Beta- Lactam Antibiotics (part I) (B)- Semisynthetic penicillins
Semisynthetic penicillins: Semi-synthetic antibiotics are derivatives of natural antibiotics with slightly different but advantageous characteristics. For example, they can act against bacteria which are resistant to the original compound, have a greater spectrum of activity or cause fewer side effects. The main aim of producing semisynthetic penicillins has been overcome the shortcomings of PnG, which are:
- Poor oral efficacy
- Narrow spectrum of activity
- Hypersensitivity reactions
- susceptibility to penicillinase
- Acid resistant alternative to penicillin G:
Phenoxymethyl penicillin (penicillin V): The antibacterial spectrum of penicillin V is identical to PnG, but it is about 1/5 as active against Neisseria, other gram negative bacteria and anaerobes. Penicillin V exerts a bactericidal action against penicillin-sensitive microorganisms during the stage of active multiplication.
Mechanism of action : It acts through the inhibition of biosynthesis of cell-wall mucopeptide by binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, which are critical in the cell wall synthesis and maintenance, as well as cell division. This disrupts the third and last stage of bacterial cell wall synthesis. This subsequently leads to cell lysis.
Pharmacokinetics: It is rapidly completely absorbed orally. Peak blood level is reached in 1hr and plasma t1/2 is of 30-60 min, about 50-80% of the drug is bound to plasma proteins. Small amounts of the drug can be found in various tissues, with the highest amount found in the kidneys, with lesser amounts in the liver, skin, and intestines. Presence of bile does not effect the activity of penicillins. Phenoxymethylpenicillin was found in the cerebrospinal fluid. About 35-70% of an oral dose is metabolized to penicilloic acid, an inactive metabolite.
The more common side effects of penicillin V can include:
- stomach upset
- black hairy tongue
- Allergic reaction. Symptoms can include:
- skin rash with or without blisters
- flu-like symptoms, such as a fever, feeling ill, or joint pain
- swelling of your throat, tongue, or mouth
- Diarrhea. Symptoms include:
- bloody or watery diarrhea with or without stomach cramps and a fever
- streptococcal upper respiratory tract infections, scarlet fever, and erysipelas infections
- pneumococcal upper respiratory infections
- staphylococcal skin and soft tissue infections
- fusospirochetosis (infection of the oropharynx or middle part of the throat)
- prevention of rheumatic fever and chorea
This drug may be used as part of a combination therapy.
2. Penicillinase resistant Penicillins:
Penicillinase-resistant Penicillins (also referred to as second-generation Penicillins) are antibiotics that are resistant to bacterial enzyme beta-lactamase and are used to treat staphylococcal and streptococcal bacterial infections. Penicillinase-resistant Penicillins are semisynthetic modifications of natural Penicillins and their basic structure includes a thiazolidine ring connected to a beta-lactam ring. Bacterial resistance to Penicillins is mediated by beta-lactamase, an enzyme that destroys the beta-lactam ring of penicillin, making it ineffective. Penicillinase-resistant Penicillins resist this hydrolysis of the beta-lactam ring by the bacterial enzyme.
a. Methicillin: It is free from acute and chronic toxic effects, except that some pain may be caused following intramuscular injection.
Mechanism of action: Methicillin was suspected to exert its bacteria-killing actions by inhibiting bacterial cell-wall synthesis, a mechanism of action similar to that of other Penicillins. Methicillin was active against certain species of Staphylococcus, including S. aureus and S. epidermis.
Pharmacokinetics: It is poorly absorbed orally, but after intramuscular injection the concentrations in the serum and in tissues are very similar to those found with penicillin G. It is excreted by the kidneys both by renal tubular secretion and glomerular filtration. It is also excreted in the bile in very high concentrations. The metabolism of the drug it is calculated that 75% is eliminated unchanged in the urine and that the remainder is probably destroyed after the excretion into the intestine via the bile.
MRSA: Methicillin resistant staphylococcus aureus, these are insensitive to all penicillinase resistant penicillin, beta lactams, as well as to erythromycin, aminoglycosides etc. The MRSAs altered PBPs which do not bind Penicillins. The drug of choice for these organism is vancomycin/ linezolid.
Side effects: Haematuria, albuminuria, reversible interstitial nephritis
b. Cloxacillin: It as an isoxazolyl side chain and is highly penicillinase as well as acid resistant. It is less active against PnG sensitive organisms. It is more active against penicillinase producing staph, but not against MRSA. It is incompletely absorbed orally, if taken ine mpty stomach. It is more than 90% plasma bound. It is excreted out through kidneys. also partly by liver. Plasma t1/2 is of 1hr.
- What are the shortcomings of PnG?
a. poor oral efficacy
b. susceptibility to penicillinase
c. hypersensitivity reactions
d. All of above
2.What type of side effect is most commonly observed in beta-lactam antibiotics?
a. Hearing loss
b. Aplastic anaemia
c. Hypersensitivity reactions
d. Yellowing of teeth
3. Which of the following statements about penicillin is false?
c. Cloxacillin is not penicillinase resistant
4. Penicillin resistance commonly occurs through the generation of beta-lactamases.
5. Penicillinase-resistant penicillins include:
6. Identification of methicillin-resistant Staphylococcus aureus (MRSA) in patients indicates:
a. the organisms are sensitive to flucloxacillin and cloxacillin
b. the organisms are sensitive to beta-lactam antibiotics
c. the organisns are resistant to erythromycin, aminoglycosides and other beta-lactam antibiotics
d. usual infection-control measures are satisfactory to manage the infections.
7. Acid resistant alternative to penicillin G includes
8.Which of the Following Does not Affect the Activity of Penicillin?
b) Hydrochloric acid
d) Sodium hydroxide
9. Uses of penicllin V
a. streptococcal upper respiratory tract infections, scarlet fever, and erysipelas infections
b. pneumococcal upper respiratory infections
c. staphylococcal skin and soft tissue infections
d. All of above
10. Side effects of penicillin V
c. stomach upset
d. All of above
11. Which drug inhibit the biosynthesis of cell-wall mucopeptide by binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall
b. Penicillin V
d. None of them
12. Penicillinase-resistant penicillins are use to treat
a. Staphylococcus infections
b. Streptococcal infections
13. Cloxacillin is highly penicillinase as well as acid resistant.
14. Phenoxymethylpenicillin was not found in the cerebrospinal fluid
15. Phenoxymethyl penicillin is
a. Penicillin G
b. Penicillin V
d. None of them
- “K,D.tripathi”, semisynthetic penicillins, page no- 689-700, 6th edition, nov 2007.
- “Rockville Pike” Medline plus, Penicillin VK , Aug 2021.