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New antibiotic effective against MRSA

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

A New Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one, from University Of Notre Dame

ANTHONYMELVINCRASTO

A New Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one, from University Of Notre Dame

University Of Notre Dame   Mayland Chang, Shahriar Mobashery, Renee BOULEY  INVENTORS

(E)-3-(3-Carboxyphenyl)-2-(4-ethynylstyryl)quinazolin-4(3H)-one

(E)-3-(2-(4-Cyanostyryl)-4-Oxoquinazolin-3(4h)-Yl)benzoic Acid;

1624273-22-8  CAS    NA SALT 1624273-21-7 CAS

The emergence of resistance to antibiotics over the past few decades has created a state of crisis in the treatment of bacterial infections.Over the years, β-lactams were the antibiotics of choice for treatment of S. aureus infections. However, these agents faced obsolescence with the emergence of methicillin-resistant S. aureus (MRSA). Presently, vancomycin, daptomycin, linezolid, or ceftaroline are used for treatment of MRSA infections, although only linezolid can be dosed orally. Resistance to all four has emerged. Thus, new anti-MRSA antibiotics are sought, especially agents that are orally bioavailable.  a new antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)one, with potent activity against S. aureus, including MRSA. We document that quinazolinones of our design are inhibitors of cell-wall biosynthesis in S. aureusand do so by binding to dd-transpeptidases involved in cross-linking of the cell wall.  quinazolinones possess activity in vivo and are orally bioavailable. This antibiotic holds promise in treating difficult infections by MRSA.

 

 

Discovery of Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one

Journal of the American Chemical Society (2015), 137(5), 1738-1741.

http://pubs.acs.org/doi/abs/10.1021/jacs.5b00056

Renee Bouley, Malika Kumarasiri, Zhihong Peng, Lisandro H. Otero, Wei Song, Mark A. Suckow§, Valerie A. Schroeder§, William R. Wolter§, Elena Lastochkin, Nuno T. Antunes, Hualiang Pi, Sergei Vakulenko, Juan A. Hermoso, Mayland Chang*, and Shahriar Mobashery*

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
Department of Crystallography and Structural Biology, Instituto de Química-Física “Rocasolano”, Consejo Superior de Investigaciones Científicas, Madrid,Spain
§ Freimann Life Sciences Center and Department of Biological Sciences,University of Notre Dame, Notre Dame, Indiana 46556, United States
J. Am. Chem. Soc., 2015, 137 (5), pp 1738–1741     http://dx.doi.org:/10.1021/jacs.5b00056    Publication Date (Web): January 28, 2015

Abstract Image

In the face of the clinical challenge posed by resistant bacteria, the present needs for novel classes of antibiotics are genuine. In silico docking and screening, followed by chemical synthesis of a library of quinazolinones, led to the discovery of (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)one (compound 2) as an antibiotic effective in vivo against methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic impairs cell-wall biosynthesis as documented by functional assays, showing binding of 2 to penicillin-binding protein (PBP) 2a. We document that the antibiotic also inhibits PBP1 of S. aureus, indicating a broad targeting of structurally similar PBPs by this antibiotic. This class of antibiotics holds promise in fighting MRSA infections.

PATENT

WO 2014138302

http://www.google.com/patents/WO2014138302A1?cl=en

Staphylococcus aureus is a common bacterium found in moist areas of the body and skin. S. aureus can also grow as a biofilm, representing the leading cause of infection after implantation of medical devices. Approximately 29% (78.9 million) of the US population is colonized in the nose with S. aureus, of which 1.5% (4.1 million) is methicillin-resistant S. aureus (MRSA). In 2005, 478,000 people in the US were hospitalized with a S. aureus infection, of these 278,000 were MRSA infections, resulting in 19,000 deaths. MRSA infections have been increasing from 2% of S. aureus infections in intensive care units in 1974 to 64% in 2004, although more recent data report stabilization. Approximately 14 million outpatient visits occur every year in the US for suspected S. aureus skin and soft tissue infections. About 76% of these infections are caused by S. aureus, of which 78% are due to MRSA, for an overall rate of 59%. Spread of MRSA is not limited to nosocomial (hospital-acquired) infections, as they are also found in community-acquired infections. Over the years, β-lactams were antibiotics of choice in treatment of S. aureus infections. However, these agents faced obsolescence with the emergence of

MRSA. Presently, vancomycin, daptomycin or linezolid are agents for treatment of MRSA infections, although only linezolid can be dosed orally. Resistance to all three has emerged. Thus, new anti-MRSA therapeutic strategies are needed, especially agents that are orally bioavailable.

