scholarly journals 173. HSV-2 Isolates from Neonates with Different Clinical Outcomes Exhibit Different in Vitro and in Vivo phenotypes

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S215-S216
Author(s):  
Lisa N Akhtar ◽  
Sue Choi ◽  
Cooper Hayes ◽  
Sita Awasthi ◽  
Orkide Koyuncu ◽  
...  
Keyword(s):  
Host Susceptibility ◽  
Cns Infection ◽  
Infection Model ◽  
Invasive Infection ◽  
Intracerebral Injection ◽  
Neonatal Brain ◽  
In Vivo Models ◽  
Cns Disease

Abstract Background Herpes simplex virus (HSV) infection of the neonatal brain causes severe meningoencephalitis and permanent neurologic deficits. However, infants infected with HSV at the time of birth follow different clinical courses. Some infants develop only external infection of the skin, eyes, or mouth (SEM disease), while others develop invasive infection of the central nervous system resulting in encephalitis (CNS disease). The factors that explain this clinical divergence are not well understood. While adults can be predisposed to HSV CNS infection by an innate immune defect, no such host susceptibility has been identified in neonates. Therefore, we have taken a novel approach to determine whether variations in the HSV genome contribute to infection of the neonatal brain. We recently defined the viral genetic diversity among HSV-2 isolates cultured from neonates with a range of clinical presentations. Isolates collected from neonates with CNS disease contained several unique amino acid variations in HSV proteins known to contribute to cell-to-cell spread and neurovirulence in mouse models. Methods To understand the relevance of these findings to neonatal CNS disease, we evaluated CNS disease- and SEM disease-associated neonatal HSV-2 isolates in neurologically-relevant in vitro and in vivo models. Results We found that HSV-2 isolates from neonates with CNS disease, as compared to those collected from neonates with SEM disease, displayed enhanced spread in human neuronally-differentiated SH-SY5Y or LUHMES cells and enhanced retrograde transport in rat neurons cultured in modified Campenot chambers. CNS disease-associated isolates also resulted in increased hind limb paralysis and zosteriform disease in a mouse flank scratch infection model, and increased death in a mouse direct intracerebral injection model of encephalitis. Notably, CNS disease and SEM disease-associated isolates resulted in equivalent outcomes following mouse intraperitoneal injection, suggesting similar systemic virulence. Conclusion These data suggest that virus-mediated differences in neuronal spread and transport may contribute to neurovirulence in neonatal HSV disease. Disclosures All Authors: No reported disclosures

Challenges with Wound Infection Models in Drug Development

2020 ◽  
Vol 21 (13) ◽  
pp. 1301-1312 ◽  
Author(s):  
Sandeep K. Shukla ◽  
Ajay K. Sharma ◽  
Vanya Gupta ◽  
Aman Kalonia ◽  
Priyanka Shaw
Keyword(s):  
Wound Healing ◽  
Wound Infection ◽  
Chronic Wound ◽  
Wound Care ◽  
Infection Model ◽  
In Vivo Models ◽  
Infection Models

: Wound research is an evolving science trying to unfold the complex untold mechanisms behind the wound healing cascade. In particular, interest is growing regarding the role of microorganisms in both acute and chronic wound healing. Microbial burden plays an important role in the persistence of chronic wounds, ultimately resulting in delayed wound healing. It is therefore important for clinicians to understand the evolution of infection science and its various etiologies. Therefore, to understand the role of bacterial biofilm in chronic wound pathogenesis, various in vitro and in vivo models are required to investigate biofilms in wound-like settings. Infection models should be refined comprising an important signet of biofilms. These models are eminent for translational research to obtain data for designing an improved wound care formulation. However, all the existing models possess limitations and do not fit properly in the model frame for developing wound care agents. Among various impediments, one of the major drawbacks of such models is that the wound they possess does not mimic the wound a human develops. Therefore, a novel wound infection model is required which can imitate the human wounds. : This review article mainly discusses various in vitro and in vivo models showing microbial colonization, their advantages and challenges. Apart from these models, there are also present ex vivo wound infection models, but this review mainly focused on various in vitro and in vivo models available for studying wound infection in controlled conditions. This information might be useful in designing an ideal wound infection model for developing an effective wound healing formulation.

scholarly journals Activities of Clindamycin, Daptomycin, Doxycycline, Linezolid, Trimethoprim-Sulfamethoxazole, and Vancomycin against Community-Associated Methicillin-Resistant Staphylococcus aureus with Inducible Clindamycin Resistance in Murine Thigh Infection and In Vitro Pharmacodynamic Models

