• First Generation Cephalosporins:  Cefadroxil

  • Individual Drug Profiles

  Cefadroxil: Audio Overview

  • Cefadroxil Introduction^2,3,4

    • Cefadroxil is an orally administered, first‑generation cephalosporin with excellent activity against methicillin‑susceptible staphylococci, streptococci, and a limited spectrum of Gram‑negative bacilli, used primarily for skin and soft‑tissue, urinary tract, and streptococcal pharyngeal infections.⁸ 

    • Cefadroxil exhibits a long elimination half‑life relative to other first‑generation agents which permits once‑ or twice‑daily dosing.⁷

      • This characteristic makes cefadroxil particularly appropriate as an attractive oral step‑down option in musculoskeletal and other deep‑seated infections when organisms are susceptible.

    •  Cefadroxil | Uses, Dosage, Side effects & Mechanism | Duricef

      Attribution He-Info  Cefadroxil | Uses, Dosage, Side effects & Mechanism | Duricef https://www.youtube.com/watch?v=KnXQaSB1o7w July 21, 2023 He_Info https://www.youtube.com/@HeInFo123

  • Cefadroxil Chemistry and Antibacterial Spectrum

    • Cefadroxil is a semisynthetic first‑generation cephalosporin, structurally related to cephalexin but with a para‑hydroxyphenyl side chain that increases oral bioavailability and prolongs elimination.⁶ 

      • Cefadroxil is bactericidal and targets primarily Gram‑positive cocci, including Staphylococcus aureus (MSSA) and Streptococcus pyogenes, with modest activity against some Enterobacterales such as Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae  when β‑lactamase production is limited.⁴

    • Clinically cefadroxil covers typical pathogens in uncomplicated skin and soft‑tissue infections, lower urinary tract infections, and streptococcal pharyngitis.^2,3,4,9

      • However, cefadroxil does not reliably cover methicillin‑resistant S. aureus, enterococci, anaerobes, or most hospital‑associated multidrug‑resistant Gram‑negative organisms. 

        • This relatively narrow spectrum may be viewed as beneficial since it limits damage to the microbiota compared with broader‑spectrum cephalosporins and fluoroquinolones.

  • Mechanism of Bactericidal Action

    • Beta-Lactam Core and Target

      • Cefadroxil belongs to the β-lactam class of antibiotics.^10,12  

        • Bactericidal activity depends on structural integrity of the highly reactive, four-membered β-lactam ring.

      • The mechanism of action is the inhibition of bacterial cell wall synthesis.¹¹ 

        • The bacterial cell wall is a unique and essential structure, one not present in eukaryotic human cells, providing the basis of drug selectivity.

          • This wall is composed of a rigid, mesh-like polymer known as peptidoglycan, meeting the requirements for structural integrity necessary to maintain the bacterial cell shape and protect it from osmotic lysis due to the hypotonic environment of the human body.¹³ 

    • Covalent Binding to Penicillin-Binding Proteins (PBPs)^3,11,14  

      • Cefadroxil and its Interactions with PBPs

      • Cefadroxil bactericidal activity involves both targeting and inactivating certain bacterial enzymes, the penicillin-binding proteins (PBPs).

        • These enzymes are anchored on the inner side of the bacterial cell wall and function as transpeptidases.

      • PBPs are responsible for the final, critical step of peptidoglycan synthesis which is cross-linking of adjacent glycan strands.

        • Cross-linking is achieved by forming peptide bridges between the D-alanyl-D-alanine termini of adjacent stem peptides.

          • Cefadroxil, which functions as a structural analog of this natural D-alanyl-D-alanine substrate, possesses a high affinity for the PBP active site.¹²

        • Cefadroxil binding to the PBP active site involves acylation forming a stable acyl-enzyme form that irreversible inhibirs the enzyme.

          • Irreversible inhibition due to acylation prevents the inhibited enzyme from participating in biosynthesis stepsenzymes from the biosynthetic process.

          • In pathogens such as Streptococcus pneumoniae, cefadroxil has been demonstrated to be an effective inhibitor of multiple essential PBPs, including PBP1a, PBP1b, and PBP2B.

    • Bacterial Cell Death^3,4  

      • By inhibiting the transpeptidase function of PBPs, cefadroxil blocks the third and final stage of bacterial cell wall synthesis.¹⁵ 

        • This blockade prevents the formation of new, stable cross-links, thereby halting the expansion, repair, and maintenance of the peptidoglycan sacculus.

      • Inhibition of transpeptidase function of PBPs is particularly consequential in bacteria actively growing and dividing.

        • Cell division under these circumstances produces defective cross-length cell walls.

        • Concurrently, bacterial autolytic enzymes, utolysins, that are normally involved in the controlled remodeling and cleavage of the cell wall during growth, continue to function.

          • Failure of bacterial cell membrane as result of cefadroxil is the combination of both inhibition of cell wall synthesis and continuing autolysis. The cell wall, weakened by these processes, are insufficient to counteract the high internal osmotic pressure of the bacterial cytoplasm, resulting in cell lysis and bacterial death.