Clinical resistance to β-lactam antibiotics by MRSA has its basis predominantly in acquisition of the mecA gene, which encodes penicillin-binding protein 2a (PBP2a). PBP2a, a cell-wall DD- transpeptidase, is refractory to inhibition by essentially all commercially available β-lactams (ceftaroline is an exception), antibiotics that irreversibly acylate the active-site serine of typical PBPs. PBPs catalyze biosynthesis of the bacterial cell wall, which is essential for the survival of the bacterium. Accordingly, new ηοη-β-lactam antibiotics that inhibit PBP2a are needed to combat drug-resistant strains of bacteria. SUMMARY

Staphylococcus aureus is responsible for a number of human diseases, including skin and soft tissue infections. Annually, 292,000 hospitalizations in the US are due to S. aureus infections, of which 126,000 are related to methicillin-resistant Staphylococcus aureus (MRSA), resulting in 19,000 deaths. A novel structural class of antibiotics has been discovered and is described herein. A lead compound in this class shows high in vitro potency against Gram-positive bacteria comparable to those of linezolid and superior to vancomycin (both considered gold standards) and shows excellent in vivo activity in mouse models of MRSA infection.

The invention thus provides a novel class of ηοη-β-lactam antibiotics, the quinazolinones, which inhibit PBP2a by an unprecedented mechanism of targeting both its allosteric and active sites. This inhibition leads to the impairment of the formation of cell wall in living bacteria. The quinazolinones described herein are effective as anti-MRSA agents both in vitro and in vivo. Furthermore, they exhibit activity against other Gram-positive bacteria. The quinazolinones have anti-MRSA activity by themselves. However, these compounds synergize with β-lactam antibiotics. The use of a combination of a quinazolinone with a β-lactam antibiotic can revive the clinical use of β-lactam antibacterial therapy in treatment of MRSA infections. The invention provides a new class of quinazolinone antibiotics, optionally in combination with other antibacterial agents, for the therapeutic treatment of methicillin- resistant Staphylococcus aureus and other bacteria.

The quinazolinone compounds described herein can be prepared using standard synthetic techniques known to those of skill in the art. Examples of such techniques are described by Khajavi et al. (J. Chem. Res. (S), 1997, 286-287) and Mosley et al. (J. Med. Chem. 2010, 53, 5476-5490). A general preparatory scheme for preparing the compounds described herein, for example, compounds of Formula

Figure imgf000030_0001

 

 

http://pubs.acs.org/doi/full/10.1021/acs.jmedchem.6b00372

Structure–Activity Relationship for the 4(3H)-Quinazolinone Antibacterials

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
Freimann Life Sciences Center and Department of Biological Sciences,University of Notre Dame, Notre Dame, Indiana 46556, United States
J. Med. Chem., Article ASAP   http://dx.doi.org:/10.1021/acs.jmedchem.6b00372Publication Date (Web): April 18, 2016
ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes
Abstract Image
We recently reported on the discovery of a novel antibacterial (2) with a 4(3H)-quinazolinone core. This discovery was made by in silico screening of 1.2 million compounds for binding to a penicillin-binding protein and the subsequent demonstration of antibacterial activity againstStaphylococcus aureus. The first structure–activity relationship for this antibacterial scaffold is explored in this report with evaluation of 77 variants of the structural class. Eleven promising compounds were further evaluated for in vitro toxicity, pharmacokinetics, and efficacy in a mouse peritonitis model of infection, which led to the discovery of compound 27. This new quinazolinone has potent activity against methicillin-resistant (MRSA) strains, low clearance, oral bioavailability and shows efficacy in a mouse neutropenic thigh infection model.

Renee Bouley, a third year graduate student in the Department of Chemistry and Biochemistry, has been selected to receive a prestigious American Chemical Society (ACS) Division of Medicinal Chemistry Predoctoral Fellowship.  Bouley is one of only four recipients chosen for the 2013-2014 cycle.

This award supports doctoral candidates working in the area of medicinal chemistry who have demonstrated superior achievements as graduate students and who show potential for future work as independent investigators. These fellowships have been awarded annually since 1991 and include one year stipend support and an invitation to present the fellow’s research results at a special awards session at the ACS National Meeting.

