résistance bactérienne et nouveaux antibiotiques

Résistance bactérienne et nouveaux antibiotiques

JNI 2021 «Séance Best of »

Aurélien DinhService des Maladies Infectieuses et Tropicales

Hôpital Raymond-Poincaré, APHPUniversité Paris Saclay

Cefiderocol

• Programme de surveillance SIDERO WT

• Collection des souches de 2014-2018

• 10 laboratoires en France • Sensibilité en microdilution• Selon Guidelines/break

point EUCAST

www.thelancet.com/infection Published online October 12, 2020 https://doi.org/10.1016/S1473-3099(20)30796-9 1

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Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trialMatteo Bassetti, Roger Echols, Yuko Matsunaga, Mari Ariyasu, Yohei Doi, Ricard Ferrer, Thomas P Lodise, Thierry Naas, Yoshihito Niki, David L Paterson, Simon Portsmouth, Julian Torre-Cisneros, Kiichiro Toyoizumi, Richard G Wunderink, Tsutae D Nagata

SummaryBackground New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections.

Methods We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23).

Findings Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8–66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9–75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2–65·5) of 23 patients in the cefiderocol group and six (43%, 17·7–71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8–77·0) of 17 patients in the cefiderocol group and one (20%, 0·5–71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug.

Interpretation Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options.

Lancet Infect Dis 2020

Published Online October 12, 2020 https://doi.org/10.1016/ S1473-3099(20)30796-9

See Online/Comment https://doi.org/10.1016/ S1473-3099(20)30828-8

Infectious Diseases Clinic, Department of Health Sciences, University of Genoa, Genoa and Hospital Policlinico San Martino IRCCS, Genoa, Italy (Prof M Bassetti MD); Infectious Disease Drug Development Consulting, Easton, CT, USA (R Echols MD); Shionogi, Florham Park, NJ, USA (Y Matsunaga MD, S Portsmouth MD); Shionogi, Osaka, Japan (M Ariyasu BPharm, K Toyoizumi PhD, T D Nagata MD); Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA (Y Doi MD); Department of Intensive Care Medicine and SODIR-VHIR Research Group, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain (R Ferrer MD); Albany College of Pharmacy and Health Sciences, Albany, NY, USA (Prof T P Lodise PharmD); Department of Medical Microbiology, Bicêtre Hospital, Paris, France (Prof T Naas MD); Department of Clinical Infectious Diseases, Showa University School of Medicine, Tokyo, Japan (Prof Y Niki MD); UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, QLD, Australia (Prof D L Paterson MD); Maimonides Institute for Biomedical Research, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain

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lable therapy) had at least one carbapenem-resistant pathogen at baseline and comprised the carbapenem-resistant micro biological ITT population (figure, table 2; appendix pp 13–14). A baumannii,

Klebsiella pneumoniae, and P aeruginosa were the most frequent carbapenem-resistant pathogens in both treat-ment groups (A baumannii in 54 patients [46%], K pneumoniae in 39 patients [33%], and P aeruginosa in

Cefiderocol (n=101)

Best available therapy (n=49)

Sex

Male 66 (65%) 35 (71%)

Female 35 (35%) 14 (29%)

Age (years)

Mean (SD) 63·1 (19·0) 63·0 (16·7)

Median (range; IQR) 69 (19–92; 52–77) 62 (19–92; 51–76)

<65 37 (37%) 27 (55%)

≥65 64 (63%) 22 (45%)

<75 72 (71%) 35 (71%)

≥75 29 (29%) 14 (29%)

BMI (kg/m²)* 25·0 (12·0–52·4; 21·3–27·8)

23·5 (14·3–48·9; 20·3–29·2)

Region

Europe 57 (56%) 28 (57%)

Asia-Pacific 29 (29%) 14 (29%)

North America 6 (6%) 3 (6%)

South America 9 (9%) 4 (8%)

Race

White 63 (62%) 32 (65%)

Asian 29 (29%) 14 (29%)

Black or African American 0 0

Other 9 (9%) 3 (6%)

Clinical diagnosis

Nosocomial pneumonia 45 (45%) 22 (45%)

HAP 20 (20%) 7 (14%)

VAP 24 (24%) 13 (27%)

HCAP 1 (1%) 2 (4%)

Bloodstream infections or sepsis†

30 (30%) 17 (35%)

