Penicillins are one of the most widely used classes of antibiotics. As broad-spectrum agents, they have several clinical indications, and are active against gram positive, gram negative and anaerobic bacteria. Penicillins are also considered safe for use in pregnancy and breastfeeding when antimicrobial therapy is indicated. Like carbapenems and cephalosporins, penicillins are classified as β-lactam antibiotics due to the presence of the β-lactam ring in their chemical structure. Mechanism of action Penicillins work by targeting bacterial cell walls which are essential for maintaining structural integrity. The β-lactam ring in penicillins binds to penicillin-binding proteins (PBP), which are transpeptidase enzymes responsible for cross-linking of the peptidoglycan cell wall. This inhibition weakens the cell wall, leading to lysis and bacterial death. Adobe stock Fig 1: the bacterial cell wall: gram negative vs gram positive Resistance Resistance can occur via several mechanisms: β-lactamase enzymes (e.g., penicillinase) that hydrolyse the β-lactam ring found in the structure of penicillins. To overcome this, some formulations combine a penicillin with a β-lactamase inhibitor (e.g., piperacillin/tazobactam, co-amoxiclav) Modified penicillin binding proteins with reduced affinity for penicillins. Reduced permeability or efflux pumps in gram-negative organisms. Mcstrother, CC BY 3.0 <https://creativecommons.org/licenses/by/3.0>, via Wikimedia Commons. https://upload.wikimedia.org/wikipedia/commons/d/d0/Penicillin_inhibition.svg Fig 2: Penicillin binding protein catalyses cross linking of bacterial peptidoglycan cell wall, penicillins bind and therefore inhibit BPB leading to bacterial cell death. Spectrum of activity and indications Amoxicillin – respiratory tract infections, UTIs; good oral absorption. Ampicillin – bronchitis, ear infections, UTIs; reduced oral absorption, inactivated by penicillinase, derivative of ampicillin but better absorbed and absorption not affected by food Co-amoxiclav (amoxicillin and clavulanic acid) – resistant Staph. aureus, E. coli, H. influenzae, Bacteroides, Klebsiella pneumoniae. Flucloxacillin – penicillinase-resistant; used in cellulitis and skin infections. Co-fluampicil (ampicillin and flucloxacillin) – streptococci and staphylococci. Phenoxymethylpenicillin (penicillin V) – gram positive bacteria and gram-negative cocci, inactivated by β-lactamase enzymes including penicillinase, used for prophylaxis against pneumococcal infections after splenectomy or following rheumatic fever; limited use in severe infections due to poor absorption. Pivmecillinam – prodrug of mecillinam; less active against gram positive bacteria and pseudomonas aeruginosa and streptococcus faecalis are practically resistant to mecillinam. Mainly used in UTIs. Benzylpenicillin sodium (penicillin G) – inactivated by beta-lactamase enzymes, used for meningitis, syphilis; only parenteral (acid labile). Piperacillin/tazobactam (piperacillin, a penicillin, and tazobactam, a β-lactamase inhibitor) – antipseudomonal; used in hospital-acquired pneumonia and septicemia, synergistic effect with gentamicin Temocillin – β-lactamase resistant; septicaemia, lower respiratory and urinary infections caused by susceptible gram negative bacteria Bezathine benzylpencillin – long acting, via IM injection, used for syphilis and prophylaxis of sensitive infections, not to be confused with benzylpenicillin sodium – a short acting preparation. Pharmacokinetics Penicillins generally distribute well into body tissues and fluids. When meninges are inflamed, they can also penetrate into the cerebrospinal fluid, with benzylpenicillin sodium commonly being indicated for bacterial meningitis. Penicillins are excreted primarily via the kidneys. The following table will describe the absorption, distribution, metabolism and excretion for commonly used penicillins: Penicillin name Route Absorption Distribution Metabolism Excretion Amoxicillin Oral/IV Tmax = 1h (oral) F~70% Protein binding = 18% 10-25% of dose is excreted as as inactive metabolite Renal Half life ~1h Ampicillin Oral/IV Tmax = 1-2 h (oral) F = <50%, ↓ with food Protein binding = 20% CSF if meninges inflamed Limited data Renal and bile Half life = 1-2 h Flucloxacillin Oral/IV F = 79%, ↓ with food Take at least 1 hour before or 2 hours after meals Protein binding = 85% Bone, small amount into CSF ~10% Renal (majority) and bile Half life = 53 minutes Pivmecilinam Oral Tmax = 1 hour Protein binding = 5-10% Pro-drug metabolised to mecillinam which is the active substance Renal (50%) and bile Half life = 1.2 hours Phenoxymethylpenicillin Oral Tmax = 45 minutes F = 60% Food ↓ Cmax but not overall exposure Take 30 minutes before meals or 2 hours after food Protein binding = 80% Widely distributed, entering pleural and ascitic fluids, CSF if meninges are inflamed Partially metabolised to penicilloic acid in the liver (inactive metabolite) Renal Small amounts bile Half life extended in renal impairment, dose adjustment may be required In renal failure, drug may be primarily excreted by liver Half life = 45 minutes Benzylpenicillin sodium IM/IV Tmax = 15-30 minutes (IM) Acid labile Protein binding = 60% Minimal (5-15%) Primarily renal (60-90%) Half life = 30 minutes Piperacillin/tazobactam IV Tmax = 30 minutes Protein binding = 30% Widely distributed Piperacillin metabolised to desethyl metabolite (low antimicrobial activity) Tazobactam metabolised to an inactive metabolite Primarily renal (80% of tazobactam and 68% of piperacillin) Dose adjustment required in renal impairment Half life = 0.7-1.2 hours: increases in renal impairment and hepatic cirrhosis 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. Accessed 20/2/25 Do you think you’re ready? Take the quiz below Pro Feature - Quiz Penicillins – Mechanism, Spectrum & Pharmacokinetics Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePharmacy Pro Challenge yourself with over 2100 multiple-choice questions to reinforce learning Learn More Rate This Article