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