Bloodstream infection 22 (22%) 9 (18%)

Complicated intra-abdominal infection

3 (3%) 2 (4%)

Skin and skin structure infection

1 (1%) 0

Intravenous line infection

4 (4%) 2 (4%)

Other‡ 5 (5%) 1 (2%)

Unknown 9 (9%) 4 (8%)

Sepsis 8 (8%) 8 (16%)


2 (2%) 1 (2%)


4 (4%) 3 (6%)


0 3 (6%)

Other‡ 2 (2%) 1 (2%)

Complicated urinary tract infection

26 (26%) 10 (20%)

Ventilation at randomisation 50 (50%) 26 (53%)

(Table 1 continues in next column)

Cefiderocol (n=101)


(Continued from previous column)

Creatinine clearance (mL/min)

Mean (SD), 85·8 (79·3) 88·9 (64·2)

Median (range; IQR) 59·2 (9·4–539·26; 33·9–107·9)

69·4 (4·6–270·8; 47·6–119·8)

≥120 20 (20%) 12 (24%)

>80 to <120 18 (18%) 10 (20%)

>50 to ≤80 20 (20%) 12 (24%)

≥30 to ≤50 23 (23%) 8 (16%)

<30 20 (20%) 7 (14%)

Empirical treatment failure 58 (57%) 27 (55%)

Previous therapy§

Antibiotics¶ 93 (92%) 49 (100%)

Carbapenems 60 (59%) 26 (53%)

Systemic corticosteroids 44 (44%) 17 (35%)

ICU at randomisation 57 (56%) 21 (43%)

Shock 19 (19%) 6 (12%)

Immunocompromised 27 (27%) 10 (20%)

Positive blood culture 25 (25%) 13 (27%)

APACHE II score

Mean (SD) 15·3 (6·5) 15·4 (6·2)

Median (range; IQR) 15 (2–29; 11–20) 14 (2–28; 11–20)

≤15 55 (54%) 27 (55%)

16–19 17 (17%) 9 (18%)

≥20 29 (29%) 13 (27%)

CPIS score||

Mean (SD) 4·9 (1·7) 4·6 (1·5)

Median (range; IQR) 5 (2–9; 4–6) 5 (0–7; 4–5)

≤5 30/45 (67%) 16/22 (73%)

≥6 14/45 (31%) 5/22 (23%)

Missing 1/45 (2%) 1/22 (5%)

SOFA score**

Mean (SD) 5·1 (4·0) 5·1 (3·8)

Median (range) 4 (0–17; 2–8) 4 (0–16; 2–8)

≤6 67 (66%) 32 (65%)

≥7 33 (33%) 17 (35%)

≤9 84 (83%) 43 (88%)

≥10 16 (16%) 6 (12%)

Missing 1 (1%) 0

CCI score

Mean (SD) 5·5 (3·1) 5·4 (3·1)

Median (range; IQR) 5 (0–12; 3–8) 6 (0–13; 3–7)

Medical history based on CCI components

101 (100%) 49 (100%)

Renal disease 40 (40%) 20 (41%)

Chronic pulmonary disease 40 (40%) 16 (33%)

Diabetes 35 (35%) 17 (35%)


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Cefiderocol (n=101)


Sex

Male 66 (65%) 35 (71%)

Female 35 (35%) 14 (29%)

Age (years)

Mean (SD) 63·1 (19·0) 63·0 (16·7)

Median (range; IQR) 69 (19–92; 52–77) 62 (19–92; 51–76)

<65 37 (37%) 27 (55%)

≥65 64 (63%) 22 (45%)

<75 72 (71%) 35 (71%)

≥75 29 (29%) 14 (29%)

BMI (kg/m²)* 25·0 (12·0–52·4; 21·3–27·8)

23·5 (14·3–48·9; 20·3–29·2)

Region

Europe 57 (56%) 28 (57%)

Asia-Pacific 29 (29%) 14 (29%)



Race

White 63 (62%) 32 (65%)

Asian 29 (29%) 14 (29%)


Other 9 (9%) 3 (6%)

Clinical diagnosis


HAP 20 (20%) 7 (14%)

VAP 24 (24%) 13 (27%)

HCAP 1 (1%) 2 (4%)


30 (30%) 17 (35%)



3 (3%) 2 (4%)


1 (1%) 0


4 (4%) 2 (4%)

Other‡ 5 (5%) 1 (2%)

