Mortality-Related Risk Factors and Novel Antimicrobial Regimens for Carbapenem-Resistant Enterobacteriaceae Infections: A Systematic Review

Figures & data

Figure 1 Flow diagram of included studies (Mortality-Related Risk Factors). *1. Children/not in adults; 2. Case report/review/experimental studies; 3. CRE colonization; 4. Risk factors about CRE infection; 5. The studies of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Pseudomonas aeruginosa, Acinetobacter baumannii and Gram-positive bacteria.

Table 1 Characteristics of the Eligible Studies (Mortality-Related Risk Factors)

Order	Study	NOS Score	Country/Region	Study Period	Design	Population	Pathogen	Infection Type	Defnition of Resistance	Resistance	Mortality Day	Sample Size	Nonsurvivor Patients (%)
1	Tuon 2017^Citation35	6	Brazil	2010–2014	R, cohort/SC	VAP patients	CRE	Ventilator-associated pneumonia	CLSI 2013	Carbapenem	30 d	112	64/112(57.1)
2	Capone 2013^Citation26	6	Italy	2010–2011	P, cohort/SC	Colistin resistance patients	CRKP	Any infection	NA	Imipenem, meropenem, gentamicin	In-hospital	91	25/91(27.5)
3	Chang 2014^Citation47	6	China	2012–2012	R, cohort/MC	ICU patients	CnsKP	Any infection	CLSI M100-S22	Imipenem, meropenem	30 d	46	23/46(50)
4	Su 2018^Citation40	7	China	2013–2014	R, cohort/MC	In patients	CRKP	Any infection	CLSI 2014	Imipenem, meropenem	14 d	99	27/99(27.3)
5	Balkan 2014^Citation43	7	Turkey	2011–2013	R, nested/SC	In patients	CRE	BSI	EUCAST 2013	Carbapenem	28 d	36	18/36(50)
6	Shen 2020^Citation13	7	China	2018	R, cohort/SC	In patients	CRKP	BSI	CLSI 2017	Carbapenem	28 d	89	41/89(46.1)
7	Zuo 2020^Citation12	6	China	2015–2017	R, matched/SC	HAP patients	CRKP	Hospital-acquired pneumonia	CLSI 2017	Imipenem, meropenem	In-hospital	74	26/74(35.1)
8	Fang 2021^Citation21	6	China	2018–2020	R, cohort/SC	In patients	CRKP	Any infection	CLSI 2020	Carbapenem	28 d	115	26/115(22.6)
9	Lin 2019^Citation41	7	China	2012–2015	R, cohort/MC	In patients	CRE	BSI	CLSI; EUCAST	Carbapenem	14 d	64	20/64(31.3)
10	Zhou 2021^Citation44	8	China	2019	P, cohort/MC	In patients	CRE	BSI	CLSI 2020	Carbapenem	30 d	208	96/208(46.2)
11	Falcone 2016^Citation31	5	Italy	2010–2014	R, cohort/SC	ICU patients with septic shock	KPC-Kp	Septic shock	EUCAST 2013	Carbapenem	In-hospital	111	44/111(39.6)
12	Zhang 2021^Citation33	7	China	2016–2018	R, case-control/SC	In patients	CRKP	Any infection	CLSI 2018	Carbapenem	In-hospital	142	41/142(28.9)
13	Bar-Yoseph 2019^Citation34	6	Israel	2016–2017	P, cohort/SC	CRE patients focus on immunosuppression	CRE	Any infection	CLSI 2013	Carbapenem	All-cause	115	66/115(57.4)
