This agent is likely best utilized as part of a combination when treating this bacterium but data regarding appropriate combinations are scarce.
Acinetobacter species (spp) have emerged as important health care– associated pathogens due to their array of intrinsic resistance mechanisms and propensity to acquire additional resistance mechanisms.1 Although carbapenems have been readily used to overcome multidrug-resistant Acinetobacter spp infections, the Centers for Disease Control and Prevention antimicrobial resistance threat report identified carbapenem-resistant Acinetobacter spp as an urgent threat.2 Carbapenem-resistant Acinetobacter baumannii (CRAB) is an especially difficult pathogen to manage, often requiring combination therapy with polymyxins or tigecycline.3 Cefiderocol, a siderophore cephalosporin, has emerged as an attractive therapeutic option for multidrug-resistant gram-negative pathogens, including CRAB, due to its relative stability in the presence of a wide array of β-lactamases and its novel mechanism of entry into the periplasmic space of gram-negative pathogens.4 Although cefiderocol retains excellent in vitro activity against gram-negative isolates, its role in the management of infections caused by CRAB remains uncertain. A key gap in our understanding of cefiderocol is whether it is an appropriate agent for monotherapy or is best reserved as a component of combination regimens against CRAB infections.
As a siderophore cephalosporin, cefiderocol contains a conjugated catechol moiety at the 3-position side chain, which allows it to chelate soluble ferric iron and subsequently undergo active transport across the outer cell membrane of gram-negative pathogens.4 This ability to utilize active transport allows cefiderocol to achieve higher concentrations at the site of action, resulting in a relative decrease in the minimum inhibitory concentration. Cefiderocol is stable in the presence of a wide array of clinically relevant β-lactamases, including extended-spectrum β-lactamases, serine carbapenemases, and metallo-β-lactamases.5 These features contribute to the potent in vitro activity of cefiderocol, making it an important therapeutic agent to manage extensively drug-resistant infections.
CEFIDEROCOL IN VITRO DATA
Overall rates of cefiderocol resistance are low, although resistance has been reported following exposure to cefiderocol or other β-lactams among both Enterobacterales and nonfermenters.6-9 Cefiderocol heteroresistance also has been reported among surveillance of carbapenem-resistant gram-negative organisms, including Acinetobacter spp, and may complicate its use in clinical practice because heteroresistance screening is not readily integrated into routine susceptibility testing.10 Heteroresistance is a phenomenon in which a susceptible population develops resistance when exposed to an antimicrobial but susceptibility is restored after cessation of antimicrobial exposure and is not detected by routine susceptibility testing. Heteroresistance is thought to be caused by the presence of resistant subpopulations that thrive under the selective pressure of antimicrobial exposure. Although the clinical relevance of cefiderocol heteroresistance is unclear at this time, colistin heteroresistance has been associated with antimicrobial failure in in vivo models of Enterobacter cloacae and Klebsiella pneumoniae infections.11,12 A surveillance study of carbapenem-resistant pathogens reported similarly low rates of resistance to cefiderocol compared with results from the CREDIBLE-CR trial (NCT02714595) (8% vs 3%), but population analysis profiling indicated that cefiderocol heteroresistance was much higher and more closely aligned with all-cause mortality results from CREDIBLE-CR (59% and 49%).10 Although this surveillance study represents in vitro data and is not directly correlated with clinical outcomes, high rates of cefiderocol heteroresistance support avoiding cefiderocol as monotherapy for serious CRAB infections because an adjunctive agent may provide antimicrobial activity against cefiderocol-resistant subpopulations.
An in vitro study of cefiderocol activity alone or as part of a combination against multidrug-resistant Acinetobacter baumannii reported synergy with multiple other agents. Synergy was most consistently observed when combined with amikacin or meropenem, despite resistance to both of these agents in all isolates tested.13
CEFIDEROCOL COMBINATION THERAPY CLINICAL DATA
Despite in vitro activity, clinical data supporting use of cefiderocol remain sparse. Results from APEKS-cUTI (NCT02321800), a phase 2 clinical trial in patients (n=371) with complicated urinary tract infections and pyelonephritis, established the clinical utility of cefiderocol for genitourinary infections but failed to establish its role in the management of carbapenem-resistant pathogens.14 As expected, none of the patients with microbiological data in this study had CRAB isolated evaluated cefiderocol use for infections outside the urinary tract.
