Efficacy evaluation of iclaprim in a neutropenic rat lung infection model with methicillin-resistant Staphylococcus aureus entrapped in alginate microspheres

In this study, a lung infection model of pneumonia in sheep ( n = 12) that included smoke inhalation injury followed by methicillin-resistant Staphylococcus aureus placement into the lungs was used to investigate hemodynamic and pulmonary dysfunctions during the course of sepsis progression. To assess the variability in disease progression, animals were retrospectively divided into survivor ( n = 6) and nonsurvivor ( n = 6) groups, and a range of physiological indexes reflecting hemodynamic and pulmonary function were estimated and compared to evaluate variability in dynamics underlying sepsis development. Blood pressure and heart rate variability analyses were performed to assess whether they discriminated between the survivor and nonsurvivor groups early on and after intervention. Results showed hemodynamic deterioration in both survivor and nonsurvivor animals during sepsis along with a severe oxygenation disruption (decreased peripheral oxygen saturation) in nonsurvivors separating them from survivor animals of this model. Variability analysis of beat-to-beat heart rate and blood pressure reflected physiologic deterioration during infection for all animals, but these analyses did not discriminate the nonsurvivor animals from survivor animals. NEW & NOTEWORTHY Variable pulmonary response to injury results in varying outcomes in a previously reported animal model of lung injury and methicillin-resistant Staphylococcus aureus-induced sepsis. Heart rate and blood pressure variability analyses were investigated to track the varying levels of physiologic deterioration but did not discriminate early nonsurvivors from survivors.

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204. Antagonistic Effect of Colistin on Vancomycin Activity Against Methicillin-Resistant Staphylococcus aureus in in vitro and in vivo Studies

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.279 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S120-S121

Author(s):

Sungim Choi ◽

Taeeun Kim ◽

Seongman Bae ◽

Eunmi Yang ◽

Su-Jin Park ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistant Staphylococcus Aureus ◽

Antagonistic Effect ◽

In Vivo Studies ◽

Infection Model ◽

Methicillin Resistant ◽

Checkerboard Assay ◽

Mrsa Strains ◽

Time Kill

Abstract Background There is a concern that the vancomycin MIC of methicillin-resistant Staphylococcus aureus (MRSA) could be increased by concomitant colistin administered against multidrug-resistant gram-negative pathogen. Methods We confirmed the molecular genotypes of MRSA blood isolates collected in a tertiary hospital in Seoul, South Korea, and selected representative strains from the community-associated MRSA strains (CA-MRSA, ST72-SCCmec IV) and hospital-acquired MRSA strains (HA-MRSA, ST5-SCCmec II). USA CA-MRSA (USA300, ST8-SCCmec IV) and MRSA standard strain (ATCC 43300, ST39-SCCmec II) were also used for comparison with representative. We identified changes of the vancomycin MIC in MRSA by colistin exposure in a checkerboard assay and performed a time-kill assay to evaluate the combined effect of vancomycin and colistin on MRSA. In addition, we administered vancomycin, colistin, and combination of two antibiotics, respectively, to a neutropenic murine thigh infection model to evaluate the in vivo antagonistic effect of colistin on vancomycin treatment. Results In the checkerboard assay, all 4 MRSA strains showed a tendency for the vancomycin MIC to increase along with increasing concentrations of colistin. However, the time-kill assay showed the antagonism of vancomycin and colistin only against ST5-MRSA, when vancomycin concentration was 2 times the vancomycin MIC (Figure 1). No antagonism was observed in other strains. In the murine thigh infection model of ST5-MRSA, vancomycin monotherapy showed a significant log CFU reduction compared with a combination of vancomycin and colistin at 24 hours, demonstrating the antagonistic effect of vancomycin and colistin combination (Figure 2). Conclusion This study showed that exposure of colistin to certain MRSA strains may reduce the susceptibility to vancomycin. Combination therapy with vancomycin and colistin for MDR pathogens infections might result in treatment failure for concurrent MRSA infection. Disclosures All authors: No reported disclosures.

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Enhancement in Site-Specific Delivery of Carvacrol against Methicillin Resistant Staphylococcus aureus Induced Skin Infections Using Enzyme Responsive Nanoparticles: A Proof of Concept Study

Pharmaceutics ◽

10.3390/pharmaceutics11110606 ◽

2019 ◽

Vol 11 (11) ◽

pp. 606 ◽

Cited By ~ 8

Author(s):

Maria Mir ◽

Naveed Ahmed ◽

Andi Dian Permana ◽

Aoife Maria Rodgers ◽

Ryan F. Donnelly ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistant Staphylococcus Aureus ◽