Unknown 9 (9%) 4 (8%)

Sepsis 8 (8%) 8 (16%)


2 (2%) 1 (2%)


4 (4%) 3 (6%)


0 3 (6%)

Other‡ 2 (2%) 1 (2%)


26 (26%) 10 (20%)



Cefiderocol (n=101)




Mean (SD), 85·8 (79·3) 88·9 (64·2)

Median (range; IQR) 59·2 (9·4–539·26; 33·9–107·9)

69·4 (4·6–270·8; 47·6–119·8)

≥120 20 (20%) 12 (24%)

>80 to <120 18 (18%) 10 (20%)

>50 to ≤80 20 (20%) 12 (24%)

≥30 to ≤50 23 (23%) 8 (16%)

<30 20 (20%) 7 (14%)


Previous therapy§

Antibiotics¶ 93 (92%) 49 (100%)

Carbapenems 60 (59%) 26 (53%)



Shock 19 (19%) 6 (12%)



APACHE II score

Mean (SD) 15·3 (6·5) 15·4 (6·2)

Median (range; IQR) 15 (2–29; 11–20) 14 (2–28; 11–20)

≤15 55 (54%) 27 (55%)

16–19 17 (17%) 9 (18%)

≥20 29 (29%) 13 (27%)

CPIS score||

Mean (SD) 4·9 (1·7) 4·6 (1·5)

Median (range; IQR) 5 (2–9; 4–6) 5 (0–7; 4–5)

≤5 30/45 (67%) 16/22 (73%)

≥6 14/45 (31%) 5/22 (23%)

Missing 1/45 (2%) 1/22 (5%)

SOFA score**

Mean (SD) 5·1 (4·0) 5·1 (3·8)

Median (range) 4 (0–17; 2–8) 4 (0–16; 2–8)

≤6 67 (66%) 32 (65%)

≥7 33 (33%) 17 (35%)

≤9 84 (83%) 43 (88%)

≥10 16 (16%) 6 (12%)

Missing 1 (1%) 0

CCI score

Mean (SD) 5·5 (3·1) 5·4 (3·1)

Median (range; IQR) 5 (0–12; 3–8) 6 (0–13; 3–7)


101 (100%) 49 (100%)

Renal disease 40 (40%) 20 (41%)


Diabetes 35 (35%) 17 (35%)


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Cefiderocol (n=101)


Sex

Male 66 (65%) 35 (71%)

Female 35 (35%) 14 (29%)

Age (years)

Mean (SD) 63·1 (19·0) 63·0 (16·7)

Median (range; IQR) 69 (19–92; 52–77) 62 (19–92; 51–76)

<65 37 (37%) 27 (55%)

≥65 64 (63%) 22 (45%)

<75 72 (71%) 35 (71%)

≥75 29 (29%) 14 (29%)

BMI (kg/m²)* 25·0 (12·0–52·4; 21·3–27·8)

23·5 (14·3–48·9; 20·3–29·2)

Region

Europe 57 (56%) 28 (57%)

Asia-Pacific 29 (29%) 14 (29%)



Race

White 63 (62%) 32 (65%)

Asian 29 (29%) 14 (29%)


Other 9 (9%) 3 (6%)

Clinical diagnosis


HAP 20 (20%) 7 (14%)

VAP 24 (24%) 13 (27%)

HCAP 1 (1%) 2 (4%)


30 (30%) 17 (35%)



3 (3%) 2 (4%)


1 (1%) 0


4 (4%) 2 (4%)

Other‡ 5 (5%) 1 (2%)

Unknown 9 (9%) 4 (8%)

Sepsis 8 (8%) 8 (16%)


2 (2%) 1 (2%)


4 (4%) 3 (6%)


0 3 (6%)

Other‡ 2 (2%) 1 (2%)


26 (26%) 10 (20%)



Cefiderocol (n=101)




Mean (SD), 85·8 (79·3) 88·9 (64·2)

Median (range; IQR) 59·2 (9·4–539·26; 33·9–107·9)

69·4 (4·6–270·8; 47·6–119·8)

≥120 20 (20%) 12 (24%)

>80 to <120 18 (18%) 10 (20%)

>50 to ≤80 20 (20%) 12 (24%)

≥30 to ≤50 23 (23%) 8 (16%)

<30 20 (20%) 7 (14%)


