. 2020 Feb 7;22(3):6. doi: 10.1007/s11908-020-0716-3

Table 3.

Summary of BL/BLI vs. BAT for treatment of CRE

Author and year	Description of study	Study arms	Patient characteristics	Outcome	Conclusion
Wunderink 2018	• Phase III Open Label Randomized Control Trial • KPC-CRE infection • n = 47	• Meropenem 2 g-vaborbactam 2 g infused over 3 h every 8 hours • Best available therapy (monotherapy or in combination) ○ Colistin/polymyxin ○ Carbapenems ○ Tigecycline ○ Aminoglycoside ○ Ceftazidime-avibactam (n = 1)	• Age, 62 years old • Region ○ North America (29.8%) ○ Europe (57.4%) • Infection type ○ BSI (46.8%) ○ HABP/VABP (10.6%) ○ cUTI/AP (34%) ○ cIAI (8.5%) • ICU admission (17%)	• Clinical cure at end of treatment ○ M-V, 21 (65.6%) ○ BAT, 5 (33.3%) ○ P = 0.03 • Clinical cure at test of cure ○ M-V, 19 (59.4%) ○ BAT, 4 (26.7%) ○ P = 0.02 • 28-day mortality ○ M-V, 5 (15.6%) ○ BAT, 5 (33.3%) ○ P = 0.20 • Renal adverse event ○ M-V, 2 (4.0%) ○ BAT, 6 (24%)	Meropenem-vaborbactam monotherapy is more efficacious than best available therapy for the treatment of CRE with less descriptive renal adverse events
Shields 2017	• Retrospective, single center • CR-KP Bacteremia • n = 109	• Ceftazidime-avibactam ± gentamicin • Best available therapy ○ Colistin ○ Carbapenem ○ Aminoglycoside ○ Other	• Age, 61 years old • ICU at time of bacteremia, 50% • APACHE-II score, 18 • Pitt score, 4 • Source ○ Primary, 26% ○ Abdominal, 46% ○ Respiratory, 13% ○ Urinary, 13% ○ Soft tissue, 3%	• 30-day clinical success ○ C-A, 11(85%) ○ CB-COL, 12 (48%) ○ CB-AG, 12 (40%) ○ Other, 15 (37%) ○ P = 0.02 • Acute kidney injury at 7 days ○ C-A, 1 (9%) ○ CB-COL, 3 (17%) ○ CB-AG, 10 (43%) ○ Other, 4 (12%) ○ P = 0.02 • Multivariate analysis of factors for 30-day clinical success ○ Receiving C-A, P = 0.01	Ceftazidime-avibactam increases clinical success compared with best available therapy and is an independent clinical factor for success
Van Duin 2017	• Multi-center, prospective, observational study • CRE Infection • n = 137	• Ceftazidime-avibactam • Colistin	• Age, 61 years old • Charlson comorbidity index, 3 • Critical illness at time of culture, 47 (34%) • Type of infection ○ BSI, 63 (46%) ○ HABP/VABP, 30 (22%) ○ UTI, 30 (22%) ○ Wound, 14 (10%) ○ Other, 11 (8%)	• All-cause 30-day mortality ○ C-A, 3 (8%) ○ CO, 33 (33%) • IPTW all-cause 30-day mortality ○ C-A. 9% ○ CO, 32% ○ P = 0.001 • IPTW adjusted better outcome with C-A, 62% (95% CI, 52–72%)	Ceftazidime-avibactam leads to better outcomes than colistin for the treatment of CRE
Tumbarello 2019	• Multi-center, retrospective, observational study • CR-KP Bacteremia • n = 208	• Ceftazidime-avibactam ± antimicrobial as salvage therapy • Best available therapy (control)	• Age, 60 years old • Charlson comorbidity index ≥ 3–38 (36.5%) • ICU admission, 39 (37.5%) • Median before ceftazidime-avibactam start, 7 days • Pitt Score, 4 • Monotherapy, 22 (21.2%)	• 30-day survival ○ C-A + Gent. 60% ○ C-A + CO, 61.5% ○ C-A + CB, 63.1% ○ C-A + Tige, 62.5% ○ C-A + Fos, 71.4% ○ C-A + Amikacin, 50% ○ C-A, 59% ○ BAT, 44.2% • Multivariate analysis predictor for clinical success ○ Treatment with C-A, p = 0.001	Ceftazidime-Avibactam is associated with improved clinical success regardless of additional therapeutic agents
Motsch 2019	• Multi-center, multi-national, randomized double blind trial • Imipenem-non-susceptible isolates • n = 31	• Imipenem 500 mg-relebactam 250 mg every 6 h • Imipenem 500 mg every 6 h and colistin 300 mg CBA loading dose + 150 mg every 12 h	• Age, 59 years old • APACHE-II > 15–9 (29%) • Infection type ○ HABP, 2 (6.5%) ○ VABP, 9 (29%) ○ cUTI, 8 (25.8%) ○ cUTI + AP, 8 (25.8%) ○ cIAI, 4 (12.9%) • Pathogen ○ P. aeruginosa, 24 (77.4%) ○ Enterobacterales, 7 (22.6%) • KPC producing, 5 (16.1%)	• Favorable overall response ○ I-R, 15 (71.4%) ○ IMI + CO, 7 (70%) • 28-day all-cause mortality ○ I-R, 2 (9.5%) ○ IMI + CO, 3 (30%) • Treatment emergent nephrotoxicity ○ I-R, 10.3% ○ IMI + CB, 56.3% ○ Adjusted difference, − 45.9% (90% CI − 69.1, − 18.4)	Imipenem-relebactam has similar favorable response to imipenem non-susceptible Gram-negative organisms compared with imipenem and colistin. Significantly less renal adverse events occur with imipenem-relebactam

