Overview

• Oxacillin

• Cloxacillin

• Dicloxacillin

• Oxacillin, cloxacillin, and dicloxacillin are narrow-spectrum β-lactams built for Methicillin-Susceptible Staphylococcus aureus (MSSA) and other penicillinase-producing staphylococci, with activity against β-hemolytic streptococci.^1,2

  • These agents have no activity against MRSA (PBP2a/mecA), Enterococcus, anaerobes, or typical Gram-negative bacteria.^1,6

  • Oxacillin,⁹ cloxacillin,⁷ dicloxacillin⁸ or flucloxacillin⁷ provide therapy of Methicillin-Sensitive Staphylococcus aureus (MSSA) infections across the severity spectrum:

    • Oral dicloxacillin or cloxacillin for mild skin/soft-tissue disease.¹ IV nafcillin might also be used.¹

    • IV oxacillin for serious invasive disease such as bacteremia, endocarditis, osteoarticular infection, and device-associated infections when the isolate is MSSA.¹⁰  

  • Guidelines for Skin and Tissue Infection (SSTI) and endocarditis place an antistaphylococcal penicillin (oxacillin/nafcillin) as first-line therapy for MSSA.¹¹

• Oxacillin

  • Oxacillin demonstrates rapid but incomplete absorption when administered orally, though the oral formulation is not available in the United States.

    • Following intravenous administration, peak serum concentrations are achieved within approximately 5 minutes.

    • A 500 mg slow intravenous dose produces peak levels of 43 µg/mL with a half-life ranging from 20 to 30 minutes.^17,18

  • The drug exhibits extensive protein binding, primarily to albumin, with reported binding rates of 94.2 ± 2.1%.

    • Oxacillin is widely distributed throughout body tissues and fluids, achieving therapeutic concentrations in pleural, bile, and amniotic fluids.

      • However, penetration into cerebrospinal fluid and ascitic fluid remains insignificant under normal conditions.^17,19

  • Elimination occurs through multiple pathways, with approximately 30% excreted unchanged in urine via glomerular filtration and active tubular secretion.

    • The elimination half-life is approximately 0.5 hours in patients with normal renal function.

    • Nonrenal elimination includes hepatic inactivation and biliary excretion.^17,18

• Dicloxacillin

  • Dicloxacillin exhibits superior oral bioavailability compared to other penicillinase-resistant penicillins.

    • The absolute bioavailability ranges from 35-76% when calculated from area under the curve data, with individual variations noted.

    • Peak serum concentrations (Tmax) are typically achieved within 0.75-1.25 hours following oral administration.^20,21

    • The pharmacokinetic profile demonstrates dose-proportional increases in both maximum concentration (C_max ) and area under the curve (AUC).

      • For doses ranging from 0.25 g to 2.0 g, C_max values increase proportionally from 13.62 to 79.97 μg/mL.

      • The elimination half-life averages 1.51 hours and remains independent of dose.^17,20,21

  • Dicloxacillin shows extensive protein binding, though specific values vary among studies.

    • Distribution is widespread throughout body tissues, with minimal penetration into cerebrospinal fluid except in the presence of meningeal inflammation.

    • Renal excretion accounts for 38-50% of the administered dose within 24 hours.^18,20,22,23

Clinical Uses

• Staphylococcal Infections

  • The primary indication for these antibiotics includes treatment of serious staphylococcal infections such as bacteremia, endocarditis, pneumonia, and deep-seated abscesses.^25,26  

  • β-lactam antibiotics, including antistaphylococcal penicillins, appear superior to vancomycin for definitive therapy of MSSA bloodstream infections.²⁴

• Skin and Soft Tissue Infections

  • Dicloxacillin is commonly prescribed for outpatient treatment of staphylococcal skin infections, including impetigo, cellulitis, folliculitis, and wound infections.⁵

  • Penicillin-susceptible Staphylococcus aureus (PSSA) accounts for approximately 9% of pediatric skin and soft tissue infections, often requiring more intensive treatment including hospitalization and surgical intervention.²⁷

• Bone and Joint Infections

  • Oxacillin and nafcillin are frequently used for treatment of osteomyelitis and septic arthritis caused by MSSA.^6,28

    • In pediatric osteoarticular infections, there has been an increasing trend toward penicillin susceptibility among MSSA isolates, with PSSA accounting for 6.7% of cases in recent studies.²⁷

• Endocarditis

  • Nafcillin is particularly favored for treatment of MSSA endocarditis, though recent research suggests that the presence of an inoculum effect in certain MSSA strains may influence treatment outcomes.

    • The choice between antistaphylococcal penicillins and cefazolin for endocarditis treatment continues to be debated, with some evidence suggesting superior outcomes with specific β-lactam agents.²⁵

    • β-Lactam antibiotics are favored over vancomycin or daptomycin for MSSA.²⁹