Showing posts with label chemistry and application. Show all posts
Showing posts with label chemistry and application. Show all posts

Sunday, 8 September 2013

5th Generation Cephalosporins by Dr Tummalapalli Venkateswara Rao

5th Generation Cephalosporins

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Presentation Transcript

5th generation Cephalosporins :

Dr.T.V.Rao MD 5 th generation Cephalosporins Dr.T.V.Rao MD 1

What are cephalosporins:

The cephalosporins structurally related to the penicillin's consist of a –beta lactam ring attached to a dihydrothiazoline ring. Substitutions of chemical groups result in varying pharmacologic properties and antimicrobial activities . What are cephalosporins Dr.T.V.Rao MD 2

History of cephalosporins :

History of cephalosporins Cephalosporin compounds were first isolated from cultures of Cephalosporium acremonium from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu He noticed that these cultures produced substances that were effective against Salmonella typhi , the cause of typhoid fever, which had beta-lactamase. Guy Newton and Edward Abraham at the Sir William Dunn School of Pathology at the University of Oxford isolated cephalosporin C. The cephalosporin nucleus, 7-aminocephalosporanic acid (7-ACA), was derived from cephalosporin C and proved to be analogous to the penicillin nucleus 6-aminopenicillanic acid, but it was not sufficiently potent for clinical use. Modification of the 7-ACA side-chains resulted in the development of useful antibiotic agents, and the first agent cephalothin ( cefalotin ) was launched by Eli Lilly in 1964. Dr.T.V.Rao MD 3


Cephalosporins are B-Lactam antibiotics isolated from Cephalosporium spp. inhibit wide variety of gram(+) and gram(-) bacteria Abraham and Newton, the suppliers of fungi cultures isolated three principal antibiotic components: Cephalosporin PI Cephalosporin N Cephalosporin C - a steroid with minimal antibacterial property - Identical with synnematin N ( also called penicillin N Resistant to S. aureus B-lactamase; antibacterial property is inferior to penicillin N. Dr.T.V.Rao MD 4

Slide 5:

Cephalosporins Cephalosporin N or Penicillin N - the amino acid in the chain confers more activity against gram(-) bacteria particularly Salmonella spp . - less active against gram(+) organism - contains thiazolidine ring S NH H H N HO NH 2 O O O CH 3 CH 3 OH O Dr.T.V.Rao MD 5

Slide 6:

Cephalosporins Cephalosporin C - congener of Penicillin N - contains dihydrothiazide ring NH H H N HO NH 2 O O O CH 3 OH O O O S Dr.T.V.Rao MD 6

Nomenclature of Cephalosporins:

Nomenclature of Cephalosporins Chemical Abstracts > fused ring is named 5-thia, 1-azabicyclo[4.2.0]oct-2-ene > CEPHALOTHIN ( is an antibiotic of the cephalosporin class. It is related to the penicillin drugs in how it kills bacteria, but cephalosporins have a much broader range of activity against bacteria than penicillins. is 3-(acetoxymethyl)-7-[2-(thienylacetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. > saturated bicyclic ring system is named as cepham > all cephalosporins and cefamycins are named as 3-cephems, to designate the position of the double bond in the structure. Dr.T.V.Rao MD 7

Spectrum of Activity:

Spectrum of Activity > are considered broad-spectrum antibiotics with similar activities to that of ampicillin. > more resistant to the inactivation by the beta-lactamases, particularly those produced by gram(+) bacteria. > exhibit potent activity against most species of Klebsiella CEPHALOSPORINS Different potencies are due to: 1. Different bacterial strains 2. Characteristics of individual bacterial species 3. Resistance to the inactivation of the beta-lactamases 4. Permeability of the bacterial cell 5. Intrinsic activity against bacterial enzymes involved in cell wall synthesis and cross linking. Dr.T.V.Rao MD 8

Generation of Cephalosporins:

Cephalosporin drugs fall into five classes or generations . Each subsequent generation of these drugs demonstrates greater efficacy against gram-negative bacteria. Generation of Cephalosporins Dr.T.V.Rao MD 9

What are 5th generation Cephalosporins :

Fifth generation cephalosporins were developed in the lab to specifically target against resistant strains of bacteria . In particular, ceftobiprole is effective against methicillin-resistant Staphylococcus aureus (MRSA ). What are 5 th generation Cephalosporins Dr.T.V.Rao MD 10

