An Evidence-Based Multidisciplinary Approach Focused at Creating Algorithms for Targeted Therapy of BSIs, cUTIs, and cIAIs Caused by Enterobacterales in Critically Ill Adult Patients

Figures & data

Figure 1 Features of multidisciplinary taskforce involved in implementation of targeted antimicrobial therapy in critically ill patients.

Abbreviations: ID, infectious disease; PCR, polymerase chain reaction; PK/PD; pharmacokinetic/pharmacodynamic; TDM, therapeutic drug monitoring.

Figure 2 Algorithms for targeted treatment of BSI, cUTI and cIAI, caused by Enterobacterales with different pattern of susceptibility in the ICU setting. *if MIC for cefepime ≤1 mg/L. ** ESCPM group includes: Enterobacter (E. cloacae complex, E. aerogenes), Serratia marcescens, Citrobacter freundii, Providencia stuartii, and Morganella morganii.

Abbreviations: CI, continuous infusion; MIC, minimum inhibitory concentration.

Table 1 Summary of the Studies Investigating the Treatment of Full-Sensitive Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Ampicillin or Ceftriaxone

Author, Year and Reference	Study Design	No. of Patients	Antibiotic and Dosing	Source of Infection	Isolates	Severity	Clinical Outcomes	Relapse Rate – Resistance Development	Comments
Ampicillin
Eckmann et al, 2011^Citation20	Guidelines	Ampicillin-sulbactam 3 g q6h recommended for community-acquired localized peritonitis (Strength of recommendation: Grade A – Quality of evidence: Level I)
Walker et al, 1993^Citation22	Prospective randomized, double-blind, multicenter	385 (194 AMP-SUL vs 191 cefoxitin)	AMP-SUL 3 g q6h vs Cefoxitin 2 g q6h	cIAI	E. coli most frequent	NA	Clinical response rate: 86% vs 78%	Persistent or recurrent infections: 14% vs 22%	AMP-SUL demonstrated no difference in efficacy when compared with cefoxitin in the treatment of serious bacterial cIAI
McKinnon et al, 1999^Citation23	Retrospective open-label, multicenter	890 (664 AMP-SUL vs 226 TIC-CVL)	AMP-SUL 1.5–3 g q6h vs TIC-CVL 3.1 g q6h	258 SSTI 257 cIAI 200 respiratory 67 cUTI 67 gynaecologic 41 other	E. coli and Klebsiella spp most frequent (frequencies not provided)	NA	Clinical response rate: 84.3% vs 77.5% Clinical response rate in cIAI: 88% vs 73% Clinical response rate in cUTI: 83.3% vs 84%	NA	AMP-SUL had efficacy comparable with that of TIC-CVL in a variety of infections in hospitalized patients
Ceftriaxone
Eckmann et al, 2011^Citation20	Guidelines	Ceftriaxone 2 g/day + Metronidazole 500 mg q8h recommended for community-acquired localized peritonitis (Strength of recommendation: Grade A – Quality of evidence: Level I)
Solomkin et al, 2010^Citation21	Guidelines	Ceftriaxone 2 g/day + Metronidazole 500 mg q8h recommended for mild-moderate community-acquired cIAI (Strength of recommendation: Grade A – Quality of evidence: Level I)
Wells et al, 2004^Citation27	Prospective randomized, double-blind, multicenter	850 (377 ceftriaxone vs 473 ertapenem)	Ceftriaxone 1 g/day vs Ertapenem 1 g/day	cUTI	64.7% E. coli 9.8% K. pneumoniae	Severe disease 41.3%	Overall microbiological response rate: 91.1% vs 89.5%	Bacterial recurrence: 7.6% vs 8.9%	No significant difference in efficacy between ceftriaxone and ertapenem in cUTI
Tomera et al, 2002^Citation25	Prospective randomized, double-blind, multicenter	592 (294 ceftriaxone vs 298 ertapenem)	Ceftriaxone 1 g/day vs Ertapenem 1 g/day	cUTI 5.9% bacteraemic	69.1% E. coli 13.1% K. pneumoniae	Severe disease 42.2%	Overall microbiological response rate: 93% vs 91.8%	Relapse and superinfection: 8.4%	No significant difference in efficacy between ceftriaxone and ertapenem in cUTI
Rubinstein et al, 1995^Citation24	Prospective randomized controlled, multicenter	580 (274 ceftriaxone + tobramycin vs 306 ceftazidime)	Ceftriaxone 2 g/day + Tobramycin 3–5 mg/kg vs Ceftazidime 2 g q12h	Serious hospital-acquired Gram-negative infections 297 pneumonia 184 sepsis 99 cUTI	23.8% P. aeruginosa 20.6% Klebsiella spp 20.1 E. coli	ICU admission 43.3% Mechanical ventilation 27.9%	Clinical response rate: pneumonia 65% vs 73% sepsis 59% vs 73% cUTI 76% vs 80%	Relapse and superinfection: 7.3% vs 4.6% (p=NS)	No significant difference in efficacy between the two groups in severe hospital-acquired gram-negative infections
Park et al, 2012^Citation28	Prospective randomized, double-blind, multicenter	271 (136 ceftriaxone vs 135 ertapenem)	Ceftriaxone 1 g/day vs Ertapenem 2 g/day	cUTI 33.6% bacteraemic	85.3% E. coli 4.6% K. pneumoniae 4.4% ESBL+	NA	Overall microbiological response rate: 88.7% vs 87.9%	NA	No significant difference in efficacy between ceftriaxone and ertapenem in cUTI
Jimenez-Cruz et al, 2002^Citation26	Prospective randomized, double-blind, multicenter	258 (83 ceftriaxone vs 175 ertapenem)	Ceftriaxone 1 g/day vs Ertapenem 1 g/day	cUTI	77.6% E. coli 6.6% K. pneumoniae	Severe infection 39.1%	Overall microbiological response rate: 84.9% vs 85.6%	Relapse and superinfection: 7.4%	No significant difference in efficacy between ceftriaxone and ertapenem in cUTI

Abbreviations: AMP-SUL, ampicillin-sulbactam; BSIs, bloodstream infections; cIAI, complicated intra abdominal infections; cUTI, complicated urinary tract infection; ESBL, extended-spectrum beta-lactamase; ICU, intensive care unit; NA, not available; NS, not significant; SSTI, skin and soft tissue infections; TIC-CVL, ticarcillin-clavulanate

Table 2 Summary of the Studies Investigating the Treatment of Extended Spectrum Beta-Lactamase (ESBL)-Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Carbapenems Compared to Piperacillin-Tazobactam or Novel Beta-Lactam/Beta-Lactamase Inhibitors (BL/BLIs)

