Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from...

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Cephalospor ins 1

Transcript of Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from...

Page 1: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Cephalosporins

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Page 2: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Cephalosporin antibiotics –derived from “cephalosporin C” –obtained from fungus Cephalosporium

acremonium

• Cephalosporin nucleus Consists of dihydrothiazine ring fused to a β–lactam ring –7-aminocephalosporanic acid

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Page 3: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• 7-aminocephalosporanic acid has been modified by addition of different side chains to create a whole family of cephalosporin antibiotics.• these have been conventionally divided

into 5 generations

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Page 4: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Mechanism of action

• All cephalosporins are bactericidal.

• MOA same as penicillin- Inhibit cell wall synthesis in a manner similar to penicillins

• Bind to different proteins than those which bind penicillin. PBP-1 &PBP-3– This explains diffenece in spectrum, potency & lack of resistance.

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Page 5: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Inhibition of transpeptidation

• Imperfect cell wall

• Osmotic drive

• Activation of autolysin enzymes

• Lysis of bacteria

• BACTERICIDAL

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Page 6: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

CLASSIFICATION

• Based on –antimicrobial spectrum –Chronological sequence of development–Divided into generations.

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Page 7: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

First-generation agents

• Cephalexin (O)• Cefadroxil (O)• Cefazolin (i.m, i.v)• Cefalothin (withdrawn)

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Page 8: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Exhibit good activity against gram-positive bacteria but modest activity against gram negative organisms.–Most gram-positive cocci – Strepto, – Pneumo, –Methicillin sens. Staph. are susceptible to first-generation

cephalosporins

• Modest activity against E. coli, K. pneumoniae & Proteus mirabilis

Most oral cavity anaerobes are sensitive.  However, the Bacteroides fragilis group is resistant.

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Page 9: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Second-generation agents

–Cefaclor (O)–Ceforanide–Cefuroxime acetil (O)–Cefuroxime (i.m , i.v) –Cefoprozil –Cefamandole (Banned)–Cefoxitin (Banned)–Cefotetan (Banned) 9

Page 10: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Exhibit somewhat increased activity against gram negative organisms, –but much less active than third generation agents.

• Less active against gram positive cocci & bacilli compared to first gen. drugs.

• Use declined• Clinically replaced by 3rd & 4th generation

drugs .

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Page 11: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Third-generation agents

• Cefotaxime

• Ceftriaxone

• Cefdinir

• Cefibuten

• Cefpodoxime

• Ceftizoxime

• Ceftazidime

• Cefoperazone (withdrawn)

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Page 12: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Highly augmented activity against gram-negative organisms

• Less active than first generation agents against gram positive cocci & anaerobes.

• All are highly resistant to β-lactamases from gram negative bacteria.

• Some inhibit psuedomonas as well; ceftazidime, cefoperazone(withdrawn)

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Page 13: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Some members of this group have enhanced ability to cross the blood-brain barrier eg. Ceftriaxone and are effective in treating meningitis caused by pneumococci, meningococci, H. influenzae and susceptible gram negative rods.

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Page 14: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Fourth-generation agents

• Cefpirome P/E (im/iv)

• Cefepime P/E (iv)

• Cefozopran P/E

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Page 15: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Highly active against G –ve organisms

• Similar to third gen drugs for g +ve bacteria• The fourth generation drugs comparable to

third generation but more resistant to hydrolysis by β-lactamases.

– Effective against bacterial infections resistant to earlier drugs

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Page 16: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Fifth-generation agents

• Ceftobiprole• Ceftaroline• Active against, g +ve cocci especially

MRSA • penicillin resistant S. pneumoniae • and enterococci

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Page 17: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Resistance • Impermeability to the antibiotic.– to reach its site of action

• Alteration in PBPs -antibiotics bind with low affinity

• Elaboration of β-lactamases; that can hydrolyze the β-lactam ring and inactivate the cephalosporin (most prevalent mech)

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Page 18: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Adverse reactions

• Pain after im injection • Thrombophlebitis of injected vein. • Diarrhoea more common with– oral Ceferadine– P/E Cefoperazone (Banned)

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Page 19: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Hypersensitivity reactions – Identical to penicillins, incidence is lower.– shared β-lactam structure– Allergic to penicillins- allergic to cephalosporins. CROSS-

REACTIVITY.

• Rashes, frequent, anaphylaxis, angioedema, asthma, urticaria have also occurred.

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Page 20: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Cephalosporins potentially nephrotoxic drugs–Cephaloridine (withdrawn) RTN–Cephalothin (withdrawn) Acute tubular necrosis

• Serious bleeding –Cefoperazone(Banned), –Moxalactam(Banned). –Due to hypoprothrombinemia.

