An Overview of Cefiderocol Resistance Among Clinical Pathogens

Cefiderocol, a siderophore cephalosporin, is a therapeutic option for previously untreatable drug-resistant pathogens. Since real-world clinical data remain scarce, integration of cefiderocol into the current antimicrobial armamentarium requires a comprehensive understanding of the agent’s novel mechanism of action and mechanisms of resistance. Cefiderocol is actively transported across the outer cell membrane of bacteria into the periplasmic space using novel siderophore iron transporters called TonB-dependent receptors.¹ Cefiderocol then exerts a bactericidal action by inhibiting cell wall biosynthesis throughpenicillin-binding proteins.1 Indeed, this novel mechanism of action allows cefiderocol to have in vitro activity against Klebsiella pneumoniae carbapenemase (KPC), Guiana extended-spectrum (GES), Imipenemase (IMP), Verona Integron-encoded MBL (VIM), New Delhi metallo-β-lactamases (NDMs), L1, and Oxacillinases (OXA) carbapenemases.¹ Furthermore, cefiderocol evades other mechanisms of carbapenem resistance, including decreased outer membrane permeability and increased expression of antibiotic efflux pumps.¹ Mechanisms through which resistance to cefiderocol develop remain to be fully elucidated. In this short review, the latest data and understanding of mechanisms leading to resistance to cefiderocol by Acinetobacter baumannii, Pseudomonas aeruginosa, andEnterobacterales are described.

Defining Resistance to Cefiderocol

The absence of robust clinical data has resulted in varying interpretative criteria across institutes (Table1).^1,2 From a pharmacokinetic standpoint, the standard dosing regimen of cefiderocol 2 g administered every 8 hours over a 3-hour infusion has been shown to achieve a ≥85% probability of target attainment for 100% fT> minimum inhibitory concentration (MIC) when applying MICs of ≤4 μg/ml across all infection sites (eg, pneumonia, bloodstream, and urinary tract) and renal function groups.³ Although clinical data remain limited, CREDIBLE-CR, a phase 3 randomized trial comparing cefiderocol with best available therapy for carbapenem-resistant pathogens, did not find clinical or microbiological cure to be associated with cefiderocol MIC values; however, most pathogens isolated from patients displayed MICs ≤4 μg/ml.⁴

From an epidemiology standpoint, the ongoing SIDERO-WT surveillance study being conducted across North America and Europe has found that among meropenem-nonsusceptible isolates, cefiderocol MICs were ≤4 mg/L against 99.6% of Enterobacterales, 99.7% of P aeruginosa, 96.1% of Acinetobacter spp, and 87.1% of B cepacia complex spp.^5,6 While resistance is infrequent at baseline, susceptibility testing prior to the initiation of treatment is recommended, and it is strongly recommended for isolates that are recovered after treatment with cefiderocol to identify MIC changes.

Iron transport receptor deletions

Unlike other beta (β)-lactam antimicrobials, cefiderocol is unique in that it is transported into the periplasmic space through siderophore iron transporters known as TonB-dependent receptors. This novel mechanism of action has led to investigation of novel mechanisms of resistance in Gram-negative bacteria. PirA, PiuA, and PiuD are genes that encode for TonB-dependent receptors in P aeruginosa and A baumannii (Table2).^7,8 Mutations in these genes can lead to a loss of function for the TonB-dependent receptors that are required for cefiderocol import. Deletion of PirA and PiuD have been shown to increase the cefiderocol MIC against P aeruginosa by 2- and 32-fold, respectively.⁸ Although there are even fewer data regarding these resistance mechanisms from a clinical standpoint, mutations in PiuD and PiuR have been reported in a P aeruginosa isolate collected from a patient without cefiderocol exposure.⁷ TonB-dependent receptor deletions have also been described in Enterobacterales. CirA and fiu encode for 2 iron transporters exclusive to E coli, and deficiency of both genes has been shown to lead to a 16-fold increase in cefiderocol MICs.⁹

Enzymatic mutations

Associations between elevated cefiderocol MICs and β-lactamases have also been reported. Perhaps the most notorious of these β-lactamases to be associated with elevated cefiderocol MICs are NDMs. In SIDERO-WT, MIC values for cefiderocol were ≤4 μg/mL against 97.7% of tested isolates; however, only 64.3% of NDM-positive isolates demonstrated a cefiderocol MIC ≤4 μg/mL.^5,6 Nonetheless, in the CREDIBLE-CR study, investigators noted a trend toward higher microbiologic eradication (63% vs 14%) and clinical cure (75% vs 14%) among patients who received cefiderocol as compared with best available therapy for treatment of infections due to metallo-β-lactamase–producing pathogens.⁴ The specific metallo-β-lactamase–producing organism was noted to be NDM in 15 of 23 such cases. Taken together, the clinical relevance of pathogens with elevated cefiderocol MICs at baseline is unknown.

