Evaluating Cefiderocol in the Treatment of Multidrug-Resistant Gram-Negative Bacilli: A Review of the Emerging Data

Figures & data

Table 1 Susceptibility to Cefiderocol of Gram-Negative Isolates from Selected Surveillance Studies

Order/Genus/Species^a	(No. Isolates)	Source^b (Years)	MIC (mg/L)		% Inhibited at 4 mg/L^c	% Inhibited at 2 mg/L^d	References
			Range	MIC90
Enterobacterales	3007	NAm (2014–15)	≤0.002–8	0.5	NR^e	NR	[^Citation73]
Enterobacterales	3080	EU (2014–15)	≤0.002–8	1	NR	NR	[^Citation73]
Enterobacterales	2470	NAm (2015)	≤0.002–128	0.5	NR	NR	[^Citation74]
Enterobacterales	3543	EU (2015)	≤0.002–8	1	NR	NR	[^Citation74]
Enterobacterales	20,949	Cumulative (2014–16)	≤0.002–>256	NR	99.4	98.6	[^Citation71]
P. aeruginosa	1530	NAm/EU (2014–15)	≤0.002–8	0.5	NR	NR	[^Citation73]
P. aeruginosa	1540	NAm/EU (2015)	≤0.002–8	0.5	NR	NR	[^Citation74]
P. aeruginosa	4942	Cumulative (2014–16)	≤0.002–8	2	99.9	NR	[^Citation71]
A. baumannii	1148	NAm/EU (2014–15)	≤0.002–64	1	NR	NR	[^Citation73]
Acinetobacter spp.	308	NAm (2015)	≤0.002–>256	1	NR	NR	[^Citation74]
Acinetobacter spp.	664	EU (2015)	≤0.002–>256	2	NR	NR	[^Citation74]
A. baumannii	2896	Cumulative (2014–16)	≤0.002–256	2	95.6	NR	[^Citation71]
S. maltophilia	152	NAm (2014–15)	≤0.002–4	0.5	100	NR	[^Citation73]
S. maltophilia	276	EU (2014–15)	0.004–2	0.25	100	100	[^Citation73]
S. maltophilia	165	NAm (2015)	0.004–64	0.5	NR	NR	[^Citation74]
S. maltophilia	175	EU (2015)	≤0.002–64	0.25	NR	NR	[^Citation74]
S. maltophilia	217	Global (2014–16)	0.004–2	0.25	100	100	[^Citation28]
S. maltophilia	1173	Cumulative (2014–16)	≤0.002–64	0.25	99.8	99.6	[^Citation71]
B. cepacia complex	40	NAm (2015)	≤0.002–32	0.5	NR	NR	[^Citation74]
B. cepacia complex	49	EU (2015)	≤0.002–32	0.12	NR	NR	[^Citation74]
B. cepacia complex	164	Cumulative (2014–16)	≤0.002–64	0.25	95.7	NR	[^Citation71]
Enterobacterales Carba-NS	1020	Global (2014–16)	0.004–32	4	NR	NR	[^Citation28]
Enterobacterales KPC+	75	NAm/EU (2014–15)	0.03–4	2	NR	NR	[^Citation75]
Enterobacterales KPC-2^+	355	NR	≤0.03–32	8	NR	NR	[^Citation76]
Enterobacterales KPC-3^+	380	NR	≤0.03–64	2	NR	NR	[^Citation76]
Enterobacterales OXA-48^+	154	Global (2000–16)	0.03–64	2	NR	NR	[^Citation77]
Enterobacterales MBL (VIM, NDM, IMP)^+	69	Global (2000–11)	≤0.12–>16	16	89.8	86.9	[^Citation78]
Enterobacterales MBL (VIM, NDM, IMP)^+	134	Global (2000–16)	0.03–64	4	NR	NR	[^Citation77]
Enterobacterales ESCR	2547	Cumulative (2014–16)	NR	NR	99.1	91.3	[^Citation71]
P. aeruginosa Carba-NS and CTZ-NS	1005	Global (2014–16)	0.004–32	4	NR	NR	[^Citation28]
P. aeruginosa Carba-NS	1154	Cumulative (2014–16)	NR	NR	99.9	98.5	[^Citation71]
P. aeruginosa Carba-NS MBL^+	30	NAm/EU (2014–15)	0.008–2	2	NR	NR	[^Citation75]
A. baumannii Carba-NS OXA-23/24/58^+	681	NAm/EU (2014–15)	≤0.002–64	1	NR	NR	[^Citation75]
A. baumannii Carba-NS	1891	Cumulative (2014–16)	NR	NR	94.8	91.8	[^Citation71]

Notes: ^aCarba-NS, carbapenem nonsusceptible; CTZ-NS, ceftolozane-tazobactam nonsusceptible; ESCR, resistant to expanded-spectrum cephalosporins (cefepime MIC >4 mg/L). ^bNAm, North America; EU, Europe. ^cCLSI susceptibility breakpoint for Enterobacterales, P. aeruginosa, Acinetobacter spp., and S. maltophilia. ^dEUCAST susceptibility breakpoint for Enterobacterales and P. aeruginosa. ^eNR, not reported.