Ceftraroline, a 5th. generation cephalosporin :

Ceftaroline is a beta-lactam of the cephalosporin class of antimicrobials with activity against aerobic and anaerobic gram-positive and aerobic gram-negative bacteria associated with skin and respiratory infections. It also has activity against methicillin-resistant Staphylococcus aureus and Streptococcus pneumonia . Ceftraroline, a 5th. generation cephalosporin Dr.T.V.Rao MD 11

Fda approves ceftaroline fosamil:

Fda approves ceftaroline fosamil On October 29th, FDA has approved Ceftaroline Fosamil under the trade name Teflaro. Ceftaroline Fosamil (previously known by the research code TAK-599, the parent drug, Ceftaroline is also known as T-91,825) is an antibiotic indicated for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive and Gram-negative microorganisms, such as Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes Streptococcus agalactiae , Escherichia coli , Klebsiella pneumoniae , and Klebsiella oxytoca , and also for the treatment of community-acquied bacterial pneumonia (CABP) caused by susceptible Gram-positive and Gram-negative bacteria, such as Streptococcus pneumoniae (including cases with concurrent bacteremia ), Staphylococcus aureus (methicillin-susceptible isolates only), Haemophilus influenzae , Klebsiella pneumoniae , Klebsiella oxytoca , and Escherichia coli . Dr.T.V.Rao MD 12

The structure of ceftaroline fosamil resembles other Cephalosporins :

(6R,7R )-7-{(2Z)-2-(ethoxyimino)-2-[5-(phosphonoamino)-1,2,4thiadiazol-3-yl]acetamido}-3-{[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylate contains a cyclic amide (the beta-lactam ring) fused with a six member ring (the cephem ring). Another notable feature of Ceftaroline Fosamil is the thiazolylthio group, which is thought to be crucial for the activity against MRSA. The structure of ceftaroline fosamil resembles other Cephalosporins Dr.T.V.Rao MD 13

How ceftaroline works:

Ceftaroline is a broad-spectrum cephalosporin. Ceftaroline has the ability to bind to penicillin-binding protein (PBP) 2a , an MRSA-specific PBP that has low affinity for most other β-lactam antibacterial. The high binding affinity of ceftaroline to PBP 2a (median inhibitory concentration 0.90 μg/mL) correlates well with its low minimum inhibitory concentration for MRSA. How ceftaroline works Dr.T.V.Rao MD 14

Ceftaroline is modified from cefozopran:

Ceftaroline was developed by modifying the structure of the fourth-generation cephalosporin cefozopran The prodrug, ceftaroline fosamil , which contains a phosphono group to increase water solubility, is rapidly converted in plasma into the bioactive agent , ceftaroline The 1,3-thiazole ring attached to the 3-position of the cephalosporin nucleus and the oxime group in the C7 acyl moiety are responsible for the enhanced anti-MRSA activity observed with ceftaroline. Ceftaroline is modified from cefozopran Dr.T.V.Rao MD 15

Advantages of ceftaroline:

Advantages of ceftaroline The high affinity of ceftaroline for penicillin-binding proteins is responsible for the potent activity observed against clinically relevant pathogens. With respect to the treatment of CABP, the activity of ceftaroline against pathogens such as S. pneumoniae , S. aureus , Haemophilus influenzae and Moraxella catarrhalis demonstrates coverage across a broad range of pathogens typically encountered in clinical practice. Ceftaroline is also very active against common pathogens seen in ABSSSIs such as S. aureus (methicillin-susceptible S. aureus and methicillin-resistant S. aureus ) and Streptococcus pyogenes . Dr.T.V.Rao MD 16

Mechanism of action of Ceftaroline:

Ceftaroline was developed by modifying the structure of the fourth-generation cephalosporin cefozopran. The prodrug, ceftaroline fosamil, which contains a phosphono group to increase water solubility, is rapidly converted in plasma into the bioactive agent, ceftaroline The 1,3-thiazole ring attached to the 3-position of the cephalosporin nucleus and the oxime group in the C7 acyl moiety are responsible for the enhanced anti-MRSA activity observed with ceftaroline. Mechanism of action of Ceftaroline Dr.T.V.Rao MD 17

Ceftaroline is active on:

Ceftaroline is active on Ceftaroline is active in vitro against Gram-positive cocci, including MRSA, methicillin-resistant Staphylococcus epidermidis , penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant Enterococcus faecalis (not E. faecium ) . The broad- spectrum activity of ceftaroline includes many Gram-negative pathogens but does not extend to extended-spectrum β-lactamase-producing or AmpC-derepressed Enterobacteriaceae or most nonfermentative Gram-negative bacilli . Dr.T.V.Rao MD 18

Ceftaroline has synergistic action :

Ceftaroline has been shown to have synergistic activity against Gram-negative species in combination with an aminoglycoside. In an in vitro study, ceftaroline plus amikacin was synergistic against 90% of isolates tested, including Pseudomonas aeruginosa , extended-spectrum β- lactamase (ESBL)-producing Escherichia coli , ESBL-producing Klebsiella pneumoniae and AmpC-derepressed Enterobacter cloacae . Synergy was also demonstrated for ceftaroline in combination with meropenem against all E. coli isolates tested Ceftaroline has synergistic action Dr.T.V.Rao MD 19

Ceftaroline has limited activity …….:

Ceftaroline demonstrates limited activity against anaerobes such as Bacteroides fragilis and non-fragilis Bacteroides spp. Limited data show that ceftaroline has a low propensity to select for resistant subpopulations. Ceftaroline has limited activity ……. Dr.T.V.Rao MD 20

Advantage of ceftaroline:

Ceftaroline is an injectable cephalosporin active against MRSA & MSSA [ & RTI pathogens] It is approved for use in cSSSI & CABP Its use may be extended when combined with NXL 104 to include ESBL +ve GNB strains It is inactive against Non fermentors GNB & Carbapenemase producers. Advantage of ceftaroline

Slide 22:

Dr.T.V.Rao MD 22

Fifth generation Ceftobiprole :

Fifth generation Ceftobiprole has been described as "fifth generation ", ] though acceptance for this terminology is not universal. Ceftobiprole (and the soluble prodrug medocaril) are on the FDA fast-track. Ceftobiprole has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance. Fifth generation Ceftobiprole Dr.T.V.Rao MD 23

Ceftobiprole (Zeftera/Zevtera) is a :

Ceftobiprole ( Zeftera / Zevtera ) is a Ceftobiprole (Zeftera/Zevtera) is a 5th generation cephalosporin antibiotic with activity against methicillin-resistant Staphylococcus aureus , penicillin-resistant Streptococcus pneumoniae , Pseudomonas aeruginosa , and Enterococci It was discovered by Basilea Pharmaceutica and was developed by Johnson & Johnson Pharmaceutical Research and Development . It has been shown to be statistically non-inferior to the combination of vancomycin and ceftazidime for the treatment of skin and soft tissue infections . Dr.T.V.Rao MD 24

Pharmacology of ceftobiprole:

Ceftobiprole inhibits the 2a penicillin-binding protein (pbp ) of Methicillin-resistant Staphylococcus aureus and the 2x pbp of Streptococcus pneumoniae as well as the classic PBP-2 of MSSA. Ceftobiprole is resistant to staphylococcal β- lactamase Pharmacology of ceftobiprole Dr.T.V.Rao MD 25

How ceftobiprole differs from other beta lactams :

How ceftobiprole differs from other beta lactams Ceftobiprole can be distinguished from other beta-lactams by its increased binding to penicillin-binding protein 2a. Penicillin-binding proteins, the targets of beta-lactam antibiotics, are enzymes found in the membrane that are the last step of peptidoglycan biosynthesis. Penicillin-binding protein 2a is the enzyme most directly related to methicillin-resistant staphylococci. Activity of ceftobiprole has been studied against both the community-acquired MRSA strains and hospital-acquired MRSA Dr.T.V.Rao MD 26

Clsi puts on the list of unnamed class:

Currently, ceftaroline and ceftobiprole are on an unnamed subclass of cephalosporins by the Clinical and Laboratory Standards Institute (CLSI). Clsi puts on the list of unnamed class Dr.T.V.Rao MD 27

5th generation cephalosporins are not ultimate solutions for antibiotic resistance :

5 th generation cephalosporins are not ultimate solutions for antibiotic resistance Antimicrobial stewardship programmes can be implemented to reduce inappropriate use of antimicrobials, thereby controlling the development of resistance. These programmes are also useful in limiting toxicity and overgrowth of pathogenic organisms such as C. difficile . Typical stewardship programmes target antimicrobials that pose a risk of development of resistance, are associated with significant toxicity, require therapeutic drug monitoring, have the potential to select for pathogenic organisms or have a high cost. Dr.T.V.Rao MD 28