Bouley’s work, conducted under the advisement of Shahriar Mobashery, Navari Family Professor in Life Sciences, and Mayland Chang, Research Professor and Director of the Chemistry-Biochemistry-Biology Interface (CBBI) Program, centers around the discovery of a new class of antibiotics that are selective against staphylococcal species of bacteria, including hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA).  She has already identified a class of compounds that has in vitro activity against bacteria and demonstrated efficacy in mice. Bouley spent three months in 2012 in the laboratory of Prof. Juan Hermoso at Consejo Superior de Investigaciones Cientificas in Madrid, Spain, where she solved the crystal structure of the lead compound in complex with its target protein. Her studies have shown an unprecedented mechanism of action that opens opportunities for clinical resurrection of β-lactam antibiotics in combination with the new antibiotics. Bouley’s work during her fellowship tenure will explore structural analogs of these compounds with the goal of optimizing their potency in vivo and improving their drug-like properties.

Bouley is already the recipient of a National Institutes of Health Ruth L. Kirschstein National Research Service Award – CBBI (Chemistry-Biochemistry-Biology Interface) Program, a CBBI Research Internship Award, and an American Heart Association Predoctoral Fellowship (declined)………..https://www.linkedin.com/in/renee-bouley-43243215

 

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newly developed oxazolidinone antibiotics

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

New Antibacterial oxazolidinones in pipeline by Wockhardt

by DR ANTHONY MELVIN CRASTO Ph.D

 

WCK ?

(5S)-N-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

MF C19 H25 F2 N3 O5, MW 413.42

Acetamide, N-​[[(5S)​-​3-​[3,​5-​difluoro-​4-​[4-​hydroxy-​4-​(methoxymethyl)​-​1-​piperidinyl]​phenyl]​-​2-​oxo-​5-​oxazolidinyl]​methyl]​-

CAS 957796-51-9

Antibacterial oxazolidinones

THIS MAY BE WCK 4086?????

PATENT

WO 2015173664, US8217058, WO 2012059823, 

 

Oxazolidinone represent a novel chemical class of synthetic antimicrobial agents.Linezolid represents the first member of this class to be used clinically. Oxazolidinones display activity against important Gram-positive human and veterinary pathogens including Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin Resistant Enterococci (VRE) and β-lactam Resistant Streptococcus pneumoniae (PRSP). The oxazolidinones also show activity against Gram-negative aerobic bacteria, Gram-positive and Gram-negative anaerobes. (Diekema D J et al., Lancet 2001 ; 358: 1975-82).

Various oxazolidinones and their methods of preparation are disclosed in the literature. International Publication No. WO 1995/25106 discloses substituted piperidino phenyloxazolidinones and International Publication No. WO 1996/13502 discloses phenyloxazolidinones having a multisubstituted azetidinyl or pyrrolidinyl moiety. US Patent Publication No. 2004/0063954, International Publication Nos. WO 2004/007489 and WO 2004/007488 disclose piperidinyl phenyl oxazolidinones for antimicrobial use.

Pyrrolidinyl/piperidinyl phenyl oxazohdinone antibacterial agents are also described in Kim H Y et al., Bioorg. & Med. Chem. Lett., (2003), 13:2227-2230. International Publication No. WO 1996/35691 discloses spirocyclic and bicyclic diazinyl and carbazinyl oxazolidinone derivatives. Diazepeno phenyloxazolidinone derivatives are disclosed in the International Publication No. WO 1999/24428. International Publication No. WO 2002/06278 discloses substituted aminopiperidino phenyloxazolidinone derivatives.

Various other methods of preparation of oxazolidinones are reported in US Patent No. 7087784, US Patent No. 6740754, US Patent No. 4948801 , US Patent No. 3654298, US Patent No. 5837870, Canadian Patent No. 681830, J. Med. Chem., 32, 1673 (1989), Tetrahedron, 45, 1323 (1989), J. Med. Chem., 33, 2569 (1990), Tetrahedron Letters, 37, 7937-40 (1996) and Organic Process Research and Development, 11 , 739-741(2007).

Indian Patent Application No. 2534/MUM/2007 discloses a process for the preparation of substituted piperidino phenyloxazolidinones. International Publication No. WO2012/059823 further discloses the process for the preparation of phosphoric acid mono-(L-{4-[(5)-5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}4-methoxymethyl piperidine-4-yl)ester.