2008 ◽  
Vol 52 (6) ◽  
pp. 2156-2162 ◽  
Author(s):  
Kerry L. LaPlante ◽  
Steven N. Leonard ◽  
David R. Andes ◽  
William A. Craig ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Inoculum Size ◽  
In Vivo Model ◽  
Infection Model ◽  
Time Curve ◽  
In Vivo Models ◽  
Methicillin Resistant ◽  
Inducible Clindamycin Resistance

ABSTRACT Controversy exists about the most effective treatment options for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and about the ability of these strains to develop inducible resistance to clindamycin during therapy. Using both in vitro pharmacodynamic and murine thigh infection models, we evaluated and compared several antimicrobial compounds against CA-MRSA. Strains with inducible macrolide lincosamide-streptogramin type B (iMLSB) resistance and strains in which resistance was noninducible were evaluated. Two levels of inocula (105 and 107) were evaluated for clindamycin activity in the in vivo model. In both models, the antimicrobial evaluation was performed in triplicate, and bacterial quantification occurred over 72 h, with drug doses that were designed to simulate the free drug area-under-the-concentration-time curve values (fAUCs) obtained from human samples. When the activity of clindamycin against the iMLSB strains was evaluated, constitutive resistance was noted at 24 h (MIC of >256), and failure was noted at an inoculum of ≥106 in the in vivo models. However, at a low inoculum (105) in the murine thigh-infection model, clindamycin demonstrated modest activity, reducing the CFU/thigh count for clindamycin resistance-inducible strains at 72 h (0.45 to 1.3 logs). Overall, administration of daptomycin followed by vancomycin demonstrated the most significant kill against all strains in both models. Against the clindamycin noninducible strain, clindamycin and doxycycline demonstrated significant kill. Doxycycline, linezolid, and trimethoprim-sulfamethoxazide (not run in the murine model) demonstrated bacteriostatic activity against clindamycin resistance-inducible isolates. This study demonstrates that clindamycin's activity against the iMLSB strains tested is partially impacted by inoculum size. At present, there are several alternatives that appear promising for treating clindamycin resistance-inducible strains of CA-MRSA.

scholarly journals Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models

2005 ◽  
Vol 49 (6) ◽  
pp. 2294-2301 ◽  
Author(s):  
Anne J. Lenaerts ◽  
Veronica Gruppo ◽  
Karen S. Marietta ◽  
Christine M. Johnson ◽  
Diane K. Driscoll ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Significant Activity ◽  
Dependent Manner ◽  
In Vivo Models ◽  
Long Term Treatment

ABSTRACT This study extends earlier reports regarding the in vitro and in vivo efficacies of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis. PA-824 was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates (MIC < 1 μg/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 μg/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis.

scholarly journals 787. The Addition of Avibactam Augments the Activity of Piperacillin Against Mycobacterium abscessus in vitro, and Is Effective in Treating M. abscessus Infection in a Galleria mellonella in vivo Model

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S281-S282
Author(s):  
Michal Meir ◽  
Daniel Barkan
Keyword(s):  
Galleria Mellonella ◽  
Inhibitory Effect ◽  
Mycobacterium Abscessus ◽  
In Vivo Model ◽  
Great Promise ◽  
Infection Model ◽  
In Vivo Models ◽  
Antimicrobial Treatments

Abstract Background Mycobacterium abscessus is an emerging multi-drug-resistant pathogen, harboring the β-lactamse BlaMAB. Avibactam is a non-β-lactam, β-lactamase inhibitor shown to inhibit BlaMAB and improve the efficacy of ampicillin for M. abscessus infections in in vitro and in vivo models. Whether the addition of avibactam to piperacillin enables use of the latter against M. abscessus is unknown Methods We used a recombinant, luminescent M. abscessus to measure the reduction of MIC to meropenem, ampicillin, and piperacillin induced by avibactam. We then used our previously established G. mellonella infection model (Figure 1)1 to evaluate the effect of antimicrobial treatments in vivo. Results Addition of avibactam (4 µg/mL) consistently decreased MIC of ampicillin and piperacillin by 16 and 16–32-fold, respectively, but as expected had no significant effect on meropenem MIC (Figure 2). We inoculated 60 G. mellonella larvae with luminescent M. abscessus on day 0, and treated larvae with meropenem, piperacillin, avibactam alone, or piperacillin combined with avibactam on days 2 and 3. Using IVIS® imaging, we measured infection progression in live infected larvae on day 4. Larvae treated with meropenem and piperacillin–avibactam had significantly lower infection burden compared with untreated controls (P &lt; 0.0001 and P = 0.004, respectively). Piperacillin and avibactam alone had no significant inhibitory effect (Figure 3). Conclusion Our findings suggest that the piperacillin–avibactam combination is effective against M. abscessus infections. This novel combination may hold a great promise for patients with cystic fibrosis suffering from M. abscessus, Pseudomonas aeruginosa, and/or Staphylococcus aureus co-infections. The G. mellonella infection model may be used in future studies to assess the efficacy of various antimicrobials and antimicrobial combinations on M. abscessus, P. aeruginosa, and S. aureus co-infections. Reference 1. Meir M et al. Antimicrob Agents Chemother. 2018. Disclosures All authors: No reported disclosures.

