Is Penicillin Effective Against MSSA?
Penicillin G or ampicillin can be highly effective against MSSA, but only for the rare strains that are truly penicillin-susceptible (penicillin G MIC ≤0.03 mg/L), which represent less than 10% of MSSA isolates. For the vast majority of MSSA infections, you must use antistaphylococcal penicillins (nafcillin, oxacillin) or cefazolin instead, as most MSSA strains produce β-lactamase that destroys penicillin G and ampicillin 1.
Understanding MSSA Penicillin Susceptibility
- Most MSSA strains (>90%) are resistant to penicillin G and ampicillin due to β-lactamase production, making these agents ineffective despite being "methicillin-susceptible" 1
- True penicillin-susceptible S. aureus (PSSA) is defined as penicillin G MIC ≤0.03 mg/L and represents only about 49% of MSSA isolates in some studies, though many of these still require specialized testing to confirm 2
- Almost all staphylococci are highly resistant to penicillin G and ampicillin, which is why the term "methicillin-susceptible" refers to susceptibility to β-lactamase-resistant penicillins, not penicillin itself 3
First-Line Treatment for MSSA Infections
For serious MSSA infections, antistaphylococcal penicillins (nafcillin or oxacillin) remain the gold standard, with cefazolin as an equally effective and often preferred alternative 3, 4:
- Nafcillin or oxacillin 1-2 g IV every 4 hours for severe infections including endocarditis, with minimum 4-6 weeks duration for native valve endocarditis 3, 4
- Cefazolin 1-2 g IV every 8 hours is equally effective and has better tolerability with lower rates of adverse events requiring discontinuation 5, 6, 7
- Cefazolin can be safely used in 90% of patients with non-immediate penicillin allergies (delayed reactions), making it the preferred β-lactam in this setting 4
When Penicillin G or Ampicillin Can Be Used
If laboratory testing confirms true penicillin susceptibility (MIC ≤0.03 mg/L), penicillin G or ampicillin can be used as definitive therapy 2:
- Penicillin G 3-4 million units IV every 4 hours or ampicillin 2 g IV every 4-6 hours for confirmed PSSA bacteremia in stable patients 2
- This approach showed no mortality in one study of PSSA bacteremia, compared to 15.2% mortality with cefazolin, though patient populations differed 2
- Requires microbiological confirmation with penicillin G MIC testing—do not assume MSSA is penicillin-susceptible without this specific testing 2
Critical Pitfalls to Avoid
- Never use penicillin G or ampicillin empirically for suspected MSSA without confirmed penicillin susceptibility testing, as treatment failure is nearly guaranteed with β-lactamase-producing strains 1
- For patients with immediate-type penicillin hypersensitivity (anaphylaxis, urticaria, angioedema, bronchospasm), vancomycin 15-20 mg/kg IV every 8-12 hours is required, though it is inferior to β-lactams and requires minimum 6 weeks duration 4, 3
- Cephalosporins should not be used in immediate-type penicillin allergy due to cross-reactivity risk, despite being safe in delayed reactions 1
- For CNS/spinal infections, nafcillin is preferred over cefazolin due to superior blood-brain barrier penetration 4
Alternative Agents for β-Lactam Allergy
When true β-lactam allergy precludes use of antistaphylococcal penicillins or cefazolin 4, 1:
- Vancomycin 15-20 mg/kg IV every 8-12 hours with target trough 10-20 µg/mL, minimum 6 weeks for serious infections
- Clindamycin 600-900 mg IV every 8 hours if local MSSA resistance rates are <10%
- Daptomycin 8-10 mg/kg IV daily for persistent bacteremia despite adequate source control