Author, Year and Reference	Study Design	No. of Patients	Antibiotic and Dosing	Source of Infection	ESBL-Producing Pathogens and Molecular Profile	Severity	Clinical Outcomes	Relapse Rate – Resistance Development	Comments
Piperacillin-tazobactam vs carbapenems
Harris et al, 2018^Citation31	Randomized controlled, open-label, parallel-group, multicentric	379 (188 PIP-TZB vs 191 MER)	PIP-TZB 4.5 g q6h II vs MER 1 g q8h II	All BSI 231 cUTI 62 cIAI 12 pneumonia 6 CR-BSI 5 SSTI 63 others	Ceftriaxone-resistant Enterobacterales 327 E. coli 52 K. pneumoniae	ICU admission 7.1% Immunocompromised 24% Neutropenia 6.6% Mean APACHE II score 17.9 vs 21	30-day mortality rate: 12.3% vs 3.7% (p=0.90 for non-inferiority)	NA	Definitive treatment with PIP-TZB compared to MER did not result in non-inferior 30-day mortality rate
Seo et al, 2017^Citation47	Randomized controlled, multicenter	66 (33 PIP-TZB vs 33 ERT)	PIP-TZB 4.5 g q6h vs ERT 1 g/day	All cUTI 16 secondary BSI	100% E. coli MIC PIP-TZB 16 mg/L (72.7% of isolates)	Septic shock 30.3% Mean APACHE II score 12.9 vs 16.6	28-day mortality rate: 6.1% vs 6.1%	0% vs 0%	No difference between PIP-TZB and ERT in mortality and clinical cure rate
Rodriguez-Bano et al, 2012^Citation35	Post-hoc analysis of six prospective cohort	204 Empiric: 35 PIP-TZB vs 31 carbapenems Definitive: 18 PIP-TZB vs 120 carbapenems	PIP-TZB vs MER/IMI/ERT	100% BSI 70% cUTI or biliary source	100% E. coli	ICU admission 13% Severe sepsis or septic shock 23% Neutropenia 5.8% Immunocompromised 13.5%	30-day mortality rate Empiric treatment: 9.7% vs 19.4% Definitive treatment: 9.3% vs 16.7%	NA	PIP-TZB is a suitable alternative to carbapenems for treating patients with BSIs caused by ESBL-producing Enterobacterales
Gutierrez-Gutierrez et al, 2016^Citation38	Retrospective international cohort	887 (Empiric: 123 PIP-TZB vs 195 carbapenems Definitive: 60 PIP-TZB vs 509 carbapenems)	PIP-TZB 4.5 g q6-8h vs MER 1 g q8-12h or ERT 1 g/day or IMP 0.5 g q6-8h	All BSIs 440 cUTI 120 biliary	73% E. coli 19% K. pneumoniae 8% Other	ICU admission 11.8% Severe sepsis or septic shock 37.7% Median Pitt score 1	30-day mortality rate Empiric treatment: 17.6% vs 20% Definitive treatment: 13.9% vs 9.8%	NA	PIP-TZB, if active in vitro, appears to be as effective as carbapenems for empiric and target therapy of BSI due to ESLB-producing Enterobacterales regardless of the source and specific species
Gudiol et al, 2017^Citation40	Retrospective propensity matched cohort	416 (Empiric: 44 PIP-TZB vs 126 carbapenems Definitive: 12 PIP-TZB vs 234 carbapenems)	PIP-TZB vs MER (223) or IMI (110) or ERT (27)	All BSIs 52.8% primary 18.1% CR-BSI 8.1% neutropenic colitis 6.9% cUTI	74% E. coli 23% K. pneumoniae 1.5% K. oxytoca 1.5% E. cloacae	ICU admission 20% Septic shock 24.3% Haematological neutropenic patients 100%	30-day mortality rate Empiric treatment: 20.8% vs 13.4% (p=0.33) Definitive treatment: 5.8% vs 15.8% (p=0.99)	Persistent BSI: 17.6% vs 4.7% (p=0.059) No difference in superinfection and colonization-infection by MDR isolates	PIP-TZB could be carbapenem-sparing alternatives for the treatment of BSI due to ESBLs in haematological patients.
Nasir et al, 2019^Citation45	Retrospective cohort, monocentric	263 (89 PIP-TZB vs 174 carbapenems)	PIP-TZB vs carbapenems	All BSIs 195 cUTI 68 cIAI 8 CR-BSI	100% E. coli (ceftriaxone-resistant)	ICU admission 38% Septic shock 17%	Overall mortality rate for definitive therapy: 13% vs 21% (p=NS)	NA	PIP-TZB showed similar efficacy compared to carbapenems
Ko et al, 2018^Citation42	Retrospective cohort, multicentric	224 (41 PIP-TZB vs 183 carbapenems)	PIP-TZB vs carbapenems	All BSIs 86 cUTI 65 cIAI 56 primary BSI 8 CR-BSI 17 other	159 E. coli 73 K. pneumoniae	ICU admission 34.4%	30-day mortality rate: 6.3% vs 11.4% Empirical use of PTZ was not associated with 30-day all-cause mortality (HR 1.21, CI 0.37–4.00)	NA	Appropriate non-carbapenems were not inferior to carbapenems as initial empirical therapy for ESBL-BSIs
Tamma et al, 2015^Citation48	Retrospective propensity score matched	213 (103 PIP-TZB vs 110 carbapenems)	PIP-TZB 3.375/4.5 g q6h II vs MER/IMI/ERT (MER 1–2 q8h II)	100% BSI 97 CR-BSI 44 cUTI 36 cIAI 20 pneumonia 19 biliary	68% K. pneumoniae 31% E. coli 1% P. mirabilis MIC PIP-TZB ≥8 mg/L 60%	ICU admission 33.8% Neutropenia 15% Immunocompromised 58.7%	14-day mortality rate: 17% vs 8% (p< 0.05) 30-day mortality rate: 26% vs 11% (p< 0.05)	NA	The adjusted risk of death was 1.92 times higher for patients receiving empiric PIP-TZB compared with empiric carbapenem therapy (95% CI: 1.07–3.45)
Sharara et al, 2020^Citation46	Retrospective cohort, multicenter	186 (45 PIP-TZB vs 141 carbapenems)	PIP-TZB vs carbapenems	100% cUTI All non-bacteraemic	56% E. coli 30% K. Pneumoniae 10% P. mirabilis 4% K. oxytoca	ICU admission 27% Septic shock 5.9% Immunocompromised 48%	30-day mortality rate: 4% vs 7%	30-day recurrent cUTI: 20% vs 25% (OR 0.75; CI 0.31–1.81) 30-day CRE isolation: 2% vs 8% (p=0.09)	PIP-TZB may be a reasonable alternative to carbapenems for the management of ESBL-producing cUTI and may mitigate the risk of emergence of carbapenem-resistant organisms
Ng et al, 2016^Citation39	Retrospective cohort multicenter	151 (94 PIP-TZB vs 57 carbapenems)	PIP-TZB 4.5 g q6h II or q8h EI vs MER 1 g q8h or ERT 1 g/day or IMP 0.5 g q6h	All BSIs 89 cUTI 14 biliary 13 pneumonia 8 cIAI 6 CR-BSI 18 other	67% E. coli 33% K. pneumoniae	ICU admission 8.6% Median Pitt score 1	30-day mortality rate: 30.9% vs 29.8% (p= NS)	30-day relapsed BSI: 3.2% vs 15.8% (p=0.05)	PIP-TZB was significantly associated with lower acquisition of MDR bacterial or fungal infections at 30-day (7.4% vs 24.6%; p=0.01)
Yoon et al, 2017^Citation41	Retrospective cohort, monocentric	150 (68 PIP-TZB vs 82 ERT)	PIP-TZB 4.5 g q8h vs ERT 1 g/day	All cUTI 23 secondary BSI	100% E. coli	ICU admission 24.7% Septic shock 16% Immunocompromised 14%	In-hospital mortality rate: 4.4% vs 13.4% (p=0.059)	NA	MIC> 4–8 mg/L for PIP-TZB was not significant associated with treatment failure. PIP-TZB could be an effective alternative to ERT for the treatment of cUTI caused by ESBL isolates
