Audio LecturePro Feature Cephalosporins 0:00 / 0:00 1x 0.25x 0.5x 0.75x 1x 1.25x 1.5x 1.75x 2x Cephalosporins are a group of beta-lactam antibiotics widely used to treat bacterial infections. They are bactericidal and act by inhibiting bacterial cell wall synthesis. Cephalosporins are classified into generations based on their antibacterial spectrum and structural characteristics, although their activity varies between individual drugs. This article explores the spectrum of activity and clinical indications of cephalosporins, comparing the key characteristics of first- to fifth-generation and newer agents. It explains their mechanism of action, pharmacokinetic properties, important adverse effects, contraindications, precautions and drug interactions. Spectrum of Activity and Indications for Use Cephalosporins are bactericidal agents with a broad spectrum of activity including gram-positive and gram-negative bacteria. They are traditionally classified into generations according to their antibacterial spectrum and structural characteristics. In general, later generations have increased activity against many Gram-negative bacteria, although this varies between individual agents. Some newer cephalosporins have activity against resistant organisms, including meticillin-resistant Staphylococcus aureus (MRSA). Cephalosporins possess a dihydrothiazine ring fused to the beta-lactam ring, leading to increased resistance to beta-lactamase enzymes (compared to that of penicillins). Cephalosporins differ in their susceptibility to beta-lactamases, and resistance can occur through beta-lactamase production, alterations in penicillin-binding proteins or reduced antibiotic penetration. Indications for use include septicaemia, pneumonia, meningitis, biliary tract infections, peritonitis and urinary tract infections. Cephalosporins will be used in line with local resistance patterns and guidance. Generation Examples Key points First generation Cefalexin, cefradine, cefadroxil, cefazolin Primarily active against Gram-positive bacteria, with limited Gram-negative activity. Second generation Cefaclor, cefuroxime, cefoxitin Cefuroxime is more resistant to some beta-lactamases than earlier cephalosporins and retains useful activity against Gram-positive bacteria, including Staphylococcus aureus. Third generation Cefixime, cefotaxime, ceftazidime, ceftriaxone Greater activity against many Gram-negative bacteria than earlier generations. Ceftazidime has activity against Pseudomonas aeruginosa. Fourth generation Cefepime Broad-spectrum activity against Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa. Cefepime is combined with Enmetazobactam; a penicillanic acid sulfone beta-lactamase inhibitor Fifth generation / advanced cephalosporins Ceftaroline fosamil, cefiderocol, ceftobiprole Ceftaroline is active against meticillin-resistant Staphylococcus aureus (MRSA). Ceftobiprole also has activity against MRSA. Cefiderocol is used for certain difficult-to-treat infections caused by aerobic Gram-negative bacteria, including some multidrug-resistant organisms. Cefiderocol is often described as a siderophore cephalosporin rather than simply a fifth-generation agent. Mechanism of Action Cephalosporins have the same mechanism of action as penicillins. Penicillin binding proteins have transpeptidase and carboxypeptidase activities, cephalosporins inhibit the final transpeptidation by forming covalent bonds with penicillin binding proteins. This leads to inhibition of the cross-linking of peptidoglycan in bacterial cell walls, structural weakening of peptidoglycan and ultimately bacterial cell swelling and death. Pharmacokinetics Cephalosporins can be administered parenterally or enterally. Important pharmacokinetic points to note are as follows: Ceftriaxone has a long half life (t 1/2) of around 8 hours, therefore is a good option to be given once a day via homecare services when suitable. Cephalosporins penetrate the cerebrospinal fluid poorly unless inflammation of the meninges is present i.e. in meningitis; cefotaxime and ceftriaxone can be used to treat central nervous system infections and cross the blood brain barrier. Cephalosporins are widely distributed and excreted mainly by the kidney via tubular secretion, however ceftriaxone is also eliminated partially in the bile (40%). The table below describes the key pharmacokinetic parameters for cephalosporins: Drug and route Absorption Distribution Metabolism Excretion Ceftriaxone IV / IM Peak plasma concentrations after IM administration are 50% of intravenous concentrations after administration of the same dose Tmax: 2-3 hours (IM) Tmax: 4-6 hours in CSF (IV) Volume of distribution 7-12 L 85-95% protein-bound Widely distributed into tissues and fluids, including CSF when the meninges are inflamed. Not metabolised systemically; converted to inactive metabolites by gut flora. 50-60% excreted unchanged in urine and 40-50% unchanged in bile. Half-life (T½) ~8 hours. Cefaclor Oral Well absorbed orally. Tmax: 30-60 minutes. Distribution parameters not separately detailed in the SmPC. No specific metabolic pathway detailed. 