14	Andrey 2020^Citation22	7	Brazil	2014–2016	R, cohort/SC	In patients	KPC-Kp	BSI	EUCAST 2018	Carbapenemase	30 d	165	100/165(60)
15	Di Domenico 2020^Citation42	5	Italy	2015–2019	R, cohort/SC	Oncological Patients	CRKP	Any infection	EUCAST	Carbapenem	30 d	53	19/53(35.8)
16	Tian 2020^Citation45	7	China	2014–2017	R, case-control/SC	In patients	CR-ECL	Any infection	CLSI 2017	Carbapenem	28 d	85	23/85(27.1)
17	Chotiprasitsakul 2018^Citation23	7	Thailand	2011–2016	R, cohort/SC	In patients	CRE	Any infection	CLSI 2013	Carbapenem	30 d	91	18/91(19.8)
18	Wang 2019^Citation32	7	China	2013–2017	R, cohort;/MC	In patients	CRE	BSI	CLSI 2015	Carbapenem	In-hospital	164	54/164(32.9)
19	Liu 2021^Citation36	7	China	2014–2017	R, cohort/SC	In patients	CRKP	BSI	EUCAST 2021	Carbapenem	30 d	89	46/89(56.7)
20	Palacios-Baena 2016^Citation19	8	Spain	2013	P, cohort;/MC	In patients	CPE	Any infection	CDC 2008	Carbapenem	In-hospital	164	14/164(8.5)
21	Mora-Guzmán 2021^Citation30	6	Spain	2013–2018	P, matched/SC	In patients	CPE	(IAI) Intra-Abdominal Infections	CLSI 2015	Carbapenem	30 d	40	7/40(17.5)
22	Seo 2020^Citation14	7	Korea	2011–2018	R, cohort/SC	In patients	CRE	BSI	CDC 2008	Carbapenem	14 d	133	32/133(24.1)
23	Li 2019^Citation38	7	China	2011–2015	R, cohort/SC	In patients	CRE	BSI	CLSI 2016	Carbapenem	30 d	98	52/98(53.1)
24	Chen 2021^Citation11	7	China	2018–2020	R, cohort/SC	In patients	CRE	BSI	CLSI 2018	Carbapenem	30 d	187	78/187(41.7)
25	Lim 2020^Citation37	7	Singapore	2013	R, cohort/SC	In patients	CP-CRE	Any infection	NA	Carbapenem	30 d	155	55/155(35.5)
26	Rivera-Espinar 2020^Citation28	6	Spain	2012–2016	R, cohort/SC	Ventilator-Associated Pneumonia	KPC-Kp	Ventilator-Associated Pneumonia	CLSI 2017	Carbapenem	30 d	39	16/39(41.0)
27	Brescini 2019^Citation46	7	Italy	2011–2015	R, cohort/SC	In patients	KPC-Kp	BSI	EUCAST 2018	Carbapenem	30 d	112	39/112(34.8)
28	Lin 2015^Citation20	7	China	2013–2013	R, cohort/MC	In patients	CnsKP	Any infection	CLSI 2012	Carbapenem	14 d	154	49/154(31.8)
29	Cristina 2018^Citation24	7	Italy	2013–2014	R, cohort/MC	In patients	CRKP	BSI	EUCAST 2016	Carbapenem	14 d	213	56/213(26.3)
30	Li 2020^Citation25	7	China	2019	R, case-control/SC	In patients	CRKP	BSI	CLSIM100-S28	Carbapenem	In-hospital	164	72/164(43.9)
31	Geng 2018^Citation27	6	China	2014–2016	R, cohort/SC	ICU patients	CRKP	BSI	CLSI 2016	Carbapenem	In-hospital	40	25/40(62.5)
32	Tumbarello 2015^Citation29	7	Italy	2013	R, cohort/MC	In patients	KPC-Kp	Any infection	EUCAST 2015	Carbapenem	14 d	661	225/661(34.1)
33	Lee 2020^Citation39	6	China	2010–2015	R, cohort/SC	In patients	CRKP	Any infection	CLSI 2018	Carbapenem	30 d	171	66/171(38.6)