APEKS-NP (NCT03032380), a phase 3 trial evaluating cefiderocol use in nosocomial pneumonia (n=292), was not designed to study carbapenem-resistant pathogens but did include a small number (n=53) of meropenem-resistant isolates, including Acinetobacter spp. Among patients with meropenem-resistant Acinetobacter spp respiratory isolates, no differences in 14- and 28-day all-cause mortality were seen between the 26 patients who received cefiderocol and the 27 patients who received meropenem. The results from the APEKS-NP trial suggest that cefiderocol monotherapy is no better than meropenem monotherapy for CRAB.15
The role of cefiderocol for the management of carbapenem-resistant pathogens from a range of clinical syndromes was further explored in the CREDIBLE-CR trial (n=150). Patients with bloodstream, pulmonary, or genitourinary infections caused by carbapenem-resistant gram-negative pathogens were assigned to receive either cefiderocol or best available therapy. Combination therapy was permitted in the trial with a maximum of 3 agents in the best available therapy arm and up to 1 adjunctive antibiotic, excluding polymyxins or β-lactams, for patients who received cefiderocol. All-cause mortality rates among 42 patients who received cefiderocol and 17 patients who received alternative therapy with infections caused by CRAB were 50% (n=21) and 18% (n= 3) respectively. Excess mortality was also compounded by lower frequency of combination therapy in the cefiderocol arm (18%) than the alternative therapy arm (71%) and more patients in the cefiderocol arm in the intensive care unit at randomization (56% vs 43%) or in septic shock (19% vs 12%).16 The exact cause of this excess mortality is not entirely clear. However, mortality did appear elevated in patients with Acinetobacter spp isolates.16
A recent observational, retrospective cohort study compared outcomes of 47 patients who received cefiderocol-based regimens and 77 patients who received colistin-based regimens for the management of infections caused by CRAB.17 The study population was critically ill, with 89% of patients in the intensive care unit and 56% of patients on mechanical ventilation. Most patients had bloodstream infections (62%) or ventilator-associated pneumonia (28%).
In contrast to cefiderocol use in CREDIBLE-CR, 68% of patients in this study received cefiderocol as part of a combination regimen, most commonly with tigecycline (n=21), followed by fosfomycin (n=8).17 Cefiderocol-based therapy was associated with a decrease in 30-day mortality compared with colistin-based regimens, 34% and 55.8% respectively.17 Improved 30-day mortality in the cefiderocol arm was largely driven by bloodstream infections (25.9% vs 57.5%), but there was no significant difference for patients treated for ventilator-associated pneumonia (58.3% vs 56.5%).17 Monotherapy with either cefiderocol or colistin therapy was associated with microbiological failure (42.9% vs 6.3%), and mortality was lower among patients who received a cefiderocol-based combination compared with cefiderocol monotherapy (6.3% vs 40%).17
The results of this study suggest that cefiderocol combination therapy for severe CRAB infections may be appropriate.
Current recommendations for the management of severe infections caused by CRAB suggest combination therapy with at least 2 agents, with in vitro activity preferred when possible.3 Cefiderocol is currently only recommended as combination therapy for CRAB in refractory infections or situations where tolerability precludes the use of other agents. Available clinical trial data report inconsistent success with cefiderocol use with outcomes possibly improved when used in combination with other agents.
Although in vitro data suggest synergy when combined with amikacin or meropenem, clinical data on these combinations are lacking. A small number of published cases of cefiderocol use for CRAB infections are available, with use reported as both monotherapy and combination therapy. Cefiderocol frequently has been combined with fosfomycin, tigecycline, or polymyxins in available published cases, similar to prospective and retrospective studies including cefiderocol as combination therapy.6,16-20 When used for infections caused by CRAB, cefiderocol should be used in combination with another in vitro active agent if possible, or with meropenem or amikacin if no other active agents are available or a third agent is used.
