Is Fetroja (cefiderocol) plus Unasyn (ampicillin/sulbactam) redundant for treating osteomyelitis caused by Proteus multidrug-resistant organism (MDRO), and should minocycline (mino) be added to the regimen?

Treatment Strategy for CRAB Osteomyelitis with Proteus MDRO Co-infection

For CRAB osteomyelitis, use high-dose ampicillin-sulbactam (Unasyn) 9g IV every 8 hours as monotherapy without adding Fetroja (cefiderocol), and add minocycline 100mg IV/PO every 12 hours to the Unasyn regimen for synergistic activity against CRAB. 1

Why Fetroja is Redundant in This Case

• Fetroja (cefiderocol) is not needed for Proteus MDRO because sulbactam (the active component of Unasyn against CRAB) also provides excellent coverage against most Proteus species, including many resistant strains 1
• Adding Fetroja to Unasyn creates unnecessary polypharmacy without additional benefit, increases cost, and raises the risk of adverse effects including potential nephrotoxicity from dual beta-lactam therapy 2, 3
• Fetroja should be reserved for situations where Unasyn alone fails or the organism is documented to be resistant to sulbactam 4, 5

Optimal Regimen for CRAB Osteomyelitis

Primary Therapy: High-Dose Ampicillin-Sulbactam

• Ampicillin-sulbactam 9g IV every 8 hours (27g total daily dose) is the cornerstone therapy for CRAB osteomyelitis 1
• This high-dose regimen achieves adequate bone penetration and targets CRAB effectively 1, 6
• Sulbactam is the active component against CRAB, while ampicillin provides additional gram-positive coverage 1

Adding Minocycline: Strongly Recommended

Yes, you should add minocycline 100mg IV or PO every 12 hours to the high-dose Unasyn regimen for the following reasons:

• Combination therapy with Unasyn plus minocycline provides synergistic activity against CRAB and reduces the risk of treatment failure and resistance development 1
• Minocycline has excellent bone penetration and biofilm activity, which is critical for osteomyelitis 2, 7
• The combination addresses the high failure rates seen with monotherapy for CRAB infections 1
• Minocycline can be given orally with bioavailability comparable to IV, making transition to outpatient therapy feasible 2, 3

Treatment Duration and Surgical Considerations

Duration of Antibiotic Therapy

• Minimum 6 weeks of total antibiotic therapy for osteomyelitis without complete surgical debridement 2, 3
• If adequate surgical debridement with negative bone margins is achieved, duration may be shortened to 2-4 weeks 2, 3
• For CRAB specifically, some experts recommend extending therapy to 8 weeks given the high relapse rates 1, 2

Surgical Management

• Surgical debridement is the cornerstone of therapy and should be performed for substantial bone necrosis, exposed bone, or progressive infection despite appropriate antibiotics 1, 3
• Without adequate debridement, antibiotic cure rates are significantly lower, and prolonged therapy (≥6 weeks) is mandatory 8, 7

Monitoring and Follow-Up

• Monitor weekly CBC, CMP, CRP, and ESR during treatment to assess response and detect adverse effects 3
• Follow clinical response and inflammatory markers rather than radiographic findings alone, as imaging may worsen initially despite clinical improvement 2, 3
• Worsening bony imaging at 4-6 weeks should not prompt treatment changes if clinical symptoms and inflammatory markers are improving 2, 3

Critical Pitfalls to Avoid

• Do not use fluoroquinolones as monotherapy for CRAB osteomyelitis due to rapid resistance development 1, 2
• Do not extend antibiotic therapy beyond 6-8 weeks without clear indication, as this increases risks of C. difficile infection, antimicrobial resistance, and adverse effects without improving outcomes 2, 3, 7
• Do not rely on superficial wound cultures to guide therapy; bone cultures obtained during debridement are the gold standard 1, 3
• Avoid treating commensal organisms isolated from single cultures, as these likely represent contaminants rather than true pathogens 1

Alternative if Unasyn Fails

If the patient fails to respond to high-dose Unasyn plus minocycline after 2-4 weeks of appropriate therapy:

• Consider switching to Fetroja (cefiderocol) 2g IV every 8 hours as salvage therapy 4, 5, 6
• Cefiderocol has demonstrated success in treating CRAB osteomyelitis in case reports, with good bone penetration and tolerability for 6-14 weeks 4, 5, 6
• Re-evaluate for adequate surgical debridement, as antibiotic failure often indicates inadequate source control 3, 8