Penicillin: Types, Mechanism of action, Pharmacology, Spectrum of Activity and Adverse effects

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Penicillin consists of a group of natural and semisynthetic antibiotics containing the chemical nucleus, 6-aminopenicillanic acid, which consists of a β-lactam ring fused to a thiazolidine ring. The naturally occurring compounds are produced by fungi of genus Penicillium. The penicillins differ from one another in the substitution at position 6, where changes in the side chain may modify the pharmacokinetic and antibacterial properties of the drug.

Mechanism of Action of Penicillin

The major antibacterial action of penicillins is due to their ability to inhibit a number of bacterial enzymes like penicillin-binding proteins (PBPs) that are essential for synthesis of peptidoglycan, a major cell wall content of gram positive bacteria. This ability to inhibit bacterial cell wall enzymes such as the transpeptidases usually confers on the penicillins bactericidal activity against gram positive bacteria. The bactericidal activity of the penicillins is often related to their ability to trigger membrane-associated autolytic enzymes that destroy the cell wall. Other minor mechanisms of action include inhibition of bacterial endopeptidase and glycosidase, enzymes involved in bacterial cell growth. There is also recent evidence suggesting that penicillins may inhibit RNA synthesis in some bacteria causing death without cell lysis, but the significance of these observations remains to be proven.

Penicillin group of antibiotics

  • Natural Penicillins
    • Benzylpenicillin (penicillin G)
    • Phenoxymethyl penicillin (penicillin V)
  • Semisynthetic Penicillins
    • Penicillinase resistant
      • Methicillin
      • Nafcillin
      • Cloxacillin
      • Dicloxacillin
      • Oxacillin
    • Extended spectrum
    • Aminopenicillins
      • Ampicillin
      • Amoxicillin
      • Bacampicillin
      • Pivampicillin
    • Carboxypenicillins
      • Carbenicillin
      • Ticarcillin
    • Ureidopenicillins
      • Azlocillin
      • Mezlocillin
      • Piperacillin
    • Penicillin + β-lactamase inhibitor combinations
      • Ampicillin-sulbactam
      • Ticarcillin-clavulanate
      • Amoxicillin-clavulanate
      • Piperacillin-tazobactam

Pharmacology of Penicillin

Oral absorption differs markedly among the penicillins. As a natural congener of penicillin G, penicillin V resists gastric acid inactivation and is better absorbed from the gastrointestinal tract than is penicillin G. Amoxicillin is a semisynthetic analog of ampicillin and has greater gastrointestinal absorption than ampicillin (95 versus 40% absorption). Bacampicillin is an ampicillin ester that is absorbed considerably better from the gastrointestinal tract than is ampicillin or amoxicillin. This ester is inactive until naturally occurring esterases in the intestinal mucosa and serum hydrolyze them to release the parent compound, ampicillin, into the serum. The isoxazolyl penicillins, such as oxacillin, cloxacillin, dicloxacillin, and nafcillin, are acid stable and are also absorbed from the gastrointestinal tract, in contradistinction to certain other antistaphylococcal penicillins, such as methicillin, which are not acid resistant and cannot be given via the oral route. Repository forms of penicillin G, available in procaine or benzathine, delay absorption from an intramuscular depot. Procaine penicillin G provides detectable levels for 12 to 24 h, suitable for treatment of uncomplicated pneumococcal pneumonia and gonorrhea due to fully susceptible organisms. Benzathine penicillin G achieves very low levels in blood for prolonged periods (3 to 4 weeks) and is useful for the therapy of syphilis and for prophylaxis of streptococcal pharyngitis and rheumatic fever. Penicillins are well distributed to many body compartments, including the lungs, liver, kidneys, muscle, bone, and placenta. Penetration into the eye, brain, cerebrospinal fluid (CSF), and prostate is poor in the absence of inflammation. These drugs are metabolized to a small degree and are rapidly excreted, essentially unchanged, via the kidneys. With average half-lives of 0.5 to 1.5 h, they are usually administered every 4 to 6 h to maintain effective levels in blood. The renal tubular excretion of penicillins can be blocked by probenecid, thus prolonging their half-lives in serum. Dosage reduction of most penicillins is necessary only in severe renal insufficiency (creatinine clearance of ≤10 ml/min). Dosages of all penicillins except nafcillin and the isoxazolyl penicillins are adjusted for hemodialysis. Peritoneal dialysis requires dosage reduction for carbenicillin and ticarcillin.

