• First Generation Cephalosporins:  Cefadroxil

  • Cefadroxil Pharmacodynamics: The fT > MIC Target ² 

    • As a β-lactam antibiotic, cefadroxil exhibits time-dependent bactericidal activity.

      • Time -dependent bactericidal activity means its efficacy is not correlated with the peak concentration (C_Max) it achieves, but rather with the duration of time that the free drug concentration remains above the minimum inhibitory concentration (fT > MIC) of the target organism.

        • "fT refers to the percentage of time the free (unbound) concentration of a beta-lactam antibiotic stays above the Minimum Inhibitory Concentration (MIC) of a pathogen during dosing interval, i.e. %fT>MIC)

      • The typical pharmacodynamic (PD) target for cephalosporins to achieve bacteriostasis and efficacy in most clinical infections is an fT > MIC of 40-50% of the dosing interval.

      • Here pharmacokinetic and pharmacodynamic relationship is apparent PK/PD integration becomes clear.^3,4

        • Cefadroxil's longer half-life results in a longer fT > MIC for any given dose and MIC value, compared to cephalexin.

          • Accordingly, cefadroxil may be dosed less frequently compared to cephalexin.

  • Cefadroxil Antimicrobial Spectrum and In Vitro Activity

     

    • As a first-generation cephalosporin, cefadroxil's spectrum of activity is focuses on Gram-positive organisms but exhibits clinically useful activity against a select group of Gram-negative bacilli.^5,6,7  

      • Gram-Positive Anaerobes: Principal Targets for Cefadroxil

         

        • Gram-Positive Anaerobes: Some Principal Targets for Cefadroxil

          Staphylococcus aureus Basics Attribution https://www.cdc.gov/staphylococcus-aureus/about/index.html

           

        • Gram-Positive Anaerobes: Some Principal Targets for Cefadroxil

          Streptococcus pyrogenes (Group A Strep) Attribution NIAID, CC BY 2.0 <https://creativecommons.org/licenses/by/2.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Streptococcus_Pyogenes_(Group_A_Strep)_(52602981880).jpg

        •  

          Gram-Positive Anaerobes: Some Principal Targets for Cefadroxil

          Streptococcus pneumoniae Attribution What is Pneumococcal Disease? National Foundation for Infectious Diseases. https://www.nfid.org/infectious-disease/pneumococcal/

        • Staphylococcus aureus^10,11,12

          • Cefadroxil demonstrates excellent activity against Methicillin-Susceptible S. aureus (MSSA), which includes strains that produce penicillinase (a beta-lactamase that hydrolyzes penicillin but not cephalosporins).

            • Cefadroxil remains a first-line oral agent for confirmed MSSA infections.^2,9

        • Streptococcus species:

          • It is highly active against Streptococcus pyogenes (Group A β-hemolytic streptococci, or GAS), the causative agent of pharyngitis

            • Cefadroxil is also active against Streptococcus pneumoniae.

        • In Vitro Potency (MIC Data)²

          • When its potency is formally tested, cefadroxil activity is confirmed.

            • For MSSA isolates collected from pediatric patients with musculoskeletal infections, the in vitro activity of cefadroxil was found to be equivalent to that of cephalexin.

              • Both drugs shared an MIC₅₀ (concentration to inhibit 50% of isolates) of 2 µg/mL and an MIC₉₀ (concentration to inhibit 90% of isolates) of 4 µg/mL.

      • Gram-Negative Aerobes (Urinary Tract Infections)^11,13  

        • Cefadroxil's Gram-negative activity is limited to a few key species, primarily those responsible for uncomplicated urinary tract infections.

          • Cefadroxil in vitro activity and activity in clinical infections include:

            •  Escherichia coli

            • Klebsiella species (e.g., K. pneumoniae), and

            • Proteus mirabilis

          • Rationale for FDA's Position on Cefadroxil

            "Cefadroxil is FDA-approved for the treatment of: Urinary tract infections caused by E. coli, P. mirabilis, and Klebsiella species. Skin and skin structure infections cause by staphylococci and/or streptococci. Pharyngitis and/or tonsillitis caused by Streptococcus pyogenes (Group A beta-hemolytic streptococci). The cefadroxil webpage on the FDA Antibacterial Susceptibility Test Interpretive Criteria (STIC) website does not provide minimum inhibitory concentration (MIC) or disk diffusion breakpoints but includes a statement that, “Susceptibility of Enterobacteriaceae to cefadroxil may be deduced from testing cefazolin.” However, the cefazolin webpage on the FDA STIC website states that,  'Separate susceptibility test interpretive criteria for Enterobacteriaceae for therapy of uncomplicated urinary tract infections are not recognized at this time.' Furthermore, it has been shown that cefazolin surrogate susceptibility breakpoints do not accurately predict cefadroxil activity against Enterobacterales due to an unacceptably high false-susceptible rate. To note, cefadroxil STIC, either direct or surrogate, are not provided by the Clinical and Laboratory Standards Institute (CLSI), CLSI M100 Ed32:2022. Based on the information noted above, the Agency has determined that the following statement should be removed from the FDA STIC webpage for cefadroxil: “Susceptibility of Enterobacteriaceae to cefadroxil may be deduced from testing cefazolin.” (5/4/2022)