US Patent No. 8217058 discloses (5S)-N-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide as an antibacterial agent and its process for preparation.

PATENT

WO2015173664

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015173664&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

 

 

PATENT

http://www.google.st/patents/WO2007132314A2?cl=en

 

Figure imgf000004_0001

Wockhardt Ltd,

Figure imgf000006_0001
Figure imgf000006_0002

(3) (4)

 

PATENT

WO 2012059823

http://www.google.co.in/patents/WO2012059823A1?cl=en

Phosphoric acid mono-(l-{4-[(S)-5-(acetylamino- methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester of Formula (A),
Figure imgf000022_0001
the process comprising the steps of:
a) Converting intermediate of Formula (1) into intermediate of Formula (3)
Figure imgf000022_0002
b) Converting intermediate of Formula (3) into intermediate of Formula (5)
Figure imgf000022_0003

c) Converting intermediate of Formula (5) into intermediate of structure (6)

Figure imgf000022_0004
(5) <6> d) Converting intermediate of Formula (6) into intermediate of Formula (10)
Figure imgf000023_0001
e) Converting intermediate of Formula (10) into intermediate of Formula (11),
Figure imgf000023_0002

f) Converting intermediate of Formula (11) into compound of Formula (A) or Pharmaceutically acceptable salts thereof

Figure imgf000023_0003

 

 

Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003

 

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Treatment for Infective Endocarditis

Curator: Larry H Bernstein, MD, FACP

UPDATED on 3/4/2019

WATCH VIDEO

https://consultqd.clevelandclinic.org/tricuspid-valve-reconstruction-for-infective-endocarditis-operative-highlights-video/amp/?__twitter_impression=true

Tricuspid Valve Reconstruction for Infective Endocarditis: Operative Highlights (Video)

There are no easy solutions for acute infective tricuspid valve endocarditis in IV drug users, as the risk of prosthetic endocarditis in this population is high. Complete valve resection without replacement is feasible but leads to progressive right-sided heart failure. Reconstruction of the tricuspid valve with autologous pericardium is an alternative option, as demonstrated in the video case study below.

A 29-year-old female drug abuser with fever, hemoptysis and MRSA bacteremia was started on IV antibiotics. She looked frail and had prominent jugular venous pressure as well as 95 percent saturation on 2 liters of nasal cannula oxygen. She was not on inotropes and had a pulmonary artery pressure of 40/20 mmHg with a good cardiac index. Chest CT showed a large left pleural effusion with associated atelectasis of the left lung. The right lung had manifestations of septic emboli and a smaller pleural effusion.

A Cleveland Clinic surgical team led by cardiothoracic surgeon Faisal Bakaeen, MD, proceeded to excise the patient’s extensive infected and devitalized tissue around the tricuspid valve, leaving only a portion of the anterior leaflet to serve as a reference for reconstruction using autologous pericardium. Dr. Bakaeen walks us through the essential surgical steps — and their underlying rationale — in the narrated operative video below.

SOURCE

https://consultqd.clevelandclinic.org/tricuspid-valve-reconstruction-for-infective-endocarditis-operative-highlights-video/amp/?__twitter_impression=true

 

An article that appeared in NEJM compares early surgery versus conventional treatment for infective endocarditis.
Early Surgery versus Conventional Treatment for Infective Endocarditis
Duk-Hyun Kang, Yong-Jin Kim, Sung-Han Kim, Byung Joo Sun, et al.

N Engl J Med June 28, 2012; 366:2466-2473. http://doi.org/10.1056/NEJMoa1112843

Background and Purpose: While current guidelines advocate surgical management for complicated left-sided infective endocarditis and early surgery for patients with infective endocarditis and congestive heart failure, the indications for surgical intervention to prevent systemic embolism remain unclear. Surgery is favored by experience with complete excision of infected tissue and valve repair, and low operative mortality, but it does not remove concerns about residual active infection, which results in two sets of guidelines, the 2006 ACC-AHA for class IIa indication only for recurrent emboli and persistent vegetation, and the 2009 ESC guidelines for class IIb indication for very large, isolated vegetations. The Early Surgery versus Conventional Treatment in Infective Endocarditis (EASE) trial was conducted to determine whether early surgical intervention woulddecrease rate of death or embolic events.

