What alternative treatment options are available for a patient with Chronic Recurrent Acute Bacterial (CRAB) osteomyelitis and a Multi-Drug Resistant Organism (MDRO) Proteus co-infection susceptible to Bactrim (trimethoprim/sulfamethoxazole), but unable to take the recommended regimen?

Alternative Treatment for CRAB Osteomyelitis with MDRO Proteus Co-infection When Bactrim Cannot Be Used

For this patient with CRAB osteomyelitis and MDRO Proteus co-infection who cannot tolerate Bactrim, use high-dose ampicillin-sulbactam (18g ampicillin/9g sulbactam daily in divided doses) if the CRAB is sulbactam-susceptible, combined with surgical debridement and an alternative agent active against the Proteus based on susceptibility testing. 1, 2

Primary Treatment Strategy for CRAB Component

Ampicillin-sulbactam remains the first-line therapy for sulbactam-susceptible CRAB, requiring aggressive dosing of 6-9g sulbactam per day (typically administered as ampicillin 18g/sulbactam 9g daily in divided doses). 1, 2 This recommendation comes from ESCMID guidelines with conditional strength based on low-certainty evidence. 1

If CRAB is Sulbactam-Resistant:

• Use polymyxin B or colistin (with loading dose for severe infections) PLUS a second in vitro active agent 1, 2
• High-dose tigecycline can be considered if active in vitro, though avoid as monotherapy for severe infections 1
• Avoid cefiderocol for CRAB treatment despite in vitro activity, as IDSA recommends against its use due to treatment-emergent resistance and limited clinical data 2, 3

Combination Therapy Requirements

Combination therapy is strongly preferred over monotherapy for CRAB infections. 2 For severe and high-risk CRAB infections, use two in vitro active antibiotics from available options including polymyxin, aminoglycoside, tigecycline, or sulbactam combinations. 1

Specific Combinations to Avoid:

• Do not use polymyxin-meropenem combination (strong recommendation against, high certainty evidence) 1
• Do not use polymyxin-rifampin combination (strong recommendation against, moderate certainty evidence) 1

Exception for Carbapenem Use:

If meropenem MIC is ≤8 mg/L, high-dose extended-infusion carbapenem dosing may be used as part of combination therapy. 1

Treatment for MDRO Proteus Component

Since Bactrim is not tolerated, select an alternative antibiotic based on susceptibility testing from the following options:

• Fluoroquinolones (if susceptible) - can be used for step-down oral therapy after stabilization 1
• Aminoglycosides - particularly useful for complicated urinary tract infections if Proteus is susceptible 1
• Carbapenems - if susceptible and not already being used for CRAB component 1
• Older beta-lactam/beta-lactamase inhibitor combinations - based on susceptibility pattern 1

Surgical Management

Chronic osteomyelitis requires surgical debridement in addition to antibiotic therapy. 4, 5 Without surgical resection of infected bone, antibiotic treatment must be prolonged (≥4-6 weeks). 4 The combination of adequate surgical debridement and appropriate antimicrobial therapy is essential for achieving remission. 4, 6

Duration and Monitoring

• Standard treatment duration is 4-6 weeks of antibiotic therapy after adequate surgical debridement 4, 5, 7
• No evidence supports treatment beyond 6 weeks improving outcomes compared to shorter regimens 5
• Use therapeutic drug monitoring when available, particularly for polymyxins and aminoglycosides 8
• Consider therapeutic drug monitoring for sulbactam to ensure adequate exposure (6-9g/day target) 2

Practical Algorithm

1. Confirm susceptibilities for both CRAB and MDRO Proteus organisms
2. Perform surgical debridement as primary intervention 4
3. For CRAB: Start ampicillin-sulbactam 18g/9g daily if sulbactam-susceptible 1, 2
4. Add combination partner for CRAB (aminoglycoside or minocycline if susceptible) 2
5. For Proteus: Add fluoroquinolone, aminoglycoside, or carbapenem based on susceptibilities 1
6. Continue therapy for 4-6 weeks with clinical monitoring 4, 5
7. Consider oral step-down after stabilization if susceptibilities allow 1, 7

Critical Pitfalls to Avoid

• Never use polymyxin monotherapy for severe infections - always combine with a second active agent 1, 8
• Avoid tigecycline monotherapy for CRAB pneumonia due to higher treatment failure rates 2
• Do not use cefiderocol for CRAB despite in vitro activity 2
• Ensure adequate sulbactam dosing reaches 6-9g/day, not just standard ampicillin-sulbactam dosing 2
• Do not rely on antibiotics alone - surgical debridement is essential for chronic osteomyelitis 4, 5

Evidence Quality Considerations

The recommendations for CRAB treatment are based on conditional recommendations with very low to low certainty evidence. 1 The AIDA and OVERCOME trials demonstrated no benefit of colistin-meropenem combinations over colistin monotherapy, contributing to high-certainty evidence against this specific combination. 1 Oral versus parenteral antibiotic routes show similar cure rates for osteomyelitis when organisms are susceptible, though this evidence is over 20 years old. 7