scholarly journals Evaluation of the Efficacy of Doxycycline, Ciprofloxacin, Levofloxacin and Co-trimoxazole using in vitro and in vivo models of Q fever.

2021 ◽  
Author(s):  
K.A. Clay ◽  
M.G. Hartley ◽  
S. Armstrong ◽  
K.R. Bewley ◽  
K Godwin ◽  
...  
Keyword(s):  
Q Fever ◽  
Clinical Signs ◽  
Infection Model ◽  
Cell Infection ◽  
In Vivo Models ◽  
Recommended Treatment ◽  
Solid Media ◽  
Aerosol Infection

Q fever, caused by the intracellular pathogen Coxiella burnetii , is traditionally treated using tetracycline antibiotics, such as doxycycline. Doxycycline is often poorly tolerated and antibiotic resistant strains have been isolated. In this study, we have evaluated a panel of antibiotics (doxycycline, ciprofloxacin, levofloxacin, and, co-trimoxazole) against C. burnetii using in vitro methods (determination of MIC using liquid and solid media; efficacy assessment in a THP cell infection model) and in vivo methods (wax moth larvae and mouse models of infection). In addition, the schedule for antibiotic treatment has been evaluated, with therapy initiated at 24 h pre or post challenge. Both doxycycline and levofloxacin limited overt clinical signs during treatment in the AJ mouse model of aerosol infection, but further studies are required to investigate the possibility of disease relapse or incomplete bacterial clearance after the antibiotics are stopped. Levofloxacin was well tolerated and therefore warrants further investigation as an alternative to the current recommended treatment with doxycycline.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

Current Challenges in the Development of Vaccines and Drugs Against Emerging Vector-borne Diseases

2019 ◽  
Vol 26 (16) ◽  
pp. 2974-2986 ◽  
Author(s):  
Kwang-sun Kim
Keyword(s):  
New Host ◽  
In Vivo Models ◽  
Vector Borne Diseases ◽  
Novel Drugs ◽  
Huge Impact ◽  
Tick Borne Disease ◽  
Vector Borne ◽  
Living Organisms

Vectors are living organisms that transmit infectious diseases from an infected animal to humans or another animal. Biological vectors such as mosquitoes, ticks, and sand flies carry pathogens that multiply within their bodies prior to delivery to a new host. The increased prevalence of Vector-Borne Diseases (VBDs) such as Aedes-borne dengue, Chikungunya (CHIKV), Zika (ZIKV), malaria, Tick-Borne Disease (TBD), and scrub typhus has a huge impact on the health of both humans and livestock worldwide. In particular, zoonotic diseases transmitted by mosquitoes and ticks place a considerable burden on public health. Vaccines, drugs, and vector control methods have been developed to prevent and treat VBDs and have prevented millions of deaths. However, development of such strategies is falling behind the rapid emergence of VBDs. Therefore, a comprehensive approach to fighting VBDs must be considered immediately. In this review, I focus on the challenges posed by emerging outbreaks of VBDs and discuss available drugs and vaccines designed to overcome this burden. Research into promising drugs needs to be upgraded and fast-tracked, and novel drugs or vaccines being tested in in vitro and in vivo models need to be moved into human clinical trials. Active preventive tactics, as well as new and upgraded diagnostics, surveillance, treatments, and vaccination strategies, need to be monitored constantly if we are to manage VBDs of medical importance.

Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules

2020 ◽  
Vol 26 (35) ◽  
pp. 4362-4372
Author(s):  
John H. Miller ◽  
Viswanath Das
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
In Vivo Models ◽  
Synthetic Compounds ◽  
Stabilizing Agents ◽  
Animal Models Of Disease ◽  
Model Studies ◽  
Models Of Disease

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick’s disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

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