Previous therapy§

Antibiotics¶ 93 (92%) 49 (100%)

Carbapenems 60 (59%) 26 (53%)



Shock 19 (19%) 6 (12%)



APACHE II score

Mean (SD) 15·3 (6·5) 15·4 (6·2)

Median (range; IQR) 15 (2–29; 11–20) 14 (2–28; 11–20)

≤15 55 (54%) 27 (55%)

16–19 17 (17%) 9 (18%)

≥20 29 (29%) 13 (27%)

CPIS score||

Mean (SD) 4·9 (1·7) 4·6 (1·5)

Median (range; IQR) 5 (2–9; 4–6) 5 (0–7; 4–5)

≤5 30/45 (67%) 16/22 (73%)

≥6 14/45 (31%) 5/22 (23%)

Missing 1/45 (2%) 1/22 (5%)

SOFA score**

Mean (SD) 5·1 (4·0) 5·1 (3·8)

Median (range) 4 (0–17; 2–8) 4 (0–16; 2–8)

≤6 67 (66%) 32 (65%)

≥7 33 (33%) 17 (35%)

≤9 84 (83%) 43 (88%)

≥10 16 (16%) 6 (12%)

Missing 1 (1%) 0

CCI score

Mean (SD) 5·5 (3·1) 5·4 (3·1)

Median (range; IQR) 5 (0–12; 3–8) 6 (0–13; 3–7)


101 (100%) 49 (100%)

Renal disease 40 (40%) 20 (41%)


Diabetes 35 (35%) 17 (35%)


§ Essai clinique ouvert, randomisé avec un contrôle actif (2:1) et une analyse descriptive

§ Patients en état critique et souffrant d’infections diverses (IU, PN, BSI) résistantes aux carbapénèmes

§ 29 régimes de contrôle différents utilisés dans 95 centres

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8 www.thelancet.com/infection Published online October 12, 2020 https://doi.org/10.1016/S1473-3099(20)30796-9

22 patients [19%]; table 2, appendix p 17). The distribution of the most frequent Gram-negative pathogens was simi-lar in the carba penem-resistant microbiological ITT and microbiological ITT popu lations (table 2; appendix p 17). Cefiderocol MIC90 values were 1 µg/mL for carbapenem-resistant A bau mannii, 4 µg/mL for carbapenem-resistant K pneu moniae, and 2 µg/mL for carbapenem-resistant P aeruginosa in the carbapenem-resistant microbiological ITT population, with similar values in the microbiological ITT population (appendix p 18). Four pathogens had cefiderocol MICs of greater than 4 µg/mL (ie, the provisional Clinical and Laboratory Standards Institute breakpoint), and an additional six pathogens had MICs of 4 µg/mL, in both the carbapenem-resistant microbiological ITT and microbiological ITT populations (appendix p 18).

In the cefiderocol group, 83% (66/80) of patients received monotherapy; in the best available therapy group, 71% (27/38) received combination therapy. 25 patients (66%) of 38 in the best available therapy group received colistin-based treatment (appendix pp 19–20). For patients with HAP, VAP, HCAP, or bloodstream infection or sepsis (who generally have

more severe disease than patients with complicated UTIs), median treatment duration was 11·0 days (IQR 8·0–14·0) with cefiderocol and 13·0 days (10·0–15·0) with best available therapy, with a maximum duration of 22 days in each group. In patients with complicated UTIs, median treatment duration was 10·5 days (IQR 8·0–15·0) with cefiderocol and 6·5 days (6·0–11·0) with best available therapy, with a maximum duration of 29 days in the cefiderocol group and 14 days in the best available therapy group (appendix p 21).

Cefiderocol (n=101)



Cancer 24 (24%) 13 (27%)

Congestive heart failure 12 (12%) 10 (20%)

Peripheral vascular disease 11 (11%) 5 (10%)

Moderate or severe liver disease

11 (11%) 4 (8%)

Hepatitis 12 (12%) 2 (4%)

Severity of infection††

Mild 5 (5%) 4 (8%)

Moderate 41 (41%) 22 (45%)

Severe 55 (55%) 23 (47%)

