unit 10.2: beta-lactam - penicillin

Penicillin

• Derivatives of 6-aminopenicillanic acid

• Contains a beta-lactam ring structure

Alexander Fleming

History of Penicillin

• first to suggest that a Penicillium mold (now known as Penicillium chrysogenum) must secrete an antibacterial substance

• first to concentrate the active substance involved, which he named penicillin, in 1928

Beta-Lactam ring

**site of hydrolysis** by bacterial penicillinase or by acid

R group

determines drug’s **stability to enzymatic or acidic hydrolysis** and affects antibacterial spectrum

Thiazolidine ring

**Beta-Lactam Compounds:**

contains sulfur

gastric acid

Pharmacokinetics

Vary in resistance to ___

oral

Pharmacokinetics

Vary in their ___ bioavailability

Polar compounds

Pharmacokinetics

Not metabolized extensively

• Glomerular filtration

• Tubular excretion

• Inhibited by Probenecid

Pharmacokinetics

Excreted unchanged in urine via ___

when meninges are inflamed

Pharmacokinetics

When does it cross the BBB?

Amoxicillin

Pharmacokinetics

Must be given on an empty stomach; except ___

Ampicillin and Nafcillin

Pharmacokinetics

Partly excreted in bile

30 min to 1 h

Pharmacokinetics

Plasma half-life

Procaine and Benzathine Penicillin G

Pharmacokinetics

• Given intramuscularly

• Long half-lives

• released slowly

• Cross blood-brain barrier when meninges are inflamed

Bactericidal drugs

Mechanism of Action

Binding of the drug to specific receptors (**penicillin-binding proteins [PBPs]**)

Mechanism of Action

Inhibit cell wall synthesis by:

1. ___ located in the bacterial cytoplasmic membrane

Inhibition of **Transpeptidation**

Mechanism of Action

Inhibit cell wall synthesis by:

2. inhibition of reaction that cross-links the linear peptidoglycan chain constituents of the cell wall

Activation of **autolytic enzymes**

Mechanism of Action

Inhibit cell wall synthesis by:

3. ___ that cause lesions in the bacterial cell wall

**Enzymatic hydrolysis** of the beta-lactam ring

Mechanism of Action

results in the lost of antibacterial activity

Beta-lactamases: **Penicillinases**

Resistance

• Hydrolysis of the β-lactam ring

• Formed by most staphylococci and gram (-) organisms

• Major mechanism for bacterial resistance

• Clavulanic acid

• Sulbactam

• Tazobactam

Resistance

Inhibitors of this enzymes are used in combination with penicillin to prevent their inactivation

• Methicillin resistance in staphylococci

• Penicillin G resistance in pneumococci

Resistance

Structural changes in target PBPs

• impeding access of penicillin to PBPs

• Resistance in some gram (-) rods

Resistance

Changes in the porin structure in the outer membrane

streptococci

cause **sore throat**

meningococci

cause **meningitis**

spirochetes

sexually transmitted

Penicillin G

Clinical Uses

Narrow-spectrum penicillinase-susceptible agents

• limited spectrum; susceptible to β-lactamases

• first line drug for syphilis (Benzathine)

• streptococci, meningococci, gram-positive bacilli, spirochetes

Penicillin V

Clinical Uses

Narrow-spectrum penicillinase-susceptible agents

• Oral; Oropharyngeal infections

Methicillin

Clinical Uses

Very Narrow-spectrum penicillinase-susceptible agents

• Treatment of known or suspected staphylococcal infections

• prototype drug

• given 4x a day every 6 hrs

• ___ resistant S. aureus (MRSA)

• Oxacillin

• Cloxacillin (Dicloxacillin)

• Nafcillin

Clinical Uses

Very Narrow-spectrum penicillinase-susceptible agents

• currently available in the market

S. epidermidis (MRSE)

Clinical Uses

Very Narrow-spectrum penicillinase-susceptible agents

• resistant to other members of this subgroup and often to multiple antimicrobial drugs

Ampicillin (IV) & Amoxicillin (Oral)

* oral ampicillin - veterinary treatment/luminal

Clinical Uses

Wider-spectrum penicillinase-susceptible agents

• Wider spectrum than Penicillin G

• Susceptible to penicillinases

  • Enhanced when used with penicillinases (BLIC)

• Synergistic (1+1=3) with aminoglycosides in enterococcal and listerial infections

**Co-amoxiclav** (amoxicillin + clavulanic acid)

Clinical Uses

Wider-spectrum penicillinase-susceptible agents: Ampicillin & Amoxicillin

• Enhanced when used with penicillinases (BLIC)

Piperacillin & Ticarcillin (IV)

Clinical Uses

Wider-spectrum penicillinase-susceptible agents

• Enhanced activity against gram negative

  • Pseudomonas, Enterobacter, Klebsiella

• Susceptible to penicillinases

  • Enhanced activity in combination with inhibitors of penicillinases

• Synergistic action with aminoglycloside

pip-tazo (piperacillin + tazo bactam) or ticarcillin + sulbactam inhibitor

Clinical Uses

Wider-spectrum penicillinase-susceptible agents: Piperacillin & Ticarcillin

• Usually also combined with penicillinase inhibitors

Allergy

Toxicity

• urticaria, pruritus, fever, joint swelling, anemia, anaphylaxis

• Kissing disease

Nafcillin

Toxicity: Allergy

neutropenia

Methicillin

Toxicity: Allergy

interstitial nephritis

Ampicillin

Toxicity: Allergy

maculopapular rashes

GI disturbances

Toxicity:

• Oral penicillins

• nausea, diarrhea

Ampicillin

Toxicity: GI disturbances

pseudomembranous colitis

• caused by fungal or resistant bacteria overgrowth which can cause the formation of a layer of pseudomembrane

β-lactamase Inhibitors

• Resemble β -lactam molecules, but have very weak antibacterial action

• available only in fixed combinations with specific penicillins and cephalosporins