What antibiotics are used to treat joint infections?

Antibiotic Treatment for Joint Infections

For native joint septic arthritis, initiate vancomycin for gram-positive coverage plus ceftazidime or an aminoglycoside for gram-negative coverage if Gram stain is negative, then narrow therapy based on culture results; for prosthetic joint infections with retained hardware, use rifampin-based combination therapy with a fluoroquinolone or other biofilm-active agent for 3 months. 1, 2

Initial Empiric Therapy for Native Joint Septic Arthritis

The choice of empiric antibiotics depends on Gram stain results from synovial fluid:

• Gram-positive cocci: Vancomycin 2
• Gram-negative cocci: Ceftriaxone 2
• Gram-negative rods: Ceftazidime 2
• Negative Gram stain with high clinical suspicion: Vancomycin plus ceftazidime or an aminoglycoside 2

Staphylococcus aureus is the most common pathogen in native joint infections, accounting for over 80% of nongonococcal septic arthritis cases. 2

Definitive Therapy Based on Culture Results

Once cultures identify the organism:

• MSSA (methicillin-sensitive S. aureus): Oxacillin/nafcillin (59% of providers prefer this) or cefazolin (33% prefer this) 3
• MRSA (methicillin-resistant S. aureus): Vancomycin 15-20 mg/kg/dose IV every 8-12 hours (target trough 15-20 μg/mL) 1, 4
  • Alternative: Daptomycin 6 mg/kg/day IV 1
  • Alternative: Linezolid 600 mg PO/IV twice daily 1

Duration: Minimum 3-4 weeks for septic arthritis, 4-6 weeks for osteomyelitis 1

Prosthetic Joint Infection (PJI) Treatment

Surgical Strategy Determines Antibiotic Duration

The antibiotic regimen varies significantly based on surgical approach:

1. Debridement, Antibiotics, and Implant Retention (DAIR)

Used for early infections (<30 days post-op) or acute hematogenous infections with symptoms <3 weeks. 1, 5

Antibiotic regimen for staphylococcal PJI with retained hardware:

• Rifampin 600 mg daily (or 300-450 mg twice daily) PLUS a companion agent 1, 6
• Companion options (in order of biofilm activity):
  • Levofloxacin 500-750 mg daily 1
  • Ciprofloxacin 750 mg twice daily 1
  • For MRSA: Vancomycin, daptomycin, or linezolid 1

Critical point: Rifampin must always be combined with another active agent to prevent resistance emergence. 1, 4 Rifampin and fluoroquinolones have superior biofilm penetration, which is essential when hardware is retained. 1, 6, 7

Duration: 3 months total for hip/knee PJI 1, 5

2. One-Stage or Two-Stage Exchange (Early Re-implantation)

Duration: 3 months of biofilm-active antibiotics 1

3. Two-Stage Exchange (Late Re-implantation >6 weeks)

Duration: 6 weeks of pathogen-directed therapy (treating residual osteomyelitis) 1

Organism-Specific PJI Regimens

Oxacillin-susceptible staphylococci:

• Oral: Cephalexin 500 mg PO 3-4 times daily OR dicloxacillin 500 mg PO 3-4 times daily 1
• Always add rifampin when hardware retained 1

Oxacillin-resistant staphylococci (MRSA):

• Oral: Trimethoprim-sulfamethoxazole 1 double-strength tablet twice daily OR minocycline/doxycycline 100 mg twice daily 1
• Add rifampin when hardware retained 1

Streptococci (including Group B Streptococcus):

• IV: Penicillin G, ceftriaxone, or vancomycin for 4-6 weeks 5
• Oral: Penicillin V 500 mg 2-4 times daily, amoxicillin 500 mg 3 times daily, or cephalexin 500 mg 3-4 times daily 1, 5
• Rifampin is NOT routinely recommended for streptococcal PJI (unlike staphylococcal infections) 5

Enterococcus (penicillin-susceptible):

• Oral: Penicillin V 500 mg 2-4 times daily OR amoxicillin 500 mg 3 times daily 1

Pseudomonas aeruginosa:

• Oral: Ciprofloxacin 250-500 mg twice daily 1

Enterobacteriaceae:

• Oral: Trimethoprim-sulfamethoxazole 1 double-strength tablet twice daily OR fluoroquinolone based on susceptibilities 1

Propionibacterium:

• Vancomycin (40% of providers), penicillin (23%), or ceftriaxone (17%) 3
• Oral: Penicillin V 500 mg 2-4 times daily 1

Early vs. Late PJI: Different Empiric Coverage

Early PJI (<4 weeks or <1 year) has significantly higher rates of:

• Resistant organisms 8
• Polymicrobial infections 8
• Gram-negative pathogens (25% vs. 6% in late PJI) 8
• Coagulase-negative staphylococci predominate 8

Empiric therapy for early PJI: Vancomycin PLUS a gram-negative agent (e.g., ceftazidime, fluoroquinolone) achieves >90% coverage 8

Late PJI (>1 year): S. aureus is most common; cefazolin or flucloxacillin often sufficient 8

Chronic Oral Suppression

When surgical options are exhausted or patient refuses further surgery, chronic oral suppression is recommended by 99% of infectious disease specialists. 3

Suppression regimens (same as Table 3 above, organism-specific) 1

Critical Warnings and Monitoring

Rifampin Considerations

• Drug interactions: Potent inducer of cytochrome P450; interacts with warfarin, DOACs, immunosuppressants, and other antimicrobials 1
• Resistance: Never use as monotherapy 1, 4

Fluoroquinolone Warnings

• FDA/EMA warnings: Risk of tendinopathy, aortic rupture/tears, and CNS effects 1
• Despite risks, quinolones remain mainstay for PJI due to biofilm activity 1

Vancomycin Monitoring

• Target trough 15-20 μg/mL for serious infections 4
• Monitor levels in obese patients, renal dysfunction, or fluctuating volume status 4
• Failure rates of 35-46% reported for MRSA osteomyelitis, possibly due to poor bone penetration 4

Linezolid Limitations

• Excellent bone penetration but toxicity profile limits long-term use (>2-4 weeks) 1, 6

Pediatric Considerations

For acute hematogenous MRSA osteomyelitis in children:

• First-line: IV vancomycin 1, 4
• Alternative: Clindamycin 10-13 mg/kg/dose IV every 6-8 hours (if local resistance <10%) 1, 4
• Duration: Minimum 3-4 weeks for septic arthritis, 4-6 weeks for osteomyelitis 1

Recent Evidence on Treatment Duration

A 2023 non-inferiority trial showed 6 weeks was inferior to 12 weeks for PJI following debridement with implant retention (18.1% vs. 9.4% persistent infection), though outcomes were similar for one- or two-stage exchanges. 1 This reinforces the 3-month recommendation for DAIR procedures with biofilm-active agents. 1

For vertebral osteomyelitis without surgical debridement, 6 weeks was non-inferior to 12 weeks (90.9% vs. 90.8% cure rate). 1