John et al, 2019^Citation44	Retrospective cohort, multicenter	117 (66 PIP-TZB vs 51 carbapenems)	PIP-TZB vs MER/ERT	All BSIs 85 cUTI 22 cIAI 1 Pneumonia 9 unknown	101 E. coli 16 K. pneumoniae	ICU admission 38.5% Septic shock 17.1% Mechanical ventilation 2.6% Immunocompromised 12%	In-hospital mortality: 3% vs 7.8%	Relapse ESBL-BSI: 7.6% vs 7.8%	Empiric PIP-TZB use and avoidance of empiric carbapenem therapy in the first 24 hours of infection can be considered until a microbiological diagnosis is confirmed.
Kang et al, 2012^Citation36	Retrospective case-control	114 (36 PIP-TZB vs 78 carbapenems)	PIP-TZB vs Carbapenems	100% BSI	68% E. coli 32% K. pneumoniae	Haematological malignancies 22.8%	30-day mortality rate 22.2% vs 26.9%	NA	At propensity score analysis, empirical therapy with PIP-TZB was not associated with mortality (OR 0.63; CI 0.17–2.27)
Ofer-Friedman et al, 2015^Citation49	Retrospective cohort	79 (10 PIP-TZB vs 69 carbapenems)	PIP-TZB vs MER/IMI/DOR/ERT	Non urinary BSIs 27 pneumonia 22 SSTI 13 biliary 7 cIAI 6 CR-BSI 4 unknown	53% E. coli 28% K. pneumoniae 19% P. mirabilis	Mean Pitt bacteraemia score 3.1 Immunocompromised 28%	30-day mortality rate: 60% vs 34% (p=NS) 90-day mortality rate: 80% vs 48% (p=0.05)	NA	In multivariate analysis, therapy with PIP-TZB was associated with increased 90-day mortality (adjusted odds ratio, 7.9, P=0.03). For ESBL BSIs of a non-urinary origin, carbapenems should be considered a superior treatment to BL/BLIs
Benanti et al, 2019^Citation43	Retrospective cohort, monocentric	63 (21 PIP-TZB vs 42 carbapenems – 41 MER/1 ERT)	PIP-TZB 4.5 g q6h vs MER 1 g q8h	All BSIs 25 cIAI 7 CR-BSI 7 pneumonia 6 cUTI 6 SSTI 12 unknown	100% E. coli	ICU admission 30.2% Haematological malignancies 100% Neutropenia 88.9% Median Pitt score 2	14-day mortality rate: 0% vs 19% (p=0.04)	Persistent bacteraemia: 36% vs 5% (p=0.03)	Empiric treatment PIP-TZB did not result in increased mortality compared to carbapenems. In multivariate logistic regression, empiric treatment with PIP-TZB was a significant predictor of persistent BSI (aOR, 27.1; CI 1.8–410.1)
Harris et al, 2015^Citation37	Retrospective observational cohort	47 (24 PIP-TZB vs 23 carbapenem)	PIP-TZB 4.5 g q6h vs MER 1 g q8h or IMI 0.5g q6h or ERT 1 g/day	All BSIs 22 cUTI 4 biliary	Cefotaxime non-susceptible BSIs 39 E. coli 8 K. pneumoniae	ICU admission 14.9% Median Pitt score 1 Median APACHE II score 24 Immunocompromised 12.8% Neutropenia 2.1%	30-day mortality rate: 8.3% vs 17.4% (p=NS)	0% vs 2%	BL/BLIs appear to have a similar efficacy to carbapenems in the treatment of cefotaxime-resistant Enterobacterales BSIs. Directed therapy with a BL/BLI, when susceptibility is proven, may represent an appropriate carbapenem-sparing option.
Novel BL/BLIs (Carba-sparing)
Solomkin et al, 2015^Citation53	Prospective, randomized, double-blind, multicentric	993 (487 LOZ-TAZ vs 506 MER)	LOZ-TAZ 1.5 g q8h + Metronidazole 0.5 g q8h vs MER 1 g q8h	993 cIAI 20 secondary BSI	Overall proportion of ESBL isolates: 7.2% 50 ESBL-producing 24 CTX-M-14/15	APACHE II score >15: 3.1%	Clinical cure in ESBL-isolates: 95.8% vs 88.5% Clinical cure in CTX-M-14/15 ESBLs: 100% vs 72.7%	NA	Treatment with LOZ-TAZ plus metronidazole was noninferior to MER in adult patients with cIAI, including infections caused by MDR pathogens
Wagenlehner et al, 2015^Citation52	Randomized, double-blind, double-dummy, non-inferiority, multicenter	800 (398 LOZ-TAZ vs 402 LEV)	LOZ-TAZ 1.5 g q8h vs LEV 750 mg/day	800 cUTI 62 secondary BSI	72 E. coli 17 K. pneumoniae	NA	Clinical cure: 76.9% vs 68.4% (percentage difference 8.5 CI 2.3–14.6) Microbiological eradication: 80.4% vs 72.1% (8.3 CI 2.4–14.1)	NA	LOZ-TAZ superior to LEV in composite cure
Mazuski et al, 2016^Citation55	Prospective, randomized, multicenter, double-dummy, double-blind, comparative	1066 (413 CAZ-AVI vs 410 MER in mMITT)	CAZ-AVI 2.5 g q8h + Metronidazole 0.5 g q8h vs MER 1 g q8h	1066 cIAI	Overall proportion of ceftazidime non-susceptible isolates: 13.5% (of which about 80% ESBL-producers)	APACHE II score >10: 15.3%	Clinical cure at TOC: 81.6% vs 85.1% (−3.5% CI −8.64–1.58%) Ceftazidime non-susceptible isolates (clinical response at TOC): 83% vs 85.9% (−3% CI −17.89–10.6%)	NA	CAZ-AVI was highly effective for the empiric and definitive treatment of cIAI (including ceftazidime non-susceptible and ESBL-producers isolates), and may offer an alternative to carbapenems in this setting
Wagenlehner et al, 2016^Citation54	Randomized, multicenter, double-blind, double-dummy, parallel-group	1033 (490 CAZ-AVI vs 492 DOR at TOC analysis)	CAZ-AVI 2.5 g q8h vs DOR 0.5 g q8h	1033 cUTI 71 secondary BSI	Overall proportion of ESBL isolates: 147 (19.6%)	NA	Clinical resolution at day 5: 70.2% vs 66.2% (4% CI −2.39–10.42%) Microbiological eradication at TOC: 71.2% vs 64.5% (6.7% CI 0.3–13.12%) Ceftazidime non-susceptible isolates (microbiological response rate): 63.2% vs 58.2% (5% CI −10.87–20.5)	NA	CAZ-AVI was highly effective for the empiric treatment of cUTI (including acute pyelonephritis), and may offer an alternative to carbapenems in this setting
Qin et al, 2017^Citation56	Prospective, randomized, multicenter, double-dummy, double-blind, comparative	432 (215 CAZ-AVI vs 217 MER)	CAZ-AVI 2.5 g q8h + Metronidazole 0.5 g q8h vs MER 1 g q8h	432 cIAI 15 secondary BSI	Overall proportion of ceftazidime non-susceptible isolates: 23.4%	APACHE II score >10: 6.7%	Clinical cure at TOC: 93.8% vs 94.2% (−0.2% CI −5.53–4.97%) Ceftazidime non-susceptible isolates (clinical response at TOC): 95.2% vs 96.0% (−0.8% CI −19.51–15.78%)	NA	CAZ-AVI was highly effective for the empiric and definitive treatment of cIAI (including ceftazidime non-susceptible and ESBL-producers isolates) in Asian patients, and may offer an alternative to carbapenems in this setting
Carmeli et al, 2016^Citation57	Prospective, randomized, multicenter, double-dummy, double-blind, comparative	333 (165 CAZ-AVI vs 168 BAT)	CAZ-AVI 2.5 g q8h	281 cUTI 21 cIAI	Ceftazidime-resistant Enterobacterales and Pseudomonas aeruginosa	APACHE II score >10: 19% (only for cIAI)	Clinical cure at TOC: 91% vs 91%	NA	CAZ-AVI was effective as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacterales and P. aeruginosa.