Author and year

Description of study

Study arms

Patient characteristics

Outcome

Conclusion

Wunderink 2018

• Phase III Open Label Randomized Control Trial

• KPC-CRE infection

• n = 47

• Meropenem 2 g-vaborbactam 2 g infused over 3 h every 8 hours

• Best available therapy (monotherapy or in combination)

○ Colistin/polymyxin

○ Carbapenems

○ Tigecycline

○ Aminoglycoside

○ Ceftazidime-avibactam (n = 1)

• Age, 62 years old

• Region

○ North America (29.8%)

○ Europe (57.4%)

• Infection type

○ BSI (46.8%)

○ HABP/VABP (10.6%)

○ cUTI/AP (34%)

○ cIAI (8.5%)

• ICU admission (17%)

• Clinical cure at end of treatment

○ M-V, 21 (65.6%)

○ BAT, 5 (33.3%)

○ P = 0.03

• Clinical cure at test of cure

○ M-V, 19 (59.4%)

○ BAT, 4 (26.7%)

○ P = 0.02

• 28-day mortality

○ M-V, 5 (15.6%)

○ BAT, 5 (33.3%)

○ P = 0.20

• Renal adverse event

○ M-V, 2 (4.0%)

○ BAT, 6 (24%)

Meropenem-vaborbactam monotherapy is more efficacious than best available therapy for the treatment of CRE with less descriptive renal adverse events

Shields 2017

• Retrospective, single center

• CR-KP Bacteremia

• n = 109

• Ceftazidime-avibactam ± gentamicin

• Best available therapy

○ Colistin

○ Carbapenem

○ Aminoglycoside

○ Other

• Age, 61 years old

• ICU at time of bacteremia, 50%

• APACHE-II score, 18

• Pitt score, 4

• Source

○ Primary, 26%

○ Abdominal, 46%

○ Respiratory, 13%

○ Urinary, 13%

○ Soft tissue, 3%

• 30-day clinical success

○ C-A, 11(85%)

○ CB-COL, 12 (48%)

○ CB-AG, 12 (40%)

○ Other, 15 (37%)

○ P = 0.02

• Acute kidney injury at 7 days

○ C-A, 1 (9%)

○ CB-COL, 3 (17%)

○ CB-AG, 10 (43%)

○ Other, 4 (12%)

○ P = 0.02

• Multivariate analysis of factors for 30-day clinical success

○ Receiving C-A, P = 0.01

Ceftazidime-avibactam increases clinical success compared with best available therapy and is an independent clinical factor for success

