Download Lecture 6 Cephalosporins MBBS 2012 Taken (2)

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
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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Cefalothin (withdrawn)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)
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• 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
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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. CROSSREACTIVITY.
• 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 alcohol
Disulfiram 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 DOCsevere 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 & are
neither penicillins
nor cephalosporins
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Monobactams
Aztreonam
• 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 βlactams .
– 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
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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.
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Carbacephems
Loracarbef
• Synthetic β-lactam antibiotic
• Similar to cefaclor
• Antibacterial activity resembles II
generation cephalosporins.
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THANK U
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