Penicillins

crop_square Key points

  • check_circle Bactericidal beta-lactam antibiotics with a 6-aminopenicillanic acid core
  • check_circle Bind to penicillin-binding proteins (PBPs) inhibiting cell wall synthesis
  • check_circle Older penicillins: narrow spectrum, mostly gram-positives
  • check_circle Newer penicillins: active against gram-negatives, improved beta-lactamase resistance
  • check_circle True penicillin allergies are rare, minor side effects common

crop_square Background and biochemistry

Penicillins, the first antibiotics produced on a large industrial scale, were originally isolated from Penicillium moulds. Scientists managed to synthesise and modify penicillins early on (1950es), which broadened their spectrum of activity. There are about 15 penicillin antibiotics in clinical use today. They all have 6-aminopenicillanic acid at their core, which is formed by a beta-lactam ring, a thiazolidine ring, and attached groups. The integrity of the beta-lactam ring is essential for penicillin antibiotics. It is the site of attack for beta-lactamases, a group of enzymes produced by bacteria resistant to (some) penicillins. When beta-lactamases cleave the beta-lactam ring, penicilloic acid is formed, which does not have antibiotic properties.

crop_square Mechanism of action

Penicillins inhibit cell wall synthesis. These bactericidal antibiotics bind to a group of proteins in the bacterial membrane, the so-called penicillin-binding proteins (PBPs). This disrupts the synthesis of peptidoglycan polymers, a major component of bacterial cell walls. (Much more so in gram-positive than in gram-negative organisms). Penicillins bound to PBPs also lower the inhibition of autolytic enzymes, which leads to cell wall lysis, and eventually, cell death. Dormant (metabolically inactive) bacteria have no active cell wall synthesis and are thus not susceptible to penicillins. The most important mechanism of resistance is bacterial beta-lactamase production (see above). Mutations affecting PBPs are also relevant. Penicillins may be combined with beta-lactamase inhibitors (e.g., clavulanic acid, tazobactam, sulbactam) to counter bacterial resistance.

crop_square Drugs and spectrum of activity

Natural penicillins
  • Penicillin G (Benzyl­penicillin)
  • Penicillin V (Phenoxy­methyl­penicillin)

Natural penicillins have a narrow spectrum of activity. They are highly effective against non-beta-lactamase producing gram-positive cocci. In many places in the world, only a fraction of Staphylococcus aureus isolates remains sensitive to natural penicillins. They are active against gram-positive rods such as Clostridium spp. and provide excellent coverage against spirochaetes. Activity against gram-negative cocci like Neisseria meningitides is limited.


Second-generation cephalosporins
  • Ampi­cillin
  • Amoxi­cillin

Aminopenicillins have a spectrum similar to natural penicillin regarding gram-positive bacteria but are more effective against Listeria monocytogenes and Enterococcus species. Aminopenicillins cover a wider range of gram-negative organisms. Many strains of the bacteria listed above are nowadays resistant to aminopenicllins, requiring them to be combined with beta-lactamase inhibitors like clavulanic acid.


Penicillinase-resistant penicillins (Antistaphylococcal Penicillins)
  • Methi­cillin
  • Naf­cillin
  • Diclox­acillin
  • Oxa­cillin

Antistaphylococcal penicillins were, as the name suggests, developed to counter Staphylococcus aureus and its ever-evolving antibiotic resistances. These drugs have a narrow spectrum of activity and are primarily indicated to treat methicillin-susceptible staphylococcus aureus (MSSA) but may be used for soft tissue infection caused by Streptococcus pyogenes.


Carboxypenicillins
  • Ticar­cillin
  • Carbeni­cillin
  • Piper­acillin
  • Mezlo­cillin
  • Azlo­cillin

Carboxypenicillins and Ureidopenicillins show improved coverage against gram-negative organisms. They are still susceptible to inactivation by beta-lactamases, despite a higher natural resistance compared to other penicillin subgroups. They are frequently combined with beta-lactamase inhibitors (piperacillin-tazobactam, ticarcillin-clavulanate) to provide broad-spectrum coverage including anaerobes. Examples of diagnoses regularly treated with these penicillins are neutropenic sepsis, hospital acquired pneumonia and mixed soft tissue and bone infections.

crop_square Pharmacokinetics

Most penicillins are rapidly absorbed with excellent tissue distribution. Due to their relatively short half-life, oral and intravenous penicillins need to administered frequently, usually every 4 to 6 hours. Slow-release drug forms, like intramuscular benzathine penicillin G, maintain stable drug concentrations for 7-10 days, allowing for the treatment of certain infections (early stages of syphilis) with a single dose. Blood-brain barrier penetration is generally limited but increased in meningitis. Penicillins are excreted by the kidneys with the notable exception of penicillase-resistant penicillins which are cleared hepatically.

crop_square Adverse drug effects

Penicillins have a reputation among the public for causing allergies, but this is likely overstated. Severe allergic reactions to penicillins are rare (less than 1%) and life-threatening events are still much rarer. Patients who reacted to penicillins in the past with minor adverse effects (e.g., delayed skin rash) may still be treated with penicillins or other beta-lactam antibiotics after discussion with a healthcare professional. Moreover, minor reactions to penicillin that occurred in the past do not necessarily persist for life. Life-threatening anaphylaxis due to penicillins usually comes on rapidly right after or during drug administration and requires immediate medical management. The very few patients with severe allergic reactions should avoid beta-lactam antibiotics for life.