Van Duin 2017

• Multi-center, prospective, observational study

• CRE Infection

• n = 137

• Ceftazidime-avibactam

• Colistin

• Age, 61 years old

• Charlson comorbidity index, 3

• Critical illness at time of culture, 47 (34%)

• Type of infection

○ BSI, 63 (46%)

○ HABP/VABP, 30 (22%)

○ UTI, 30 (22%)

○ Wound, 14 (10%)

○ Other, 11 (8%)

• All-cause 30-day mortality

○ C-A, 3 (8%)

○ CO, 33 (33%)

• IPTW all-cause 30-day mortality

○ C-A. 9%

○ CO, 32%

○ P = 0.001

• IPTW adjusted better outcome with C-A, 62% (95% CI, 52–72%)

Ceftazidime-avibactam leads to better outcomes than colistin for the treatment of CRE

Tumbarello 2019

• Multi-center, retrospective, observational study

• CR-KP Bacteremia

• n = 208

• Ceftazidime-avibactam ± antimicrobial as salvage therapy

• Best available therapy (control)

• Age, 60 years old

• Charlson comorbidity index ≥ 3–38 (36.5%)

• ICU admission, 39 (37.5%)

• Median before ceftazidime-avibactam start, 7 days

• Pitt Score, 4

• Monotherapy, 22 (21.2%)

• 30-day survival

○ C-A + Gent. 60%

○ C-A + CO, 61.5%

○ C-A + CB, 63.1%

○ C-A + Tige, 62.5%

○ C-A + Fos, 71.4%

○ C-A + Amikacin, 50%

○ C-A, 59%

○ BAT, 44.2%

• Multivariate analysis predictor for clinical success

○ Treatment with C-A, p = 0.001

Ceftazidime-Avibactam is associated with improved clinical success regardless of additional therapeutic agents

Motsch 2019

• Multi-center, multi-national, randomized double blind trial

• Imipenem-non-susceptible isolates

• n = 31

• Imipenem 500 mg-relebactam 250 mg every 6 h

• Imipenem 500 mg every 6 h and colistin 300 mg CBA loading dose + 150 mg every 12 h

• Age, 59 years old

• APACHE-II > 15–9 (29%)

• Infection type

○ HABP, 2 (6.5%)

○ VABP, 9 (29%)

○ cUTI, 8 (25.8%)

○ cUTI + AP, 8 (25.8%)

○ cIAI, 4 (12.9%)

• Pathogen

○ P. aeruginosa, 24 (77.4%)

○ Enterobacterales, 7 (22.6%)

• KPC producing, 5 (16.1%)

• Favorable overall response

○ I-R, 15 (71.4%)

○ IMI + CO, 7 (70%)

• 28-day all-cause mortality

○ I-R, 2 (9.5%)

○ IMI + CO, 3 (30%)

• Treatment emergent nephrotoxicity

○ I-R, 10.3%

○ IMI + CB, 56.3%

○ Adjusted difference, − 45.9% (90% CI − 69.1, − 18.4)

Imipenem-relebactam has similar favorable response to imipenem non-susceptible Gram-negative organisms compared with imipenem and colistin. Significantly less renal adverse events occur with imipenem-relebactam

C-A, ceftazidime-avibactam; M-V, meropenem-vaborbactam; I-R, imipenem-relebactam; BAT, best available therapy; CO, colistin; CB, carbapenem; AG, aminoglycoside; Tige, tigecycline; Fos, fosfomycin; IMI, imipenem; Gent, gentamicin; HABP, healthcare-associated bacterial pneumonia; VABP, ventilator-associated bacterial pneumonia; BSI, bloodstream infection; cUTI, complicated urinary tract infection; cIAI, complicated intra-abdominal infection; AP, acute pyelonephritis; CR-KP, carbapenem-resistant Klebsiella pneumonia; KPC, Klebsiella pneumoniae carbapenemase; CRE, carbapenem-resistant Enterobacterales; ICU, intensive care unit; IPTW, inverse probability of treatment weighting