Is amoxicillin or flucloxacillin better for skin infections?

October 12, 2025 •

4 min read

According to the National Institutes of Health, skin and soft-tissue infections are a common reason for antibiotic prescribing in the community. Choosing the correct medication, such as deciding whether amoxicillin or flucloxacillin is better for skin infections, is crucial for effective treatment and preventing antibiotic resistance.

Quick Summary

Flucloxacillin is typically superior for skin infections due to its effectiveness against penicillinase-producing bacteria like Staphylococcus aureus, a common culprit. Amoxicillin, vulnerable to these enzymes, is less suitable for many staph-related skin conditions unless combined with a beta-lactamase inhibitor like clavulanate.

Key Points

Flucloxacillin for Staph: Flucloxacillin is the preferred antibiotic for many skin infections because it is effective against Staphylococcus aureus, a common cause, and is resistant to the penicillinase enzyme produced by these bacteria.
Amoxicillin Vulnerability: Amoxicillin alone is often ineffective for staph-related skin infections because the penicillinase enzyme produced by the bacteria can inactivate it.
Combined Therapy: To combat penicillinase-producing bacteria, amoxicillin must be combined with a beta-lactamase inhibitor like clavulanic acid (amoxicillin-clavulanate), which provides broader coverage but is less targeted than flucloxacillin.
Specific Infections: For common skin conditions like cellulitis, folliculitis, and impetigo, flucloxacillin is often the first-line oral treatment choice.
Allergy and Side Effects: Patients with a history of penicillin allergy or liver issues may need alternative treatments. Both drugs can cause side effects like nausea and diarrhea.
Antimicrobial Stewardship: Using a narrow-spectrum antibiotic like flucloxacillin when appropriate is a better practice for preventing the development of widespread antibiotic resistance.

Understanding the Bacteria Behind Skin Infections

To determine if amoxicillin or flucloxacillin is better for skin infections, it is important to first understand the common bacteria that cause these conditions. The two most frequent culprits are Staphylococcus aureus and Streptococcus pyogenes.

Staphylococcus aureus (Staph): A major cause of infections like impetigo, folliculitis, and cellulitis. Many strains produce penicillinase, an enzyme that inactivates certain penicillin antibiotics.
Streptococcus pyogenes (Strep): Another common cause of skin infections like cellulitis and erysipelas. S. pyogenes remains highly susceptible to penicillin-based drugs.

Mechanism of Action and Spectrum of Activity

Both amoxicillin and flucloxacillin are beta-lactam antibiotics that inhibit bacterial cell wall synthesis. However, flucloxacillin has a key advantage for many skin infections.

Amoxicillin: A broad-spectrum aminopenicillin effective against Streptococcus species and some Gram-negative organisms. It is degraded by penicillinase, making it ineffective against many S. aureus strains unless combined with a beta-lactamase inhibitor like clavulanic acid.
Flucloxacillin: A narrow-spectrum, penicillinase-resistant penicillin. Its structure makes it resistant to penicillinase, allowing it to effectively target S. aureus. It is also effective against S. pyogenes and focuses on Gram-positive bacteria common in skin infections.

Clinical Applications for Skin Infections

The choice between amoxicillin and flucloxacillin depends heavily on the suspected causative organism.

Cellulitis

For suspected or unconfirmed staphylococcal cellulitis, flucloxacillin is the first-line oral antibiotic due to its coverage of S. aureus and S. pyogenes and good tissue penetration.
Amoxicillin alone is generally not recommended for cellulitis because of penicillinase-producing S. aureus. Amoxicillin-clavulanate might be used for complex cases, but it is a broader-spectrum option.

Impetigo

Flucloxacillin is the recommended first-line oral treatment for more extensive impetigo as it targets the usual causes, S. aureus and S. pyogenes.
Amoxicillin is inappropriate for impetigo due to penicillinase-producing S. aureus. Topical antibiotics are often used for mild cases.

Folliculitis

Flucloxacillin is a standard oral treatment for bacterial, particularly staphylococcal, folliculitis.
Amoxicillin is not the typical choice for folliculitis unless caused by a penicillinase-negative organism.

