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Discussion & Comparison Between 3Discussion & Comparison Between 3rdrd & 4 & 4thth Generation Generation CephalosporinCephalosporin

Group MembersMd. Ekram HossainID. 2008-3-70-031Kohinoor BannyaID. 2008-3-70-015

Zarin Tasneem ID. 2008-3-70-013

PHRM-304

The contents of our discussion -

► What is Cephalosporin. ► Classification of Cephalosporin. ► Mechanism of action. ► Why Cephalosporin. ► Limitations of Cephalosporin ► Dosages and administration. ► Comparison between 3rd & 4th generation. ► Summary.

What is Cephalosporin ?

Cephalosporin :Cephalosporins are antibacterial agents which inhibit bacterial cell wall synthesis.It is the second major group of β-lactam antibiotics.β-lactam is the ring which inhibit the synthesis of bacterial cell wall.

Background :The first cephalosporin was cephalosporin C isolated in 1948 from a fungus obtained from sewer waters on the island of Sardinia.

Molecular modification of cephalosporin C gave origin to Cephalosporins ;most of them are semisynthetic substances obtained by reaction of 7-aminocephalosporanic acid (7-ACA) with appropriate compounds.

Structure :Cephalosporins are beta-lactam compounds in which the beta-lactam ring is fused to a 6-membered dihydrothiazine ring, thus forming the cephem nucleus.

Stereochemistry :The cephalosporin structure contains two chiral centers (6C &7C).Thus four optically active forms are possible.The natural isomer (6R & 7R) has the following Stereochemistry ..

The Cephalosporin skeleton reveals that it can be derived from the same biosynthetic precursors as

penicillin,ie. Cystein & valine.

Structural Porperties & SARs of Cephalosporin

Structural Porperties :

♦The β-lactam ring is essential. ♦ A free carboxyl group is needed at C4. ♦ The bicyclic is essential. ♦ The stereochemistry of the side groups and the rings is important.

The places where modification can be made are as follows. ♦ The 7-acylamino side chain ♦ The 3-acetoxy side chain ♦ Substitution at C7

SARs of Cephalosporin : Different cephalosporins are developed by changing the moieties attached at the 3/7 position of the 7-ACA.Usually substituent at C-3(R2) modify the pharmacokinetic properties whereas those at C-7 alter the antibacterial spectrum

R1 - the substituent at this position effects the β-lactamase resistance and its activity against Gram (+)ve & Gram (-)ve.

R2 - the substituents primarily effects the pharmacokinetics:the oral activity,the extent of metabolism and the duration of action.Electron withdrawn group provide resonance structure and this incrase stability of the structure.

Carboxylic acid group - necessary for activity.This functional group mimics the carboxylic acid group of alanine when binding the enzyme active site.

Classification of Cephalosporins 1st Generation

2nd Generation

3rd Generation

4th Generation

Cefazolin

Cephalothin

Cephapirin

Cephalexin

Cefadroxil

Cephradine

Cefaclor Cefamandole

Cefoxitin

Cefotetan

Cefmetazole

Cefprozil

Cefpodoxime

Cefotaxime Ceftriaxone

Ceftizoxime

Ceftazidime

Cefoperazone

Cefixime

Cefipime

First Generation

It generally shows activity against Gram (+)ve bacteria.It is well-absorbed even in presence of fat.

Effective against : Streptococcus Methicillin sensitive Staphylococcus aureus E. Coli Klebsiella Proteus mirabilis

First Generation

Not effective against :Pseudomonas and Enterococcus. H. InfluenzaeM. catarrhalisOther gram negative β-lactamase organisms

First Generation

Clinical uses :Uncomplicated, community-acquired infections of the skin and soft tissue and urinary tract.

First generation drugs:CefadroxilCephapirin Cefazolin etc.

