All-cause mortality rates in adults with carbapenem-resistant Gram-negative bacterial infections: a comprehensive review of pathogen-focused, prospective, randomized, interventional clinical studies

Figures & data

Table 1. Study characteristics and inclusion and exclusion criteria of studies investigating carbapenem-resistant Gram-negative infections

	CARE^a NCT01970371 [29]		TANGO II NCT02168946 [30]		CREDIBLE-CR NCT02714595 [31]		AIDA NCT01732250 [32]		Durante-Mangoni NCT01577862 [33]		Sirijatuphat NCT01297894 [34]		Ji et al. IRB approved [35]		RESTORE-IMI 1 NCT02452047 [36]
Study period	2014–2016		2014–2017		2016–2019		2013–2016		2008–2011		2010–2011		2011–2012		2015–2017
No. of screened patients	>2000		85		257		802		449		NA		Unknown		65
No. of enrolled patients	69		77		152		406		210		99		62		50
No. (location) of study site(s)	5 (Brazil, Greece, Italy, Turkey, USA)		27 (Argentina, Brazil, Colombia, Greece, Israel, Italy, UK, USA)		95 (16 countries)^b		6 (Israel, Greece, Italy)		5 (Italy)		1 (Thailand)		1 (China)		35 (17 countries)
Antibiotic	PLAZ	COL	MEM/ VAB	BAT	CFDC	BAT	COL + MEM	COL	COL + RIF	COL	COL + FOS	COL	FEP + AMC	TIG + other^c	IMI/REL	IMI + COL
Dose	15 mg/kg	5 mg/kg	2 g/2 g, q8h	–	2 g, q8h	–	9 MIU loading dose + 4.5 MIU q12h + 2 g q8h	9 MIU loading dose + 4.5 MIU q12h	2 MIU q8h + 600 mg q12h	2 MIU q8h	5 mg/kg BW + 4 g q12h	5 mg/kg BW q12h	1 g q6h + 1.2 g q6h	100 mg loading dose + 50 mg q12h	500 mg/ 250 mg q6h	500 mg q6h + 300 mg loading dose + 150 mg q12h
Design	Open label^d		Open label		Open label		Open label		Open label		Open label		Open label		Double blind
Phase	3		3		3		4		3		3		4		3
Randomization	1:1		2:1		2:1		1:1		1:1		1:1		1:1		2:1
Treatment duration, days	7–14		7–14		7–14		7–14		10–21		7–14		NA		5–21
Pathogen focus	CR Enterobacterales		CR Enterobacterales		CR Enterobacterales and CR non-fermenters		CR Enterobacterales and CR non-fermenters		XDR/CR A. baumannii		CR A. baumannii		CR Klebsiella pneumoniae		CR Enterobacterales, CR P. aeruginosa
Key inclusion criteria	• Hospitalized adults 18–85 years • BSI, HAP/VAP, or cUTI/AP caused by suspected/ confirmed CRE infection		• Hospitalized adults ≥18 years • cUTI, HAP/ VAP, BSI, or cIAI • Suspected/ confirmed CRE infection		• Hospitalized adults ≥18 years • HAP/VAP/HCAP, BSI, or cUTI caused by CR GN bacteria		• Hospitalized adults with severe infections caused by CR NS, COL-susceptible, GN bacteria BSI, HAP/VAP, or urosepsis		• Hospitalized adults ≥18 years • BSI, HAP/VAP, or cIAI • Life-threatening nosocomial infection due to XDR A. baumannii		• Hospitalized adults ≥18 years • CR A. baumannii infection requiring COL therapy		• Hospitalized adults in the ICU • Pneumonia, cIAI, BSI, cUTI, and other sites		• Hospitalized adults ≥18 years • HAP/VAP, cUTI, or cIAI caused by IMI-non-susceptible, IMI/RELE-susceptible, colistin-susceptible organisms • Failure on prior antibiotic therapy
Key exclusion criteria	• Antibiotic therapy for >72 h (HAP/VAP) or <48 h (cUTI) before enrollment • CRE pathogen resistance to colistin		• Antibiotic therapy for >24 h before enrollment • Confirmed CRE-producing NDM, VIM, or OXA-encoded beta-lactamases • APACHE II score >30		• Antibiotic therapy <72 h before enrollment with a continuous duration of >24 h for cUTI or >36 h for other infections • APACHE II score >30		• Prior COL for >96 h • Polymicrobial CS GN bacteria		• Prior treatment with COL or RIF during the index hospitalization		• Infections caused by CS pathogens		• No criteria specified		• APACHE II score >30
Endpoints	Day 28 ACM		Clinical and microbiological cure, Day 28 ACM		1°: clinical and microbiological outcome 2°: Day 14 and 28 ACM and others		1°: clinical success at Day 14 2°: Day 14 and 28 ACM and others		1°: Day 30 mortality 2°: infection-related death, microbiological eradication		1°: favorable clinical response 2°: microbiological eradication, Day 28 ACM		1°: Day 28 ACM 2°: microbiological eradication, clinical efficacy, cost of antibiotic treatment, duration of antibiotic treatment, hospital length of stay		1°: Day 28 ACM (HAP/VAP); Day 28 clinical response (cIAI); composite clinical and microbiological response at EFU visit (cUTI) 2°: clinical response, Day 28 ACM
Primary analysis population	Microbiological modified ITT (confirmed CRE and ≥1 dose of study drug)		Microbiological CRE-modified ITT (confirmed CRE and ≥1 dose of study drug)		CR microbiological ITT (confirmed CR GN pathogen and ≥1 dose of study drug)		ITT		ITT		ITT		Not specified (includes all randomized + treated patients)		Microbiological modified ITT (confirmed qualifying CR GN pathogen and ≥1 dose of study drug)

