension, diabetes mellitus and comorbidity in primary care].

Wittchen H U HU Krause P P Höfler M M Pfister H H Ritz E E Göke B B Lehnert H H Tschöpe D D Kirch W W Pittrow D D Sharma A M AM Bramlage P P Küpper B B Unger T T

Fortschritte der Medizin. Originalien 20030201

Almost every second patient seeing a primary care doctor suffers from arterial hypertension and about every fifth has diabetes mellitus. These diseases often occur at the same time. They are associated in more than 80% of the cases with other severe concomitant and subsequent diseases (heart attack, stroke, renal failure, neuropathy etc.). The magnitude especially of subsequent and concomitant diseases, the dimension of the personal suffering and the immense diagnostic and therapeutic challenges ...[more]

PMID: 14732946

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Project description:Cefquinome sulfate has a strong killing effect against Staphylococcus aureus (S. aureus), but bacterial resistance has become increasingly widespread. Experiments were conducted to investigate the pattern of adaptive resistance of S. aureus to cefquinome sulfate under different dosage regimens by using pharmacokinetic-pharmacodynamics (PK-PD) modeling, and the adaptive-resistant bacteria in different states were screened and subjected to transcriptomic sequencing. The results showed that the minimum inhibitory concentration of Staphylococcus aureus under the action of cefquinome sulfate was 0.5 μg/mL, the anti-mutation concentration was 1.6 μg/mL, and the mutation selection window range was 0.5~1.6 μg/mL. In the in vitro pharmacokinetic model to simulate different dosing regimens in the animal body, there are certain rules for the emergence of adaptive drug-resistant bacteria: the intensity of bacterial resistance gradually increased with culture time, and the order of emergence was tolerant bacteria (TO) followed by persistent bacteria (PE) and finally resistant bacteria (RE). The sequence reflected the evolution of adaptive drug resistance. Transcriptome Gene Ontology (GO) analysis revealed that differentially expressed genes were involved in cellular respiration, energy derivation by oxidation of organic compounds, and oxidation-reduction processes. The differentially expressed genes identified functioned in the synthesis of cell membranes, cytoplasm, and intracellular parts. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis found that 65 genes were differentially expressed after cefquinome sulfate treatment, of which 35 genes were significantly upregulated and 30 genes were significantly downregulated. Five genes, sdhB, sdhA, pdhA, lpdA, and sucC, may be involved in network regulation. This study revealed the cross-regulation of multiple metabolic pathway networks and the targets of network regulation of S. aureus to produce adaptive drug resistance. The results will provide guidance for clinical drug use in animals infected with S. aureus.

Dataset Information

Pharmacokinetic/Pharmacodynamic Correlation of Cefquinome Against Experimental Catheter-Associated Biofilm Infection Due to Staphylococcus aureus.

Publications

[Hypertension, diabetes mellitus and comorbidity in primary care].

Similar Datasets

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