In an in vitro study evaluating Acinetobacter spp, cefiderocol MICs were >8 mg/L in 8 of 9 isolates that produced Pseudomonas extended resistant (PER) β-lactamases.¹⁰ In a separate collection of 15 PER-producing P aeruginosa, cefiderocol MICs were ≤4 mg/L against 73%.¹¹ Therefore, it remains unclear if PER alone can explain resistance to cefiderocol; however, preemptive susceptibility testing is recommended for isolates known to harbor PER β-lactamases. Notably, the addition of avibactam to cefiderocol has been shown restore the activity of cefiderocol against isolates harboring PER.¹⁰

Mutations in the chromosomal ampC β-lactamase also warrant close attention in the development of resistance to cefiderocol. An anecdotal report of a patient being treated for septic shock secondary to Enterobacter cloacae complex described cefepime exposure as a possible risk factor for the induction of resistance to cefiderocol via a 2-amino acid deletion in the R2 loop of ampC β-lactamase.¹² Of concern, the terminal isolate found prior to the patient’s death displayed resistance to both ceftazidime-avibactam and cefiderocol despite the absence of exposure to either agent.¹² Mutations in ampC were also found to confer resistance to cefiderocol in another patient with E cloacae complex that was recovered from a respiratory specimen.¹³ To date, limited experience with cefiderocol in the treatment of pathogens with potential to harbor ampC β-lactamases exists since < 5% of patients included in the phase 3 trials had infections due to Enterobacter cloacae complex.^4,14 Caution should be exercised if cefiderocol is required for the treatment of Enterobacteraleswith inducible β-lactamases.

Finally, the mean cefiderocol MIC for Klebsiella pneumoniae isolates with blaSHV genes encoding for extended spectrum β-lactamases (ESBLs) were 1.1 mg/L + 1.09 mg/L compared with that of isolates lacking ESBL (0.24 + 0.18 mg/L; P = .04).¹⁵ The same study identified higher cefiderocol MICs against A baumannii isolates with ESBLs compared with those without ESBLs (MIC range, 8.04-11.58 vs 0.86-1.08 mg/L; P = .02).¹⁵ Therefore, in A baumannii, the recommendation to avoid cefiderocol in blaSHV-encoding ESBLs can be made when applying a breakpoint of < 4 mg/L. However, for K pneumoniae, although there was a 4-fold increase in MICs, all isolates remained below the susceptibility breakpoint and therefore conclusive recommendations cannot be made.

Risk Factors for Resistance to Cefiderocol

A delay in time to optimal antimicrobial therapy for drug-resistant pathogens is common in real-world studies, and such delays have been shown to be associated with worse outcomes.¹⁶ Confirming resistance to cefiderocol can be further delayed in many institutions since cefiderocol is not yet available on automated susceptibility testing devices.⁵ In order to preserve cefiderocol’s efficacy, empiric cefiderocol use is generally discouraged unless there is a known risk factor for infection due to the presence of extensively drug-resistant pathogens. Nevertheless, when cefiderocol is used empirically, risk factors for phenotypic resistance should be considered. In a post hoc analysis of MICs from CREDIBLE-CR, 12 isolates from 12 different patients had at least a 4-fold MIC increase from baseline following exposure.³ Importantly, only 3 of the 12 isolates demonstrated a cefiderocol MIC of >4 mg/L, which would be classified as resistant by all available criteria (Table 1). A similar rate was observed in the APEKS-NP trial, underscoring that the single most important risk factor for the development of resistance to cefiderocol is prior exposure.⁴

As with all other antimicrobials, failure to exercise judicious antimicrobial stewardship may also jeopardize the efficacy of cefiderocol over the long term. As previously described, exposure of β-lactams that have potential to induce ampC β-lactamases in Enterobacterales may represent a risk factor for the development of resistance to cefiderocol.¹³ Furthermore, excessive use of ceftazidime/avibactam has been shown to select for metallo-β-lactamases and for NDMs, for which cefiderocol MICs are elavated.¹⁷

Finally, the patient’s travel history and geographical location may represent risk factors for resistance to cefiderocol. For instance, although pathogenic bacteria have been rarely reported to harbor NDM worldwide, Egypt, India, Pakistan, Serbia, and the United Arab Emirates have a prevalence of NDM-positive strains among Enterobacterales species of ≥5%. Similarly, PER β-lactamases are not unusual in Switzerland and Turkey, but they are uncommon in the United States.

Conclusions

Cefiderocol is a novel antimicrobial with a unique mechanism of action. Risk factors leading to the development of resistance to cefiderocol are not clear, but they likely include geographic location and prior antimicrobial exposures. Mechanisms of resistance to cefiderocol include both β-lactamases and novel mechanisms through mutations in genes involved in the iron transport pathway. Real-world data remain limited, and thus the significance of higher baseline MICs or 4-fold shifts following cefiderocol exposure is unknown. Ultimately, further clinical data are needed to establish this antimicrobial’s place in therapy and to understand mechanisms leading to resistance.