Abbreviations: BAT, best available therapy; BL/BLIs, beta-lactam/beta-lactamase inhibitors; BSIs, bloodstream infections; CAZ-AVI, ceftazidime-avibactam; CI, confidence interval; cIAI, complicated intra abdominal infections; CR-BSI, catheter-related bloodstream infections; CRE, carbapenem-resistant Enterobacterales; cUTI, complicated urinary tract infection; DOR, doripenem; EI, extended infusion; ERT, ertapenem; ESBL, extended-spectrum beta-lactamase; HR, hazard ratio; ICU, intensive care unit; IMI, imipenem; LEV, levofloxacin; LOZ-TAZ, ceftolozane-tazobactam; MDR, multidrug-resistant; MER, meropenem; MIC, minimum inhibitory concentration; mMITT, modified microbiological intention-to-treat; NA, not available; NS, not significant; OR, odds ratio; PIP-TZB, piperacillin-tazobactam; SSTI, skin and soft tissue infections; TOC, test of cure.

Table 3 Summary of the Studies Investigating the Treatment of AmpC-Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Carbapenems and Cefepime

Author, Year and Reference	Study Design	No. of Patients	Antibiotic and Dosing	Source of Infection	AmpC-Producing Pathogens and Molecular Profile	Severity	Clinical Outcomes	Relapse Rate – Resistance Development	Comments
Carbapenems vs Cefepime
Harris et al, 2015^Citation59	Systematic review with meta-analysis	11 studies (6 retrospective 5 prospective)	Carbapenems vs BL/BLIs – cefepime - FQ	BSI	Enterobacter spp Citrobacter spp Serratia spp Morganella spp	8 studies including cefepime vs carbapenems. No significant difference in mortality rate was found for both empiric (OR 0.60; CI 0.17–2.20) or definitive therapy (OR 0.61; CI 0.27–1.38).
Tamma et al, 2013^Citation61	Prospective propensity score matched cohort	78 (46 CEF vs 32 MER)	Cefepime (1–2 g q8h) vs Meropenem (1–2 g q8h) Dose adjustment for renal impairment	40 HAP 38 BSI 38 cIAI	51 E. cloacae 31 E. aerogenes 13 S. marcescens 1 C. freundii	ICU admission 42.7% vs 62.5% Mechanical ventilation 29.2% vs 37.5% Septic shock 22.9% vs 34.4% Immunocompromised 29.2% vs 50%	No difference in 30-day mortality rate (OR 0.63 95% CI 0.23–2.11) No difference in hospital length of stay (OR 0.96 95% CI 0.79–1.26)	Relapse 25% Resistance 1.6% (in cefepime group)	Cefepime may be a reasonable option for the treatment of invasive infections due to AmpC β- lactamase–producing organisms
Tan et al, 2020^Citation64	Retrospective cohort study	241 of which 189 with definitive therapy with CEF (N=57) or carbapenems (N=132)	CEF (N=57) vs IMI (N=16) or MER (N=55) or ERT (N=61)	55 cUTI 53 CR-BSI 46 cIAI 30 Pneumonia 13 SSTI 44 others All BSI	140 Enterobacter spp 54 Serratia spp 40 M. morganii 5 C. freundii 2 Providencia spp	ICU admission 21.6%	30-day mortality rate: 5.3% CEF vs 18.9% carbapenems (p=0.02) At multivariate analysis carbapenems not associated with significant higher mortality compared to CEF (OR 2.25; CI 0.86–5.91)	NA	Empirical PIP/TZB and definitive CEF were not associated with 30-day mortality compared to carbapenems
Cheng et al, 2017^Citation66	Retrospective matched case-control	165 (88 PIP/TZB vs 77 CEF or MER)	PIP-TZB vs CEF or MER	33 cIAI 31 cUTI 28 HAP/VAP 22 CR-BSI 15 SSTI 36 others All BSI	85 E. cloacae 43 S. marcescens 17 Citrobacter spp 15 E. aerogenes 2 S. liquefaciens 2 E. absuriae 1 E. cancerogenus	ICU admission 40% RRT 17% Septic shock 24.2% Neutropenia 6.1% Immunocompromised 26.1%	30-day mortality rate: 10% PIP/TZB vs 12% CEF or MER	Persistent BSI 16% PIP/TZB vs 13% MER	Piperacillin-tazobactam may be a suitable alternative for the treatment of BSIs with AmpC-producing Enterobacter, Serratia, and Citrobacter spp
Lee et al, 2015^Citation65	Retrospective cohort study	144 (72 CEF vs 72 carbapenems)	CEF (2–6 g/day) vs IMI (0.5 g q6h) or MER (1 g q8h) or ERT (1 g/day)	53 CR-BSI 45 primary BSI 13 HAP 11 cUTI 11 cIAI 8 SSTI All BSI	144 E. cloacae	Pitt score ≥ 4 38.9% Neutropenia 9%	30-day mortality rate: 26.4% CEF vs 22.6% carbapenems Higher mortality rate with CEF vs carbapenems in CEF-SDD isolates (71.4% vs 18.2%; p=0.045)	NA	CEF-SDD isolates (MIC 4–8 mg/L) independently associated with 30-day mortality at multivariate analysis
Siedner et al, 2014^Citation62	Retrospective cohort study	271 of which 52 (36 CEF monotherapy vs 16 carbapenem monotherapy)	Cefepime (<2 – 6 g/day)	All BSI 76% primary BSI 7% cUTI 6% pneumonia 4% cIAI 4% CR-BSI	271 Enterobacter spp	ICU admission 22% Neutropenia 19% Pitt score ≥5 7% Solid organ transplant 6% Haematopoietic stem cell transplant 6%	No difference in-hospital mortality rate 17% CEF vs 26% carbapenem	Persistent bacteraemia: 25% carbapenem vs 0% CEF (p=0.002) in monotherapy	In patients who received cefepime with evaluable MIC results, only 2 of 74 (3%) patients with an isolate with a cefepime MIC of ≤2 μg/mL had persistent bacteraemia within 24 hours vs 6 of 23 (26%) patients with an MIC ≥ 4 μg/mL (P < 0.001)
Blanchette et al, 2014^Citation60	Retrospective matched case-control	48 (32 CEF vs 16 ERT)	Cefepime vs Ertapenem	15 cUTI 10 BSI 9 SSTI 9 HAP 6 cIAI	32 Enterobacter spp 9 Citrobacter spp 7 Serratia spp	ICU admission 18.8% Immunocompromised 20.8% Median APACHE II score 11 vs 13.5	Clinical success: 88% CEF vs 69% ERT (p=0.138)	Resistance: 25% ERT vs 17% CEF	Cefepime may be a reasonable option for the treatment of invasive infections due to AmpC β- lactamase–producing organisms
Hilty et al, 2013^Citation63	Retrospective cohort study	43	Cefepime (2 g/day – 2 g q8h) Meropenem (1 g/day – 2 g q8h) Piperacillin-TZB Ceftriaxone	51 primary BSI 6 cUTI 3 CR-BSI 67.4% Hospital-acquired	57 E. cloacae	ICU admission 11.6% Septic shock 2.3% Mechanical ventilation 25.6% Immunocompromised 41.9% Neutropenia 30.2%	Clinical cure rate: 88.9% CEF vs 92.3% carbapenems	NA	Cefepime represents a safe therapeutic option and an alternative to carbapenems to treat BSIs due to Ecl when the prevalence of ESBL-producers is low.