Abbreviations: NOS, Newcastle-Ottawa Scale; P, prospective; R, retrospective; MC, multicenter; SC, single center; NA, not available; VAP, ventilator-associated pneumonia; HAP, hospital-acquired pneumonia; ICU, intensive care unit; CRE, carbapenem resistant Enterobacteriaceae; CRKP, carbapenem-resistant Klebsiella pneumoniae; KPC-Kp, (Klebsiella pneumoniae carbapenemase–producing K. pneumoniae); CnsKP, carbapenem non-susceptible Klebsiella pneumoniae; CR-ECL, carbapenem-resistant Enterobacter cloacae; CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antimicrobial Susceptibility Testing guidelines.

Table 2 Proportion of Studies Demonstrating an Association Between Chosen Risk Factors and the Mortality of CRE in Univariate Analysis

Risk Factors Groups	Studies Examining Risk Factor Grouping, n (%)	Studies Showing Significant Association
		Overall, n (%)	Odd Ratio (OR)	Sample Size of Study
				N>200	50<N<200	N<50
Demographics
Age	31 (93.9)	12/31 (38.7)	1.027, 1.03	1/3	10/23	1/5
Comorbidities	26 (78.8)	23/26 (88.7)	NA	2/2	18/20	3/4
Hematological malignancy	11 (33.3)	8/11 (72.7)	2.29,3.18	0/2	6/7	2/2
Chronic kidney disease	21 (63.6)	7/21 (33.3)	1.86	1/2	5/15	1/4
COPD	15 (45.5)	5/15 (33.3)	2.68	1/1	4/12	0/2
Cardiovascular disease	19 (57.6)	5/19 (26.3)	5.08, 1.91	1/1	3/14	1/3
Solid tumor	10 (30.3)	4/10 (40)	7.07, 0.61	2/2	2/5	0/3
Neutropenia	5 (15.2)	3/5 (60)	NA	0/1	2/2	1/2
Diabetes mellitus	22 (66.7)	2/22 (9.1)	3.56, 1.56	1/2	1/16	0/4
Immunocompromised status	21 (63.6)	2/21 (9.5)	NA	--	2/18	--
Chronic respiratory failure	4 (12.1)	2/4 (50)	2.14,	--	2/4	--
Other	16(48.5)	5/16 (31.3)	3.21, 4.9	0/1	5/13	0/2
Clinical severity assessment scores	28 (84.8)	23/28 (82.1)	NA	1/3	19/21	3/4
Charlson index	21 (63.6)	13/21 (61.9)	1.18, 1.119, 2.94	2/3	9/14	2/4
APACHE II Score	17 (51.5)	10/17 (58.8)	1.13, 1.07, 1.15, 7.3	0/2	9/13	1/2
Pitt Score	7 (21.2)	6/7 (85.7)	1.32, 10.2	1/1	5/5	0/1
SOFA Score	5 (15.2)	5/5 (100)	NA	-	4/4	1/1
Hospital-related factors	29 (87.9)	24/29 (82.8)	NA	1/3	20/23	3/3
ICU stay	21 (63.6)	7/21 (33.3)	3.237, 1.37	2/2	4/17	1/2
Length of Hospital stay	14 (42.4)	7/14 (50)	NA	1/2	6/9	0/3
ICU length of stay	5 (15.2)	2/5 (40)	NA	-	2/4	0/1
Hospital-acquired infection	7 (21.2)	2/7 (28.6)	6.04, 3.05	1/1	1/6	-