References

^{1. Cefiderocol. Prescribing information. Shionogi; 2021. Accessed September 14, 2021.}

^{2. Susceptibility breakpoints for cefiderocol. Presentation at: the January Clinical Laboratory and Standards Institute meeting. Clinical and Laboratory Standards Institute; 2021; Wayne, PA.}

^{3. Kawaguchi N, Katsube T, Echols R, Wajima T. Population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses of cefiderocol, a parenteral siderophore cephalosporin, in patients with pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection. Antimicrob Agents Chemother. 2020;65(3):e01437-20. doi:10.1128/AAC.01437-20}

^{4. Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2020;21(2):226-240. doi:10.1016/S1473-3099(20)30796-9}

^{5. Karlowsky JA, Hackel MA, Tsuji M, Yamano Y, Echols R, Sahm DF. In vitro activity of cefiderocol, a siderophore cephalosporin, against Gram-negative bacilli isolated by clinical laboratories in North America and Europe in 2015-2016: SIDERO-WT-2015. Int J Antimicrob Agents. 2019;53(4):456-466. doi:10.1016/j.ijantimicag.2018.11.007}

^{6. Yamano Y. In vitro activity of cefiderocol against a broad range of clinically important Gram-negative bacteria. Clin Infect Dis. 2019;69(Suppl 7):S544-S551. doi:10.1093/cid/ciz827}

^{7. Streling AP, Al Obaidi MM, Lainhart WD, et al. Evolution of cefiderocol non-susceptibility in Pseudomonas aeruginosa in a patient without previous exposure to the antibiotic. Published online January 7, 2021. Clin Infect Dis. doi:10.1093/cid/ciaa1909}

^{8. Luscher A, Moynié L, Saint Auguste P, et al. TonB-dependent receptor repertoire of Pseudomonas aeruginosa for uptake of siderophore-drug conjugates. Antimicrob Agents Chemother. 2018;62(6):e00097-18. doi:10.1128/AAC.00097-18}

^{9. Ito A, Sato T, Ota M, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria. Antimicrob Agents Chemother. 2017;62(1):e01454-xx17. doi:10.1128/AAC.01454-17}

^{10. Poirel L, Sadek M, Nordmann P. Contribution of PER-type and NDM-type ß-lactamases to cefiderocol resistance in Acinetobacter baumannii. Published online July 12, 2021. Antimicrob Agents Chemother. doi:10.1128/AAC.00877-21}

^{11. Mushtaq S, Sadouki Z, Vickers A, Livermore DM, Woodford N. In vitro activity of cefiderocol, a siderophore cephalosporin, against multidrug-resistant Gram-negative bacteria. Antimicrob Agents Chemother. 2020;64(12):e01582-20. doi:10.1128/AAC.01582-20}

^{12. Shields RK, Iovleva A, Kline EG, Kawai A, McElheny CL, Doi Y. Clinical evolution of ampC-mediated ceftazidime-avibactam and cefiderocol resistance in Enterobacter cloacae complex following exposure to cefepime. Clin Infect Dis. 2020;71(10):2713-2716. doi:10.1093/cid/ciaa355}

^{13. Kawai A, McElheny CL, Iovleva A, et al. Structural basis of reduced susceptibility to ceftazidime-avibactam and cefiderocol in Enterobacter cloacae due to ampC R2 loop deletion. Antimicrob Agents Chemother. 2020;64(7):e00198-20. doi:10.1128/AAC.00198-20}

^{14, Wunderink RG, Matsunaga Y, Ariyasu M, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2021;21(2):213-225. doi:10.1016/S1473-3099(20)30731-3}

^{15. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resistance. 2020;26(7):722-726. doi:10.1089/mdr.2019.0298}

^{16. Bassetti M, Vena A, Giacobbe DR, et al; CEFTABUSE Study Group. Ceftolozane/tazobactam for treatment of severe ESBL-producing enterobacterales infections: a multicenter nationwide clinical experience (CEFTABUSE II study). Open Forum Infect Dis. 2020;7(5):ofaa139. doi10.1093/ofid/ofaa139}

^{17. Papadimitriou-Olivgeris M, Bartzavali C, Lambropoulou A, et al. Reversal of carbapenemase-producing Klebsiella pneumoniae epidemiology from blaKPC- to blaVIM-harbouring isolates in a Greek ICU after introduction of ceftazidime/avibactam. J Antimicrob Chemother. 2019;74(7):2051-2054. doi:10.1093/jac/dkz125}

^{18. Wu W, Feng Y, Tang G, Qiao F, McNally A, Zong Z. NDM metallo-β-lactamases and their bacterial producers in health care settings. Clin Microbiol Rev. 2019;32(2):e00115-18. doi:10.1128/CMR.00115-18}