Abbreviations: BSIs, bloodstream infections; CEF, cefepime; cIAI, complicated intra abdominal infections; CR-BSI, catheter-related bloodstream infections; cUTI, complicated urinary tract infection; ERT, ertapenem; FQ, fluoroquinolones; HAP, hospital-acquired pneumonia; ICU, intensive care unit; IMI, imipenem; MER, meropenem; MIC, minimum inhibitory concentration; NA, not available; PIP-TZB, piperacillin-tazobactam; RRT, renal replacement therapy; SDD, susceptible dose dependent; SSTI, skin and soft tissue infections.

Table 4 Summary of the Studies Investigating the Treatment of Klebsiella pneumoniae Carbapenemase (KPC)-Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Ceftazidime-Avibactam, Meropenem-Vaborbactam, Imipenem-Relebactam and Cefiderocol

Author, Year and Reference	Study Design	No. of Patients	Antibiotic and Dosing	Source of Infection	CPE-producing Pathogens and Molecular Profile	Severity	Clinical Outcomes	Relapse Rate – Resistance Development	Comments
Ceftazidime-avibactam
van Duin et al, 2018^Citation67	Prospective observational multicentric, comparative	137 (38 CAZ-AVI vs 99 colisitn-based treatment)	CAZ-AVI 100% target therapy	16 primary BSIs 9 HAP 6 cUTIs 6 SSTIs 2 others	37 K. pneumoniae 1 Enterobacter spp All KPC-2 or −3	ICU admission 53% Pitt score > 4 18% Immunosuppressed 29%	Mortality rate at 30-day: 8% vs 33% (p=0.001)	NA	64% of probability of better outcome with CAZ-AVI compared to colistin at DOOR analysis
Tumbarello et al, 2021^Citation75	Retrospective observational, non-comparative	577	CAZ-AVI 2 g/0.5 g q8h 100% target therapy Prolonged infusion 42.6% Monotherapy 28.6%	391 BSI 71 cUTI 59 HAP 35 cIAI 21 others	All KPC-producing K. pneumoniae	ICU admission 23.7% Mechanical ventilation 28.1% Neutropenia 3.8% Transplant recipient 14.9% Immunocompromised 7.8%	Overall mortality rate at 30-day: 25.3%	Relapse 10.9% Resistance development 3.5%	Prolonged infusion of CAZ-AVI was negatively associated with mortality at multivariate analysis. No difference in mortality rate between monotherapy and combination therapy (26.1% vs 25.0%; p=0.79)
Tumbarello et al, 2019^Citation69	Retrospective observational multicentric, comparative	138 treated with CAZ-AVI Case-control matching between 104 BSIs treated with CAZ-AVI and 104 BSI patients treated with other treatments*	CAZ-AVI 2 g /0.5 g q8h 100% target therapy Dose adjustment for renal impairment according to manufacturer’s instruction	104 BSI 13 HAP 12 cIAI 6 cUTI 3 others	138 K. pneumoniae 138 KPC (93.5% meropenem MIC ≥16 mg/L)	ICU admission 33.3% Mechanical ventilation 31.2% Septic shock 31.2% Median Pitt index 4 Neutropenia 10.9%	Overall mortality rate at 30-day: 34.1% Mortality rate at 30-day (only BSIs) 36.5% vs 55.8% (p=0.005)	Relapse 8.7% Resistance development 2.2%	At multivariate analysis CAZ-AVI was the only variable independently associated with survival.
Shields et al, 2017^Citation70	Retrospective observational, comparative	109 (13 CAZ-AVI vs 96 other treatments*)	CAZ-AVI 100% target therapy	3 primary BSIs 10 secondary BSIs (5 cUTI; 3 HAP; 2 cIAI)	13 K. pneumoniae 9 KPC-2 4 KPC-3 (CAZ-AVI MIC 0.25–2 mg/L)	ICU admission 46% RRT 15% Median Pitt score 4 Median APACHE II score 20 Immunocompromised 38% Solid organ transplant recipient 23%	Mortality rate at 30-day: 8% vs 31.3% (p=0.01) Mortality rate at 90-day: 8% vs 44.8% Clinical cure rate at 14-day: 85% vs 40.6% (p=0.006)	Relapse 15%	At multivariate analysis CAZ-AVI was an independent predictor of clinical success.
Shields et al, 2018^Citation74	Retrospective observational, non-comparative	77	CAZ-AVI 2 g /0.5 g q8h 100% target therapy Dose adjustment for renal impairment according to manufacturer’s instruction	34 HAP 20 primary BSI 8 cUTI 7 cIAI 6 SSTI 1 mediastinitis 1 meningitis	60 K. pneumoniae 9 E. coli 5 E. cloacae 1 E. aerogenes 1 K. oxytoca 1 Serratia marcescens 58 KPC	Median SOFA 5 Median SAPS II 41 CRRT 21% Transplant recipient 26%	Overall mortality rate at 30-day: 19% Overall mortality rate at 90-day: 31% Overall clinical cure rate: 55%	Relapse 32% Resistance development 10%	Pneumonia was an independent predictor of clinical and microbiological failure at multivariate analysis. RRT was an independent predictor of clinical failure and resistance development at multivariate analysis.
King et al, 2017^Citation72	Retrospective observational multicentric, non-comparative	60	CAZ-AVI 100% target therapy Dosage according to manufacturer’s instruction	23 primary BSI 17 cUTI 16 HAP 8 SSTI 4 cIAI 2 osteomyelitis	50 K. pneumoniae 5 E. coli 4 Enterobacter spp 1 Providencia stuartii 1 Serratia marcescens 1 K. oxytoca	ICU admission 59% Mechanical ventilation 38% Septic shock 21% RRT 23% Median Pitt score 2 Solid organ transplant recipient 25%	Overall in-hospital mortality rate: 32% Overall clinical cure rate: 65%	NA	Patients who required a renal adjustment of CAZ-AVI trended toward high in-hospital mortality (42% versus 19% without renal adjustment, p= 0.0567).
Temkin et al, 2017^Citation71	Retrospective observational multicentric, non-comparative	38	CAZ-AVI 100% target therapy	15 cIAI 7 HAP 4 SSTI 3 cUTI 7 primary BSI or CR-BSI 2 endocarditis 3 osteomyelitis 2 surgical site infection 3 Others	34 K. pneumoniae 1 K. oxytoca 1 E. coli 2 P. aeruginosa 23 KPC 13 OXA-48	Septic shock 44.7% Mechanical ventilation 36.8% Immunosuppression 23%	Overall mortality rate: 39.5% Overall clinical/microbiological cure rate: 73.7%	5.3% relapse