60-85% excreted unchanged in urine within 8 hours. T½: 0.6–0.9 hours; prolonged in renal impairment Cefalexin Oral Almost completely absorbed. Tmax ~1 hour. 10-15% protein-bound Not significantly metabolised 75-100% excreted as active drug in urine. T½: 1 hour Cefadroxil Oral Almost completely absorbed. Tmax: 1-1.3 hours. Approximately 18-20% protein-bound Not significantly metabolised ~90% excreted unchanged in urine within 24 hours. T½: 1.4-2.6 hours. Cefoxitin (Renoxitin) IV Bioavailability (F): 100% – given intravenously Protein binding 65–80%. Distributed into extracellular fluids, bone, lungs, bile and other tissues; CSF penetration varies. Not significantly metabolised Excreted unchanged by the kidneys. T½: 45 mins with normal renal function, CrCl 10-30ml/min T½ > 6 hours Cefixime (Suprax) Oral F: 22–54%. Approximately 70% protein-bound to albumin. Not significantly metabolised Excreted unchanged by the kidneys. Cefotaxime IV / IM Tmax: 5 minutes (IV), 30 minutes (IM) Volume of distribution 21-37 L; protein binding 25-40%. Widely distributed, including into CSF when meninges are inflamed. 15-25% metabolised to O-desacetylcefotaxime (active metabolite). Excreted as cefotaxime and o-desacetylcefotaxime by the kidneys, 2% by bile T½: 50-80 minutes for cefotaxime, 90 minutes for o-desacetylcefotaxime Ceftazidime IV / IM Peak concentrations reached rapidly with IM and IV administration 10% protein-bound, distributed into tissues and fluids; CSF penetration increases with meningeal inflammation. Not significantly metabolised Excreted unchanged by kidneys. T½: 2 hours. Ceftobiprole medocaril (Zevtera) IV Peak concentrations reached rapidly with IV administration Volume of distribution approximately 18 L; 16% protein-bound Prodrug; metabolised to active substance ceftobiprole; minimal further metabolism occurs. Excreted unchanged by kidneys. T½: 3 hours. Does not undergo renal tubular secretion. Cefepime/enmetazobactam (EXBLIFEP) IV Peak concentrations reached rapidly with IV administration Volumes of distribution: 16.9 L (cefepime), 20.6 L (enmetazobactam) 20% protein bound (cefepime), negligible for enmetazobactam Cefepime undergoes limited (7% of dose) metabolism; enmetazobactam undergoes minimal hepatic metabolism. Both are primarily excreted unchanged by kidneys. T½ 2.7 (cefepime) and 2.6 hours (enmetazobactam) Ceftaroline fosamil (Zinforo) IV Peak concentrations reached rapidly with IV administration Volume of distribution approximately 20.3 L; 20% protein bound. Prodrug; converted by plasma phosphatases to active ceftaroline, then to the inactive metabolite ceftaroline M-1. Primarily excreted by the kidneys. T½: 2.5 hours. Cefiderocol (Fetcroja) IV Peak concentrations reached rapidly with IV administration Volume of distribution approximately 18 L; 40-60%, protein bound, primarily to albumin. Not significantly metabolised Primarily excreted unchanged by the kidneys. T½: 2-3 hours. Contraindications Cephalosporins are contraindicated in patients with a known serious hypersensitivity to the relevant medicine or its excipients, according to the product information. A history of immediate or severe hypersensitivity to penicillins, other carbapenems, cephalosporins or other beta-lactams requires careful assessment because cross-reactivity is possible. Cross sensitivity between penicillins and first and early second generation cephalosporins is more likely (reported in up to 10% of patients) compared to third generation cephalosporins (reported in 2-3% of patients) Adverse Effects and Cautions Gastrointestinal Effects Cephalosporins can commonly cause gastrointestinal upset. Due to the broad spectrum of activity they can also (less commonly) cause antibiotic associated colitis. Neurotoxicity Neurotoxicity has been reported with cephalosporin treatment; symptoms include encephalopathy, myoclonus and seizures. Risk increases with severe renal impairment especially without dose adjustment. Nephrotoxicity Nephrotoxicity is more likely with first generation cephalosporins. For example reversible interstitial nephritis has been rarely reported with cefaclor and tubulointerstitial nephritis with cefixime. Ceftriaxone-associated precipitation Ceftriaxone can form a precipitate in the gall bladder and the kidneys which may look like gallstones and kidney stones on sonograms. Precipitates disappear after discontinuation and rarely cause symptoms. Furthermore, pancreatitis has been reported; in these cases most patients had risk factors for biliary stasis however ceftriaxone-related biliary precipitation cannot be ruled out as a causative factor in these cases. Immune mediated haemolytic anaemia Immune mediated haemolytic anaemia has been observed in patients receiving cephalosporins in adults and children. Skin reactions Severe cutaneous adverse reactions (SCAR), including Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP) have been reported with beta-lactam antibiotics. Effect on laboratory tests Cephalosporins can cause a false positive urinary glucose (if tested for reducing substances) and a false positive Coombs’ test. Interactions Warfarin Cephalosporins have an anti-vitamin K effect via inhibiting the reduction of vitamin K. Administration of cephalosporins with warfarin may augment its anticoagulant