Penicillin Pharmacology: Mechanism of Action, Spectrum, Therapeutic Uses and Adverse Effects

  • -Penicillin discovered by alexander Fleming in 1928 when he found out that his staphylococcal culture has been contaminated by something that kills the bacteria
  • -Later he found out that was penicillin mold
  • -Penicillin is from cell wall inhibitors class

Pharmacokinetics

  • Administration
    • -Some penicillin types had to be taken IV (benzyl penicillin)
    • -IM penicillin like benzathine penicillin
    • -Some other penicillin that taken oral
    • -If taken oral penicillin then either before or after food by 1 hour
    • -Because most antibiotics get affected by food (should be taken on empty stomach)
    • -When choosing type of penicillin you must take into account type and severity of infection
  • Distribution
    • – Penicillin molecular weight 300- 500 according to type of penicillin
    • -Penicillin non ionized in usual form but when it enter the body ph 7.4 turn into ionized compound which can’t cross blood brain barrier except if there is meningitis
    • -blood vessels can leak compounds into peripheral tissues except in brain the cells lining the blood vessels have tight junctions which make them not leaking
    • -But when there is inflammation the vessels in brain start leaking compounds so it leak penicillin
    • -Although penicillin can’t cross blood brain barrier, it can cross the placenta but it is not teratogenic so it is safe in pregnancy because the fetal tissue does not have transpeptidase
  • Excretion
    • -Penicillin excreted by kidney except nafcillin and oxacillin which excreted through bile
    • -Probenecid which used to treated gout by increasing the excretion of uric acid lead to decrease excretion of penicillin and leaving it in plasma for longer time

Mechanism of action

  • -Penicillin is group of drugs
  • -Gram positive bacteria cover itself with thick cell wall while in gram negative has thin cell wall
  • -Cell wall consist of peptidoglycan = protein +carbohydrate
  • -Cell wall has multiple glycan units that cross linked to each other by the transpeptidase enzyme by transpeptidation reaction
  • Mechanism of action 1
    • Penicillin inhibits the transpeptidase enzyme and lead to dissolving of the cell wall and bacteria become exposed to external environment and lead to lysis by osmotic pressure => bactericidal
    • -Some books call transpeptidase enzyme = penicillin binding protein
    • -Penicillins work on rapidly dividing bacteria
  • Mechanism of action 2
    • Penicillin enter the cell and activate autolysin
    • -Autolysin used by the bacterial cell to dissolve its own cell wall during reproduction
    • -So when penicillin activate autolysin leads to more destruction to cell wall and lead to cell rupture and lysis
    • -Penicillin works well with gram positive bacteria because it has developed cell wall
    • -Penicillin works well on actively multiplying bacteria => bactericidal

Penicillin antibacterial spectrum

  • -Various penicillin are active against almost all types of bacteria
  • -Penicillin G is active against gram positives like streptococci, clostridium perfringens (cause gas gangrene), pneumococci and staph that doesn’t produce penicillinase and it is active against gonococci , treponema pallidium
  • -Anti staph penicillin is active against MSSA
  • -Amino penicillins active against penicillin G spectrum and listeria monocytogenes (gram + cause eneterococcal infection) the salmonella (typhoid) and shigella (dysentery) (both gram -)
  • -Anti pseudomonal penicillins active against pseudomonas, and active against multiple gram negatives and some gram positives and anaerobes

Resistance

  • Bacteria develops resistance mechanisms to Penicillins, those include natural and acquired resistance
  • Natural resistance
    • Natural resistance like in bacteria that lack the peptidoglycan cell wall (mycoplasma pneumonia)
  • Acquired resistance
    • Effect of penicillin depends on the beta lactam ring
    • -Some bacteria secrete beta lactamase enzyme (penicillinase) the lead to destruction of the beta lactam ring
    • -We have multiple types of bacteria that secretes beta lactamase including staph aureus , some strains of E coli (penicillinase secreting E coli, pseudomonas, some strains of proteus , some strains of streptococci , H influenza
  • -To avoid that penicillin added to tazobactam, sulbactam or clavulanic acid which are beta lactamase inhibitors
  • -Presence of efflux pump reduce amount of intracellular drug (klebsiella pneumonia)

Therapeutic uses

  • -Penicillin used to treat bacterial infections and it is active against all types of bacteria
  • -The only antibiotic used for prophylaxis benzathine penicillin (long acting) used for prophylaxis against rheumatic fever every 3 to 4 weeks ;; also used for prophylaxis against endocarditis in kids with congenital heart disease caused by strep viridans that infect the heart and cause vegitations on valves ;;; any dental work in patient susceptible to endocarditis should be using pencillin for prophylaxis

Adverse Effects

  • -Hypersensitivity reactions , 5-10% have hypersensitivity against penicillin ; hypersensitivity range from simple skin rash to angioedema to anaphylactic shock ; patient that might go into anaphylactic shock after taking penicillin is 1/10000 ;;; hypersensitivity reactions might be immediate after 1 to 2 minutes (type I hypersensitivity that might go into anaphylactic shock) after taking the drug or delayed until 12 days (type III hypersensitivity reactions) ;;; sensitivity comes from metabolic products of penicillin after getting metabolized by liver because penicillin works on transpeptidase enzyme which is available in bacteria only;;; sensitivity more with IV route and couldn’t be predicted (ask patient if have penicillin hypersensitivity, or do test were you give the penicillin G intradermally in low dose and watch if there is hypersensitivity reaction in that area then that person have penicillin hypersensitivity) ;;; person might have hypersensitivity originally or developed over time ;;;; you ask about hypersensitivity in history
  • -Seizures, procaine penicillin might cause seizures if given intrathecally
  • -Nafcillin might cause bone marrow depression
  • -Methicillin might cause interstitial nephritis (not used anymore because of MRSA) Co amoxiclav have clavulanic acid which is hepatotoxic

Drug Interactions

  • -Penicillin is bactericidal (destroy cell wall) and better work on the dividing bacteria to kill it by destroying its cell wall, if added with bacteriostatic like erythromycin => erythromycin would make the bacteria static and slow its division making the penicillin not effective
  • -Antipseudomonal penicillin have –ve charged and when mixed with positive charge like aminoglycosides both deactivated like piperacillin and gentamicin