Patient Enrollment: The study enrolled 76 consecutive patients, 18 years of age or older, with left-sided, native-valve infective endocarditis and a high risk of embolism. For all patients with suspected infective endocarditis, blood cultures were obtained and transthoracic echocardiography was performed within 24 hours after hospitalization. Patients were only eligible for enrollment if they had received a diagnosis of definite infective endocarditis and had severe mitral valve or aortic valve disease and vegetation with a diameter greater than 10 mm. Patients were excluded if they had moderate-to-severe congestive heart failure, infective endocarditis complicated by heart block, annular or aortic abscess, destructive penetrating lesions requiring urgent surgery, or fungal endocarditis, or were over 80 years age, or coexisting major embolic stroke with a risk of hemorrhagic transformation at the time of diagnosis, and a serious coexisting condition. Patients were also excluded if they had infective endocarditis involving a prosthetic valve, right-sided vegetations, or small vegetations (diameter, ≤10 mm) or had been referred from another hospital more than 7 days after the diagnosis of infective endocarditis.
The protocol specified that patients who were assigned to the early-surgery group should undergo surgery within 48 hours after randomization. Patients assigned to the conventional-treatment group were treated according to the AHA guidelines, and surgery was performed only if complications requiring urgent surgery developed during medical treatment or if symptoms persisted after the completion of antibiotic therapy. Details of the study procedures are provided in the Supplementary Appendix, available at NEJM.org.

Study End Points: The primary end point was a composite of in-hospital death or clinical embolic events that occurred within 6 weeks after randomization. An embolic event was defined as a systemic embolism fulfilling both prespecified criteria: the acute onset of clinical symptoms or signs of embolism and the occurrence of new lesions, as confirmed by follow-up imaging studies. Prespecified secondary end points, at 6 months of follow-up, included death from any cause, embolic events, recurrence of infective endocarditis, and repeat hospitalization due to the development of congestive heart failure.

Clinical and Echocardiographic Characteristics of the Patients at Baseline, According to Treatment Group:

The mean age of the patients was 47 years, and 67% were men. The mitral valve was involved in 45 patients, the aortic valve in 22, and both valves in 9. Severe mitral regurgitation was observed in 45 patients, severe aortic regurgitation in 23, severe aortic stenosis in 3, severe mitral regurgitation and stenosis in 1, and both severe mitral regurgitation and aortic regurgitation in 4. The median diameter of vegetation was 12 mm (interquartile range, 11 to 17). All patients met the Duke criteria for definite endocarditis; the most common pathogens in both groups were viridans streptococci (in 30% of all patients), other streptococci (in 30%), and Staphylococcus aureus (in 11%). Characteristics of Antibiotic Therapy, According to Treatment Group: There were no significant between-group differences in terms of control of the underlying infection, the antibiotic regimen used, or the duration of antibiotic therapy.

Surgical Procedures: All patients in the early-surgery group underwent valve surgery within 48 hours after randomization; the median time between randomization and surgery was 24 hours (interquartile range, 7 to 45). Of the 22 patients with involvement of the mitral valve, 8 patients underwent mitral-valve repair and 14 underwent mitral-valve replacement with a mechanical valve. Of the 15 patients with involvement of the aortic valve or both the mitral and aortic valves, 14 underwent mechanical-valve replacement and 1 underwent valve replacement with a biologic prosthesis. Concomitant coronary-artery bypass grafting at the time of valve surgery was performed in 2 patients (5%).

Conventional Therapy: Of the 39 patients assigned to the conventional-treatment group, 30 (77%) underwent surgery during the initial hospitalization (27 patients) or during follow-up (3). The surgical procedures included 11 mitral-valve repairs, 6 mitral-valve replacements (with 5 patients receiving a mechanical valve and 1 a biologic prosthesis), 11 aortic-valve replacements (with 9 patients receiving a mechanical valve and 2 a biologic prosthesis), and 2 combined aortic-valve replacements (with 1 patient receiving a mechanical valve and 1 a biologic prosthesis) and mitral-valve repairs. In 8 patients (21%), indications for urgent surgery developed during hospitalization (median time to surgery after randomization, 6.5 days [interquartile range, 6 to 10]). Elective surgery was performed in an additional 22 patients owing to symptoms or left ventricular dysfunction more than 2 weeks after randomization. Surgical results are shown in the Supplementary Appendix.