Table 2 Dosage Regimens of Cefiderocol Focused at Achieving 90% of PTAs of 75% T>MIC Against Pathogens with an MIC Up to 4 mg/L in Patients with Different Classes of Renal Function⁴⁴

CLCr	Dosage Regimen
≥ 120 mL/min° (ARC)	2g q6h over 3h
≥ 90 mL/min/1.73 m^2*	2g q8h over 3h
60-<90 mL/min/1.73 m^2*	2g q8h over 3h
30-<60 mL/min/1.73 m^2*	1.5 g q8h over 3h
15 to 30 mL/min/1.73 m^2*	1 g q8h over 3h
< 15 mL/min/1.73 m^2*	0.75 g q12h over 3h
IHD**	0.75 g q12h over 3h

Notes: °Estimated by means of the Cockcroft and Gault formula. *Estimated by means of the modified diet renal diseases (MDRD) formula. **A supplemental dose of 0.75g over 3h should be administered after completion of IHD on the dialysis day.

Abbreviations: ARC, augmented renal clearance; CLCr, creatinine clearance; IHD, intermittent hemodialysis.

Table 3 Published Case Reports and Case Series of Compassionate Use of Cefiderocol

Age, Sex (Reference)	Underlying Condition of the Patient	Type of Infection Pathogen (in vitro Susceptibility)	Antimicrobial Therapy History	Outcome
46, Male^Citation57	Partial right great toe amputation treated with daptomycin and levofloxacin for a vancomycin-resistant Enterococcus faecium and Pseudomonas aeruginosa stump infection with residual osteomyelitis. Hemodialysis-dependent for end-stage renal disease, diabetes mellitus, coronary disease.	Perforation of the colon with intraabdominal abscess. End ileostomy and right hemicolectomy. Pseudomonas aeruginosa (carbapenem-resistant, cefiderocol susceptible), Escherichia coli, Bacteroides fragilis.	First line: Meropenem, daptomycin, linezolid. Second line: Ceftazidime/avibactam, polymyxin B, metronidazole. polymyxin B was discontinued due to suspect of neurotoxicity. Third line: cefiderocol plus metronidazole.	Decrease in size of intraabdominal abscess on day 5 of cefiderocol therapy. Complete resolution of paracolic gutter abscess on day 19 of therapy. Discontinuation of treatment after 28 days therapy.
Adult, male^Citation58	Severe H1N1 influenza complicated by bilateral pneumonia and respiratory failure. Intubation and extracorporeal membrane oxygenation.	Bacteremia. Acinetobacter baumannii (extensively drug-resistant, susceptible to colistin); Klebsiella pneumoniae (carbapenem resistant; colistin, gentamicin, ceftazidime/avibactam, and cefiderocol susceptible).	First line empiric: piperacillin-tazobactam, clarithromycin, linezolid, zanamivir. Second line: meropenem, vancomycin, anidulafungin. Third line: colistin, fosfomycin, tigecycline, daptomycin. Fourth line: cefiderocol, linezolid	Patient conditions rapidly improved with resolution of fever and normalization of procalcitonin levels after start of cefiderocol therapy. After 14 days of cefiderocol treatment, chest X-rays showed complete resolution of lung infiltrates.
78, female^Citation56	Hydronephrosis secondary to a spontaneous ureteric hematoma. She had a past medical history of aortic stenosis, ischemic heart disease, and cerebral infarction and was in remission from breast cancer. Thickened aortic valve.	Bacteremia complicated by aortic valve endocarditis, Pseudomonas aeruginosa (susceptible only to colistin, gentamicin and amikacin); (resistant also to ceftazidime/avibactam and ceftolozane/tazobactam. No synergy between antipseudomonal agents and fosfomycin and rifampicin).	First line: colistin plus gentamicin. Second line: colistin plus meropenem Third line: colistin plus meropenem plus cefiderocol for one week followed by colistin plus cefiderocol for an additional 3 weeks.	Aortic valve replacement was performed on day 2 of cefiderocol. Blood culture taken the day of surgery was negative and persisted negative up to day 275.