Shields et al, 2016^Citation73	Retrospective observational, non-comparative	37	CAZ-AVI 2 g /0.5 g q8h 100% target therapy Dose adjustment for renal impairment according to manufacturer’s instruction	13 HAP 10 primary BSI 4 cIAI 4 SSTI 4 cUTI 1 mediastinitis 1 meningitis	31 K. pneumoniae 3 E. coli 2 E. cloacae 1 E. aerogenes 16 KPC-3 13 KPC-2 7 CTX-M 4 OXA-1-like 1 ESBL 1 AmpC	Mean SOFA 5 Mean SAPS-II 34 CRRT 16.2% Transplant recipient 30%	Overall mortality rate at 30-day: 24% Overall clinical cure rate: 59%	Relapse 27% Resistance development 8%	Success rates were lower for patients who required CRRT: 17% vs 68%; p= 0.03.
Caston et al, 2017^Citation68	Retrospective observational multicentric, comparative	31 (8 CAZ-AVI vs 23 other treatments*)	CAZ-AVI 2 g /0.5 g q8h 100% target therapy Dose adjustment for renal impairment according to manufacturer’s instruction	2 HAP 2 BSI 1 CR-BSI 1 cIAI 1 SSTI 1 other	6 K. pneumoniae 1 E. coli 1 K. oxytoca 5 OXA-48 3 KPC	ICU admission 16.7% Septic shock 37.5% Renal failure 25.0% Median Pitt index 3 Neutropenia 62.5%	Clinical cure at-14 day: 85.7% vs 34.8% (p=0.03) Mortality rate at 30-day: 25.0% vs 52.2% (p=0.24)	NA	CAZ-AVI associated with higher clinical cure rate compared to combination of other treatments. Trend to lower mortality rate with CAZ-AVI.
Meropenem-vaborbactam
Wunderink et al, 2018^Citation77	Phase 3, randomized, prospective, multicenter, open-label	47 (32 MER-VAB vs 15 BAT)	MER-VAB 2 g/2 g q8h (3h-infusion) 100% target therapy Dose adjustment for renal impairment according to manufacturer’s instruction	14 primary BSI 12 cUTI/AP 4 HAP/VAP 2 cIAI	29 K. pneumoniae 3 E. coli 1 E. cloacae 1 S. marcescens	ICU admission 15.6% Immunocompromised 34.4%	Clinical cure rate at the end of treatment: 65.6% vs 33.3% (p=0.03) Clinical cure rate at test of cure: 59.4% vs 26.7% (p=0.02) Mortality rate at 28-day: 15.6% vs 33.3%	NA	Monotherapy with MER-VAB for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT
Ackley et al, 2020^Citation78	Retrospective observational cohort, multicenter, comparative	131 (26 MER-VAB vs 105 CAZ-AVI)	MER-VAB 2 g/2 g q8h 100% target therapy	12 HAP/VAP (2) 8 cIAI (3) 3 SSTI (1) 1 primary BSI 1 cUTI (1) 1 other (1) () number of secondary BSIs	15 Klebsiella spp 8 Enterobacter spp 3 E. coli 2 Citrobacter spp 1 Serratia spp	ICU admission 65.4% Median APACHE II score 27 RRT 4.8% Immunocompromised 15.4%	Overall clinical success: 69.2% vs 61.9% Mortality rate at 30-day: 11.5% vs 19.1%	Relapse 11.5% No resistance development	Similar rates of clinical success between MER-VAB and CAZ-AVI in KPC-producing CRE infections
Alosaimy et al, 2020^Citation79	Retrospective observational, multicenter, non-comparative	40	MER-VAB 2 g/2 g q8h 100% target therapy	13 HAP/VAP 11 BSI 8 cUTI 5 cIAI 5 SSTI	21 K. pneumoniae 9 E. cloacae 6 E. coli 3 B. cepacian 2 P. aeruginosa 1 A. baumannii 1 M. morganii 1 P. mirabilis 1 S. marcescens	ICU admission 70% Median APACHE II score 17	Overall clinical success: 70% Mortality rate at 90-day: 22.5%	Relapse 12.5%
Shields et al, 2020^Citation80	Prospective observational, non-comapartive	20	MER-VAB 2 g/2 g q8h 100% target therapy Dose adjustment for renal impairment according to manufacturer’s instruction	8 BSI 6 HAP/VAP 2 SSTI 2 UTRI 1 cUTI 1 cIAI	14 K. pneumoniae 2 K. oxytoca 2 E. coli 1 E. cloacae 1 C. freundii 10 KPC-3 7 KPC-2 1 KPC-31	ICU admission 70% RRT 35% Median SOFA 5 Median APACHE II score 20	Clinical success at 30-day: 65% Mortality rate at 30-day: 10%	Relapse 15% Resistance development 5%
Imipenem-relebactam
Motsch et al, 2019^Citation81	Phase 3, randomized, prospective, multicenter, open-label	31 (21 IMI-REL vs 10 IMI + COL)	IMP-REL 0.5 g/0.25 g q6h 100% target therapy Dose adjustment according to renal function	11 cUTI 8 HAP/VAP 2 cIAI	16 P. aeruginosa 3 K. pneumoniae 1 E. cloacae 1 C. freundii 4 KPC	APACHE II score > 15: 33.3%	Overall response rate: 71.4% vs 70% Clinical response at 28-day: 71.4% vs 40% (p< 0.05) Mortality rate at 28-day: 9.5% vs 30.0%	Relapse 9.5%	IMI-REL as a suitable treatment option for serious gram-negative infections, including CRE in high-risk patients. IMI/REL had comparable efficacy but significantly less nephrotoxicity and other AEs compared to COL.
Cefiderocol
Bassetti et al, 2020^Citation82	Phase 3, randomized, prospective, multicenter, open-label	150 (101 cefiderocol vs 49 BAT)	Cefiderocol 2 g q8h (3h-infusion) 100% target therapy Dose adjustment according to renal function	45 HAP/VAP 30 BSI 26 cUTI	37 A. baumannii 27 K. pneumoniae 12 P. aeruginosa 5 S. maltophilia 2 E. coli 2 E. cloacae 2 A. nosocomialis	ICU admission 56% Septic shock 19% Mechanical ventilation 50% Immunocompromised 27% Mean SOFA score 5.1	Mortality rate at 14-day: 19% vs 12% Mortality rate at 28-day: 25% vs 18% Overall clinical cure at the end of treatment: 66% vs 58% Overall microbiological cure at the end of treatment: 48% vs 26%		A numerically higher proportion of patients with CRE infections achieved a clinical cure in the cefiderocol group than in the BAT group (66% vs 45%)

Abbreviations: AP, acute pyelonephritis; BAT, best available therapy; BSIs, bloodstream infections; CAZ-AVI, ceftazidime-avibactam; cIAI, complicated intra abdominal infections; COL, colistin; CR-BSI, catheter-related bloodstream infections; CRE, carbapenem-resistant Enterobacterales; CRRT, continuous renal replacement therapy; cUTI, complicated urinary tract infection; DOOR, desirability of outcome ranking; ICU, intensive care unit; IMI, imipenem; IMI-REL, imipenem-relebactam; KPC, Klebsiella pneumoniae-producing carbapenemase; MER-VAB, meropenem-vaborbactam; MIC, minimum inhibitory concentration; NA, not available; RRT, renal replacement therapy; SOFA, sequential organ failure assessment; SSTI, skin and soft tissue infections; URTI, upper respiratory tract infections; VAP, ventilator-associated pneumonia.