     

    • FDA-Approved Indications

      • Skin and Skin Structure Infections (SSTIs)

      • Pharyngitis and/or Tonsillitis

      • Urinary Tract Infections (UTIs)

        • • Skin and Skin Structure Infections (SSTIs)

            • Indication

              • Cefadroxil is indicated for the treatment of mild-to-moderate SSTIs.

                • These indications include common presentations such as cellulitis, cutaneous abscesses (post-incision and drainage), furunculosis, and impetigo.^10,12,13 

            • Pathogens

              • Cefadroxil indicated use is specifically for infections caused by Staphylococci (MSSA) and/or Streptococci, the two most common pathogens in this setting.

            • Clinical Evidence^15,16,17

              • In appropriate settings, see above, cefadroxil appears to be both they highly effective and reasonable choice.

                • Its pharmacological profile is ideally suited for this indication, given excellent skin and soft tissue distribution with improved penetration into skin-blister fluid compared to cephalexin.

                • These factors, along with potent activity against both staphylococcal and streptococcal infection makes cefadroxil a first-line agent for uncomplicated, non-purulent cellulitis (likely streptococcal) or as oral therapy for mild purulent infections (staphylococcal).

          • Pharyngitis and Tonsillitis (Group A Streptococcus)

            • Indication^10,12,13

              • Cefadroxil is indicated for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (Group A β-Hemolytic Streptococci, or GAS).

            • Clinical Context¹⁸

              • Treatment of pharyngitis and tonsillitis highlight some pharmacological advantages of cefadroxil administration.

                • Primary goals of treating Group A β-Hemolytic Streptococci pharyngitis involves not only symptomatic improvement, but also complete bacteriological eradication of S. pyogenes from the nasopharynx.

                • This approach addresses prevention of non-suppurative sequelae of acute rheumatic fever.

          • Urinary Tract Infections (UTIs)

            • Indication

              • Cefadroxil is indicated for the treatment of uncomplicated UTIs (e.g., cystitis) due to susceptible strains of E. coli, P. mirabilis, and Klebsiella species.^10,12,13

            • Clinical Discussion¹⁹ 

              • The role of cefadroxil in treating UTIs describes evolution of antimicrobial agents of choice.

                • For many years, first-generation cephalosporins were relegated to second-line status, as result of perceived superiority of trimethoprim-sulfamethoxazole and, more recently, the widespread use of fluoroquinolones.¹⁹ 

            • Fluoroquinolone-Sparing Approach

              • The contemporary antibacterial era is defined both by widespread antimicrobial resistance and a new appreciation for antibiotic-associated toxicity.

              • Amidst the crisis of "bad bugs, few drugs"¹⁹   and mounting concerns over fluoroquinolone-driven resistance and their black-box warnings for serious adverse events (e.g., tendon rupture, aortic dissection), cefadroxil is being  reevaluated as a highly valuable, narrow-spectrum, fluoroquinolone-sparing alternative.¹⁹ 

            • The pharmacokinetic profile of cefadroxil appears ideal for treating cystitis.

              • Cefadroxil is well-absorbed orally, is not metabolized, and administration results in bactericidal concentrations of active drug directly at the site of infection, the urine.

              • For a confirmed susceptible E. coli cystitis, cefadroxil (or cephalexin) is now considered a preferred, first-line choice.^5,19

  • Adverse Reactions

    • The most common adverse reactions are gastrointestinal and hypersensitivity.^20,21,22

      • Gastrointestinal adverse effects include:

        • Diarrhea

        • Nausea

        • Vomiting

        • Abdominal discomfort, and

      • Hypersensitivity reactions include benign maculopapular rash or urticaria, which are usually mild and reversible upon discontinuation.

    • Cefadroxil administration has been associated with:

      •  Clostridioides difficile–associated diarrhea ss well as pseudomembranous colitis

        • These effects  may appear during therapy or weeks afterward and should be considered in patients with new‑onset severe or bloody diarrhea.

December 2025