Cephalosporins - Ceutics

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Questions and Answers

Which oral cephalosporin has the highest bioavailability?

Cefixime

Cefaclor (correct)

Cephalexin (correct)

Cefadroxil (correct)

What characteristic enhances the absorption of drugs across the intestinal epithelium?

Lipophilicity (correct)

Low molecular weight

High acidity

Hydrophilicity

Why are some oral cephalosporins esterified?

To decrease bioavailability

To enhance lipid solubility (correct)

To increase acid stability

To reduce intestinal absorption

What is the main factor affecting the bioavailability of cefixime?

The presence of food Signup and view all the answers

What happens to prodrugs like cefuroxime axetil after intestinal absorption?

They are hydrolyzed into active metabolites Signup and view all the answers

What is a critical consideration regarding ceftriaxone administration in neonates with hyperbilirubinemia?

It may displace bilirubin from albumin, raising the risk of bilirubin encephalopathy. Signup and view all the answers

How does hypoalbuminaemia affect the pharmacokinetics of ceftriaxone?

Shortens the half-life and increases volume of distribution. Signup and view all the answers

What characteristic of carbapenems makes them useful against beta-lactamase enzymes?

They have a five-membered ring fused to a beta-lactam structure. Signup and view all the answers

Why are sustained concentrations of a drug above the MIC preferred over high peak concentrations?

They maintain effective antimicrobial activity for a longer duration. Signup and view all the answers

Which of the following carbapenems is NOT FDA-approved?

Cilastatin Signup and view all the answers

Which first-generation cephalosporin is known for high plasma protein binding?

Cefazolin Signup and view all the answers

What is the primary route of excretion for first-generation cephalosporins?

Renal excretion Signup and view all the answers

Which of the following cephalosporins requires dose adjustment in cases of renal impairment?

Cefazolin Signup and view all the answers

Which second-generation cephalosporin is known to have poor oral bioavailability?

Cefuroxime sodium Signup and view all the answers

Which cephalosporin is described as a prodrug that offers better oral absorption?

Cefuroxime Signup and view all the answers

Which of the following is NOT a characteristic of cefadroxil?

Parenteral administration Signup and view all the answers

Cefuroxime can be combined with which substance for better effectiveness?

Clavulanic acid Signup and view all the answers

Which of the following characteristics describes Cefaclor?

More lipophilic due to its chlorine group Signup and view all the answers

Which cephalosporin is known for its long half-life and high protein binding?

Ceftriaxone Signup and view all the answers

What is a shared feature of Cefotaxime and Ceftazidime in terms of metabolism?

Both require dose adjustment with renal dysfunction Signup and view all the answers

Cefixime's bioavailability is affected by food to what extent?

40 – 50% regardless of food Signup and view all the answers

Which cephalosporin is specifically noted for its effectiveness against gonorrhea?

Ceftriaxone Signup and view all the answers

What describes the excretion process for Cefoxitin?

Excreted unchanged by the kidney Signup and view all the answers

What is the average half-life of Ceftriaxone?

8 hours Signup and view all the answers

Which of the following statements about metabolism of Cefotaxime is correct?

It forms desacetyl-cefotaxime, which is less active Signup and view all the answers

Ceftazidime is primarily administered via which method?

Intravenous or intramuscular injection Signup and view all the answers

What characteristic is notable about the absorption of Cefaclor?

More lipophilic, leading to better oral absorption Signup and view all the answers

Study Notes

Oral Cephalosporins

Many oral cephalosporins are acid-stable and have high bioavailability (80% - 95%)
Cefixime has lower bioavailability (40% - 50%)
Absorption across the intestinal epithelium is enhanced if the drug is lipophilic.
Some oral cephalosporins are esterified (e.g., cefuroxime axetil) to increase lipid solubility and enhance absorption.
These prodrugs (esterified) are hydrolyzed after intestinal absorption by esterases in the intestinal epithelium to their active metabolites.
Their bioavailability is relatively low (25% - 50%) and is enhanced by concomitant food intake.

1st Generation Cephalosporins

Examples: Cephalexin, Cephradine, Cefadroxil, Cefazolin
Cefazolin has high plasma protein binding (85%)
Excretion: mainly renally excreted unmetabolized by glomerular filtration in urine.
Dose adjustment (reduction) is necessary in case of renal impairment.

2nd Generation Cephalosporins

Cefuroxime: Parenteral (IV) as cefuroxime sodium has poor oral bioavailability, oral (suspension, tablets) as Cefuroxime axetil prodrug has better oral absorption.
Cefuroxime can be orally combined with clavulanic acid and can cross the blood-brain barrier.
Cefaclor: Oral, more lipophilic (due to Cl) better oral absorption.
Cefprozil: Oral, long-acting, IV parenterally only.
Cefoxitin: IV only, very short half-life (< 1h), excreted unchanged by the kidney.

