Although penicillins remain some of the most important and widely used antibiotics in clinical practice, their use requires careful consideration of safety. Allergic reactions are the most common contraindication, ranging from mild rashes to life-threatening anaphylaxis. In addition, penicillins are associated with a range of adverse effects and have several drug-drug interactions, which this article aims to outline. Contraindications A penicillin allergy is the most commonly reported drug allergy in the United Kingdom, and a history of severe and immediate hypersensitivity reaction to any 𝛃-lactam agent contraindicates the use for penicillins. However, estimations suggest that only ~20% of patients labelled to have a penicillin allergy, have a true allergy. Other contraindications for penicillin use include: Previous acute generalised exanthematous pustulosis (AGEP) Flucloxacillin – previous history of flucloxacillin-associated jaundice/hepatic dysfunction Pivmecillinam – impaired esophageal transit, genetic metabolism anomalies that would lead to severe carnitine deficiency. Pivmecilinam is a pro drug metabolised to pivalic acid and mecillinam (active metabolite), pivalic acid can increase urinary secretion of carnitine as it is excreted partly as a conjugate with carnitine. Genetic anomalies such as carnitine transporter defect, methylmalonic aciduria or propionic acidaemia can cause carnitine deficiency alongside pivmecillinam. Adverse effects and cautions Penicillins are generally safe and most commonly may cause mild gastrointestinal disturbance, thrush and antibiotic-associated colitis. Severe cutaneous reactions including AGEP, Steven Johnsons syndrome and toxic epidermal necrolysis have been reported. Renal impairment increases risk of bleeding manifestations (including abnormal clotting tests) and neurological complications e.g. convulsions (higher risk in a history of seizures, epilepsy or meningeal disorders) Interference with laboratory tests: urinary glucose test, Coomb’s test, urinary or serum protein tests, tests using bacteria such as Guthrie test Side effects and cautions specific for certain penicillins have also been reported: Amoxicillin Kounis syndrome – serious allergic reaction that can lead to myocardial infarction Jarisch-Herxheimer reaction – when treating lyme disease Crystalluria – more likely with IV amoxicillin therapy (frequency unknown) → kidney injury Flucloxacillin Very rarely hepatitis and cholestatic jaundice (not related to dose or route of administration, can be delayed for up to 2 months post exposure) Hyperbilirubinemia in newborns, due to displacement of bilirubin from plasma protein sites Hypokalaemia at high doses, which can be resistant to potassium supplementation Pivmecillinam Can cause acute attacks of porphyria Risk of carnitine depletion; symptoms include muscle ache, fatigue and confusion. Can cause interference with neonatal screening test for isovaleric acidemia Can lead to oesophageal ulcer/oesophagitis Phenoxymethylpenicillin Patients with a past history of rheumatic fever receiving prophylaxis should consider an alternative antibiotic choice as they may harbour penicillin-resistant organisms Markedly impaired renal function increases risk of encephalopathy Benzylpenicillin sodium Contains sodium (1200mg contains 3.36mmol of sodium) – care with patients on a sodium restriction e.g. heart failure Large doses → hypokalaemia and hypernatraemia – use of a potassium sparing diuretic may be required Jarisch-Herxheimer reaction may occur when using for syphilis Benzylpenicillin sodium is incompatible with solutions that contain metal ions and drugs such as amphotericin, cimetidine, flucloxacillin and methylprednisolone, in the absence of evidence of compatibility, benzylpenicillin sodium should not be mixed with other medicinal products. Piperacillin/tazobactam Can cause leukopenia and neutropenia (especially with prolonged therapy) Contains sodium (9.44mmol per vial) – care with patients on a sodium restriction e.g. heart failure Hypokalaemia may present in patients who are taking medicinal products that also cause hypokalaemia or in patients with low potassium reserves (uncommon side effect) Haemophagocytic lymphohistiocytosis (HLH) (especially with prolonged therapy) Incompatible with sodium bicarbonate, lactated ringers solution, and should be administered separately from other antibiotics (mixing piperacillin/tazobactam with an aminoglycoside can result in inactivation of aminoglycoside) Ampicillin Maculopapular rashes can occur with glandular fever, however this may not represent a true penicillin allergy Interactions General class effects: Bacteriostatic drugs such as tetracyclines may interfere with the bactericidal effects of penicillins Reduced excretion of methotrexate Penicillins readily and actively undergo secretion by renal tubules: probenecid decreases renal tubular secretion of penicillins, leading to increased exposure to penicillins Inactivate oral typhoid vaccine Sulfinpyrazone may reduce excretion of penicillins Drug-specific: Flucloxacillin With paracetamol: ↑ risk of high anion gap metabolic acidosis (very rare) Probenecid and sulfinpyrazone ↓ renal tubular secretion of flucloxacillin → ↑ exposure to flucloxacillin ↓ response to sugammadex ↓ voriconazole levels (CYP450 inducer) Pivmecilinam Valproic acid, valproate or any medications that liberate pivalic acid due to risk of carnitine depletion Phenoxymethylpenicillin Neomycin ↓ absorption of phenoxymethylpenicillin Piperacillin/tazobactam Vecuronium: prolongation of neuromuscular blockade when used with piperacillin Created in BioRender. Boucher, M. (2025) https://BioRender.com/p37cgu2 Fig 2: renal tubular secretion of drugs inhibited by probenecid and aspirin References https://bnf.nice.org.uk/treatment-summaries/penicillins/ accessed 13/2/25 Amoxicillin 500mg Capsules – Summary of Product Characteristics (SmPC) – (emc) accessed 19/2/25 Flucloxacillin 250 mg capsules, hard – Summary of Product Characteristics (SmPC) – (emc) accessed 19/2/25 Pivmecillinam 200mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc). Last updated on emc: 22 Oct 2024. Accessed 19/2/25 Phenoxymethylpenicillin 250 mg Tablets – Summary of Product Characteristics (SmPC) – (emc) last updated on emc: 17 Sept 2024. Accessed 20/2/25 Phenoxymethylpenicillin 250mg Film-coated Tablets – Summary of Product Characteristics (SmPC) – (emc) last updated on emc: 04 Dec 2024. Accessed 23/2/25 Benzylpenicillin sodium 1200mg Powder for Injection – Summary of Product Characteristics (SmPC) – (emc) last updated on emc: 12 Sep 2021. 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