effects; INR should be monitored. Calcium-containing intravenous solutions Ceftriaxone can precipitate with solutions containing calcium Ceftriaxone is contraindicated in neonates who may require calcium containing intravenous solutions such as parenteral nutrition Diluents containing calcium, such as Hartmann’s solution, should not be used to reconstitute ceftriaxone Precipitation can also occur if ceftriaxone is administered through the same intravenous line as calcium containing solutions, therefore ceftriaxone should never be administered through the same line via Y site or multiway connectors. Simultaneous administration through separate lines is also not recommended. No reports of interactions have occurred with intramuscular or oral ceftriaxone and calcium containing medicines. Precipitation can also occur when Ceftobiprole medocaril is mixed with or administered in the same line as calcium containing solutions – this is not recommended Additive Nephrotoxicity Increased risk of nephrotoxicity when cephalosporins (which can cause nephrotoxicity) are concomitantly administered with nephrotoxic drugs such as aminoglycosides, amphotericin and high dose loop diuretics. Probenecid Probenecid can inhibit renal tubular secretion of certain cephalosporins, increasing their plasma concentrations. The clinical significance varies between agents. Cholestyramine Cefadroxil binds to cholestyramine, reducing the absorption of cefadroxil. References Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019. Hitchings BSc, M., Lonsdale, D., Burrage, D., Baker, E. (2022). The Top 100 Drugs – E-Book. Netherlands: Elsevier. Cephalosporins | Treatment summaries | BNF | NICE Cefaclor 500mg capsules – Summary of Product Characteristics (SmPC) – (emc) | 15784 Accessed 15/10/26 Cefalexin 250mg Capsules – Summary of Product Characteristics (SmPC) – (emc) | 555 Accessed 15/10/26 Cefadroxil 500mg Capsules – Summary of Product Characteristics (SmPC) – (emc) | 6543 Accessed 15/10/26 Renoxitin 1g Powder for solution for injection or Infusion – Summary of Product Characteristics (SmPC) – (emc) | 10505 Accessed 15/10/26 Suprax 200mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 15047 Accessed 15/10/26 Cefotaxime 1 g Powder for solution for injection vial – Summary of Product Characteristics (SmPC) – (emc) | 100184 Accessed 15/10/26 Ceftazidime 1g Powder for Solution for Injection or Infusion – Summary of Product Characteristics (SmPC) – (emc) | 6346 Accessed 15/10/26 Zevtera 500 mg powder for concentrate for solution for infusion – Summary of Product Characteristics (SmPC) – (emc) | 9164 Accessed 15/10/26 Ceftriaxone 1 g Powder for solution for injection vial – Summary of Product Characteristics (SmPC) – (emc) | 100176 Accessed 15/10/26 EXBLIFEP 2 g/0.5 g powder for concentrate for solution for infusion – Summary of Product Characteristics (SmPC) – (emc) | 15727 Accessed 15/10/26 Zinforo 600 mg powder for concentrate for solution for infusion – Summary of Product Characteristics (SmPC) – (emc) | 4297 Accessed 15/10/26 Fetcroja 1 g powder for concentrate for solution for infusion – Summary of Product Characteristics (SmPC) – (emc) | 11771 Accessed 15/10/26 Suprax 200mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 15047 Accessed 15/10/26 Do you think you’re ready? Take the quiz below QuizPro Feature Cephalosporins 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 400 multiple-choice questions to reinforce learning. Learn More Frequent questions **What are cephalosporins and how do they work?** Cephalosporins are bactericidal beta-lactam antibiotics that kill bacteria by inhibiting cell wall synthesis. They bind to penicillin-binding proteins and prevent peptidoglycan cross-linking, causing bacterial cell weakening, swelling and death. **What infections are cephalosporins used to treat?** Cephalosporins are used to treat infections including septicaemia, pneumonia, meningitis, biliary tract infections, peritonitis and urinary tract infections. Selection should follow local resistance patterns and treatment guidance. **How do the different generations of cephalosporins differ?** First-generation cephalosporins mainly target Gram-positive bacteria, whereas later generations generally provide greater activity against Gram-negative organisms. Specific agents also have additional activity, such as ceftazidime and cefepime against *Pseudomonas aeruginosa*, and ceftaroline and ceftobiprole against MRSA. **Which cephalosporins cross the blood–brain barrier?** Cefotaxime and ceftriaxone can enter the cerebrospinal fluid when the meninges are inflamed and may be used for central nervous system infections. Most cephalosporins penetrate cerebrospinal fluid poorly without meningeal inflammation. **What are the main adverse effects and precautions of cephalosporins?** Common or important risks include gastrointestinal upset, antibiotic-associated colitis, neurotoxicity, nephrotoxicity, immune-mediated haemolytic anaemia and severe skin reactions. Neurotoxicity is more likely in severe renal impairment without dose adjustment, while serious beta-lactam hypersensitivity requires careful assessment because cross-reactivity can occur. Rate This Article