3rd Generation Cephalosporins

Ceftriaxone: Parenteral (IV, IM), high potency, long-acting, high protein binding, crystallization with calcium, used to treat gonorrhea and meningitis.
Cefotaxime: Parenteral (IV, IM), short half-life (1h), good distribution in CNS, metabolized into a less active metabolite, used to treat meningitis.
Ceftazidime: Parenteral (IV, IM), short half-life (1.5 h), excreted unchanged renally, dose adjustment with renal dysfunction.
Cefixime: Oral suspension, tablets, and capsules, oral bioavailability 40 – 50% regardless of food, moderate half-life (3 - 4 h) excreted unchanged renally, dose adjustment with renal dysfunction

ADME

Absorption: Half-life varies significantly (Cefixime 3-4h, Ceftriaxone 8h).
Metabolism: Most are unmetabolized, Cefotaxime is metabolized to a less active metabolite.
Excretion: Glomerular filtration and excreted in urine & bile, dose adjustment is needed for renal impairment.

Ceftriaxone & Protein Binding

Ceftriaxone extensively binds to plasma proteins (albumin) which contributes to its long half-life.
Antimicrobial activity and elimination are limited to the unbound fraction of the drug.
The free/unbound drug concentration should exceed the minimal inhibitory concentration (MIC) at steady state.
Patients with hypoalbuminaemia (low albumin level) will affect the pharmacokinetics of ceftriaxone by reducing protein binding, leading to a higher level of free drug in blood, shorter half-life, and higher volume of distribution.

Safety Criteria for Ceftriaxone Administration to Neonates

Ceftriaxone should be avoided in neonates with hyperbilirubinemia (high bilirubin blood level) due to the potential risk for displacement of bilirubin from albumin which increases the risk of bilirubin encephalopathy.
Ceftriaxone competes with bilirubin for binding to human serum albumin.
This displacement can lead to higher concentrations of free bilirubin in the blood. High levels of bilirubin in the blood can deposit in brain tissue and cause irreversible damage (bilirubin encephalopathy).

Ceftriaxone & Calcium

Ceftriaxone should not be mixed or co-administered with a calcium-containing solution ( e.g., IV fluids) as it can lead to precipitation of calcium-ceftrixone which can block blood vessels and veins.

General Features of Carbapenems

Four FDA-approved carbapenems: imipenem, meropenem, ertapenem, and doripenem
Carbapenems resemble penicillins with a beta-lactam ring fused to a five-membered ring.
They are highly resistant to a variety of beta-lactamases, making them broad-spectrum antimicrobials.
They are administered via intravenous infusion due to poor oral absorption.
Imipenem-cilastatin and ertapenem can also be administered intramuscularly.
Carbapenems are distributed widely in the body and are mostly excreted by the kidneys.
Dose adjustment is required for patients with reduced renal function to avoid drug accumulation.

Imipenem Formulations

Imipenem is rapidly metabolized by the human kidney enzyme dehydropeptidase-1 (DHP-1) which leads to a deactivated metabolite and potential for nephrotoxicity.
Coadministration with the DHP-1 inhibitor, cilastatin, increases the in vivo half-life, increases tissue penetration, and prevents nephrotoxicity.
Combination of imipenem-cilastatin with relebactam extends the spectrum against carbapenemase-producing bacteria, MDR G-ve bacteria.

Meropenem & Ertapenem:

Meropenem and ertapenem show greater stability towards the DHP-1 system and can be administered without cilastatin.
Ertapenem has a longer half-life than meropenem, allowing for once daily dosing (IV infusion).
Meropenem (70% of the dose) is excreted unchanged in urine over 12 h.
Ertapenem (80% of the dose) is recovered in urine, with nearly half intact and the other half as the ring-opened metabolite.

Contraindication of Carbapenems & Valproic Acid

Coadministration of meropenem with the antiepileptic agent valproic acid significantly lowers the serum concentrations of valproic acid to subtherapeutic levels which can lead to aggravation of seizures.
Therapeutic drug monitoring (TDM) of the serum valproate concentration is recommended to manage this interaction.

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Description

This quiz focuses on the bioavailability, absorption, and properties of oral cephalosporins, emphasizing comparisons between 1st and 2nd generation cephalosporins. Explore critical factors affecting their effectiveness and therapeutic use, including the impact of renal impairment on dosing. Test your knowledge on these important antibiotics in pharmacology.