Second GenerationHave increased gram-negative activity, but decreased

gram-positive activity. They have improved activity against common β-lactamase producing respiratory

Pathogens.Effective against :Methicillin sensitive S. aureusH. InfluenzaeN. CaterrhalisE. ColiKlebsiellaProteus mirabilis

Clinical uses : for mixed aerobic/anaerobic infections of the skin and soft tissues, intra-abdominal, and gynecologic infections, and

surgical prophylaxis. Indicated second line: Otitis media Bronchitis Sinusitis

Second Generation

Second generation drugs:

Cefaclor

Cephalothin

Cefoxitin etc.

Third Generation

Better resistance to plasmid mediated

β-lactamase activity.So they have expanded coverage of gram negative as

compared to 1st and 2nd generationConvenient dosage-once or twice dailyExpensive

They have variable loss of efficacy against gram positive coverage especially - Streptococcus pneumoniae and - Staphylococcus speciesThis limits their usefulness in otitis media and respiratory infections.They are most useful oral 3rd generation antibiotics.

Cefotaxime

How it works?

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. .

Cefotaxime Cefotaxime

Clinical Use: Clinical Use:

Cefotaxime is used for infections of the respiratory Cefotaxime is used for infections of the respiratory tracts, bones, joints, urogenital system, meningitis, tracts, bones, joints, urogenital system, meningitis, and septicemia . It generally has good coverage and septicemia . It generally has good coverage against most Gram Negetive Bacteria.against most Gram Negetive Bacteria.

CefotaximeCefotaxime

ChemistryChemistry The methoxyimino moiety confers stability to β-lactamase The methoxyimino moiety confers stability to β-lactamase

enzymes produced by many Gram-negetive bacteria. Such enzymes produced by many Gram-negetive bacteria. Such stability to β-lactamases increases the activity of cefotaxime stability to β-lactamases increases the activity of cefotaxime against otherwise resistant Gram-negative organisms. against otherwise resistant Gram-negative organisms.

CefotaximeCefotaxime

Side effectsSide effects Allergic reactions (rash; hives; itching; difficulty Allergic reactions (rash; hives; itching; difficulty

breathing)breathing) Nausea or vomiting; stomach pain/cramps; unusual Nausea or vomiting; stomach pain/cramps; unusual

bruising or bleeding; unusual tiredness; vaginal bruising or bleeding; unusual tiredness; vaginal irritation or discharge.irritation or discharge.

Fourth Generation Cephalosporine

Fourth generation cephalosporins are extended spectrum agents with similar activity against gram-positive organisms. They also have a greater resistance to beta-lactamases than the third generation cephalosporins. Many can cross blood brain barrier and are effective in meningitis. E.g cefepime, cefpirome, cefaclidine, cefepime, cefpirome, cefaclidine, cefozoporancefozoporan

Zwitterion structure can easily penetrate the outer cell Zwitterion structure can easily penetrate the outer cell membrane porins.membrane porins.

Enhanced stability against beta-lactamase .Enhanced stability against beta-lactamase .

CefepimeCefepime

Cefepime was developed in early 1990s. It was marketed in Cefepime was developed in early 1990s. It was marketed in 1994 . It is effective in treating both Gram-positive and 1994 . It is effective in treating both Gram-positive and Gram-negative organisms., Gram-negative organisms.,

CefepimeCefepime

Clinical Use:Clinical Use:

It is used to treat complicated episodes of urinary It is used to treat complicated episodes of urinary tract infections, skin infections, and intra-abdominal tract infections, skin infections, and intra-abdominal infections. It is also often used as an Empiric infections. It is also often used as an Empiric Therapy for Febrile Neutropenic Patients. The Therapy for Febrile Neutropenic Patients. The effectiveness of Cefepime over other antibacterial effectiveness of Cefepime over other antibacterial drugs lies in its great activity against susceptible drugs lies in its great activity against susceptible bacteria.bacteria.

CefepimeCefepime

Side effects:Side effects: This medication may cause headache, nausea,dizziness,vaginal This medication may cause headache, nausea,dizziness,vaginal

yeast infection.yeast infection.