68, female^Citation55	End-stage renal disease secondary to diabetes who had been on hemodialysis for 8 years. Renal transplant complicated by cardiac arrest with pulseless electronic activity, requiring initiation of extracorporeal membrane oxygenation and continuous renal replacement therapy. Hematoma surrounding the kidney allograft and placement of abdominal drains	Isolation from peritoneal drain cultures and blood. Klebsiella pneumoniae positive for both NDM-1 and OXA-48 group enzymes (resistant to carbapenems, ceftazidime/avibactam, meropenem/vaborbactam, and gentamycin; susceptible to colistin, tigecycline, eravacycline, and cefiderocol).	First line: polymyxin B plus tigecycline. Second line: polymyxin B, ceftazidime/avibactam, aztreonam. Third line: polymyxin B, ceftazidime/avibactam, cefiderocol (1.5 g/12h)	Subsequent blood cultures and peritoneal fluid culture were all negative after cefiderocol was started, with clinical improvement. The patient developed vancomycin-resistant Enterococcus faecium bacteremia, invasive candidiasis due to Candida glabrata, and Clostridioides difficile-infection, which were treated with daptomycin, caspofungin, and oral vancomycin, respectively. Eventually the patient developed fatal ischemic colitis.
15, male^Citation54	Femur fracture after a motor vehicle accident, intramedullary pin placement.	Recurrent wound infection treated with various antibiotics (details not available). Chronic osteomyelitis of the left femur, with phlegmonous changes extending to the skin. Pseudomonas aeruginosa (extensively drug resistant, susceptible only to colistin and cefiderocol), Extended-spectrum β-lactamases-producing Klebsiella pneumoniae (susceptible to carbapenem, ceftazidime/avibactam, colistin, cefiderocol, aminoglycosides).	First line empiric: levofloxacin, metronidazole, trimethoprim-sulfamethoxazole, antibiotic-cement nail containing tobramycin and vancomycin. Second line: cefepime, vancomycin, metronidazole. Third line: ceftazidime/avibactam plus aztreonam Fourth line: polymyxin B, aztreonam, tigecycline. Fifth line: cefiderocol plus aztreonam. Aztreonam discontinued after two weeks. Bone graft and antibiotic nail exchange. Cefiderocol was administered for a total of 14 weeks.	After 9 weeks of cefiderocol therapy bone cultures were sterile, and a histopathology report showed benign bone without associated acute or chronic inflammation.
84, male^Citation59	Diabetes mellitus, chronic renal failure, previous non-Hodgkin’s lymphoma, vascular diseases, hallux amputation.	BSI secondary to an infected, wet gangrenous left foot, caused by OXA- and NDM-producing K. pneumoniae (susceptible to colistin, tigecycline, and cefiderocol).	First line empiric: piperacillin-tazobactam, clindamycin, and amikacin, in addition to surgical debridement Second line: colistin, tigecycline Third line: cefiderocol plus colistin, then de-escalated to cefiderocol monotherapy. Treated with cefiderocol for 14 days	Improvement and discharge from ICU, subsequent death in a medical ward without signs of infection relapse
63, male^Citation60	Obesity, diabetes mellitus, cardiac ischemic disease, gout arthritis.	Para-duodenal pancreatic collection with extensively drug resistant (XDR) P. aeruginosa (susceptible to colistin and cefiderocol) isolated from pancreatic pus.	First line: colistin, meropenem Second line: cefiderocol	Favorable resolution after 6 weeks of treatment. Subsequent isolation of a cefiderocol-resistant strain from ischial eschar. Subsequent death due to XDR P. aeruginosa pneumonia
65, male 70, female 56, female^Citation61	Patient 1: hypertension, cardiac tamponade, septic thrombosis due to carbapenemase-producing K. pneumoniae Patient 2: diabetes mellitus, K. oxytoca septic shock with bacteraemic pyelonephritis Patient 3: Staphylococcus aureus spinal implant infection.	Patient 1: BSI due to pan-drug resistant Acinetobacter baumannii Patient 2: BSI due to colistin-susceptible Acinetobacter baumannii, complicated by XDR P. aeruginosa bacteremia Patient 3: wound superinfection and spondylodiscitis due to XDR A. baumannii (bone culture positive)	Patient 1: First line empiric: trimethoprim/sulfamethoxazole Second line: cefiderocol Patient 2: First line: colistin Second line: cefiderocol Patient 3: First line: colistin, tigecycline Second line: cefiderocol	Patient 1: Improvement and discharge from ICU, subsequent death in a medical ward without signs of infection relapse Patient 2: Resolution of A. baumannii but not P. aeruginosa BSI. Subsequent death due to intercurrent HSV-1 disseminated infection Patient 3: Bone culture negative after 21 days of cefiderocol treatment. Subsequent completion of a 6-week treatment with oral minocycline and no signs of relapse at 9-week follow-up
