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Introduction of penicillins

Penicillins are a β-lactam antibiotic and it is accidentally derived from Penicillium chrysogenium (initially: Penicillium notatum). The penicillins were discovered by Alexander Fleming in 1929 but clinically used in 1941. The prototype drug of penicillin is Benzylpenicillin.

Mechanism of action of penicillin

The cell wall synthesis inhibition by binding to penicillin-binding proteins (PBPs) which include transpeptidase enzymes. The inhibition of ‘transpeptidase’ by beta-lactam ring prevents cross-linking of  N-acetyl-muramic acid (NAM) and N-acetyl-glucosamine (NAG)  and finally Lysis of the cell (bactericidal).

penicillins

The penicillin must overcome the bacterial defenses and penetrate the outer cell-wall layers to the inner cytoplasmic membrane, where the PBPs including transpeptidase enzyme are located. In gram-negative bugs, penicillin must pass through channels known as porins. It is not interfered with by blood, pus, or tissue fluid. The resistance may develop due to penicillinase, mutation, and tolerance.

Mechanism of bacterial resistance to penicillins

  • By producing β-lactamases, which destroy the β-lactam ring for example S. aureus, E. coli, gonococci, H. influenzae, etc.
  • Due to altered PBPs which have less affinity for β-lactams, for example, S. pneumoniae
  • Due to decreased ability of a drug to penetrate to its site of action.

Some drugs of penicillin

  • Penicillin V
  • Aminopenicillins
  • Isoxazolyl penicillins
  • Carboxypenicillins
  • Ureidopenicillins
  • Benzylpenicillin (Penicillin G)

Benzylpenicillin (Penicillin G)

  • It is primarily active against Gram-positive bacteria and very few gram-negative bacteria.
    • Streptococci (except enterococci),
    • Bacillus anthracis, Cl. diphtheriae Cl. tetani / welchi
    • Listeria, T. pallidum & Borrelia, Leptospira
    • Gonococci, meningococci
    • E. coli and proteus (some species)
  • Acid-labile & also destroyed by penicillinase

Pharmacokinetics

It is well absorbed when given IM because when penicillin G was given orally it is destroyed by gastric acid (acid-labile).

It is distributed extracellularly (mainly) and poor penetration through BBB or synovial membrane (except when inflamed).

The excretion of a drug by active Tubular secretion ~90% and probenecid prevents it and prolongs its action.

Penicillin G  Preparations:

  • Penicillin G (Na+ or K+ salts, Crystalline penicillin): 6 hourly through IV /IM
  • Repository penicillins-IM :
    • Procaine penicillin:  12 hourly
    • Benzathine penicillin:  every 2 – 4 weeks
      • Should not be given  IV: Chance of thromboembolism
  • 1 MU = 600 mg

Adverse effects

  • Hypersensitivity
    • Rashes, itching, urticaria, fever, Dermatitis, bronchospasm, angioedema, joint pain, serum sickness, or anaphylactic reaction.
    • Anaphylaxis (rare but may be fatal)
    • Cross sensitivity among
      • Different types of penicillins
      • Other β-lactam antibiotics
      • Intradermal test before giving a full dose: 2-10 IU
  • Local irritation
    • Oral:  nausea, vomiting
    • IM: pain at the injection site
    • I.V: thrombophlebitis
  • Super-infection:  not common
  • Seizures on high dose (esp. in renal failure)
  • Jarish-Herxheimer reaction
    • Occurs during treatment of Syphilis (not common)
    • Shivering, fever,  myalgia, Exacerbation of lesions
    • Relief within 72 hours

Treatment of anaphylactic shock

  • Injection Adrenaline 0.3-0.5 mL of 1:1000 solution IM.
  • Injection Hydrocortisone 200 mg IV.
  • Injection Diphenhydramine 50-100 mg IV or IM.

Precautions before using penicillin

  • Before giving penicillin, a history of the previous administration and allergic manifestations, if any, must be noted.
  • In patients with a history of asthma, allergic rhinitis, hay fever, etc., there is an increased risk of penicillin allergy, hence it should be avoided.
  • Injection Adrenaline and hydrocortisone should be kept ready before injecting penicillin to treat the anaphylactic reaction.
  • A sensitivity test should be performed by intradermal test on the ventral aspect of the forearm. Itching, erythema, and wheal formation are observed. A negative skin test does not ensure absolute well beings or safety.