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Page 21: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Intolerance to alcoholDisulfiram like reaction– Cefamandole (Banned)– Cefotetan (Banned) – Moxalactam (Banned)– Cefoperazone (Banned)

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Page 22: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Therapeutic Uses• Extensively used & therapeutically

important antibiotics• Effective therapeutic & prophylactic

agents

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Page 23: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

First Gen agents

• Excellent for skin & soft tissue infections

• Surgical prophylaxis first generation drugs are the preferred for prophylaxis in procedures in which skin flora are likely pathogens.

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Page 24: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Second Gen agents

• Displaced by third generation agents for Gram negative infections

• Oral-RTI (replaced by augmentin)

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Page 25: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Third Gen agents• With/without aminoglycosides DOC-

severe G -ve infections caused by • Kleibsiella • Enterobacter • Proteus • Providencia • Serratia & haemophillus species.

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Page 26: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Ceftriaxone is the therapy of choice for all forms of Gonorrhea – 250 mg i.m as single dose

• i.v ceftriaxone for enteric fever

• Cefotaxime & ceftriaxone–Community aquired pneumonia

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Page 27: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Cefotaxime/ceftriaxone are used for initial treatment of meningitis because of their– antimicrobial activity, – good penetration into CSF– & record of clinical success

• They are DOC - Meningitis due to • H. influenzae• Sensitive S. pneumonae• N. meningitidis• G-ve enteric bacteria

• Ceftazidime + aminoglycosides–Psuedomonas meningitis DOC

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Page 28: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Fourth Generation Agents

• Same as third generation drugs• Indicated for hospital acquired

infections resistant to commonly used antibiotics

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Page 29: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Other β -lactam antibiotics

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Page 30: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Other β -lactam antibiotics• Newer classes of β-lactam antibiotics are the

•Monobactams•Carbapenems•Carbacephems

• Important therapeutic agents with a β-lactam structure & areneither penicillinsnor cephalosporins

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Page 31: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

MonobactamsAztreonam• Isolated from chromobacterium violaceum– Only monobactam currently in clinical use

• β - lactam ring, lacking the thiazolidine ring.- a monobactam

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Page 32: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Antimicrobial activity differs from those of other β -lactam antibiotics & more closely resembles that of an aminoglycoside

• Primarily affects :– Aerobic gram negative microorganisms– gram positive bacteria & anaerobic organisms are resistant

• Preferred-all sorts of gram negative infections in patients with renal impairment where aminoglycosides are to be avoided.

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Page 33: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• Stable to most β-lactamases elaborated by gram negative bacteria.

• i.m / i.v• Therapeutic conc. in CSF in the presence of

inflammed meninges, Alternative to cephalosporins for therapy of meningitis caused by G-ve bacilli

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Page 34: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Carbapenems• β-lactam antibiotic• Broader spectrum of activity : than most other β-

lactams . – gram-negative rods – gram-positive bacteria –and anaerobes.

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Page 35: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Carbapenems

• Imipenem• Meropenem• Ertapenem

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Page 36: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Imipenem

• Derived from compound produced by Streptomyces cattleya

• Mechanism same as penicillins • Bactericidal• Resistant to hydrolysis by β-lactamase

• Marketed in combination with cilastin– Inhibits degradation – by renal dipeptidase– Without cilastin renal dehydropeptidases inactivate the

drug which results in low urinary tract concentrations.

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Page 37: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Adverse effects

• Nausea ,vomiting• Seizures• Patients allergic to other β-lactam

antibiotics may have hypersenstivity reactions when given imipenem

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Page 38: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

 Meropenem

• Therapeutic equivalence with imipenem

• Coadministration with cilastin not required

• Meropenem is less seizure producing compared to imipenem.

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Page 39: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Ertapenem

• Differs from imipenam & meropenem larger serum half life, OD.– Co-administration with cilastin not required– less seizure producing compared to imipenem.

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Page 40: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

• All are parenteral – i.v, im painful

• Imipenem 6 hrly• Meropenam 8 hrly• All are resistant to β – lactamases• All bactericidal• MOA same • Patients allergic to other β-lactam antibiotics may

have hypersenstivity reactions when given imipenem/carbapenems.

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Page 41: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

Therapeutic uses• Urinary tract infections• Lower respiratory tract infections • Intra-abdominal & gynaecological

infections• Skin, bone, joint, & soft tissue

infections• Especially cephalosporin/ penicillin

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Page 42: Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from fungus Cephalosporium acremonium Cephalosporin nucleus Consists.

CarbacephemsLoracarbef• Synthetic β-lactam antibiotic• Similar to cefaclor• Antibacterial activity resembles II

generation cephalosporins.

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