ACM: all-cause mortality, AMC: amoxicillin/clavulanic acid, AP: acute pyelonephritis, APACHE II: Acute Physiology and Chronic Health Evaluation II, BAT: best available therapy, BSI: bloodstream infection, BW: body weight, CFDC: cefiderocol, cIAI: complicated intra-abdominal infection, COL: colistin, CR: carbapenem resistant, CRE: carbapenem-resistant Enterobacterales, CS: carbapenem susceptible, cUTI: complicated urinary tract infection, EFU: early follow-up, FEP: cefepime; FOS: fosfomycin, GN: Gram-negative, HAP: hospital-acquired pneumonia, IMI: imipenem, IRB: institutional review board, ITT: intention-to-treat population, MEM: meropenem, NDM: New Delhi metallo-beta-lactamase, MIU: million unit, NA: not available, NS: non-susceptible, OXA: oxacillinase, PLAZ: plazomicin, q6h: every 6 hours; q8h: every 8 hours, q12h: every 12 hours, REL: relebactam, RIF: rifampicin, TIG: tigecycline, VAB: vaborbactam, VAP: ventilator-associated pneumonia, VIM: Verona integron-encoded metallo-beta-lactamase, XDR: extensively drug resistant, –: not applicable.

^aThe trial was stopped prematurely due to slow enrollment.

^bUSA 9; Brazil 9; Guatemala 2; Italy 6; Spain 12; Greece 7; France 2; Turkey 4; Germany 3; Israel 10; Croatia 5; UK 5; Japan 3; Taiwan 7; South Korea 8; Thailand 3.

^cAs monotherapy or in combination with amikacin + levofloxacin, meropenem, fosfomycin, cefepime, cefoperazone/sulbactam.

^dThe study was open label, but the sponsor remained blinded to the results throughout its course.

Table 2. Demographic and baseline details in the primary analysis populations of recent studies in adult patients with infections caused by carbapenem-resistant Gram-negative pathogens