CRAB is a difficult-to-manage nosocomial pathogen with limited treatment options. Current expert recommendations prefer combination therapy, often relying on high-dose ampicillin/sulbactam or an intolerable, highly toxic agent such as a polymyxin.3 The arrival of cefiderocol initially offered hope for a single-agent regimen for the management of CRAB infections. However, available data do not support its use as monotherapy. In clinical practice, cefiderocol may be an option as a component of combination therapy, but data regarding the use of cefiderocol as a component of combination therapy are scarce and no preferred combination has been identified.
1. Dijkshoorn L, Nemec A, Seifert H. An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii. Nat Rev Microbiol. 2007;5(12):939-951. doi: 10.1038/nrmicro1789
2. Antibiotic resistance threats in the United States, 2019. US Department of Health and Human Services. Accessed June 5, 2022. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf.
3. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America guidance on the treatment of AmpC β-lactamase-producing Enterobacterales, carbapenem-resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia infections. Clin Infect Dis. Published online December 5, 2021. doi:10.1093/cid/ciab1013
4. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2016;60(12):7396-7401. doi:10.1128/AAC.01405-16
5. Ito-Horiyama T, Ishii Y, Ito A, et al. Stability of novel siderophore cephalosporin S-649266 against clinically relevant carbapenemases. Antimicrob Agents Chemother. 2016;60(7):4384-4386. doi:10.1128/AAC.03098-15
6. Bleibtreu A, Dortet L, Bonnin RA, et al; On Behalf Of The Cefiderocol French Study Group. Susceptibility testing is key for the success of cefiderocol treatment: a retrospective cohort study. Microorganisms. 2021;9(2):282. doi:10.3390/microorganisms9020282
7. Malik S, Kaminski M, Landman D, Quale J. Cefiderocol resistance in Acinetobacter baumannii: toles of β-lactamases, siderophore receptors, and penicillin binding protein 3. Antimicrob Agents Chemother. Published online October 20, 2020. doi:10.1128/AAC.01221-20
8. 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
9. 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. Clin Infect Dis. 2021;73(11):e4472-e4474. doi:10.1093/cid/ciaa1909
10. Choby JE, Ozturk T, Satola SW, Jacob JT, Weiss DS. Widespread cefiderocol heteroresistance in carbapenem-resistant gram-negative pathogens. Lancet Infect Dis. 2021;21(5):597-598. doi:10.1016/S1473-3099(21)00194-8
11. Band VI, Crispell EK, Napier BA, et al. Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae. Nat Microbiol. 2016;1(6):16053. doi:10.1038/nmicrobiol.2016.53
12. Band VI, Satola SW, Burd EM, Farley MM, Jacob JT, Weiss DS. Carbapenem-resistant Klebsiella pneumoniae exhibiting clinically undetected colistin heteroresistance leads to treatment failure in a murine model of infection. mBio. Published online March 6, 2018. doi:10.1128/mBio.02448-17
13. Abdul-Mutakabbir JC, Nguyen L, Maassen PT, et al. In vitro antibacterial activity of cefiderocol against multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2021;65(9):e0264620. doi:10.1128/AAC.02646-20
14. Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319-1328. doi:10.1016/S1473-3099(1318)30554-1
15. 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
16. 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. 2021;21(2):226-240. doi:10.1016/S1473-3099(20)30796-9
17. Falcone M, Tiseo G, Leonildi A, et al. Cefiderocol- compared to colistin-based regimens for the treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2022;66(5):e0214221. doi:10.1128/aac.02142-21
18. Bavaro DF, Belati A, Diella L, et al. Cefiderocol-based combination therapy for "difficult-to-treat" gram-negative severe infections: real-life case series and future perspectives. Antibiotics (Basel). 2021;10(6):652. doi:10.3390/antibiotics10060652
19. Oliva A, Ceccarelli G, De Angelis M, et al. Cefiderocol for compassionate use in the treatment of complicated infections caused by extensively and pan-resistant Acinetobacter baumannii. J Glob Antimicrob Resist. 2020;23:292-296. doi:10.1016/j.jgar.2020.09.019
20. Zingg S, Nicoletti GJ, Kuster S, et al. Cefiderocol for extensively drug-resistant gram-negative bacterial infections: real-world experience from a case series and review of the literature. Open Forum Infect Dis. Published online May 21, 2020. doi:10.1093/ofid/ofaa185