PENICILLINS

1. Penicillins are thiazolidine rings attached to a β-lactam ring.
2. They can be classified into three groups based on function:
   • Penicillins (e.g. penicillin G)
     1. Effective against GPC, GNC, GPR but NOT GNR.
     2. Very susceptible to β-lactamases.
   • Anti-staphylococcal penicillins (flucloxacillin, oxacillin, diclox, nafcillin)
     1. Resistant to staphylococcal β-lactamase
     2. Active against staph and strep, but not against enterococci, anaerobic bacteria, GNC and GNRs.
   • Extended spectrum penicillins (amoxicillin, piperacillin and ticarcillin)
     1. Effective against GPC, GNC, GPR and GNR.
     2. Susceptible to β-lactamases.

1. They function as cell wall inhibitors by interfering with the transpeptidation reaction of bacterial cell wall synthesis.
   • Bacterial cell wall is made up of peptidoglycan, whose synthesis is catalysed by the enzyme penicillin binding protein (PBP)
   • PBP is bound covalently by the β-lactam ring, and thus the bacterial cell wall breaks down and the bacteria dies.
   • Note that because of its mechanism of action, β-lactamase antibiotics only kill bacteria that are actively dividing and generating cell wall.
2. Resistance
   • Four basic mechanisms
     1. Producing β-lactamase (most common)
     2. Modifying the PBP
     3. Impaired penetration of drug to PBP
     4. Drug efflux.

Note that modifying the target PBP is the main mechanism of resistance in MRSA. The PBP has a very low affinity for penicillin, and are only inhibited at high, clinically unachievable concentrations.

Impaired penetration of antibiotic to PBP only occurs in Gram-ve bacteria due to their impermeable outer cell wall membrane.

Efflux pumps may be present in Gram-ve bacteria too.

1. Clinical indications
   • Penicillins: streptococci, meningococci, staph (non-β-lactamase producing staph), treponema pallidum and spirochetes (syphilis), clostridium spp., actinomyces and other GPR and non-β-lactamase producing GNB.
   • Anti-staph penicillins: β-lactamase producing staph (but note that the non-β-lactamase producing staphs and streps are also susceptible). Importantly, enterococci, listeria (GPR) and MRSA are all resistant.
   • Extended spectrum penicillins
     1. These penicillins have greater Gram-ve cover due to increased ability to penetrate the outer cell membrane.
     2. Amoxycillin/ampicillin is especially useful in treating respiratory tract infections – sinusitis, otitis and LRTIs.
     3. Ticarcillin and piperacillin are effective against GNRs – Klebsiella and Pseudomonas.

Note that usually a penicillin is combined with an aminoglycoside or a fluroquinolone in order to treat Pseudomonas infections.

Penicillins may also be combined with a β-lactamase inhibitor to extend the spectrum to cover β-lactamase producing staph and β-lactamase producing GNB.

1. PO or IV

Note that all penicillins (Except amoxicillin) should be given 1-2 hours before/after meals to minimize binding to food proteins and acid inactivation.

Probenecid (A drug that inhibits secretion of weak acids) may be used to prolong half-life.

1. Penicillin concentration in most tissues equals that of serum.
2. Penicillin is also secreted in saliva and breast milk to levels ~3-15% that of serum.
3. However, important to remember that penetration to eye, prostate and CNS is poor.
   • Penetration to CNS is improved in meningitis.

1. Mainly by kidneys. 10% by glomerular filtration and 90% by tubular secretion.
2. The T ½ is 30-60 minutes, but may extend to 10 hours in renal failure. Hence, it is important to adjust the dose.
   • However, the anti-staph penicillins are cleared by biliary secretion and therefore do not need dose adjustments.
3. Overall, penicillin clearance is poorer in the newborn.

1. As above

1. Hypersensitivity reactions
   • All penicillins are cross reactive. Allergy is due to the degradation products of penicillin.
   • Note that a prior history of allergy is quite unreliable.
   • Rarely, a patient may develop interstitial nephritis, haemolytic anaemia or a vasculitis.
2. In renal failure, high doses of penicillin may cause seizures.
3. Nafcillin is associated with neutropenia.
4. Oxacillin is associated with hepatitis.
5. Methicillin causes interstitial nephritis
6. Large doses of penicillins may cause GIT upset – nausea, vomiting and diarrhea.