Other	4 (12.1)	2/4 (50)	NA	0/1	2/3	-
Invasive procedures	25 (75.8)	11/25 (44)	NA	2/2	9/19	0/4
Mechanical ventilation	18 (54.5)	7/18 (38.9)	2.703, 2.93, 10.18, 1.39	1/2	5/13	1/3
Central venous catheter	17 (51.5)	4/17 (23.5)	1.30	1/3	2/11	1/3
Urinary catheter	10 (30.3)	3/10 (30)	NA	1/2	2/8	0/1
Arterial cannula	5 (15.2)	2/5 (40)	2.435	1/2	1/3	-
Other	7 (21.2)	2/7 (28.6)	2.703, 2.73	1/1	1/6	-
Type of infection	33(93.9)	25/31(80.6)	NA	2/3	2025	3/5
Septic shock	21 (63.6)	16/21 (76.2)	4.592, 10.40, 6.03, 11.899, 14.67, 3.1	3/3	12/14	1/4
Bloodstream infection	8 (24.2)	6/8 (75)	1.97	1/1	4/6	1/1
Pneumonia	10 (30.3)	4/10 (40)	2.55, 3.9	-	4/10	-
Other	17 (51.5)	3/17 (17.6)	5.09	-	2/16	0/1
Antibiotic use	28 (84.8)	26/28 (92.9)	NA	2/3	21/21	3/4
Duration of antibiotic treatment	5 (15.2)	3/5 (50)	4.802	0/1	1/3	1/1
Exposure to Carbapenems	11 (33.3)	4/11 (36.4)	3.028	0/1	4/8	0/2
Inappropriate definitive therapy	2 (6.1)	2/2 (100)	11.52, 1.73	-	2/2	-
Gentamicin included	3 (9.1)	2/3 (66.7)	NA	--	2/2	-
Colistin monotherapy	3 (9.1)	2/3 (66.7)	4.05, 1.44	-	1/2	-
Other	10 (30.3)	4/10 (25)	2.383	1/1	3/9	-
Clinical index	5 (15.2)	3/5 (60)	NA	-	3/4	0/1
Creatinine	3 (9.1)	2/3 (66.7)	1.007	-	2/2	-
PCT	3 (9.1)	1/3 (33.3)	1.028	-	1/1	0/1
Other	4 (12.1)	2/4 (50)	NA	-	1/3	1/1
Type of CRE pathogens	7 (21.2)	5/7 (71.4)	NA	-	5/6	1/1
KPC-Kp colonization	3 (9.1)	2/3 (66.7)	NA	-	2/2	0/1
Klebsiella pneumoniae strain	3 (9.1)	2/3 (66.7)	NA	-	2/2	-
Other	1 (6.1)	1/2 (50)	NA	-	2/2	-
Other risk factors	26 (78.8)	18/26 (69.2)	NA	2/3	15/19	1/4
Antibiotic resistance	12 (36.4)	6/12 (50)	1.99, 2.167, 1.2, 3.062	2/3	4/9	-
Co-infection with other resistant bacteria	3 (9.1)	2/3 (66.67)	3.486	-	2/3	-
Dialysis	3 (9.1)	2/3 (66.7)	2.4,	1/1	0/1	1/1
Solid organ transplantation	3 (9.1)	2/3 (66.7)	1.74	1/2	1/1	-
Steroid use ≥ 3 months	6 (18.2)	3/6 (50)	1.56, 4.75	1/1	2/4	-
Protective factors with OR< 1
Appropriate antibiotic therapy	20 (60.6)	11/20 (55)	0.1, 0.09	0/2	8/14	2/4
Combination therapy	16 (48.5)	8/16 (50)	0.21, 0.69, 0.35	1/3	7/12	0/1
Colistin-based combination	5 (15.2)	4/5 (80)	0.52	0/1	3/3	1/1
Carbapenem included	8 (24.2)	2/8 (25)	0.59	1/2	1/5	0/1
Microbiological eradication	4 (12.1)	4/4 (100)	0.17	-	3/3	1/1

