Β-lactam Antibiotics and Other Cell Wall Synthesis

Inhibitors
(Part 2)

CEPHALOSPORINS
PHL 428-2021-422

Reference: Basic & Clinical Pharmacology, 14th Edn

 CEPHALOSPORINS

- 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.

- C7 modifications alter antibacterial activity

- C3 substitutes change metabolism and kinetic properties

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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

Antimicrobial Spectrum Pharmacokinetic Properties

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Beta-lactam compounds: Cephalosporine

Classifications of cephalosporins

1st generation 2nd generation 3rd generation 4th generation

cefazolin, cefamandole cefoperazone

cefaclor, cefotaxime,
cefadroxil,
cefonicid, ceftazidime, Cefepime
cephalexin, ceftizoxime,
cefuroxime,
cephalothin, cefixime,
cefprozil, moxalactam. Cefpirome
cephapirin, loracarbef, ceftriaxone,
cephradine, Ceforanide, ceftriaxone,

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Beta-lactam compounds: Cephalosporine

Mechanism of Action (MOA)

• Cephalosporins are bactericidal (such as
penicillins) but are less susceptible to β-
lactamases.
• They disrupt the synthesis of the peptidoglycan
(PG) layer forming the bacterial cell wall by
inhibiting transpeptidase enzyme.
• Iinhibition of transpeptidase enzyme leads to
failure of cross linking of peptide chains of
strands, no stability of cell wall.

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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

• Generally broader spectrum than Penicillins.

• Generally, more effective than Penicillins against B- lactamase-producing microbes (except

enterococci, Methicillin-resistant Staph. aureus and Staph. epidermis)

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Beta-lactam compounds: Cephalosporine
1. FIRST GENERATION

Good activity against gram (+)

Not used in serious systemic
and modest against gram (-)
infections
microbes

UTI, minor staph lesions,

Penetration of the
minor polymicrobial
cerebrospinal fluid (CSF) is
infections-cellulitis, soft tissue
inadequate
abscess

- They are resistant to the staphylococcal Penicillinase

- They have activity against Proteus mirabilis, E. coli, and K. pneumoniae.
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 Beta-lactam compounds: Cephalosporine
1. FIRST GENERATION
Pharmacokinetics and dosages

• 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

• Treatment of urinary tract infection (UTI).

• Treatment of staphylococcal or streptococcal infections, including cellulitis or soft tissue abscess.

• Oral cephalosporins should not be relied on in serious systemic infections.

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

Better activity Only Cefuroxime

against anaerobes can produce
and gram (-) aerobes sufficient CSF level

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.

• 10-15 mg twice daily.

Parenteral

• Most of drug from this generation are given as 1 g intravenous infusion.

• 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

• Treatment of sinusitis, otitis, and lower respiratory tract infection.

• 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.

• Active against Beta-lactamase-producing H influenzae or Moraxella catarrhalis

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Beta-lactam compounds: Cephalosporine
3. THIRD GENERATION

Some are able to cross the

blood-brain barrier
They have expanded
(Cefoperazone, Cefixime,
Gram-negative coverage.
Ceftibuten and Cefpodoxime
proxetil).

They are also effective

against β-lactamase- Ceftazidime is the only agent
producing strains of with useful activity against P
Haemophilus and aeruginosa.
Neisseria.

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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 approved for treatment of meningitis.

• 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

More resistant to Good activity against P.

hydrolysis by beta aeruginosa,
lactamases (eg. Those enterobacteriaceae, staph.
produced by enterobacter) aureus, S. pneumoniae

Good activity against most

Highly active against
penicillin resistant strains of
Haemophilus & Neisseria
streptococci

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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

• Useful in the treatment of enterobacter infections

• Cefepime is commonly used empirically in patients presenting with febrile neutropenia, in

combination with other agents.

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Beta-lactam compounds: Cephalosporine

1st Gen 2nd Gen 3rd Gen 4th Gen

> Gram +ve Extended spectrum > Gram -ve > Gram -ve
< Gram –ve < Gram +ve < Gram +ve

No CSF No CSF CSF bioavailability CSF bioavailability

bioavailability bioavailability
t1/2 2 hrs t1/2 4 hrs t1/2 8 hrs t1/2 8 hrs

Inactivated by B- Inactivated by B- Some resistance to High resistance to B-

lactamase lactamase B-lactase lactamase

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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

• Approved for the treatment of complicated intra-abdominal infections and UTIs

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Beta-lactam compounds: Cephalosporine

ADVERSE EFFECTS

Allergy Toxicity

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Beta-lactam compounds: Cephalosporine

ADVERSE EFFECTS

1. Allergy

• Hypersensitivity reactions, including anaphylaxis, fever, skin rashes, nephritis,

granulocytopenia, and hemolytic anemia.

• Patients with documented penicillin anaphylaxis have an increased risk of

reacting to cephalosporins vs patients without a history of penicillin allergy.

• Patients with a history of anaphylaxis to penicillins should not receive

first- or second-generation cephalosporins, while third and fourth-generation
cephalosporins should be administered with caution, preferably in a monitored
setting.

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Beta-lactam compounds: Cephalosporine

ADVERSE EFFECTS…

2. Cross-Allergy (Allergenicity) between two groups – 5-10 %

3. Local irritation/pain after IM injections (Thromophelbitis)

4. Hypoprothrombinemia and bleeding disorders (Antidote Vitamin K 10 mg twice weekly)

5. Severe disulfiram like reaction with alcohol/containing medications

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