Table 5 Summary of the Studies Investigating the Treatment of OXA-48 Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Ceftazidime-Avibactam and Cefiderocol

Author, Year and Reference	Study Design	No. of Patients	Antibiotic and Dosing	Source of Infection	CPE-Producing Pathogens and Molecular Profile	Severity	Clinical Outcomes	Relapse Rate – Resistance Development	Comments
Ceftazidime-avibactam
Sousa et al, 2018^Citation86	Prospective observational, non-comparative	57	CAZ-AVI 2 g /0.5 g q8h 100% target therapy Dose adjustment for renal impairment according to manufacturer’s instruction	16 cIAI 15 HAP/VAP 14 cUTI 6 CR-BSI 3 SSTI 1 meningitis 1 osteomyelitis 1 mediastinitis	54 K. pneumoniae 2 E. coli 1 E. cloacae All OXA-48	ICU admission 38% Septic shock 35% Mechanical ventilation 30% Median APACHE II score 24	Overall clinical cure rate: 77% Mortality rate at 30-day: 22%	10% relapse	CAZ-AVI showed similar clinical cure and survival rate in OXA-48 infection compared to KPC
Temkin et al, 2017^Citation71	Retrospective observational multicentric, non-comparative	38	CAZ-AVI 100% target therapy	15 cIAI 7 HAP 4 SSTI 3 cUTI 7 primary BSI or CR-BSI 2 endocarditis 3 osteomyelitis 2 surgical site infection 3 Others	34 K. pneumoniae 1 K. oxytoca 1 E. coli 2 P. aeruginosa 23 KPC 13 OXA-48	Septic shock 44.7% Mechanical ventilation 36.8% Immunosuppression 23%	Overall mortality rate: 39.5% Overall clinical/microbiological cure rate: 73.7%	5.3% relapse	A trend to lower documented microbiological cure (25% vs 75%; p=0.07) and survival to hospital discharge (22.7% vs 77.3%; p=0.07) was found for the treatment of OXA-48 compared to KPC infections with CAZ-AVI
Alraddadi et al, 2019^Citation84	Retrospective observational cohort, comparative	38 (10 CAZ-AVI vs 28 other agents)	CAZ-AVI 2 g /0.5 g q8h 100% target therapy	5 HAP 3 cUTI 3 cIAI 2 SSTI 1 CR-BSI	7 K. pneumoniae 3 E. coli 8 OXA-48 1 NDM 1 NA	Transplant recipient 50%	Overall clinical cure rate: 80% vs 53.6% Overall mortality rate: 50% vs 57.1%	20% relapse	No difference in clinical cure (75% vs 40%; p=0.21) and mortality rate (37.5% vs 50%; p=0.69) after restricting analysis on patients with OXA-48 infections
De la Calle et al, 2019^Citation85	Retrospective observational, non-comparative	24	CAZ-AVI 2 g /0.5 g q8h 100% target therapy Dose adjustment for renal impairment according to manufacturer’s instruction	7 cIAI 6 cUTI 5 HAP 4 SSTI 1 meningitis 1 CR-BSI	23 K. pneumoniae 1 E. coli All OXA-48 (range MIC CAZ-AVI 0.5–1 mg/L)	ICU admission 33.3% Septic shock 16.7% Mean SOFA score 3.3 Immunosuppression 21.7% Solid organ transplantation 21.7%	Overall clinical cure rate: 62.5% Mortality rate at 30-day: 8.3%	29.2% relapse	CAZ-AVI showed similar clinical cure and survival rate in OXA-48 infection compared to KPC
Cefiderocol
Contreras et al, 2019^Citation87	Case report	1	Cefiderocol 1.5 g q12h	bacteraemic cIAI	K. pneumoniae NDM-1-OXA-48	ICU admission CRRT/ECMO Kidney transplant recipient	Clinical and microbiological cure, but death due to ischaemic colitis	No relapse
Dobias et al, 2017^Citation88	In vitro study	154 OXA-48 isolates	88 K. pneumoniae, 42 E. coli, 24 Enterobacter spp. Cefiderocol MIC range: 0.03–64 (MIC50 0.25 mg/L; MIC90: 2 mg/L)
Delgado-Valverde et al, 2020^Citation91	In vitro study	57 OXA-48 isolates	25 ST11/OXA-48 + CTX-M-15 K. pneumoniae. Cefiderocol MIC range ≤0.03–4 (MIC50 0.25 mg/L; MIC90: 2 mg/L) 25 ST15/OXA-48 + CTX-M-15 K. pneumoniae. Cefiderocol MIC range ≤0.03–4 (MIC50 0.25 mg/L; MIC90: 4 mg/L) 3 ST147/OXA-48 K. pneumoniae. Cefiderocol MIC range 0.06–0.5 (MIC50 0.25 mg/L; MIC90: 0.5 mg/L) 4 ST392/OXA-48 + CTX-M-15 K. pneumoniae. Cefiderocol MIC range 0.06–1 (MIC50 0.25 mg/L; MIC90: 1 mg/L)
Kazmierczak et al, 2019^Citation89	In vitro study	32 OXA-48 isolates	21 K. pneumoniae, 4 E. cloacae, 3 E. coli, 3 C. freundii, 1 K. Oxytoca. Cefiderocol MIC range: 0.03–4 (MIC50 0.5 mg/L; MIC90: 4 mg/L)
Jacobs et al, 2019^Citation90	In vitro study	7 OXA-48 isolates	7 K. pneumoniae. Cefiderocol MIC range ≤0.03–1 (MIC50 0.25 mg/L; MIC90: 1 mg/L)

Abbreviations: BSIs, bloodstream infections; CAZ-AVI, ceftazidime-avibactam; cIAI, complicated intra abdominal infections; CR-BSI, catheter-related bloodstream infections; CRRT, continuous renal replacement therapy; cUTI, complicated urinary tract infection; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; MIC, minimum inhibitory concentration; NA, not available; NDM, New-Delhi metallo-beta-lactamase; SSTI, skin and soft tissue infections; VAP, ventilator-associated pneumonia.