Abbreviations: CRE, carbapenem resistant Enterobacteriaceae; COPD, chronic obstructive pulmonary disease; APACHE, Acute Physiology and Chronic Health Evaluation; SOFA, Sequential Organ Failure Assessment; ICU, intensive care unit; PCT, procalcitonin; NA, not available.

Table 3 The Proportion of Risk Factors Groups in Univariate Analysis and Multivariate

Risk Factor Groups	Univariate Analysis	Multivariate Analysis
Antibiotic use	26/28 (92.9)	17/21 (81)
Comorbidities	23/26 (88.7)	9/18 (50)
Hospital-related factors	24/29 (82.8)	4/11 (36.4)
Clinical severity assessment scores	23/28 (82.1)	14/19 (73.6)
Type of infection	25/31(80.6)	14/18 (77.8)
Type of CRE pathogens	6/7 (71.4)	2/4 (50)
Clinical index	3/5 (60)	0/2 (0)
Invasive procedures	11/25 (44)	3/5(60)
Age	12/31 (38.7)	1/9 (11.1)

Abbreviation: CRE, carbapenem resistant Enterobacteriaceae.

Table 4 Mortality of Infections Caused by CRE Among Different Antibiotic Treatment Regimens

Order	First Author and Year	Study Design; Period, Country	Population Char acteristics; Most Common Underlying Diseases	No. of Patients	Site of Infection	Organisms	Susceptibility Breakpoints	Mortality	Combination Therapy (No. of Dead, % Mortality)	Monotherapy (No. of Dead, % Mortality)
1	Gutiérrez-Gutiérrez 2017^Citation56	M, cohort/SC, 2004–2013, ten countries	Inpatients (52.4% severe sepsis or septic shock)	437 (78% received appropriate therapy)	BSIs	CPE	CLSI 2012	30 d	Combination 41(35); Tige-included 29(35); Coli-included 28(38); AG-included 19(34); Carba-included 14(38); Fos-included 3(33)	Monotherapy 85(41); Coli 40(54); Mero or Imip 16(37); Cefepime 1(8); Azt 1(25); Tige 14(38); AG 11(41);
2	Navarro-San Francisco2013^Citation48	R, cohort/SC, 2010–2012, Spain	Inpatients (57.5% previous malignancy)	40 (78% received appropriate therapy)	40 Bacteremia (the sources: 12 UTI, 10 IAIs, 7 primary, 4 catheter related)	OXA-48-producing Enterobacteriaceae	CLSI 2012	30 d	Combination 13/21(48.7) carba-not included 11(52.4); carba-included 2(33.3);	Monotherapy 2(28.8) Coli 0(0); Tige 0(0); Ami 1(33.3); Carba 1(100);
3	Balkan2014^Citation43	R, nested /SC, 2011–2013, Turkey	Inpatients (41.6% solid tumor)	36 (100% received appropriate therapy)	36 BSIs (the sources: 22 primary, 8 IAIs, 2 pulmonary)	OXA-48-like producing Enterobacteriaceae	EUCAST 2013	28 d	Coli-dual 7(58.3); Coli-triple 3(33.3); Non-coli-based 6(85.7);	Carba 2(40)
4	Villegas 2016^Citation52	P, cohort/MC, 2013–2014, Seven Latin American Countries	Inpatients (49% surgery and 49% immunosuppression)	53 (91% received definitive therapy)	53 BSIs (the sources: 16 catheter-related, 9 UTIs, 8 SSTIs, 7 RTIs, 5 GTIs, 5 primary)	CPE	CLSI 2014	28 d	Combination (mainly including Carba-containing regimens) 17(59)	Monotherapy (mainly including carba) 5(63)
5	Shen 2019^Citation13	R, cohort/SC, 2018, China	Inpatients (57.3% severe sepsis or septic shock)	89 (78.7% received appropriate therapy)	BSIs	CRKP	EUCAST 2019	28 d	Combination (35 tige-based, 20 poB-based, 9 CAZ-AVI-based) 15(50)	NA
6	Lee 2020^Citation39	R, cohort/SC, 2010–2015, Japan	Inpatients (63.4% diabetes mellitus)	171 (100% received appropriate therapy)	171 Bacteremia (the sources: 27 vascular catheter- related, 25 primary, 14 pneumonia, 15 urosepsis, 9 SSTIs, 6 IATs)	nCP-CRKP	CLSI 2018	30 d	Coli-based 17(28.8); Carba-sparing 5(25); Carba-containing 15(39.5)	Carba-sparing 22(56.4); Carba-containing 24(50)
7	Li 2019^Citation38	R, cohort/SC, 2011–2015, China	Inpatients	98(83.7% received definitive therapy)	BSIs	CRE	CLSI 2016	30 d	Carba-containing 7(53.8); Carba-sparing 16(53.3); Tige-containing 20(69); Tige-sparing 3(21.4)	Colistin 2(66.7);
