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Cephalosporine Antibiotics PHL428 - II (2) D
Cephalosporine Antibiotics PHL428 - II (2) D
Inhibitors
(Part 2)
CEPHALOSPORINS
PHL 428-2021-422
- Cephalosporins are similar to penicillins but are more stable to many bacterial β-lactamases
and, therefore, have a broader spectrum of activity.
- Cephalosporins are not active against L monocytogenes, and of the available cephalosporins,
only ceftaroline has some activity against enterococci.
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CEPHALOSPORINS
Chemistry:
- 7-amino cephalosporanic acid – parent compound
- Bears a close resemblance to 6-aminopenicillanic acid.
- Contains an R2 that makes the compound stable in dilute acid and highly
penicillinase resistant
- MW – 400-450.
- Soluble in water and relatively stable to pH and temperature changes.
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Beta-lactam compounds: Cephalosporine
Classifications of cephalosporins
Cephalosporins have traditionally been classified into four major groups or generations.
Basis for
classification
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Beta-lactam compounds: Cephalosporine
Classifications of cephalosporins
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Beta-lactam compounds: Cephalosporine
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Beta-lactam compounds: Cephalosporine
Mechanism of Action (MOA)
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Beta-lactam compounds: Cephalosporine
Mechanism of Resistance
- Changes in drug target of penicillin binding
proteins (methicillin-resistant Staphylococcus
aureus)
- Lack of access of the drug to the penicillin
binding protein target (efflux pumps as in
Pseudomonas aeruginosa)
- Alteration of drug itself by hydrolysis by beta-
lactamase (numbers and types of beta-lactamases
increase)
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Beta-lactam compounds: Cephalosporine
Antimicrobial spectrum
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Beta-lactam compounds: Cephalosporine
1. FIRST GENERATION
• Drugs that block tubular secretion, eg, probenecid, may increase serum levels substantially
• Oral
• Cephalexin is widely used and orally.
• 0.25-0.5 g four times daily.
• Excreted by kidney therefore, the dose should be reduced with patients with renal impairment.
Parenteral
• The only drug among the first generation used in IV form is Cefazolin.
• 0.5- 2 g intravenously every 8 hours.
• Can be used intramuscularly (IM).
• Excreted by kidney therefore, the dose should be reduced with patients with renal impairment.
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Beta-lactam compounds: Cephalosporine
1. FIRST GENERATION
Clinical uses
ORAL
Parenteral
• Used for surgical prophylaxis and for many streptococcal and staphylococcal (Bacteremia).
• Cefazolin does not penetrate the central nervous system and cannot be used to treat meningitis.
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Beta-lactam compounds: Cephalosporine
2. SECOND GENERATION
Sinusitis, otitis,
mixed anaerobic
infections such as
peritonitis
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Beta-lactam compounds: Cephalosporine
2. SECOND GENERATION
Pharmacokinetics and dosgaes
ORAL
• Cefuroxime and Cefaclor is a widely orally antibiotic from the second generation.
Parenteral
• There are differences in half-life, protein binding and interval between doses between them.
• Excreted by kidney therefore, the dose should be reduced with patients with renal impairment.
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Beta-lactam compounds: Cephalosporine
2. SECOND GENERATION
Clinical uses
• Because of their activity against anaerobes (including many B fragilis strains), cefoxitin and
cefotetan can be used to treat mixed anaerobic infections such as peritonitis, diverticulitis, and
pelvic inflammatory disease.
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Beta-lactam compounds: Cephalosporine
3. THIRD GENERATION
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Beta-lactam compounds: Cephalosporine
3. THIRD GENERATION
Pharmacokinetics and dosgaes
• They penetrate body fluids and tissues well and IV cephalosporins achieve levels in the CSF
sufficient to inhibit most susceptible pathogens.
• The half-lives vary greatly: ceftriaxone (half-life 7–8 hours) can be injected once every 24 hours.
• A single daily 1-g dose is sufficient for most serious infections, with 2 g every 12 hours
recommended for treatment of meningitis and 2 g every 24 hours recommended for endocarditis.
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Beta-lactam compounds: Cephalosporine
3. THIRD GENERATION
Pharmacokinetics and dosgaes
• The remaining drugs in the group (half-life 1–1.7 hours) can be infused every 6–8 hours in
dosages between 2 and 12 g/d, depending on the severity of infection.
• Ceftriaxone excretion is mainly through the biliary tract, and no dosage adjustment is required in
renal insufficiency.
• The other third-generation cephalosporins are excreted by the kidney and therefore require dosage
adjustment in renal insufficiency.
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Beta-lactam compounds: Cephalosporine
3. THIRD GENERATION
Clinical uses
• Ceftriaxone and cefotaxime are the most active cephalosporins against penicillinnon- susceptible
strains of pneumococci and are recommended for empirical therapy of serious infections that
may be caused by these strains.
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Beta-lactam compounds: Cephalosporine
3. THIRD GENERATION
Clinical uses
• Meningitis caused by strains of pneumococci with penicillin MICs >1 mcg/mL may not respond
even to these agents, and addition of vancomycin is recommended.
• They also used for empirical therapy of sepsis in both the immunocompetent and the
immunocompromised patient and treatment of infections for which a cephalosporin is the least
toxic drug available.
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Beta-lactam compounds: Cephalosporine
4. FOURTH GENERATION
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Beta-lactam compounds: Cephalosporine
4. FOURTH GENERATION
Pharmacokinetics and dosgaes
• Penetrates well into CSF
• Cleared by kidneys therefore, the dose should be reduced with patients with renal impairment
• T1/2 – 2 hrs
• The standard dose for cefepime is 1–2 g infused every 12 hours
Clinical uses
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Beta-lactam compounds: Cephalosporine
> Gram +ve Extended spectrum > Gram -ve > Gram -ve
< Gram –ve < Gram +ve < Gram +ve
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Cephalosporins Active against Methicillin-
Resistant Staphylococci
• Ceftaroline fosamil, the prodrug of the active metabolite ceftaroline approved for clinical use
• It has increased binding to penicillin-binding protein 2a, which mediates methicillin resistance
in staphylococci, resulting in bactericidal activity against these strains
• Used for skin and soft tissue infections and community-acquired pneumonia
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Cephalosporins Combined with a-lactamase Inhibitors
• Ceftolozane-tazobactam
• Ceftazidime-avibactam
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Beta-lactam compounds: Cephalosporine
ADVERSE EFFECTS
Allergy Toxicity
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Beta-lactam compounds: Cephalosporine
ADVERSE EFFECTS
1. Allergy
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Beta-lactam compounds: Cephalosporine
ADVERSE EFFECTS…
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