DR.T.V.RAO MD 1

Dr.T.V.Rao MD

5TH GENERATION

CEPHALOSPORINS

DR.T.V.RAO MD 2

• 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 3

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 4

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 PICephalosporin NCephalosporin 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 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

SNH

H H

N

HO

NH2

O

OO

CH3

CH3

OHO

DR.T.V.RAO MD 6

Cephalosporins• Cephalosporin C

- congener of Penicillin N

- contains dihydrothiazide ring

NH

H H

N

HO

NH2

O

OO

CH3

OH

O

O

O

S

DR.T.V.RAO MD 7

NOMENCLATURE OF CEPHALOSPORINSChemical 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 8

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 9

• 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 10

• 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 5TH GENERATION CEPHALOSPORINS

DR.T.V.RAO MD 11

• 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 12

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 13

• (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 14

• 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 15

• 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 16

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 17

• 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 18

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 19

• 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 20

• 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 …….

• 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

DR.T.V.RAO MD 22

DR.T.V.RAO MD 23

• 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 24

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 25

• 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 26

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 27

• 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 28

5TH 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 29

• Created by Dr.T.V.Rao MD for “ e ‘ learning resources for Medical Microbiologists in

Developing World

• Email

• doctortvrao@gmail.com