 

Spectrum of Activity of Penicillins

Penicillins have activity against most gram-positive and many gram-negative and anaerobic organisms. Penicillin G is very effective against penicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, viridians group streptococci, Streptococcus bovis, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, anaerobic cocci, Clostridium spp., Fusobacterium spp., Prevotella spp., and Porphyromonas spp. However, the occurrence of Penicillin resistant Pneumococci has recently been increasing worldwide. Penicillin is the drug of choice for syphilis and Actinomyces infections. Penicillin V has a spectrum of activity similar to that of penicillin G except that it is less active against N. gonorrhoeae. Penicillinase-resistant penicillins, of which methicillin is the prototype, are primarily effective against penicillinase-producing staphylococci. The agents are at least 25 times more active than other penicillins against penicillinase-positive staphylococci. Although they are also active against S. pneumoniae and S. pyogenes, their MICs for these organisms are higher than those of penicillin G. They are not active against enterococci, members of the family Enterobacteriaceae, Pseudomonas spp., or members of the Bacteroides fragilis group. Ampicillin and amoxicillin have spectra of activity similar to that of penicillin G, but they are more active against enterococci and Listeria monocytogenes. Although they are also more active against Haemophilus influenzae and Haemophilus parainfluenzae, up to 35% of H. influenzae isolates are resistant, usually because of β -lactamase production. Salmonella and Shigella spp., including Salmonella enterica serovar Typhi, are susceptible to these agents. Ampicillin is more effective against shigellae, whereas amoxicillin is more effective against salmonellae. Both of these agents are degraded by β -lactamase and are inactive against many Enterobacteriaceae and Pseudomonas spp.The carboxypenicillins and ureidopenicillins have increased activity against gram-negative bacteria that are resistant to ampicillin. Although these drugs are susceptible to staphylococcal penicillinase, they are more stable against hydrolysis by the β -lactamases of Enterobacteriaceae and Pseudomonas aeruginosa. Carbenicillin and ticarcillin are relatively active against streptococci as well as against Haemophilus spp., Neisseria spp., and a variety of anaerobes. They inhibit Enterobacteriaceae but are inactive against Klebsiella spp. Although carboxypenicillins are not particularly active against the enterococci, they may act synergistically with aminoglycosides against these organisms.The ureidopenicillins have greater in vitro activity against streptococci and enterococci than do the carboxypenicillins, and they inhibit more than 75% of Klebsiella spp. They have excellent activity against many Enterobacteriaceae and anaerobic bacteria, including members of the B. fragilis group. On a weight basis, their activities in decreasing order of potency against P. aeruginosa are as follows: piperacillin, azlocillin> mezlocillin> ticarcillin > carbenicillin. These agents also act synergistically with aminoglycosides against P. aeruginosa.

 

Adverse Effects of Penicillins

Common reactions to penicillins include allergic skin rashes, diarrhea, and drug fever. Severe anaphylactic reactions, which can be fatal, may occur in previously sensitized patients rechallenged with penicillins, but fortunately, such reactions are quite rare. At high doses (usually >30 x106 U/day), penicillin G can cause myoclonic twitching and seizures due to central nervous system toxicity. All of the penicillins may cause interstitial nephritis on an allergic basis, but methicillin is more likely than the other penicillins to cause this complication. Hepatitis has been associated with prolonged use of oxacillin. High-dose carbenicillin can result in sodium overload and hypokalemia. Neutropenia may occur with any of the penicillins. Thrombocytopenia and Coombs-positive hemolytic anemia are rare complications of penicillin therapy. Bleeding tendencies due to interference with platelet function can occur with the use of carboxypenicillins and ureidopenicillins. Although pseudomembranous colitis has been associated with all the penicillins, it occurs more frequently with ampicillin.

Reference: Manual of clinical Microbiology; Volume 1; 9th Edition:Patrick R. Murray, Ellen JO Barron, James H. Jorgensen, Marry Louise Landry and Michael A. Pfaller.

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