How does the efficacy of oral flucloxacillin compare to doxycycline against Staphylococcus aureus infections?

Oral Flucloxacillin vs Doxycycline for Staphylococcus aureus Infections

For methicillin-sensitive Staphylococcus aureus (MSSA) infections, oral flucloxacillin is superior to doxycycline and should be the first-line choice, while doxycycline is reserved as a second-line alternative when beta-lactams cannot be used. 1, 2

Treatment Hierarchy for MSSA

First-Line Therapy

• Flucloxacillin (or dicloxacillin/cloxacillin) represents the optimal oral treatment for MSSA skin and soft tissue infections, with dicloxacillin dosed at 500 mg four times daily and cephalexin at 500 mg four times daily as equivalent first-line options 1, 2
• The WHO and IDSA both list flucloxacillin/dicloxacillin as first-choice antibiotics for mild MSSA infections 2
• Flucloxacillin remains the empirical choice for putative S. aureus infections, with resistance rates as low as 1% in ICU settings 3

Second-Line Therapy

• Doxycycline (100 mg twice daily) is considered a second-line oral option after flucloxacillin/dicloxacillin for MSSA infections, particularly when patients have beta-lactam allergies 1
• Doxycycline is bacteriostatic rather than bactericidal, which limits its effectiveness compared to the bactericidal activity of flucloxacillin 1

Key Efficacy Differences

Flucloxacillin Advantages

• Flucloxacillin demonstrates bactericidal activity against MSSA, making it more effective for serious infections compared to the bacteriostatic mechanism of doxycycline 1
• Clinical trials show flucloxacillin effectively eliminates S. aureus in burn patients when dosed at 250 mg six-hourly 4
• Combination therapy with flucloxacillin plus netilmicin shows equivalent efficacy to teicoplanin-based regimens for S. aureus bacteremia 5

Doxycycline Limitations

• Doxycycline has poor activity against beta-hemolytic streptococci, requiring combination with a beta-lactam (e.g., amoxicillin) when coverage for both staphylococci and streptococci is needed 6, 1
• For nonpurulent cellulitis typically caused by streptococci, beta-lactam antibiotics are recommended as first-line rather than doxycycline 1
• Tetracycline resistance monitoring is important with prolonged doxycycline use 1

MRSA Considerations

For MRSA infections, the treatment hierarchy reverses completely:

• Doxycycline is recommended as an oral treatment option for MRSA skin and soft tissue infections 6, 1
• Neither flucloxacillin nor dicloxacin is effective against MRSA; alternatives such as doxycycline, trimethoprim-sulfamethoxazole, clindamycin, or linezolid must be used 2
• The IDSA recommends doxycycline (100 mg twice daily) for outpatient treatment of purulent skin infections likely caused by CA-MRSA 1

Critical Absorption Issue with Flucloxacillin

A major caveat is that oral flucloxacillin absorption is highly variable between patients:

• Approximately 10-13% of patients demonstrate inadequate oral flucloxacillin absorption (increase <10 mg/L) 7, 8
• An oral absorption test should be performed in patients requiring long-term flucloxacillin therapy to ensure adequate serum levels 7, 8
• The simplified oral absorption test involves giving 1 g oral flucloxacillin after a one-hour fast (while continuing IV therapy if applicable) and measuring serum levels at baseline, 1 hour, and 2 hours 7, 8
• Adequate absorption is defined as ≥10 mg/L increase in flucloxacillin concentration at 1 or 2 hours after dosing 7, 8

Contraindications and Special Populations

• Doxycycline should not be used in children under 8 years of age 6, 1
• For pregnant women in the third trimester and infants younger than 2 months, doxycycline is not recommended 6
• Compliance may be better with doxycycline (twice daily) compared to flucloxacillin/dicloxacillin (four times daily), though this should not override efficacy considerations 1

Practical Algorithm

1. Confirm methicillin susceptibility - If MSSA, proceed to step 2; if MRSA, use doxycycline or other MRSA-active agents 1, 2
2. Assess for beta-lactam allergy - If no allergy, use flucloxacillin/dicloxacillin as first-line 1, 2
3. If beta-lactam allergy present, use doxycycline 100 mg twice daily as alternative 1
4. For long-term oral flucloxacillin therapy, perform oral absorption test to confirm adequate absorption 7, 8
5. If streptococcal co-infection suspected, either use clindamycin alone (if susceptible) or combine doxycycline with amoxicillin 6, 1