How effective is cefiderocol against other Gram-negative organisms?

Cefiderocol Activity Against Gram-Negative Organisms

Cefiderocol demonstrates excellent in vitro activity against a broad spectrum of multidrug-resistant Gram-negative organisms, with susceptibility rates of 99.8% for Enterobacterales, 99.6% for Pseudomonas aeruginosa, 97.7% for Acinetobacter species, and 100% for Stenotrophomonas maltophilia, making it one of the most potent agents available for resistant Gram-negative infections. 1

Spectrum of Activity by Organism

Enterobacterales

• Cefiderocol achieved 99.8% susceptibility against 8,047 Enterobacterales isolates collected from U.S. and European hospitals in 2020 1
• Against carbapenem-resistant Enterobacterales (CRE), susceptibility remained high at 98.2% 1
• The drug demonstrated activity against isolates producing extended-spectrum beta-lactamases (ESBLs) including TEM, SHV, CTX-M, and OXA variants 2
• Cefiderocol showed activity against serine-carbapenemases (KPC, OXA-48) with MIC90 values of 2-4 µg/mL 3
• Against metallo-beta-lactamase producers, activity varied: 100% of IMP-positive isolates (MIC range 1-2 µg/mL), 99.3% of VIM-positive isolates (MIC90 2 µg/mL), but only 64.3% of NDM-positive isolates (MIC90 8 µg/mL) 3

Pseudomonas aeruginosa

• Cefiderocol was the most active antimicrobial tested against all P. aeruginosa isolates with MIC50/90 values of 0.12/0.5 mg/L and 99.6% susceptibility 1
• Among 256 extensively drug-resistant (XDR) P. aeruginosa isolates, 97.3% remained susceptible to cefiderocol compared to only 7.4% susceptible to meropenem 1
• The drug demonstrated activity against P. aeruginosa isolates containing VIM, IMP, GES, and AmpC carbapenemases 2
• Activity was maintained against isolates with porin deletions (OprD) and efflux pump upregulation (MexAB-OprM, MexCD-OprJ, MexEF-OprN, MexXY) 2

Acinetobacter Species

• Overall susceptibility to cefiderocol was 97.7% among 650 Acinetobacter isolates 1
• However, the ESCMID guidelines conditionally recommend against cefiderocol for carbapenem-resistant A. baumannii (CRAB) infections due to higher mortality (49% with cefiderocol versus 18% with best available therapy). 4, 5
• Despite this mortality concern, cefiderocol showed in vitro activity against isolates containing OXA-23 (97.2% susceptible, MIC90 1 µg/mL), OXA-24/40 (95.2% susceptible), OXA-51, and OXA-58 variants 2, 3

Stenotrophomonas maltophilia

• Cefiderocol achieved 100% susceptibility (CLSI 2021 criteria) or 97.9% (CLSI 2022 criteria) against 338 S. maltophilia isolates 1
• Activity was demonstrated against isolates containing metallo-carbapenemase (L1) and serine beta-lactamases (L2) 2
• This represents a significant advantage as S. maltophilia has limited treatment options 6, 7

Other Gram-Negative Organisms

• Cefiderocol showed activity against Burkholderia cepacia and Achromobacter species 8, 6
• Against colistin-resistant Enterobacterales, including mcr-1 positive isolates, 99.3% of 136 isolates remained susceptible with MIC90 of 2 µg/mL 3
• Activity was demonstrated against isolates resistant to meropenem, ciprofloxacin, amikacin, cefepime, ceftazidime-avibactam, and ceftolozane-tazobactam 2

Clinical Efficacy Evidence

Complicated Urinary Tract Infections

• In the APEKS-cUTI study, cefiderocol achieved 73% composite clinical and microbiological cure versus 55% with imipenem-cilastatin (treatment difference 18.58%, p=0.0004) 6
• Efficacy was demonstrated against E. coli, K. pneumoniae, P. aeruginosa, Proteus mirabilis, Enterobacter cloacae, Morganella morganii, and Citrobacter freundii 6

Nosocomial Pneumonia

• The APEKS-NP study demonstrated non-inferiority of cefiderocol versus high-dose extended-infusion meropenem for all-cause mortality at day 14 in nosocomial pneumonia 8

Critical Limitations and Caveats

Lack of Activity Against Certain Organisms

• Cefiderocol has no clinically relevant in vitro activity against most Gram-positive bacteria and anaerobic bacteria, including Bacteroides fragilis 2, 6
• This necessitates combination therapy when polymicrobial infections involving Gram-positive or anaerobic organisms are suspected 6

Resistance Mechanisms

• Approximately 2.3% of meropenem-non-susceptible isolates exhibited cefiderocol MIC ≥8 µg/mL, with no clear correlation to specific carbapenemase carriage 3
• Resistance can develop through combinations of multiple beta-lactamases, PBP modifications, and mutations affecting siderophore expression 2
• The frequency of resistance development at 10× MIC ranged from 10⁻⁶ to <10⁻⁸ 2

Testing Considerations

• Cefiderocol susceptibility testing must be performed in iron-depleted cation-adjusted Mueller-Hinton broth, as standard testing conditions may yield inaccurate results 1
• Commercial susceptibility tests have current accuracy and reliability issues that require careful evaluation 8
• Addition of beta-lactamase inhibitors (avibactam, clavulanic acid, dipicolinic acid) can lower MICs in vitro for some isolates with high baseline MICs 2

Guideline-Based Positioning

• For metallo-beta-lactamase producing CRE, ceftazidime-avibactam plus aztreonam is strongly recommended as first-line (moderate certainty), with cefiderocol as a conditional alternative (low certainty) 4, 5
• For difficult-to-treat resistant P. aeruginosa, ceftolozane-tazobactam and ceftazidime-avibactam are positioned as first-line options, with cefiderocol as an alternative 9
• Cefiderocol should be reserved as a last-line agent and avoided for third-generation cephalosporin-resistant Enterobacterales when other options exist 5