10 patients (4 males and 6 females) with a mean age of 69 years^Citation62	Hypertension (9/10), COVID-19 (5/10), burns (4/10), obesity (2/10), bipolar disorder (1/10), bladder cancer (1/10), colonic perforation (1/10), intravenous drug use (1/10).	Six BSI and 4 ventilator-associated pneumonia (VAP) due carbapenem-resistant organisms (7 A. baumannii, 1 NDM-producing Stenotrophomonas maltophilia, 1 NDM-producing K. pneumoniae, 1 A. baumannii plus NDM-producing K. pneumoniae)	First line: 7 colistin-based combination, 1 colistin monotherapy, 1 tigecycline plus ampicillin-sulbactam, 1 ceftazidime/avibactam plus aztreonam plus fosfomycin Second line: cefiderocol (9 monotherapy, 1 combined with fosfomycin)	Clinical outcome at day 30 was favorable in 7/10 cases (70%), 30-day mortality was 10% (1/10)
67, male^Citation63	Atrial fibrillation, chronic Glaucoma, previous left knee replacement, aortic stent, right knee replacement.	Acute prosthetic joint infection of the right knee managed with debridement, antibiotics and implant retention (DAIR). Isolation from intraoperative material of XDR Enterobacter hormaechei (susceptible to colistin and tigecycline).	First line empirical: vancomycin, piperacillin/tazobactam Second line: colistin, tigecycline Third line: cefiderocol	Improved, discharged, and treated for 12 weeks (including 10 weeks of cefiderocol monotherapy). Follow-up at 12 weeks after end of antibiotic treatment showed full recovery.
45, female^Citation64	Hemangioblastoma requiring multiple neurosurgical interventions, esophageal-pleural fistula, esophageal perforation repaired with jejunostomy and gastrostomy tube placement.	Esophageal leak with fistula and growth of cefiderocol-susceptible XDR P. aeruginosa from plural fluid culture, treated surgically and with antibiotic therapy.	First line: ceftazidime/avibactam, polymyxin B Second line: cefiderocol	Full recovery after 3 weeks of cefiderocol treatment. Subsequent respiratory colonization by cefiderocol-resistant XDR P. aeruginosa, without infection and need for antibiotic therapy.
29, male 64, male 62, male^Citation65	Patient 1: polytrauma with external fixation of an open fracture of the tibia Patient 2: polytrauma Patient 3: blunt thoracic trauma with lung injury, hemothorax, rib fractures.	Patient 1: early postoperative, polymicrobial, implant-associated wound infection due to VIM-producing P. aeruginosa, OXA-23-producing A. baumannii, and KPC-producing Enterobacter cloacae Patient 2: postoperative implant-associated spine infection due to OXA-40 and NDM- producing A. baumannii Patient 3: pleural empyema due to XDR A. baumannii and subsequent acute osteomyelitis and urinary tract infection due to XDR A. baumannii.	Patient 1: Treatment: multiple surgeries plus cefiderocol for 2 weeks and colistin and ceftazidime-avibactam for 4 weeks Patient 2: Treatment: removal of osteosynthesis and colistin plus cefiderocol for 14 days, then cefiderocol monotherapy for a total of 6 weeks Patient 3: Treatment: cefiderocol plus colistin (for 14 days) for pleural empyema and cefiderocol (6 weeks) for osteomyelitis	Patient 1: Definite implantation and not signs of relapse at 8 weeks of follow-up Patient 2: Novel osteosynthesis with no signs of relapse at 13 weeks of follow-up Patient 3: No signs of relapse at 6 weeks of follow-up
57, male^Citation66	Hypertension, diabetes mellitus, left tibia and fibula fracture with external fixation followed by two surgical debridements.	Osteomyelitis of left leg with intraoperative cultures positive for Enterococcus faecalis, Corynebacterium striatum, And XDR A. baumannii.	First line empirical: piperacillin/tazobactam with subsequent addition of vancomycin Second line: Polymyxin B, minocycline, and vancomycin (the latter subsequently substituted by daptomycin) Third line: Daptomycin, meropenem, tigecycline Fourth line: Daptomycin, cefiderocol	Cefiderocol discontinued after 102 days and no signs of relapse at 128 days after antibiotics discontinuation.

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