            • Cefadroxil is classified as the bactericidal drug is the result of drug-induced bacterial cell lysis.

      • Sources (1) Bush, K  Bradford  P  β-Lactams and β-lactamase inhibitors: An overview. Cold Spring Harbor Perspectives in Medicine, 6(8), a025247. https://pmc.ncbi.nlm.nih.gov/articles/PMC4968164/ Comprehensive review of β-lactam antibiotics, including inhibition of penicillin-binding proteins (PBPs) and downstream effects on cell wall integrity. (2) Cho, H., Uehara, T., & Bernhardt, T. G. Beta-lactam antibiotics induce a lethal malfunction in the of the bacterial cell wall synthesis machinery. Cell. 2014 December 4;159(6) : 1300-1311. https://pmc.ncbi.nlm.nih.gov/articles/PMC4258230/ Details how inhibition of peptidoglycan cross-linking triggers autolytic enzymes, contributing to osmotic lysis.

         

  • Cefadroxil Pharmacokinetics

    • Cefadroxil Absorption^3,11

      • Cefadroxil is rapidly and almost completely absorbed from the gastrointestinal tract following oral administration.

        •  Cefadroxil is noted for its excellent oral bioavailability, likely at least 90%.¹⁶

      • Efficient uptake is not based on passive diffusion..

        • Cefadroxil, like other aminocephalosporins and aminopenicillins, is a substrate for the high-capacity, proton-coupled intestinal peptide transporter, PepT1 (SLC15A1).^17,18  

          • This transporter, located on the apical membrane of enterocytes in the small intestine, translocates drug into the portal circulation, accounting for its high bioavailability.

        • Sources Daniel, H., & Kottra, G. (2004) The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pflügers Archiv – European Journal of Physiology, 447(5), 610–618. https://pubmed.ncbi.nlm.nih.gov/12905028/ This paper provides a foundational description of PepT1 structure, proton-coupled transport mechanics, and substrate promiscuity that explains why β-lactam antibiotics such as cefadroxil are efficiently absorbed. Brandsch, M. (2013) Drug transport via the intestinal peptide transporter PepT1. Current Opinion in Pharmacology, 13(6), 881–887. https://pubmed.ncbi.nlm.nih.gov/24007794/ A modern, authoritative review integrating molecular structure, proton coupling, and clinical relevance—directly supporting the transporter conformation and proton gradient depicted in the image.

      • An important clinical advantage of cefadroxil, distinguishing it from many other oral antibiotics (such as ampicillin or cefaclor), is that its absorption is not significantly affected by the presence of food.

      • While co-administration with a meal may slightly delay the time to peak concentration (T_max), the total extent of absorption remain unchanges. This characteristic encourages, patients to take the medication with meals to minimize the common gastrointestinal side effects, without concern for compromising therapeutic efficacy.¹⁹

    • Cefadroxil Distribution

      • After absorption, cefadroxil is widely distributed throughout the body, into various tissues and fluids.^4,20 

        • An important parameter affecting drug distribution is plasma protein binding.^4,11,16 

          • Cefadroxil exhibits low protein binding, a highly favorable characteristic.

            • Cefadroxil is found bound to plasma proteins at a level of about 20% (low).

              • This low binding is clinically important.

                • Only the unbound, or "free," fraction of a drug is pharmacologically active and capable of diffusing from the vasculature into the interstitial space to reach the site of infection.

                • With approximately 80% of the drug in the plasma free and available, cefadroxil can readily achieve effective concentrations at target sites.

      • Cefadroxil's volume of distribution (V_d) is approximately 0.31 L/kg, suggesting good distribution into the extracellular fluids of the body.^4,11,21

        • Cefadroxil achieves excellent penetration into key infection sites.

          • The presence of cefadroxil has been described in  sputum, muscle, and prostate tissue.

            • Cefadroxil appears especially effective at penetrating skin-blister fluid, where its penetration appears better than that observed with cephalexin.

              • Such observations support cephalexin first-line use in skin and skin structure infections (SSTIs).

            • Cefadroxil crossed the placenta and is distributed in low, but detectable, concentrations into breast milk.

    • Cefadroxil Metabolism

      • Cefadroxil exhibits very minimal metabolism.²⁰

    • Cefadroxil Excretion ^3,4,11

      • Cefadroxil is eliminated almost entirely by the kidneys.

        • Over 90% of an administered dose is excreted unchanged as active, parent drug in the urine within a 24-hour period.

        • Renal elimination involves two mechanisms.^4,23 

          • (1) Glomerular filtration in which the free, unbound fraction of the drug is filtered at the glomerulus.

          • (2) Active tubular secretion also occurs in which cefadroxil is "pumped" into the tubular lumen by transporters in the proximal tubule.

        • This reliance on renal function for elimination means that in patients with renal impairment, the drug's clearance is severely compromised, and the drug will accumulate to potentially toxic levels.

         

    • Summary: Cefadroxil Pharmacokinetics

December 2025