Is amoxicillin effective against Methicillin-Sensitive Staphylococcus Aureus (MSSA) infections?

Amoxicillin Coverage for MSSA

Amoxicillin alone does NOT provide reliable coverage for MSSA and should not be used as monotherapy for these infections. However, amoxicillin-clavulanate (the combination with a beta-lactamase inhibitor) does have activity against MSSA and is listed as an acceptable option for certain MSSA infections.

Why Amoxicillin Alone is Inadequate

• Most S. aureus strains produce beta-lactamase enzymes that degrade amoxicillin, rendering it ineffective 1
• The FDA drug label for amoxicillin lists Staphylococcus species in its spectrum, but this does not account for the reality that the vast majority of clinical S. aureus isolates produce penicillinase 2
• Penicillinase-resistant penicillins (nafcillin, oxacillin, dicloxacillin) remain the antibiotics of choice for serious MSSA infections because they are not degraded by staphylococcal beta-lactamases 1

Amoxicillin-Clavulanate for MSSA

The addition of clavulanate (a beta-lactamase inhibitor) to amoxicillin restores activity against MSSA by protecting amoxicillin from enzymatic degradation 3, 4:

• The FDA label for amoxicillin-clavulanate explicitly lists Staphylococcus aureus as a covered organism 3
• For impetigo and mild skin/soft tissue infections, amoxicillin-clavulanate 875/125 mg twice daily is an acceptable oral option 5
• Clinical studies demonstrate that amoxicillin-clavulanate was adequate for empirical treatment of MSSA bacteremia in 86 patients, though it is not considered first-line for severe infections 4

Preferred First-Line Agents for MSSA

The Infectious Diseases Society of America and European guidelines consistently recommend antistaphylococcal penicillins or cefazolin as superior first-line agents 6, 7:

• Nafcillin or oxacillin 1-2 g IV every 4 hours for serious infections 5
• Cefazolin 1-2 g IV every 8 hours as an equally effective alternative 6, 8
• Dicloxacillin 500 mg PO four times daily for oral therapy of less severe infections 5
• Cephalexin 500 mg PO four times daily as an oral alternative 5

Clinical Context and Pitfalls

A critical pitfall is assuming that amoxicillin's activity against streptococci translates to MSSA coverage—it does not 1:

• For empiric coverage when MSSA is suspected but not confirmed, guidelines recommend piperacillin-tazobactam, cefepime, levofloxacin, or carbapenems—not amoxicillin 5
• Vancomycin is explicitly inferior to beta-lactams for MSSA and should only be used when beta-lactams cannot be administered 6
• For patients with severe penicillin allergy requiring MSSA coverage, consider penicillin desensitization rather than accepting inferior alternatives 6

Summary Algorithm

For confirmed MSSA infections:

• Severe/invasive infections: Use nafcillin, oxacillin, or cefazolin IV 5, 6, 7
• Mild skin/soft tissue infections: Use dicloxacillin, cephalexin, or amoxicillin-clavulanate PO 5
• Never use amoxicillin alone for MSSA 1