Combined treatment with atorvastatin and imipenem improves survival and vascular functions in mouse model of sepsis

Choudhury, Soumen; Kandasamy, Kannan; Addison, M. Pule; Darzi, Sazad A.; Singh, Vishal; Singh, Thakur Uttam; Thangamalai, Ramasamy; Dash, Jeevan Ranjan; Parida, Subhashree; Debroy, Biplab; Paul, Avishek; Mishra, Santosh Kumar

doi:10.1016/j.vph.2015.03.012

Cited by 18 publications

(15 citation statements)

References 47 publications

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“…Our results showed that combined treatment with atorvastatin and imipenem significantly inhibited mortality in mice infected with K. pneumoniae and improved survival compared to treatment with drugs alone. Consistent with our data, Choudhury et al reported that combined treatment with atorvastatin and imipenem dampened sepsis-induced acute lung injury (63). The results observed in this study clarify that combined therapy with atorvastatin and imipenem improves the survival of the host by a mechanism associated with the antiinflammatory effect of the statin on neutrophil accumulation and modulation of cytokine production and the reduction of bacterial load by administration of the antibiotic.…”

Section: Discussionsupporting

confidence: 92%

Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice

Paula

Santos

Arifa

et al. 2018

Antimicrob Agents Chemother

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The clinical pathogen is a relevant cause of nosocomial infections, and resistance to current treatment with carbapenem antibiotics is becoming a significant problem. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) used for controlling plasma cholesterol levels. There is clinical evidence showing other effects of statins, including decrease of lung inflammation. In the current study, we show that pretreatment with atorvastatin markedly attenuated lung injury, which was correlated with a reduction in the cellular influx into the alveolar space and lungs and downmodulation of the production of proinflammatory mediators in the initial phase of infection in C57BL/6 mice with However, atorvastatin did not alter the number of bacteria in the lungs and blood of infected mice, despite decreasing local inflammatory response. Interestingly, mice that received combined treatment with atorvastatin and imipenem displayed better survival than mice treated with vehicle, atorvastatin, or imipenem alone. These findings suggest that atorvastatin could be an adjuvant in host-directed therapies for multidrug-resistant , based on its powerful pleiotropic immunomodulatory effects. Together with antimicrobial approaches, combination therapy with anti-inflammatory compounds could improve the efficiency of therapy during acute lung infections.

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Section: Discussionsupporting

confidence: 92%

Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice

Paula

Santos

Arifa

et al. 2018

Antimicrob Agents Chemother

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“…None of the isolates was found to be sensitive to atorvastatin when used as a sole agent. The finding that atorvastatin did not exhibit antibacterial effect on its own is in stark contrast with many other previous studies [14], [15] but this finding is in complete agreement with the study conducted by Manalo et al (2017) [16], which also reported that atorvastatin did not display any antibacterial activity, when used as a sole agent.…”

Section: Discussionsupporting

confidence: 89%

In-vitro synergistic antibacterial effect of atorvastatin and ampicillin against resistant Staphylococcus spp and E.coli isolated from bovine mastitis

Sankar

Thangamalai

Sriram

et al. 2019

Preprint

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The colossal rise in antimicrobial resistance has led to treatment failures and so mastitis has become cumbersome to treat. The objective of this study was to evaluate the antibacterial effect of non-antibiotic drug, atorvastatin in combination with antimicrobial, ampicillin against two commonly isolated bacterial species Staphylococcus spp and E. coli from bovine mastitis. Milk samples were collected from mastitis cows, visiting Veterinary Clinical Complex. Bacterial isolation was performed using Eosin Methylene Blue (EMB) agar and Mannitol Salt Agar (MSA), followed by characterization and identification by biochemical tests and gram staining. Genotypic confirmation was done by Polymerase Chain Reaction (PCR) with subsequent screening for resistant genes-mec A, bla TEM . Antibiotic Sensitivity Test (ABST) of the isolates against 12 different antimicrobials, atorvastatin only, and combination of atorvastatin with ampicillin were performed using Kirby-Bauer disc diffusion method. Minimum Inhibitory Concentration (MIC) of ampicillin alone and ampicillin in combination with atorvastatin were determined by modified microdilution method.Staphylococcus spp (77.5%) and E.coli (35%) were the two major pathogens isolated in the current study and multi-drug resistance was observed. Among the antimicrobials, the ampicillin showed 100% resistance against Staphylococcus spp and 85.71% resistance against E. coli. Atorvastatin did not display antibacterial effect as a sole agent but displayed synergistic antibacterial activity with ampicillin. There was an average increase in Minimum Inhibitory Concentration of ampicillin for E.coli and Staphylococcus spp isolates and atorvastatin decreased the Minimum Inhibitory Concentration of ampicillin in combination.The ampicillin shows more resistance against both Staphylococcus spp and E.coli, while atorvastatin improves the effect of ampicillin in-vitro. So, atorvastatin may be combined with ampicillin for the treatment of Gram-positive and Gram-negative infections. However, further studies are required to ascertain the exact mechanism of action of atorvastatin with respect to their antibacterial effect for them to be redeployed as an antimicrobial drug in the future.

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“…More importantly, the effects of antibiotics and other antimicrobials on brain function and sepsis-associated neurological impairment are not well studied. [168][169][170][171][172][173] Thus, a complete knowledge of drug mechanisms in the CNS is essential for identifying an appropriate drug regimen and therapeutic approach to treat the neurological impairment associated with sepsis. 174,175 The most common drug classes used to treat sepsis are shown in Table 3.…”

Section: Pharmaceutical Interventions In Sepsis Antimicrobial Delivermentioning

confidence: 99%

Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

Nwafor

Brichacek

Mohammad

et al. 2019

J Cent Nerv Syst Dis

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Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors.

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Combined treatment with atorvastatin and imipenem improves survival and vascular functions in mouse model of sepsis

Cited by 18 publications

References 47 publications

Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice

Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice

In-vitro synergistic antibacterial effect of atorvastatin and ampicillin against resistant Staphylococcus spp and E.coli isolated from bovine mastitis

Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

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