	CARE [29]		TANGO II [30]		CREDIBLE-CR [31]		AIDA [32]		Durante-Mangoni [33]		Sirijatuphat [34]^a		Ji et al. [35]		RESTORE-IMI 1 [36]
Arm	PLAZ	COL	MEM/ VAB	BAT	CFDC	BAT	COL + MEM	COL	COL + RIF	COL	COL + FOS	COL	FEP + AMC	TIG-based therapy	IMI/REL	IMI + COL
No. of analyzed patients	17	20	32	15	80	38	208	198	104	105	47	47	26	25	21	10
Patient population
Male, n (%)	12 (70.6)	10 (50.0)	14 (43.8)	10 (66.7)	55 (69)	29 (76)	76 (37)	75 (38)	67 (64.4)	70 (66.7)	20 (42.6)	24 (51.1)	18 (39.2)	13 (52.0)	13 (61.9)	7 (70.0)
Age (mean), years	66.7	63.1	63.5	60.2	63.1	62.1	66	66	62	61	67.4	69.2	67.1	63.6	59^b	61^b
Age ≥65 years, n (%)	NA	NA	8 (25.0)	3 (20.0)	50 (63)	17 (45)	NA	NA	NA	NA	NA	NA	NA	NA	6 (28.6)	5 (50.0)
Baseline diagnosis, n (%)
BSI	14 (82.4)	15 (75.0)	14 (43.8)	8 (53.3)	23 (29)^c	14 (37)^c	97 (47)	76 (38)	21 (20.2)	21 (20.0)	2 (4.3)	3 (6.4)	4 (15)	2 (8)
HAP/VAP	3 (17.6)	5 (25.0)	4 (12.5)	1 (6.7)	40 (50)^d	19 (50)^e	99 (48)	108 (55)	81 (77.9)	81 (77.1)	37 (78.7)	35 (74.5)	8 (31)	5 (20)	8 (38.1)	3 (30.0)
cUTI	–	–	12 (37.5)	4 (26.7)	17 (21)	5 (13)	12 (6)	14 (7)	NA	NA	3 (6.4)	2 (4.3)	1 (4)	0	11 (52.4)	5 (50.0)
cIAI Other	– –	– –	2 (6.3) –	2 (13.3) –	– –	– –	NA –	NA –	2 (1.9) –	3 (2.9) –	2 (4.3) –	4 (8.5) –	3 (12) 0	10 (40) 1 (4)	2 (9.5) –	2 (20.0) –
Baseline pathogens, n (%)
Enterobacterales							39	34					26 (100)	25 (100)	5 (23.8)	2 (20.0)
K. pneumoniae	16 (94.1)	20 (100)	29 (90.6)	12 (80.0)	27 (34)	12 (32)	NA	NA	–	–	2 (4.3)	6 (12.8)	26 (100)	25 (100)	3 (14.3)	1 (10.0)
Other	1 (5.9)	0	5 (15.6)	6 (40.0)	4 (5)	1 (3)	NA	NA	NA	NA	NA	NA	NA	NA	2 (9.5)	1 (10.0)
Non-fermenters
A. baumannii	NA	NA	NA	NA	37 (46)	17 (45)	161 (77)	151 (76)	104 (100)	105 (100)	47 (100)	47 (100)	NA	NA	NA	NA
P. aeruginosa	NA	NA	NA	NA	12 (15)	10 (26)	8 ^f	13 ^f	0	0	3 (6.4)	1 (2.1)	NA	NA	16 (76.2)	8 (80.0)
Other	NA	NA	NA	NA	7 (8.8)	0	0	0	0	0	0	0	NA	NA	NA	NA
CCI ≥2, n (%) or Median (IQR)	NA	NA	28 (87.5)^g	14 (93.3)^g	5.5 (3–8)^h	5.0 (3–7)^h	2 (0–4)^h	2 (0–3)^h	64 (61.5)	63 (60.0)	NA	NA	NA	NA	NA	NA
APACHE II score, n (%) or Mean (±SD)
≤15	0	0	NA	NA	41 (51)	21 (55)	NA	NA	NA	NA	23.0 (±6.4)^j	21.9 (±7.9)^j	16.0 (±8.8)^j	17.1 (±9.3)^j	7 (33.3)	8 (80.0)
>15	17 (100)^i	20 (100)^i	NA	NA	39 (49)	17 (45)	NA	NA	NA	NA	–	–			14 (66.7)	2 (20.0)
ICU admission, n (%)	NA	NA	5 (15.6)	3 (20.0)	52 (65)	19 (50)	71 (34)^k	77 (39)^k	62 (59.6)^l	65 (61.9)^l	NA	NA	19 (73.1)	18 (72.0)	NA	NA

AMC: amoxicillin/clavulanic acid; APACHE II: Acute Physiology and Chronic Health Evaluation II, BAT: best available therapy, BSI: bloodstream infection, CCI: Charlson Comorbidity Index, CFDC: cefiderocol, cIAI: complicated intra-abdominal infection, COL: colistin, cUTI: complicated urinary tract infection, FEP: cefepime; FOS: fosfomycin, HAP: hospital-acquired pneumonia, HCAP: healthcare-associated pneumonia, ICU: intensive care unit, IMI: imipenem, IQR: interquartile range, MEM: meropenem, NA: not available, PLAZ: plazomicin, REL: relebactam, RIF: rifampicin, SD: standard deviation, TIG: tigecycline; VAB: vaborbactam, VAP: ventilator-associated pneumonia, –: not applicable.

^an numbers calculated from percentages provided.

^bMedian.

^cSepsis included in BSI category.

^dIncludes 1 patient with HCAP.

^eIncludes 2 patients with HCAP.

^fPseudomonas and others.

^gCCI >2. ^hMedian (IQR).

ⁱAPACHE II score ≥15.

^jMean (±SD).

^kAcquisition of infection in the ICU.

^lEmergency/ICU admission.

Figure 1. Day 28 all-cause mortality rates in carbapenem-resistant Enterobacterales infections. ACM: all-cause mortality, BAT: best-available therapy, CI: confidence interval, CR: carbapenem resistant. In the TANGO II and CREDIBLE-CR studies, patients were randomized 2:1 (investigational therapy:control).

Figure 2. Day 28 all-cause mortality rates in carbapenem-resistant Acinetobacter spp. infections. ACM: all-cause mortality, BAT: best-available therapy, CI: confidence interval, CR: carbapenem resistant. In the CREDIBLE-CR study, patients were randomized 2:1 (cefiderocol:BAT). Acinetobacter spp. include: A. baumannii; A. nosocomialis.

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