Uses of penicillins

  1. Streptococcal infections:
    • Pharyngitis(S. pyogens always sensitive), pneumonia, otitis media, meningitis
  2. Meningococcal meningitis
  3. Diphtheria
  4. Tetanus/gas gangrene
  5. Syphilis
  6. Rare infections :  Anthrax / Actinomycosis
  7. Prophylaxis
    • Rheumatic fever, gonorrhea, endocarditis

Drawbacks of benzylpenicillin

  • Degraded by acid in the stomach
  • Short half-life
  • Narrow spectrum, low efficacy against gram-negative bacteria
  • Destroyed by a penicillinase
  • Hypersensitivity reaction

Semi-synthetic Penicillin

  • Acid-resistant penicillins
    • Phenoxymethyl penicillin ( Penicillin V )
    • Aminopenicillins
  • Penicillinase-resistant penicillins
    • (Methicillin) cloxacillin, flucloxacillin, dicloxacillin, nafcillin
  • Extended-spectrum penicillins
    • Amino / Carboxy / Ureidopenicillins

Phenoxy-methyl penicillin (Penicillin V)

  • It is a semi-synthetic Penicillin
  • Acid stable
  • Can be given orally
  • Efficacy slightly lower than  Penicillin G
    • Especially for Neisseria  and Gram-negative bacteria
    • Used only for non-severe infections like streptococcal pharyngitis and prophylaxis

Penicillinase-resistant penicillins

  • Methicillin: no more used clinically
  • Cloxacillin/flucloxacillin, dicloxacillin, nafcillin: oral and/or parenteral
  • Relatively stable in acidic medium, absorbed  adequately after oral administration (30-80%)
  • Absorption is more  when taken on an empty stomach
  • Efficacy lower than penicillin G for penicillin-sensitive bacteria 
  • Methicillin:
    • First penicillinase-resistant penicillin
    • Acid labile and can not be given orally: only IV
    • MRSA: insensitive to all penicillinase-resistant penicillins as well as cephalosporins
      • Vancomycin, linezolid, etc. are used
    • Nephrotoxic (no more used therapeutically)
  • Cloxacillin/Flucloxacillin
    • Acid-resistant  and resistant to  penicillinases
    • Lower activity against penicillin G sensitive organisms
      • Should not  be used as a substitute
    • Not effective against MRSA
    • Flucloxacillin better absorbed when given orally and has longer t1/2.
  • Nafcillin
    • Also, a penicillinase-resistant penicillin
    • More stable than isoxazolyl penicillins against penicillinases but equally ineffective against MRSA
    • When given orally absorption is not predictable and erratic
    • Given intravenously to treat systemic staphylococcal infections.

Aminopenicillins

  • Amino substitution in the side chain
  • Oral absorption is reliable
  • It is commonly used penicillins
  • All have similar antibacterial effects and destroyed by penicillinases
  • Drugs: Ampicillin and Amoxicillin 
  • Ampicillin
    • Extended-spectrum:
      • Gram-positive bacteria and some additional gram-negative bacteria, some example shown below
        • H. influenzae, E. Coli, Proteus,
        • Salmonella and Shigella
        • Streptococcus viridans and enterococci
          • No effect on Pseudomonas, Klebsiella, or Bacteroids
    • Pharmacokinetics
      • It is not degraded by gastric acid
      • Adequate but incomplete oral absorption
        • Food interferes with the absorption
      • Excreted through kidney
      • Partly excreted in bile
        • Enterohepatic circulation
    • Bacampicillin:
      • Prodrug of Ampicillin
      • Higher plasma levels
      • Better tissue penetration
      • Less incidence of diarrhea
  • Amoxicillin
    • Better oral absorption
    • Less affected by food
    • Higher plasma levels
    • Less incidence of diarrhea
    • Less active against Shigella & H. influenzae

Uses

  1. Respiratory tract infections
  2. Urinary tract infection in pregnancy
  3. Meningitis due to listeria and H. influenzae
  4. SABE
  5. Typhoid, dysentery, cholecystitis
  6. Mixed infections or empirical treatment of severe infections in combination with other antimicrobial drugs

Adverse effects

  • Diarrhea: more common with ampicillin
  • Rash without true hypersensitivity especially in patients with lymphatic system diseases e.g. IM, ALL, or renal failure
  • Pseudomembranous colitis
  • Hypersensitivity

Anti-pseudomonal penicillins

  • Carboxypenicillins
    • Carbenicillin / Ticarcillin
  • Ureidopenicillin
    • Piperacillin
  • Carbenicillin
    • Active mainly against pseudomonas and proteus (increasing resistance)
    • Carbenicillin is less active than ampicillin against enterococci
    • Acid labile and destroyed by penicillinases
      • Inactive orally
    • The bleeding tendency on high doses
  • Ticarcillin
    • More potent and less adverse effects
  • Piperacillin
    • 8 times more potent than carbenicillin
    • Crosses BBB
    • Good activity against klebsiella also
    • Used mainly in systemic Pseudomonas infections usually with a second AMA.

β-Lactamase inhibitors

  • Weak antimicrobial action on their own
  • Protect β-lactams from inactivation by β-lactamase by suicide inhibition
  • Synergism with penicillins and cephalosporins resulting in efficacy against beta-lactamase-producing organisms.

β-Lactamase inhibitors drugs

  • Clavulanic acid
    • With amoxicillin (or ticarcillin, cephalosporins)
      • For respiratory tract and soft tissue infections, gonorrhea, etc.
  • Sulbactam
    • With ampicillin For gonorrhea  due to PPNG and mixed aerobic-anaerobic infections
  • Tazobactam
    • With piperacillin
    • For severe GI, respiratory, or urinary tract infections due to gram-negative bacteria mostly in combination with other AMAs.

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