Increased activity of linezolid in combination with rifampicin in a murine pneumonia model due to MRSA

We investigate the antimicrobial activity of combined colistin and gamithromycin against nine Pasteurella multocida strains by testing in vitro susceptibility. Two high-colistin minimal inhibitory concentration (MIC) isolates (D18 and T5) and one low-colistin MIC isolate (WJ11) were used in time-kill tests and therapeutic effect experiments using a neutropenic murine pneumonia model over 24 h. Pharmacokinetics (PK) in plasma was calculated along with pharmacodynamics (PD) to determine the PK/PD index. Synergy between colistin and gamithromycin was observed using high-colistin MIC isolates, equating to a 128- or 256-fold and 4- or 8-fold reduction in colistin and gamithromycin concentration, respectively. Interestingly, no synergistic effect of the combination on low-colistin MIC isolates was observed. However, regardless of the MIC difference among isolates, each drug tended to reach the same concentration in all isolates subjected to combined treatments, which was verified by the time-kill tests presenting similar rates and extent of killing for isolates D18, T5, and WJ11. The AUC ( 0 – 24 h) /MIC index was used to evaluate the relationship between PK and PD, and the correlation was >0.89. The relevant gamithromycin doses for combined therapy were determined, and the value decreased from 6- to 35-fold compared with monotherapy. Combined colistin and gamithromycin therapy provides a more potent therapeutic regimen than monotherapy against P. multocida strains.

Section: Methodsmentioning

confidence: 99%

Increased Antimicrobial Activity of Colistin in Combination With Gamithromycin Against Pasteurella multocida in a Neutropenic Murine Lung Infection Model

Xie

Zhou

et al. 2020

“…Ten well-characterized MRSA strains were used in this study Zhou et al, 2018). Human clinical MRSA strains (161402, 161400, 161494, and 161813) were kindly provided by the Third Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) that obtained from hospitalized patients with pulmonary infections.…”

Section: Bacterial Strains and Background Informationmentioning

confidence: 99%

“…All strains were identified by MALDI-TOF MS system (Ostergaard et al, 2015). Four MRSA strains of human origin were typed as ST 764 and spa-type t1081, and the remaining six strains were typed as ST 398 and ST 9 Zhou et al, 2018). The ST 764 MRSA has emerged as a novel hybrid variant of the ST 5 HA-MRSA lineage with the characteristics of CA-MRSA in Asia, causing invasive infections (necrotizing fasciitis and bacteremia) in both hospital and community settings (Takano et al, 2013).…”

Section: Bacterial Strains and Background Informationmentioning

confidence: 99%

“…To assess the therapeutic efficacy of linezolid and rifampicin alone and in combination, mice were randomized at 24 h (bacteremia model) and 48 h (SSSI model) post-infection to receive: (i) no therapy (control); (ii) linezolid at 100 mg/kg, orally twice daily; (iii) rifampicin at 5 mg/kg, orally twice daily; or (iv) a combination of linezolid and rifampicin. The linezolid and rifampicin doses were selected to mimic the pharmacokinetic profiles of recommended human clinical doses (i.e., 600 mg and 300 mg, orally twice daily for linezolid and rifampicin, respectively) (Chik et al, 2010;Zhou et al, 2018). Treatments lasted for 3 and 5 days for the bacteremia and SSSI models, respectively.…”

Section: In Vivo Murine Bacteremia and Sssi Modelsmentioning

confidence: 99%

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Linezolid and Rifampicin Combination to Combat cfr-Positive Multidrug-Resistant MRSA in Murine Models of Bacteremia and Skin and Skin Structure Infection

Zhou

Tao

et al. 2020

Self Cite

Linezolid resistance mediated by the cfr gene in MRSA represents a global concern. We investigated relevant phenotype differences between cfr-positive and -negative MRSA that contribute to pathogenesis, and the efficacy of linezolid-based combination therapies in murine models of bacteremia and skin and skin structure infection (SSSI). As a group, cfr-positive MRSA exhibited significantly reduced susceptibilities to the host defense peptides tPMPs, human neutrophil peptide-1 (hNP-1), and cathelicidin LL-37 (P < 0.01). In addition, increased binding to fibronectin (FN) and endothelial cells paralleled robust biofilm formation in cfr-positive vs. -negative MRSA. In vitro phenotypes of cfr-positive MRSA translated into poor outcomes of linezolid monotherapy in vivo in murine bacteremia and SSSI models. Importantly, rifampicin showed synergistic activity as a combinatorial partner with linezolid, and the EC 50 of linezolid decreased 6-fold in the presence of rifampicin. Furthermore, this combination therapy displayed efficacy against cfr-positive MRSA at clinically relevant doses. Altogether, these data suggest that the use of linezolid in combination with rifampicin poses a viable therapeutic alternative for bacteremia and SSSI caused by cfr-positive multidrug resistant MRSA.

“…The mortality rates of S. aureus community-acquired pneumonia was reported to be as high as 60% (David and Daum, 2010). Treatment of these infections is complicated because 40% of S. aureus isolates from patients with pneumonia are methicillin-resistant S. aureus (MRSA; Zhou et al, 2018). The development and spread of MRSA has become a growing challenge.…”

Section: Introductionmentioning

confidence: 99%

An Inhibitory Effect of Dryocrassin ABBA on Staphylococcus aureus vWbp That Protects Mice From Pneumonia

Jin

Xiang

et al. 2019

Von Willebrand factor-binding protein (vWbp), secreted by Staphylococcus aureus (S. aureus), can activate host prothrombin, convert fibrinogen to fibrin clots, induce blood clotting, and contribute to pathophysiology of S. aureus-related diseases, including infective endocarditis, staphylococcal sepsis and pneumonia. Therefore, vWbp is an promising drug target in the treatment of S. aureus-related infections. Here, we report that dryocrassin ABBA (ABBA), a natural compound derived from Dryopteris crassirhizoma, can significantly inhibit the coagulase activity of vWbp in vitro by directly interacting with vWbp without killing the bacteria or inhibiting the expression of the vWbp. Using molecular dynamics simulations, we demonstrate that ABBA binds to the “central cavity” in the elbow of vWbp by interacting with Arg-70, His-71, Ala-72, Gly-73, Tyr-74, Glu-75, Tyr-83, and Gln-87 in vWbp, thus interfering with the binding of vWbp to prothrombin. Furthermore, in vivo studies demonstrated that ABBA can attenuate injury and inflammation of mouse lung tissues caused by S. aureus and increase survival of mice. Together these findings indicate that ABBA is a promising lead drug for the treatment of S. aureus-related infections. This is the first report of potential inhibitor which inhibit the coagulase activity of vWbp by directly interacting with vWbp.