Ex Vivo ◽

Infection Model ◽

Skin Infections ◽

Site Specific ◽

Methicillin Resistant ◽

Hydrogel Matrix ◽

Skin Retention

Methicillin resistant Staphylococcus aureus (MRSA) induced skin infections have become a challenging problem due to the escalating antibiotic resistance. Carvacrol (CAR) has been reported to be effective against MRSA. However, due to its characteristics, CAR exhibits low skin retention. In this study, CAR was formulated into site-specific nanoparticle (NPs) delivery system using poly(ε-caprolactone) (PCL), following incorporation into a hydrogel matrix to facilitate dermal delivery. The release study exhibited significantly higher release of CAR from PCL NPs in the presence of bacterial lipase, highlighting its potential for differential delivery. Moreover, encapsulation of CAR in PCL NPs resulted in a two-fold increase in its anti-MRSA activity. Dermatokinetic studies revealed that the NPs loaded hydrogel was able to enhance skin retention of CAR after 24 h (83.29 ± 3.15%), compared to free CAR-loaded hydrogel (0.85 ± 0.14%). Importantly, this novel approach exhibited effective antimicrobial activity in an ex-vivo skin infection model. Hence, these findings have proven the concept that the loading of CAR into a responsive NPs system can lead to sustained antimicrobial effect at the desired site, and may provide a novel effective approach for treatment of MRSA induced skin infections. However, further studies must be conducted to investigate in-vivo efficacy of the developed system in an appropriate infection model.

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Inflammatory and Antimicrobial Responses to Methicillin-Resistant Staphylococcus aureus in an In Vitro Wound Infection Model

PLoS ONE ◽

10.1371/journal.pone.0082800 ◽

2013 ◽

Vol 8 (12) ◽

pp. e82800 ◽

Cited By ~ 37

Author(s):

Elisabeth M. Haisma ◽

Marion H. Rietveld ◽

Anna de Breij ◽

Jaap T. van Dissel ◽

Abdoelwaheb El Ghalbzouri ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Wound Infection ◽

Methicillin Resistant Staphylococcus Aureus ◽

Infection Model ◽

Methicillin Resistant

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Telavancin Is Active against Experimental Aortic Valve Endocarditis Caused by Daptomycin- and Methicillin-Resistant Staphylococcus aureus Strains

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01877-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 5

Author(s):

Wessam Abdelhady ◽

Arnold S. Bayer ◽

Rachelle Gonzales ◽

Liang Li ◽

Yan Q. Xiong

Keyword(s):

Staphylococcus Aureus ◽

Aortic Valve ◽

Untreated Control ◽

Methicillin Resistant Staphylococcus Aureus ◽

Infection Model ◽

Methicillin Resistant ◽

Content Type ◽

Mrsa Strains ◽

Culture Negative

ABSTRACT We compared the efficacy of telavancin (TLV) and daptomycin (DAP) in an experimental rabbit endocarditis model caused by two clinically derived daptomycin-resistant (DAPr) methicillin-resistant Staphylococcus aureus (MRSA) strains. TLV treatment significantly reduced MRSA densities in all target tissues and increased the percentage of these organs rendered culture negative compared to those with the untreated control or DAP-treated animals. These results demonstrate that TLV has potent in vivo efficacy against DAPr MRSA isolates in this invasive endovascular infection model.

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Therapeutic efficacy of BO-3482, a novel dithiocarbamate carbapenem, in mice infected with methicillin-resistant Staphylococcus aureus.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.10.2278 ◽

1997 ◽

Vol 41 (10) ◽

pp. 2278-2281 ◽

Cited By ~ 25

Author(s):

R Nagano ◽

K Shibata ◽

T Naito ◽

A Fuse ◽

K Asano ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Therapeutic Efficacy ◽

Methicillin Resistant Staphylococcus Aureus ◽

Infection Model ◽

Dependent Manner ◽

Methicillin Resistant ◽

Mrsa Strains ◽

Systemic Infections

The in vivo activity of BO-3482, which has a dithiocarbamate chain at the C-2 position of 1beta-methyl-carbapenem, was compared with those of vancomycin and imipenem in murine models of septicemia and thigh infection with methicillin-resistant Staphylococcus aureus (MRSA). Because BO-3482 was more susceptible than imipenem to renal dehydropeptidase I in a kinetic study of hydrolysis by this renal enzyme, the therapeutic efficacy of BO-3482 was determined during coadministration with cilastatin. In the septicemia models, which involved two homogeneous MRSA strains and one heterogeneous MRSA strain, the 50% effective doses were, respectively, 4.80, 6.06, and 0.46 mg/kg of body weight for BO-3482; 5.56, 2.15, and 1.79 mg/kg for vancomycin; and >200, >200, and 15.9 mg/kg for imipenem. BO-3482 was also as effective as vancomycin in an MRSA septicemia model with mice with cyclophosphamide-induced immunosuppression. In the thigh infection model with a homogeneous MRSA strain, the bacterial counts in tissues treated with BO-3482-cilastatin were significantly reduced in a dose-dependent manner compared with the counts in those treated with vancomycin and imipenem-cilastatin (P < 0.001). These results indicate that BO-3482-cilastatin is as effective as vancomycin in murine systemic infections and is more bactericidal than vancomycin in local-tissue infections. The potent in vivo activity of BO-3482-cilastatin against such MRSA infections can be ascribed to the good in vitro anti-MRSA activity and improved pharmacokinetics in mice when BO-3482 is combined with cilastatin and to the bactericidal nature of the carbapenem.

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