Table 6 Summary of the Studies Investigating the Treatment of Metallo-Beta-Lactamase (MBL) Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Aztreonam-Avibactam, Cefiderocol and Combination Therapy with Meropenem and Fosfomycin

Author, Year and Reference	Study Design	No. of Patients	Antibiotic and Dosing	Source of Infection	CPE-Producing Pathogens and Molecular Profile	Severity	Clinical Outcomes	Relapse Rate – Resistance Development	Comments
NDM+ pathogens
Ceftazidime-avibactam + Aztreonam
Falcone et al, 2020^Citation93	Prospective observational, multicenter with propensity score analysis	102 (52 CAZ-AVI + Aztreonam vs 50 other active antibiotics)	CAZ-AVI (2.5 g q8h – 50% of cases CI) + Aztreonam (2 g q8h) vs Colistin (LD 9 MU – MD 4.5 MU q12h); Tigecycline (LD 100 mg – MD 50 mg q12h); Fosfomycin (4–6 g q6h); Meropenem (2 g q8h); Gentamicin (3–5 mg/kg/day)	All BSIs 33 cUTI 32 CR-BSI 12 SSTI 9 HAP/VAP 7 cIAI 14 unknown	93 K. pneumoniae 5 Enterobacter spp 3 E. coli 1 M. morganii 82 NDM-producing 20 VIM-producing	ICU admission 34.3% Solid organ transplantation 7.8% Septic shock 27.5% Mechanical ventilation 30.4% Median SOFA 4	30-day mortality rate: 19.2% vs 44% (p=0.007)	NA	CAZ-AVI + ATM was associated with lower 30-day mortality (HR 0.37; P=0.01), lower clinical failure at day 14 (HR 0.30; P=0.002), and shorter length of stay (HR 0.49; P=0.007)
Shaw et al, 2017^Citation94	Case series	10	CAZ-AVI (0.94 g/day – 2.5 g q8h EI) + Aztreonam (1 g q8h – 2g q8h CI)	4 cUTI 2 cIAI 2 HAP 1 CR-BSI 1 mediastinitis 50% bacteraemic	10 K. pneumoniae 10 NDM-1/OXA-48/CTX-M-15 (outbreak)	Mean SOFA: 3.7 Solid organ transplant recipient: 40% Immunocompromised: 50%	Clinical cure rate at 30-day: 60% Mortality rate at 30-day: 30%	Relapse 30%
Benchetrit et al, 2019^Citation95	Case series	2	CAZ-AVI (0.94 g/day – 2.5 g/day EI) + Aztreonam 2 g q12-24 EI	1 BSI 1 VAP	2 K. pneumoniae 2 NDM-1 (MIC 0.032–0.064 mg/L)	ICU admission: 100% Solid transplant recipient: 100% Immunocompromised: 100%	Overall clinical cure rate: 100% Overall survival rate: 0%	Relapse 100%
Shah et al, 2019^Citation96	Case report	1	CAZ-AVI 0.94 g q12h + Aztreonam 1 g q8h	bacteraemic cUTI	K. pneumoniae No genotypification	-	Clinical failure	-
Hobson et al, 2019^Citation97	Case report	1	CAZ-AVI 150 mg/kg/day + Aztreonam (100 mg/kg/day)	BSI	Morganella morganii NDM-1 (MIC 0.016 mg/L)	Haematological malignancy	Clinical and microbiological cure	No relapse at 6-month
Sieswerda et al, 2019^Citation98	Case report	1	CAZ-AVI 2.5 g q8h CI + Aztreonam 1 g q8h EI	cUTI	K. pneumoniae NDM-1 (MIC 0.5 mg/L)	Kidney transplant recipient	Clinical cure	Relapse at one month with the same strain. No difference in susceptibility
Yasmin et al, 2020^Citation99	Case report	1	CAZ-AVI 50 mg/kg q8h (EI 3h) + Aztreonam 50 mg/kg q8h	BSI	E. hormaechei NDM-1/KPC-4 (MIC 2/4 + 2 mg/L)	Haematological malignancy	Clinical and microbiological cure	No relapse
Bocanegra-Ibarias et al, 2020^Citation100	Case report	1	CAZ-AVI 2.5 g q8h + Aztreonam 2 g q8h	BSI	K. pneumoniae NDM-1 (MIC 4/4 mg/L)	Haematological malignancy	Clinical and microbiological cure	No relapse
Cefiderocol
Contreras et al, 2019^Citation87	Case report	1	Cefiderocol 1.5 g q12h	bacteraemic cIAI	K. pneumoniae NDM-1-OXA-48	ICU admission CRRT/ECMO Kidney transplant recipient	Clinical and microbiological cure, but death due to ischaemic colitis	No relapse
Dobias et al, 2017^Citation88	In vitro study	134 NDM-VIM-IMP+ isolates	67 E. coli, 38 K. pneumoniae, 29 Enterobacter spp. Cefiderocol MIC range: 0.03–64 (MIC50 1 mg/L; MIC90: 4 mg/L)
Mushtaq et al, 2020^Citation102	In vitro study	61 NDM isolates	21 E. coli, 20 Klebsiella spp, 10 Enterobacter spp, 3 Citrobacter spp, 3 Providencia spp, 2 Morganella spp, 1 Serratia spp, 1 Proteus spp. Cefiderocol MIC range: 0.25–32 (MIC 2 S 41%; MIC 4 S 72.1%)
Kazmierczak et al, 2019^Citation89	In vitro study	12 NDM isolates	11 K. pneumoniae, 1 E. cloacae. Cefiderocol MIC range: 1–8 (MIC50 4 mg/L; MIC90: 8 mg/L)
Meropenem + fosfomycin
Seija et al, 2015^Citation103	Case report	1	Meropenem 2 g q8h EI + Fosfomycin 4 g q8h	bacteraemic cUTI	Morganella morganii NDM-1	Kidney transplant recipient	Clinical and microbiological cure	No relapse
Sengel et al, 2020^Citation104	In vitro study	10 NDM isolates (5 NDM + 5 OXA-48/NDM)	10 K. pneumoniae. Synergic activity in 100% of isolates
IMP/VIM+ pathogens
Ceftazidime-avibactam + Aztreonam
Cairns et al, 2020^Citation101	Case series	4	CAZ-AVI 0.94 q12h - 2.5 g q8h + Aztreonam 1.5–2 g q8h	2 bacteraemic cUTI 1 sternal osteomyelitis 1 CR-BSI	4 E. cloacae IMP-4 (MIC 0.125–0.25 mg/L)	ICU admission 50% 3 Solid organ transplant recipients 1 Haematological malignancy	Clinical and microbiological cure: 100%	Relapse 25%
Cefiderocol
Mushtaq et al, 2020^Citation102	In vitro study	62 VIM/IMP+ isolates	22 Klebsiella spp, 20 E. coli, 12 Enterobacter spp, 8 Citrobacter spp. Cefiderocol MIC range: 0.03–8 (MIC 2 S 80.9%; MIC 4 S 95.7%)
Kazmierczak et al, 2019^Citation89	In vitro study	27 VIM+ isolates	8 K. pneumoniae, 7 E. cloacae, 7 C. freundii, 3 S. marcescens, 1 K. Oxytoca, 1 C. amanolaticus. Cefiderocol MIC range: 0.12–4 (MIC50 1 mg/L; MIC90: 4 mg/L)

Abbreviations: BSIs, bloodstream infections; CAZ-AVI, ceftazidime-avibactam; CI, continuous infusion; cIAI, complicated intra abdominal infections; CR-BSI, catheter-related bloodstream infections; CRRT, continuous renal replacement therapy; cUTI, complicated urinary tract infection; ECMO, extracorporeal membrane oxygenation; EI, extended infusion; HR, hazard ratio; ICU, intensive care unit; LD, loading dose; MD, maintenance dose; MIC, minimum inhibitory concentration; NA, not available; NDM, New-Delhi metallo-beta-lactamase; SSTI, skin and soft tissue infections; VAP, ventilator-associated pneumonia; VIM, Verona-integrase metallo-beta-lactamase

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