Primary End Point: The primary end point of in-hospital death or embolic events within the first 6 weeks after randomization occurred in one patient (3%) in the early-surgery group, as compared with nine (23%) in the conventional-treatment group (hazard ratio, 0.10; 95% confidence interval [CI], 0.01 to 0.82; P=0.03). In the early-surgery group, one patient died in the hospital and no patients had embolic events; in the conventional-treatment group, one patient died in the hospital and eight patients had embolic events (Table 3TABLE 3).
http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2012/nejm_2012.366.issue-26/nejmoa1112843/production/images/small/nejmoa1112843_t3.gif

At 6 weeks after randomization, the rate of embolism was 0% in the early-surgery group, as compared with 21% in the conventional-treatment group (P=0.005). No patient in either group had an embolic event or was hospitalized for congestive heart failure during follow-up. Recurrence of infective endocarditis within 6 months after discharge was not observed in any patient in the early-surgery group but was reported in 1 patient in the conventional-treatment group. Among the 11 patients (28%) in the conventional-treatment group who were treated medically and discharged without undergoing surgery, 1 (3%) died suddenly, 7 (18%) had symptoms related to severe valve disease or recurrence of infective endocarditis (3 of whom underwent surgery during follow-up), and 3 (8%) had no symptoms or embolic events (Table S3 in the Supplementary Appendix).
There was no significant difference between the early-surgery and conventional-treatment groups in all-cause mortality at 6 months (3% and 5%, respectively; hazard ratio, 0.51; 95% CI, 0.05 to 5.66; P=0.59) (Figure 2AFIGURE 2).
http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2012/nejm_2012.366.issue-26/nejmoa1112843/production/images/small/nejmoa1112843_f2.gif
Kaplan–Meier Curves for the Cumulative Probabilities of Death and of the Composite End Point at 6 Months, According to Treatment Group.

At 6 months, the rate of the composite of death from any cause, embolic events, recurrence of infective endocarditis, or repeat hospitalization due to the development of congestive heart failure was 3% in the early-surgery group, as compared with 28% in the conventional-treatment group (hazard ratio, 0.08; 95% CI, 0.01 to 0.65; P=0.02). The estimated actuarial rate of end points was significantly lower in the early-surgery group than in the conventional-treatment group (P=0.009 by the log-rank test) (Figure 2B).

Conclusion: Early surgery performed within 48 hours after diagnosis reduced the composite primary end point of death from any cause or embolic events by effectively reducing the risk of systemic embolism. Moreover, these improvements in clinical outcomes were achieved without an increase in operative mortality or recurrence of infective endocarditis.

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Curated and Reported by: Dr. Venkat S. Karra, Ph.D.

Know How We ALL Knowingly or Unknowingly Consume Antibiotics and How it Effects Our Health

Billions of microbial cells live in the guts of humans and other animals. Research on these vast bacterial populations, called microbiomes, is just getting started, but scientists already know that some microbial boarders play a crucial role in breaking down nutrients in our diet. Some have also suspected that low-dose antibiotics, given to farm animals to make them grow bigger, could work by altering the gut microbiome.

To test this hypothesis, a team led by microbiologist Martin Blaser of the New York University School of Medicine in New York City added antibiotics to the drinking water of mice that had just been weaned. The medicine—either penicillin, vancomycin, a combination of the two, or chlortetracycline—was given at doses comparable to those approved by the U.S. Food and Drug Administration as growth promoters in farm animals. After 7 weeks, the group of mice on antibiotics had significantly more fat than a control group drinking plain water, the team reports online today in Nature. “This confirms what farmers have shown for 60 years, that low-dose antibiotics cause their animals to grow bigger,” Blaser says.

Read more at:  The Global Innovations

Now, Researchers at the University of Copenhagen, Denmark, and University College Cork, Ireland, found that antibiotic concentrations within limits set by US and European Union (EU) regulators are high enough to slow fermentation, the process that acidifies the sausages and helps destroy foodborne pathogens like Salmonella or E. coli.

“At low concentrations and at regulatory levels set by authorities, they could see that the lactic acid bacteria are more susceptible to the antibiotics than the pathogens are.

“Residual antibiotics in the meat can prevent or reduce fermentation by the lactic acid bacteria, but these concentrations do not effect survival or even multiplication of pathogens.”

Antibiotics used as growth promoters or to treat disease in livestock can eventually end up in meat, and regulators in the US and EU have set limits on the concentrations of antibiotics in meat for consumption by humans.

Researchers say that fermented sausages occasionally cause serious bacterial infections, but it’s never been understood why that might be….

Read more at: sciencecodex

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