Can Cefiderocol alone treat osteomyelitis with a co-infection of Proteus mirabilis that is a Multi-Drug Resistant Organism (MDRO)?

Treatment of Osteomyelitis with CRAB and Co-infection with MDRO Proteus mirabilis

Cefiderocol monotherapy is NOT recommended for this clinical scenario—you must use combination therapy targeting both organisms, with cefiderocol addressing the CRAB component while adding a separate agent for Proteus mirabilis based on susceptibility testing. 1, 2

Critical Contraindication for CRAB Monotherapy

• The American College of Clinical Pharmacy conditionally recommends AGAINST cefiderocol monotherapy for CRAB infections due to significantly higher mortality (49% with cefiderocol versus 18% with best available therapy). 1
• The CREDIBLE-CR trial demonstrated 28-day mortality of 24.8% with cefiderocol versus 18.4% with best available therapy for carbapenem-resistant infections, with end-of-follow-up mortality reaching 33.7% versus 18.4%. 1
• Despite this mortality signal, cefiderocol remains one of the few agents with in vitro activity against CRAB, particularly strains containing OXA-23, OXA-24/40, OXA-51, and OXA-58 carbapenemases. 2

Recommended Treatment Algorithm

Step 1: Obtain Susceptibility Testing

• Perform comprehensive susceptibility testing for both CRAB and Proteus mirabilis isolates immediately. 3
• Request MIC determination for cefiderocol against both organisms, as MIC values ≤4 mcg/mL correlate with better outcomes in animal models of osteomyelitis. 2

Step 2: Design Combination Regimen

• For CRAB component: Consider cefiderocol 2g IV every 8 hours (infused over 3 hours) PLUS a second agent with anti-CRAB activity based on susceptibilities (e.g., high-dose ampicillin-sulbactam, polymyxins, or tigecycline). 1, 2, 4
• For Proteus mirabilis component: Add targeted therapy based on susceptibility results—if susceptible to first or second-generation cephalosporins, de-escalate to these agents; if MDRO, consider fluoroquinolones, aminoglycosides, or carbapenems depending on resistance profile. 3

Step 3: Ensure Adequate Source Control

• Surgical debridement is mandatory and complementary to antimicrobial therapy for osteomyelitis—inadequate source control is a primary reason for treatment failure even with appropriate antibiotics. 3, 4, 5
• Multiple surgical debridements may be necessary, as demonstrated in successful case reports of CRAB osteomyelitis treated with cefiderocol. 4, 5, 6

Step 4: Optimize Dosing for Osteomyelitis

• Standard cefiderocol dosing: 2g IV every 8 hours infused over 3 hours. 2, 7
• For augmented renal clearance (CrCl ≥120 mL/min): Increase to 2g IV every 6 hours infused over 3 hours to maintain adequate drug exposure. 2
• Treatment duration: Plan for 6-12 weeks of therapy for osteomyelitis, with successful case reports documenting 6-week courses for CRAB bone infections. 4, 8, 5, 6

Evidence Supporting Cefiderocol Use in Osteomyelitis

• Case reports demonstrate successful treatment of extensively drug-resistant Acinetobacter baumannii osteomyelitis with cefiderocol combined with surgical debridement. 4, 5, 6
• A 6-week course of cefiderocol for CRAB hip osteomyelitis was well-tolerated without adverse reactions or laboratory abnormalities, with infection considered cured at end of treatment. 6
• Cefiderocol has demonstrated activity in animal models against A. baumannii with MICs ≤2 mcg/mL in pneumonia models and ≤4 mcg/mL in thigh infection models. 2

Critical Pitfalls to Avoid

• Never use cefiderocol monotherapy for polymicrobial infections—each pathogen requires targeted coverage, and cefiderocol has no activity against Gram-positive organisms or anaerobes. 2
• Do not assume Proteus mirabilis susceptibility—while historically susceptible to many agents, MDRO Proteus requires documented susceptibility testing before selecting therapy. 3
• Avoid inadequate surgical debridement—antibiotic therapy alone is insufficient for osteomyelitis, particularly with biofilm-forming organisms like Acinetobacter. 3, 4, 5
• Monitor for treatment-emergent resistance—the risk of resistance development with MBL-producing organisms and potentially CRAB requires surveillance cultures if clinical response is inadequate. 1
• Assess renal function carefully—cefiderocol is primarily renally excreted (61-71% unchanged), requiring dose adjustment for both renal impairment and augmented renal clearance. 2, 7

Monitoring During Therapy

• Obtain repeat cultures if clinical improvement does not occur within 5-7 days to assess for treatment-emergent resistance or inadequate source control. 3
• Monitor inflammatory markers (CRP, ESR) and clinical signs of infection resolution throughout the prolonged treatment course. 8, 6
• Assess for cefiderocol-related adverse effects, though the drug is generally well-tolerated with a side effect profile comparable to other cephalosporins (primarily gastrointestinal effects and phlebitis). 7
• Consider monitoring iron homeostasis with extended treatment duration, as cefiderocol's siderophore mechanism may theoretically affect iron metabolism. 8