Penicillins

Penicillins

·        Alexander Fleming reported his discovery of penicillin 1929.

·        Limited production in 1940.

·        Unlimited production 1950.

Bacterial Cell wall Active agents:

1-    Cycloserine.

2-    Bacitracin.

3-    Vancomycin.

4-    Beta-Lactam Antibiotics.

Beta-Lactam Antibiotics:

   A-  Penicillins.

   B-   Cephalosporins.

   C-  Carbapenems.

   D- (Monobactams) = Aztreonam

   Classification of Penicillins:

    1-    Natural penicillins.

    2-    Anti-staphylococcal penicillins.

    3-    Extended spectrum penicillins.

    4-    Anti- pseudomonal Penicillins.

Mechanism of action:

 - They inhibit bacterial growth by blocking bacterial cell wall synthesis resulting in cell lysis.

 - Penicillin binding proteins are involved (PBP)

Mechanism of Resistance:

1-    Inactivation by beta lactamase.

2-    Modification of target PBP.

3-    Impared penetration of drug to target PBP.

4-    The presence of efflux pump.

Beta lactamase is the most common mechanism of resistance.

More than 100 different beta lactamase are identified

1-Natural Penicillins:

- Penicillin G = (Crystalline Penicillin)

- Penicillin V = (Phenoxy methyl Penicillin)

Penicillin G is given parenterally: IV or IM injection.

Penicillin V is Oral

Penicillin unites and formulations:

In Crystalline Penicillin

1,000,000 unites = 600 mg = 0.6 gm (Mega Unite)

Due to the short half-life of Penicillin G it was formulated to increase the duration of action into:

1-    Procaine Penicillin.

2-    Benzathine Penicillin.

 (Intramuscular use only)  (NEVER IV!)

·        Benzathine and procaine penicillin are formulated to delay absorption prolonged blood and tissue concentration.

·        Single IM injection 1.2 million units of Benzathine penicillin produce effective concentration for 10 days. And preventive concentration for 3 weeks.

·        A single injection of Benzathine penicillin 1.2 million IM is effective to treat beta hemolytic streptococcal pharyngitis

·        Benzathine penicillin provide effective prophylaxis for 3-4 weeks.

·        600,000 units of procaine penicillin gives clinically useful concentration for 12-24 hours.

·        Penicillin concentration in tissues is equal to serum concentration.

·        Eye, prostate and CNS penetration is poor.

·        However in active inflammation in meningitis the penetration to CNS is increased.

Penicillin g is the drug of choice in:

·        Streptococci

·        Meningococci

·        Penicillin susceptible pneumococci

·        Non beta-lactamase producing staphylococci

·        Treponema Pallidum and other spirochetes

·        Bacillus anthracis, Clostridium.

As well as:

Actinomyces 

Non beta-lactamase producing gram negative anaerobic bacteria

Penicillin v the oral form of penicillin is indicated for mild infection, it has poor bioavailability, given 4 time per day.

Penicillin v has and narrow spectrum of activity.

Excretion:

·        Penicillins are excreted from the kidneys into urine 10% by filtration. 90 % by Secretion.

·        Simultaneous administration of probenicid 500 mg impairs tubular secretion

·        Half Life of Penicillin G = 30 mints.

·        In Renal Failure = 10 hours.

2- Penicillns resistant to staphylococcal Penicillinase.           (Anti-staphylococcal Penicillins)

·        Methicillin (Not used clinically)

·        Nafcillin

·        soxazolyl Penicillins

o   Cloxacillin.

o   Oxacillin.

o   Dicloxacillin.

ü The only indication is infection by beta lactamase producing staphylococci.

ü 500 mg every 4-6 hours

ü Food interferes with absorption

ü For serious systemic infection IV injection is given 4-6 hourly.

3- Extended spectrum penicillins (Amino-Penicillins)

ü Greater activity on gram negative bacteria.

ü They are inactivated by b-lactamase

·        Ampicillin

·        Amoxicillin have the same activity

ü Amoxicillin is better absorbed

ü Beta- lactamase inhibitors are commonly used with Ampicillin/Amoxicillin to protect the drug from the action of beta-lactamase.

1-    Clavulanic acid.

2-    Sulbactam.

3-    Tazobactam.

ü Augmentin = Amoxicillin + Clavulanic Acid (Co-Amoxiclav)

Clinical uses:

·        UTI

·        Sinusitis

·        Otitis media

·        Lowe respiratory tract infection

·        Ampicillin in IV dose of 4 gms is useful in treating serious infection including gram negative cocci and bacilli.

·        E coli

·        H influenzae

·        Salmonellae

Many organisms are now producing beta lactamase and are resistant to Ampicillin.

Pseudomonas, citrobacter, serratia are commonly resistant to Ampicillin.

Ampicillin/Amoxicillin are available in combination with clavulanic acid a beta lactamase inhibitor.

Extend the activity to include s.aureus

As well as other beta lactamase producing gram negative Bactria.

4- Anti-Pseudomonal Penicillins:

A-  Carbinicillin the first anti pseudomonal carboxypenicillin. Not commonly used

B-   Ticarcillin    (IV) is better choice.

C-  Piparacillin (IV). Is commonly used in combination with aminoglycoside.

Adverse reaction:

Penicillins are remarkably non toxic

Most of serious hypersensitivity reactions are due to allergy.

All penicillins are cross sensitizing and cross reacting.

*It depends on duration and total amount of penicillins received in the past.

Because of the potential to produce anaphylaxis penicillin should be administered with caution

1.     Allergic reaction:

       -Anaphylactic shock very rare 0.05%

       -Serum sickness

       -Hemolytic anemia

2.     Skin rashes (Direct toxicity, or in EB virus infection)

3.     Interstitial nephritis.

4.     Convulsion (Very rare).

5.     In patient with renal impairment high dose can induce convulsion

6.     GIT upset nausea vomiting diarrhea

7.     Ampicillin has been linked to Pseudomembranous colitis

Skin testing can be used before Parenteral Penicillin injections to minimize the risk of anaphylaxis.

Redness, Swelling, Itching …etc.