Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from...
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Transcript of Cephalosporins 1. Cephalosporin antibiotics – derived from “cephalosporin C” – obtained from...
Cephalosporins
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• 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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• 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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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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• Inhibition of transpeptidation
• Imperfect cell wall
• Osmotic drive
• Activation of autolysin enzymes
• Lysis of bacteria
• BACTERICIDAL
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CLASSIFICATION
• Based on –antimicrobial spectrum –Chronological sequence of development–Divided into generations.
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First-generation agents
• Cephalexin (O)• Cefadroxil (O)• Cefazolin (i.m, i.v)• Cefalothin (withdrawn)
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• 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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Second-generation agents
–Cefaclor (O)–Ceforanide–Cefuroxime acetil (O)–Cefuroxime (i.m , i.v) –Cefoprozil –Cefamandole (Banned)–Cefoxitin (Banned)–Cefotetan (Banned) 9
• 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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Third-generation agents
• Cefotaxime
• Ceftriaxone
• Cefdinir
• Cefibuten
• Cefpodoxime
• Ceftizoxime
• Ceftazidime
• Cefoperazone (withdrawn)
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• 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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• 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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Fourth-generation agents
• Cefpirome P/E (im/iv)
• Cefepime P/E (iv)
• Cefozopran P/E
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• 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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Fifth-generation agents
• Ceftobiprole• Ceftaroline• Active against, g +ve cocci especially
MRSA • penicillin resistant S. pneumoniae • and enterococci
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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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Adverse reactions
• Pain after im injection • Thrombophlebitis of injected vein. • Diarrhoea more common with– oral Ceferadine– P/E Cefoperazone (Banned)
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• 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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• 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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• Intolerance to alcoholDisulfiram like reaction– Cefamandole (Banned)– Cefotetan (Banned) – Moxalactam (Banned)– Cefoperazone (Banned)
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Therapeutic Uses• Extensively used & therapeutically
important antibiotics• Effective therapeutic & prophylactic
agents
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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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Second Gen agents
• Displaced by third generation agents for Gram negative infections
• Oral-RTI (replaced by augmentin)
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Third Gen agents• With/without aminoglycosides DOC-
severe G -ve infections caused by • Kleibsiella • Enterobacter • Proteus • Providencia • Serratia & haemophillus species.
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• 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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• 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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Fourth Generation Agents
• Same as third generation drugs• Indicated for hospital acquired
infections resistant to commonly used antibiotics
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• Other β -lactam antibiotics
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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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MonobactamsAztreonam• Isolated from chromobacterium violaceum– Only monobactam currently in clinical use
• β - lactam ring, lacking the thiazolidine ring.- a monobactam
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• 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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• 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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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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Carbapenems
• Imipenem• Meropenem• Ertapenem
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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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Adverse effects
• Nausea ,vomiting• Seizures• Patients allergic to other β-lactam
antibiotics may have hypersenstivity reactions when given imipenem
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Meropenem
• Therapeutic equivalence with imipenem
• Coadministration with cilastin not required
• Meropenem is less seizure producing compared to imipenem.
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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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• 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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Therapeutic uses• Urinary tract infections• Lower respiratory tract infections • Intra-abdominal & gynaecological
infections• Skin, bone, joint, & soft tissue
infections• Especially cephalosporin/ penicillin
resistant nosocomial bacteria. 41
CarbacephemsLoracarbef• Synthetic β-lactam antibiotic• Similar to cefaclor• Antibacterial activity resembles II
generation cephalosporins.
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