Adverse effects:Adverse effects: Mental/mood changes, vomiting, severe stomach cramps, Mental/mood changes, vomiting, severe stomach cramps,

watery or bloody diarrhoea, fever or unusual weakness, muscle watery or bloody diarrhoea, fever or unusual weakness, muscle twitching (myoclonus), unusual bleeding or bruising, yellowing twitching (myoclonus), unusual bleeding or bruising, yellowing of the eyesof the eyes

Mechanism of action

Mechanism of action: inhibit transpeptidases (PBPs) responsible for cell wall synthesis. Transpeptidase enzyme is one of the penicillin binding proteins that normally reside in the bacterial inner membrane and perform construction ,repair and housekeeping functions maintaining the cell wall function and play a vital role in cell growth and division.Cephalosporin antibiotics bind to penicillin binding proteins (PBPs) to bacteria and inhibit the formation of cell well

Mechanism of action

Time-dependent, bactericidal activity versus most pathogens. Spectrum of activity determined by:Affinity for target PBPsAbility to penetrate through porins in the gram-negative cell wall.Stability to beta-lactamase degradation

Mechanism of action

Why Cephalosporins

Broad spectrum of activityStability to -lactamaseOral and parenteral preparationsWidely acceptedTreats ‘day to day’ as well as

‘serious infections’High safety profile

Broad spectrum of activity

In general, 1st generation cephalosporins have better activity against gram-positive bacteria and less gram-negative activity, while 3rd generation agents, with a few exceptions, have better gram-

negative activity and less gram-positive activity. The only fourth generation agent has both gram-positive

and gram-negative activity.

Stability to -lactamase

An enzyme called -lactamase is present in many different types of bacteria, which serves to 'break' the beta lactam ring, which effectively nullifies the antibiotic's effectiveness.But Cephalosporins show quiet stability to -lactamase.

Oral and parenteral preparations

Cephlosporins are prepared as the oral and parenteral preparation for the convenient of the consumers.

Widely accepted & High safety profile

As it is convenient for the consumers and show less side effects so it is accepted and has safety profile.

Limitations of Cephalosporins

Emerging resistance patterns

Side effects

III & IV generation cephalosporins were

available only as parenteral formulations

Pharmacoeconomics

Emerging resistance patterns :Sometime the bacteria produces a lot of Beta-lactamase enzye which destory the activity of the β-lactam ring by opening the ring.

Three important in medicine which are used in the resistance :Clavulanic acidSulbactamTazobactam

Side effects :Serious, adverse reactions to the cephalosporins are uncommon. As with most antibiotics, the full spectrum of hypersensitivity reactions may occur, including rashes, fever, eosinophilia, serum sickness and anaphylaxisThe incidence of immediate-type allergic reactions to the cephalosporins is increased among patients known to be allergic to penicillins

Dosage and Administration

Adults (Age 13 years & older)Upper respiratory tract infections :100 mg bid for 5-

10 daysAcute exacerbation of chronic bronchitis :200 mg bid

for 10 daysAcute community acquired pneumonia :200 mg bid

for 14 daysUncomplicated gonorrhoea: 200 mg single doseUncomplicated urinary tract infections:100 mg bid

for 7 days

Adults (Age 13 years & older)

Skin & skin structure infections : 400 mg bid for 7-14 days

Children (Age 5 months to 12 years)

Acute otitis media : 10 mg/kg (max 100 mg/dose) OD or 5mg/kg (max 200 mg/dose) bid for 10 days

Pharyngitis and /or tonsillitis : 5 mg/kg/dose (max100 mg/dose) bid for 5-10 days

Comparison between 3rd & 4th generation

Contents 3rd generation 4th generation

Broad spectrum Show less activity against Gram (+)ve much,but very much against Gram (-) ve bacteria.

Show activity against both Gram (+)ve & Gram (-) ve bacteria.

Stability to -lactamase Show little stability to the -lactamase enzyme.

Show strong stability to the -lactamase enzyme.

Side effects Pyelonephritis, CAP, SBP, meningitis Nosocomial infections including pneumonia, sepsis, febrile neutropenia sporin places in therapy

meningitis Used to treat meningitis. Used to treat meningitis

Blood Brain Barrier Can cross blood brain barrier,ex Ceftazidine

Can cross blood brain