Comparison of Amoxicillin and Flucloxacillin for Skin Infections


Feature	Amoxicillin	Flucloxacillin
Mechanism of Action	Inhibits cell wall synthesis.	Inhibits cell wall synthesis.
Penicillinase Resistance	No, susceptible to bacterial penicillinase enzymes.	Yes, resistant to penicillinase enzymes produced by Staphylococcus aureus.
Target Bacteria (Key for Skin)	Primarily effective against Streptococcus pyogenes and some Gram-negatives.	Effective against Staphylococcus aureus and Streptococcus pyogenes.
Suitability for Staph Infections	Poor, unless combined with clavulanate.	Excellent, as it is resistant to penicillinase.
Side Effects (Common)	Diarrhea, nausea, rash.	Nausea, diarrhea, abdominal discomfort.
Serious Side Effects	Severe allergic reactions (anaphylaxis), liver problems, severe diarrhea.	Allergic reactions, liver problems (cholestatic hepatitis).
Key Indications for Skin	Rarely used alone for skin infections due to resistance.	First-line choice for many staphylococcal and streptococcal skin infections.

When is Amoxicillin a Possibility for Skin Infections?

Amoxicillin may be considered in specific circumstances:

Confirmed Strep infection: Effective if infection is solely Streptococcus pyogenes, although flucloxacillin is also effective.
Combined with a beta-lactamase inhibitor: Amoxicillin-clavulanate is effective against penicillinase-producing S. aureus but is a broader-spectrum option for more complex cases.
For cellulitis in lymphoedema: Sometimes considered, though current guidelines often favor anti-staphylococcal agents.

Potential Side Effects and Contraindications

Both drugs have potential side effects and contraindications.

Flucloxacillin Considerations

Side Effects: Common side effects include nausea, diarrhea, and rashes. Rare serious side effects include cholestatic hepatitis.
Contraindications: Avoid if history of penicillin or cephalosporin allergy, or previous cholestatic jaundice/hepatitis from flucloxacillin.
Administration: Best absorbed on an empty stomach.

Amoxicillin Considerations

Side Effects: Common side effects include diarrhea, nausea, and rash. Rare serious reactions include severe allergic responses and liver issues.
Contraindications: Avoid if history of severe allergic reaction to penicillin.

Conclusion

For most community-acquired skin infections likely involving Staphylococcus aureus, flucloxacillin is the better choice due to its resistance to penicillinase. Amoxicillin alone is often ineffective against these infections.

The appropriate treatment requires a proper diagnosis. A physician considers patient history, local resistance patterns, and infection nature before prescribing. Alternatives like cephalexin or clindamycin may be used in case of penicillin allergy or other contraindications. Always follow medical advice and complete the full antibiotic course.

The Role of Penicillinase in Antibiotic Selection

Penicillinase inactivates amoxicillin by attacking its beta-lactam ring. Flucloxacillin's structure protects this ring, making it effective against penicillinase-producing S. aureus and a targeted therapy choice. Using flucloxacillin helps prevent the need for broader-spectrum alternatives that can contribute to resistance.

When is Amoxicillin-Clavulanate an Option?

Amoxicillin combined with clavulanate can cover both penicillinase-producing staph and other bacteria. It can be used for skin infections but is a less targeted approach than flucloxacillin for suspected staph infections. Using narrower-spectrum antibiotics like flucloxacillin when possible is better antimicrobial stewardship, reducing resistance risk.

Guidelines on the Management of Cellulitis in Adults

Frequently Asked Questions

Flucloxacillin is the traditional first-line oral antibiotic for mild to moderate cellulitis because it is effective against Staphylococcus aureus and Streptococcus pyogenes, the most common causative bacteria.

Amoxicillin is not effective against many staph infections because many strains of Staphylococcus aureus produce an enzyme called penicillinase, which inactivates amoxicillin.

No, amoxicillin is not recommended as a first-line treatment for impetigo. Flucloxacillin is the preferred oral treatment, while topical antibiotics like mupirocin are used for mild cases.

Amoxicillin is a standard penicillin that is vulnerable to penicillinase. Amoxicillin-clavulanate includes clavulanic acid, a beta-lactamase inhibitor that protects the amoxicillin, allowing it to work against penicillinase-producing bacteria.

If you have a penicillin allergy, your doctor will prescribe an alternative antibiotic, such as a first-generation cephalosporin (like cephalexin) or a macrolide (like erythromycin). Always inform your doctor of any known allergies.

Yes, although rare, flucloxacillin has been associated with cholestatic hepatitis, a liver problem that can occur even after finishing the course of medication. This risk is higher in the elderly and those with pre-existing liver impairment.

Completing the full course of antibiotics is essential to ensure all the infection-causing bacteria are eliminated. Stopping early can lead to a resurgence of the infection and can contribute to the development of antibiotic-resistant bacteria.