What is the difference between penicillin and oxacillin?

Difference Between Penicillin and Oxacillin

Oxacillin is a penicillinase-resistant penicillin specifically designed to treat infections caused by beta-lactamase-producing Staphylococcus aureus, while standard penicillin (penicillin G or V) is destroyed by these bacterial enzymes and should only be used for non-resistant streptococcal and other penicillin-susceptible infections. 1, 2

Structural and Mechanistic Differences

• Oxacillin contains a modified acyl side chain that prevents beta-lactamase enzymes from disrupting the beta-lactam ring, making it resistant to penicillinase produced by Staphylococcus aureus 2, 3
• Standard penicillin (penicillin G and penicillin V) lacks this protective modification and is rapidly inactivated by penicillinase-producing bacteria 4, 3
• Both agents share the same core beta-lactam ring structure and kill bacteria by the same mechanism—inhibiting bacterial cell wall synthesis 2

Spectrum of Activity: Critical Clinical Distinction

Penicillin G/V:

• Penicillin has been the gold standard for 50+ years for streptococcal pharyngitis, with no documented resistance ever developing in Group A Streptococcus 5
• Highly effective against streptococci, pneumococci, meningococci, and non-penicillinase-producing staphylococci 4
• Narrow spectrum of activity, which is actually advantageous for minimizing antimicrobial resistance and preserving the microbiome 5
• Completely ineffective against penicillinase-producing Staphylococcus aureus 6, 4

Oxacillin:

• The sole indication for oxacillin is suspected or confirmed penicillinase-producing Staphylococcus aureus (methicillin-susceptible S. aureus, MSSA) 1, 6
• Oxacillin is the treatment of choice for MSSA infections, particularly deep-seated infections like endocarditis 5, 7
• Has limited activity against gram-negative bacteria and is inferior to standard penicillin for streptococcal infections 7, 6
• Should NOT be used when standard penicillin would be effective, as it has a broader spectrum and contributes more to resistance 1

Clinical Decision Algorithm

When to use Penicillin:

• Streptococcal pharyngitis (Group A Strep)—penicillin V 500mg PO 2-3 times daily for 10 days or benzathine penicillin G IM single dose 5
• Pneumococcal infections, meningococcal disease, and other penicillin-susceptible organisms 4
• Any infection where Staphylococcus aureus is NOT suspected 5

When to use Oxacillin:

• Confirmed or highly suspected MSSA infections (skin/soft tissue infections, bacteremia, endocarditis)—oxacillin or nafcillin IV for 4-6 weeks for endocarditis 5, 1
• Never use oxacillin for streptococcal pharyngitis or other non-staphylococcal infections 1
• If susceptibility testing shows the organism is susceptible to penicillin G, switch from oxacillin to penicillin 1

Pharmacokinetic Considerations

• Penicillin V is preferred over penicillin G for oral administration because it is more acid-stable in the stomach 5
• Oxacillin can be given orally or IV, but IV nafcillin or oxacillin is standard for serious MSSA infections 5
• Penicillin is significantly less expensive than oxacillin 5

Common Clinical Pitfalls

• Never use oxacillin empirically for pharyngitis—this is inappropriate spectrum expansion and contributes to resistance 5, 1
• Do not assume "penicillin" means oxacillin when treating suspected staphylococcal infections—standard penicillin will fail against penicillinase-producing strains 6, 4
• For skin and soft tissue infections where both Streptococcus and Staphylococcus are possible, oxacillin (or dicloxacillin orally) covers both, but cefazolin is often preferred as an alternative 5, 7
• In penicillin-allergic patients, cephalosporins (like cefazolin) can substitute for oxacillin in non-immediate hypersensitivity reactions, but approximately 10% will have cross-reactivity 5, 7
• Oxacillin is completely ineffective against MRSA—vancomycin or other agents must be used 5

Resistance Patterns

• Group A Streptococcus has never developed resistance to penicillin in over 70 years of use 5
• Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to ALL penicillins including oxacillin, nafcillin, and methicillin 5
• Oxacillin should only be used after confirming methicillin susceptibility or in settings where MRSA prevalence is very low 5, 1