Slide 29:

Created by Dr.T.V.Rao MD for “ e ‘ learning resources for Medical Microbiologists in Developing World Email d Dr.T.V.Rao MD 29

Saturday, 7 September 2013

7 Amazing Medicinal Properties of the Banana Plant

Go Bananas! 7 Amazing Nutrition Facts We Bet You Didn't Know
There is much more than meets the eye with the banana. A household favorite, a lost-leader at the grocery store, a metaphor for psychiatric problems, a mainstay of comic slap stick, the banana has woven itself deeply into human affairs, on both gut and mental levels. And this relationship is at least 10,000 years old, as far as conscious human cultivation of the species goes.
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Thursday, 22 August 2013

Bayer's Stivarga sets second OK in Japan

Bayer chalked up another approval for blockbuster-in-waiting Stivarga after Japan gave a green light for the drug's use in gastrointestinal stromal tumour (GIST).
This is the second approval for Stivarga (regorafenib) in Japan, having been cleared for the treatment of advanced or recurrent colorectal cancer in March. The product has already been approved for both indications in the US and is under review for the colorectal cancer indication in Europe

Sunday, 4 August 2013

Cinnamon's Infection and Diabetes-Fighting Properties Revealed

Cinnamon's Infection and Diabetes-Fighting Properties Revealed
Cinnamon's medicinal potential is as rich and complex as its flavor and aroma, with blood sugar balancing and infection fighting top on the list.
Cinnamon is a familiar spice, but few are aware of just how diverse are its medicinal properties.  TheUS National Library of Medicine houses well over 1300 abstracts on the subject of the various forms of cinnamon's potential health benefits.

Friday, 26 July 2013

5 Must To Have Foods To Keep The Levels Of High Cholesterol Under Control

A condition called high cholesterol slowly creeps on you and you are unable to see its ill-effects until it becomes unbearable with spike to several complications such as diabetes, heart diseases and much more.

Other than just to pop up pills to keep the level of bad cholesterol or LDL under check, it is always a good choice to go for 5 must to have foods to keep the levels of high cholesterol under control. Thus, let’s go straight and see them.
  1. Oats- Oats are believed to have soluble fiber whose intake can easily lower the cholesterol level. Adding oatmeal every day at breakfast can lower your high cholesterol level.
  2. Beans- Similarly like oats beans are also especially rich in soluble fiber that can easily help your cholesterol level to keep low. Beans can also help to lose weight and makes one feel fuller as they take longer to digest.
  3. Nuts- Several studies all across have shown that nuts are a superb food choice when dealing with high cholesterol level as it can significantly lower your high LDL levels. What’s more, it is also a great option to keep your heart healthy.
  4. Stereos and Stalons rich foods- Foods rich in sterols and stallions can lower the cholesterol as they have the power to absorb cholesterol from foods. Always check food labels to see if they contain these substances.
  5. Fatty Fish- Are you a fish fan? If so, you are lucky as fish such as Salmon and Tuna possess Omega 3 fatty acids that can lower down the level of cholesterol. It would cut your intake of meat as it can increase cholesterol level and instead go for fish.
video on cholesterol reduction one more

Why Vertex Earnings Prospects Are So Bright

Why Vertex Earnings Prospects Are So Bright
Motley Fool
With few drugs targeting cystic fibrosis and almost half of patients suffering from the particular mutation that the study targeted, Vertex could well have identified a blockbuster in the space. Moreover, with an ongoing phase 3 trial of another ...

Vertex Pharmaceuticals has a couple of approved drugs, including its Kalydeco cystic fibrosis drug and its Incivek treatment for hepatitis C. But it also has some promising prospects in the development stage. With the company having reported some positive study results during the quarter, Vertex saw its shares soar as more investors got aboard the biotech's bandwagon. Let's take an early look at what's been happening with Vertex Pharmaceuticals over the past quarter and what we're likely to see in its quarterly report

Thursday, 25 July 2013

Scripps Research Institute Scientists Find a Potential Cause of Parkinson’s Disease that Points to a New Therapeutic Strategy

 For a high-resolution image see:

LA JOLLA, CA – July 24, 2013 – Biologists at The Scripps Research Institute (TSRI) have made a significant discovery that could lead to a new therapeutic strategy for Parkinson’s disease.
The findings, recently published online ahead of print in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson’s disease. Precisely how the loss of this enzyme leads to the deaths of neurons has been unclear. But the TSRI researchers showed that parkin’s loss sharply reduces the level of another protein that normally helps protect neurons from stress.