8	Liu 2021^Citation36	R, cohort/SC, 2014–2017, Taiwan	Inpatients (64% cardiovascular disease)	89(58.4% received appropriate therapy)	BSIs	CRKP	EUCAST 2021	30 d	Coli-included 18(64.3); Amk-included 4(30.8); Carba-included 20(54.1); Tige-included 3(100)	Monotherapy 1(8.3)
9	Falcone 2016^Citation31	R, cohort/SC, 2010–2014, Italy	ICU patients with septic shock	111(77.5% received appropriate therapy)	BSIs (the sources: 53 Primary. 25 CVCs, 52 Pneumonia, 25 UTIs, 18 SSTI, 12 IAIs)	KPC-Kp	EUCAST 2013	30 d	Coli-included 14(22.6); Carba-included 29(34.9); Tige-included 35(39.3); No use of in vitro active antibiotics 16(64); Two or more in vitro active antibiotics used within 24 hours 8(22.2);	Only one in vitro active antibiotic used within 24 hours 20(40)
10	Tumbarello 2018^Citation59	R, matched/SC, 2016–2017, Italy	Inpatients (use CAZ-AVI as salvage therapy)	138(100% received CAZ-AVI therapy); 104(100% received other therapy)	BSIs	KPC-Kp	EUCAST 2017	30 d	Combination 66(41.5); CAZ-AVI-included 29(35.4); CAZ-AVI+Gen 8(32); CAZ-AVI+Coli 7(38.5); CAZ-AVI+Carba 7(36.9); CAZ-AVI+Tige 6(37.5); CAZ-AVI+Fos 2(39.6); CAZ-AVI+Amk 1(50)	Monotherapy 30(61.2); CAZ-AVI monotherapy 9(40.9)
11	Chen 2021^Citation11	R, cohort/MC, 2018–2020, China	Inpatients	187(88.8% received definitive therapy)	BSIs (53 CVC, 45 LRTIs, 43 IAIs, 34 UTIs; 12 Primary)	CRE	CLSI 2018	30 d	CAZ-AVI + tige 2(15.4); CAZ-AVI + tige + poB 1(11.1); Tige + poB 19(41.3); Carba + tige 16(36.4); Carba + AG 8(50); Carba + tige + poB 16(36.4); Carba + poB + AG 5(38.5);	CAZ-AVI 3(23.1); Tige 13(68.4)
12	Medeiros 2019^Citation54	R, cohort/SC, 2015–2016, Brazil	Inpatients	82(100% received definitive therapy)	BSIs (the source: 11 Catheter-associated BSI, 25 Pulmonary, 14 IAIs, 9 UTIs, 9 SSTIs)	KPC-Kp	CLSI 2015	30 d	Combination 18(37.5)	Monotherapy 22(64.7)
13	De Oliveira 2015^Citation60	R, cohort/MC, 2009–2013, Brazil	Inpatients	78(100% received antibiotic therapy)	78 BSIs (51 primary, 4 pneumonia, 12 IAIs)	CPE	CLSI 2010	30 d	2-drug combination 16(44.4), PoB + carba 7(58.3), AG + carba 2(40), 3-drug combination 13(68.4)	Monotherapy 21(36.8); Carba 6(24); poB 13(61.9), AG 1(11.1), tige 1(50)
14	Wang 2019^Citation32	R, cohort/MC, 2013–2017, China	Inpatients	164(60% received active therapy)	BSIs	CRE	CLSI 2018	In hospital	Combination 2(10); Tige-based 0(0); AG-based 1(33.3);	Monotherapy 27(34.6); Tige 19(61.3); Carba 5(20); AG 1(5.8)
15	Giannella 2017^Citation57	R, cohort/MC, 2010–2015, Italy	Inpatients	595(71.9% received high dose carbapenem based combination therapy)	BSIs	CRKP	EUCAST	14 d	Carba-containing 86(19.9); Carba-sparing 42(25.1)	NA
16	Lin 2019^Citation41	R, cohort/MC, 2012–2015, Taiwan	Inpatients	64(100% received appropriate therapy)	BSIs	CRKP	CLSI 2012	14 d	Combination 3(33.3);	Monotherapy 17(30.9); Coli 12(57.1); Tige 2(18.2); Carba 1(20); FQ 1(25)
17	De Pascale 2017^Citation55	R, matched/MC, 2012–2015, Italy	ICU patients (critically ill patients)	48(100% received double carbapenem therapy); 96(100% received standard therapy);	48 (25 pneumonia, 9 IAIs; 8 CVC; 6 primary 3 UTIs; 1 SSTIs)	CRKP	EUCAST	30 d	DC 14 (29.2); standard treatment (ie, Coli, Tige, or Gen), 46(47.9)	NA
18	Sousa 2018^Citation58	P, cohort/SC, 2015–2016, Spain	Inpatients	74(100% received CAZ-AVI therapy);	26 BSIs, 15 pulmonary, 14 UTIs,7 ventilator-associated	OXA-48-producing Enterobacteriaceae	EUCAST	30 d	CAZ-AVI-based 3(27);	CAZ-AVI 10(22);
19	Fang 2021^Citation21	R, cohort/MC, 2018–2020, China	Inpatients	105(67.8% received polymyxin B therapy, 32.2% received CAZ/AVI therapy);	105(66 Pneumonia, 58 BSIs, 32 IAIs, 12 UTIS)	CRKP	CLSI 2020	28 d	2 active antibiotic 13(25.5); 3 active antibiotic 10 (22.7)	1 active antibiotic 3(15)
