- Penicillins are thiazolidine rings attached to a β-lactam ring.
- They can be classified into three groups based on function:
- Penicillins (e.g. penicillin G)
- Effective against GPC, GNC, GPR but NOT GNR.
- Very susceptible to β-lactamases.
- Anti-staphylococcal penicillins (flucloxacillin, oxacillin, diclox, nafcillin)
- Resistant to staphylococcal β-lactamase
- Active against staph and strep, but not against enterococci, anaerobic bacteria, GNC and GNRs.
- Extended spectrum penicillins (amoxicillin, piperacillin and ticarcillin)
- Effective against GPC, GNC, GPR and GNR.
- Susceptible to β-lactamases.
- 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.
- Four basic mechanisms
- Producing β-lactamase (most common)
- Modifying the PBP
- Impaired penetration of drug to PBP
- 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.
- 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
- These penicillins have greater Gram-ve cover due to increased ability to penetrate the outer cell membrane.
- Amoxycillin/ampicillin is especially useful in treating respiratory tract infections – sinusitis, otitis and LRTIs.
- 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.
- 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.
- Penicillin concentration in most tissues equals that of serum.
- Penicillin is also secreted in saliva and breast milk to levels ~3-15% that of serum.
- However, important to remember that penetration to eye, prostate and CNS is poor.
- Penetration to CNS is improved in meningitis.
- Mainly by kidneys. 10% by glomerular filtration and 90% by tubular secretion.
- 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.
- Overall, penicillin clearance is poorer in the newborn.
- As above
- 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.
- In renal failure, high doses of penicillin may cause seizures.
- Nafcillin is associated with neutropenia.
- Oxacillin is associated with hepatitis.
- Methicillin causes interstitial nephritis
- Large doses of penicillins may cause GIT upset – nausea, vomiting and diarrhea.