Wednesday, 24 July 2013

Isis Phase II drug APOIIIRx slashes triglycerides by 64%

Isis Pharmaceuticals is "very encouraged" by a second set of mid-stage data for its heart drugAPOIIIRx, which shows that it can substantially slash levels of dangerous fats in the blood. 

In a 26-patient Phase II trial, patients with severely high levels of triglycerides taking Isis' drug alongside fibrates experienced 64% drop in triglycerides, and a 70% drop in apolipoprotein C-III (apoC-III), a component of 'bad' low-density lipoprotein
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Monday, 22 July 2013

Fadrozole (marketed as Afema by Novartis) for the treatment of breast cancer.


Fadrozole (INN, marketed as Afema by Novartis) is an aromatase inhibitor[1] that has been introduced in Japan for the treatment of breast cancer.
It is selective.[2]

  1. Raats JI, Falkson G, Falkson HC (January 1992). "A study of fadrozole, a new aromatase inhibitor, in postmenopausal women with advanced metastatic breast cancer". J. Clin. Oncol. 10 (1): 111–6. PMID 1530798.
  2. Browne LJ, Gude C, Rodriguez H, Steele RE, Bhatnager A (February 1991). "Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease". J. Med. Chem. 34 (2): 725–36.doi:10.1021/jm00106a038. PMID 1825337.

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer and ovarian cancer inpostmenopausal women. AIs may also be used off-label to treat or prevent gynaecomastia in men.
Aromatase is the enzyme that synthesizes estrogen. As breast and ovarian cancers require estrogen to grow, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors.

Types of AIs

There are 2 types of aromatase inhibitors (AIs) approved to treat breast cancer:
  • Irreversible steroidal inhibitors, such as exemestane (Aromasin), forms a permanent and deactivating bond with the aromatase enzyme.
  • Non-steroidal inhibitors, such as anastrozole (Arimidex), inhibit the synthesis of estrogen via reversible competition for the aromatase enzyme.

Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue. The main source of estrogen is the ovaries inpremenopausal women, while in post-menopausal women most of the body's estrogen is produced in peripheral tissues (outside the CNS), and also a few CNS sites in various regions within the brain. Estrogen is produced and acts locally in these tissues, but any circulating estrogen, which exerts systemic estrogenic effects in men and women, is the result of estrogen escaping local metabolism and spreading to the circulatory system.

Cancer drug tested in pet dogs is now bound for human trials

Thanks to a new $2 million investment, a drug that spurs cancer cells to self-destruct while sparing healthy cells is on the road to human clinical trials. The compound, known as PAC-1, has so far proven safe and has promising anti-cancer effects in cell culture, in mouse models of cancer and in pet dogs with spontaneously occurring lymphomas and osteosarcomas.

If PAC-1 (pack one) makes it through the U.S. Food and Drug Administration’s Investigational New Drug review, the first human (Phase I) clinical trial of the drug will begin in mid-2014. The investor, who wishes to remain anonymous, has an option to invest another $2 million to take the drug into human trials. The clinical work will be conducted at the University of Illinois Cancer Center in Chicago.

Photo by
L. Brian Stauffer

University of Illinois chemistry professor Paul Hergenrother, left, and veterinary clinical medicine professor Tim Fan led a study of an anti-cancer compound in pet dogs that is now headed for human clinical trials.
PAC-1 (first procaspase activating compound) is a synthesized chemical compound that selectively induces apoptosis, or cell suicide, in cancerous cells. PAC-1 has shown good results in mouse models and is being further evaluated for use in humans. In 2010 a published study showed PAC-1 to be safe to research dogs, and a second study published later that same year reported that a PAC-1 derivative (called S-PAC-1) was well tolerated in a small Phase I Clinical Trial of pet dogs with lymphoma. Even at low doses of S-PAC-1, tumors regressed in 1/6 dogs, and the disease was stabilized (no additional tumor growth) in 3/6 dogs

Friday, 19 July 2013