20	Capone 2013^Citation26	P, cohort/SC, 2010–2011, Italy	Inpatients (High rate of colistin resistance)	91(93.8% received appropriate therapy)	97(34 BSIs, 29 UTIs, 14 LRTIs, 11 SSTIs, 3 IAIs)	CRKP	CLSI	In-hospital	Coli-based 6(23.1), Coli + Tige 4(25); Coli + Fos 0(0); Coli+Gen 2(40); Tige+Fos 2(33.3)	Gen 1(6.25); Coli 4(40);
21	Su 2018^Citation40	R, cohort/MC, 2013–2014, Taiwan	Inpatients	99(67% received appropriate therapy)	49 Pneumonia, 36 UTIs, 9 IAIs, 3 Primary BSIs	CRKP	CLSI 2014	14 d	Appropriate combination therapy 2(33.3)	Appropriate monotherapy 13(21.3), Tige 4(26.6), Coli 6(40), Carba 3(25)
22	Van Duin 2018^Citation53	P, cohort/MC, 2011–2015, United States	Inpatients	38 treated first with CAZ-AVI and 99 with colistin	63 BSIs and 30 RTIs	CRE	CLSI 2014	30 d	CAZ-AVI-based 3(9); Coli-based 33(32)
23	Tumbarello 2021^Citation51	R, cohort/MC, 2018–2020, Italy	Inpatients	577 (165 received CAZ-AVI monotherapy, 412 received CAZ-AVI combination therapy)	391 BSIs and 71 UTIs, 59 LRTIs, and 35 IAIs)	KPC-Kp	EUCAST 2020	30 d	CAZ-AVI-based 103 (25.0)	CAZ-AVI 43 (26.1)
24	Gu 2021^Citation50	R, cohort/SC, 2019–2020, China	Inpatients	42 patients were treated with CAZ-AVI and 48 with other active antibiotics	67 RTIs and 45 BSIs	CRKP	EUCAST 2020	30 d	CAZ-AVI-based therapy 8(19); other active antibiotics 15(31.3)
25	King 2017^Citation61	R, cohort/MC, 2015–2016, United States	Severely ill patients	60 (33 received CAZ-AVI monotherapy, 27 received CAZ-AVI combination therapy)	23 BSIs, 17 UTIs, 16 Pneumonia, 8 Wound, 4 IAIs	CRE	CLSI 2015	In-hospital	CAZ-AVI-based 9(33)	CAZ-AVI 10 (30)
26	Zheng 2021^Citation49	R, cohort/MC, 2019–2020, China	Critically ill Patients	62 (21 received CAZ-AVI monotherapy and 41 received CAZ-AVI combination therapy)	9 Primary BSIs, 25 RTIs, 12 IAIs, 11 UTIs	CRKP	CLSI 2019	30 d	CAZ-AVI-based 10(24.4)	CAZ-AVI 11(47.6)
27	Satlin 2022^Citation62	R, cohort/MC, 2016–2018, United States	Inpatients	137 (68 received Single active agent, 23 received≥2 active agents)	BSIs (the source: 45 IAIs,18 Vascular catheter, 17 UTIs, 18 RTIs, 13 GTIs, 7 SSTIs)	CRE	CLSI 2020	30 d	≥2 active agents 10 (43.5)	Single active agent 12 (17.6); CAZ-AVI 32 (10.0); Poly 45 (30.0)
28	Chen 2022^Citation63	R, case-control/SC, 2019–2021, China	Inpatients	191 (47 received monotherapy,93 received 2 drug combination, 51 received 3 drug combination)	120 Pneumonia; 15 IAIs; 27 UTIs; 18 BSIs	CRKP	CLSI 2021	30 d	Two drug combination 26 (30.0); Three drug combination 8 (15.7)	Monotherapy 17 (36.2)

Abbreviations: P, prospective; R, retrospective; MC, multicenter; SC, single center; NA, not available; BSIs, bloodstream infections; UTIs, urinary tract infections; IAIs, intra-abdominal infections; RTIs, respiratory tract infections; LRTI, lower RTI; SSTIs, skin and soft tissue infections; GTIs, gastrointestinal tract infections; CVC, central venous catheter; ICU, intensive care unit; CPE, carbapenemase–producing Enterobacteriaceae; CRE, carbapenem resistant Enterobacteriaceae; KPC-Kp, Klebsiella pneumoniae carbapenemase–producing K. pneumoniae; CRKP, carbapenem-resistant Klebsiella pneumoniae; Carba, carbapenem; Coli, colistin; PoB, polymyxin B; Tige, tigecycline; Fos, fosfomycin, AG, aminoglycoside, Mero, meropenem; Iimi, imipenem; Azt, aztreonam; Amk, amikacin; CAZ-AVI, ceftazidime/avibactam; Gen, gentamicin; FQ, fluoroquinolone; DC, double carbapenem; PoB, polymyxin B.

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