Data are n (%), n/N (%), mean (SD), or median (range; IQR). BMI=body-mass index. HAP=hospital-acquired pneumonia. VAP=ventilator-associated pneumonia. HCAP=health care-associated pneumonia. ICU=intensive care unit. APACHE II=Acute Physiology and Chronic Health Evaluation II. CPIS=Clinical Pulmonary Infection Score. SOFA=Sequential Organ Failure Assessment. CCI=Charlson Comorbidity Index. *Data available for 99 patients assigned cefiderocol and 49 assigned best available therapy. †Definitions of bloodstream infection and sepsis are in the appendix (p 6). Sepsis diagnoses were based on Systemic Inflammatory Response Syndrome criteria that were valid at the time of study design. ‡Including biliary tract infection, pelvic infection, respiratory tract infections other than infection sites identified as HAP, VAP, HCAP (eg, community-acquired pneumonia, lung abscess, pleural space, or empyema). §A patient taking two or more medications was counted only once within a treatment classification; however, the same patient might have contributed to two or more Preferred Terms in the same classification, according to the Medical Dictionary for Regulatory Activities (version 18.1). ¶Previous antimicrobial therapy taken within 2 weeks before randomisation. ||Shown only for patients with nosocomial pneumonia; data available for 44 patients assigned cefiderocol and 21 assigned best available therapy. **Data available for 100 patients assigned cefiderocol and 49 assigned best available therapy. ††Based on the investigators’ clinical judgement (ie, there were no pre-defined criteria for infection severity).

Table 1: Baseline characteristics of the intention-to-treat and safety populations

Cefiderocol (n=80)


Number of carbapenem-resistant Gram-negative pathogens from appropriate specimens*

One 62 (78%) 30 (79%)

Two 13 (16%) 8 (21%)

Three 4 (5%) 0

Four 1 (1%) 0

Type of carbapenem-resistant Gram-negative pathogen

All patients N=87† N=40‡

Acinetobacter baumannii 37 (46%) 17 (45%)

Klebsiella pneumoniae 27 (34%) 12 (32%)

Pseudomonas aeruginosa 12 (15%) 10 (26%)

Stenotrophomonas maltophilia

5 (6%) 0

Acinetobacter nosocomialis 2 (3%) 0

Enterobacter cloacae 2 (3%) 0

Escherichia coli 2 (3%) 1 (3%)

Nosocomial pneumonia

A baumannii 26/40 (65%) 10/19 (53%)

P aeruginosa 6/40 (15%) 5/19 (26%)

K pneumoniae 6/40 (15%) 5/19 (26%)

S maltophilia 5/40 (13%) 0

A nosocomialis 2/40 (5%) 0

E cloacae 2/40 (5%) 0

E coli 0 1/19 (5%)

Bloodstream infections or sepsis

K pneumoniae 10/23 (44%) 4/14 (29%)

A baumannii 10/23 (44%) 7/14 (50%)

P aeruginosa 2/23 (9%) 3/14 (21%)

E coli 1/23 (4%) 0

Complicated urinary tract infections

K pneumoniae 11/17 (65%) 3/5 (60%)

P aeruginosa 4/17 (24%) 2/5 (40%)

A baumannii 1/17 (6%) 0

E coli 1/17 (6%) 0

Data are n (%) or n/N (%), where N is the total number of patients with at least one Gram-negative pathogen at baseline. *Based on data from the central microbiology laboratory if available. Polymicrobial infections could include carbapenem-resistant and carbapenem-susceptible bacteria present at the primary infection site. †Total number of baseline carbapenem-resistant Gram-negative pathogens in the cefiderocol group. ‡Total number of baseline carbapenem-resistant Gram-negative pathogens in the best available therapy group.

Table 2: Baseline carbapenem-resistant Gram-negative pathogen distribution in the carbapenem-resistant microbiological intention-to-treat population

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In the carbapenem-resistant microbiological ITT popu lation, the proportions of patients with HAP, VAP, or HCAP achieving a clinical cure at test of cure were 50% (95% CI 33·8–66·2; 20 of 40) of the cefiderocol group and 53% (28·9–75·6; ten of 19) of the best available therapy group (table 3). For patients with bloodstream infection or sepsis, a clinical cure at test of cure was achieved by 43% (23·2–65·5; ten of 23) of the cefiderocol group and 43% (17·7–71·1; six of 14) of the best available therapy group (table 3). For patients with

complicated UTIs, micro biological eradication at test of cure was achieved by 53% (27·8–77·0; nine of 17) of the cefiderocol group and 20% (0·5–71·6; one of five) of the best available therapy group (table 3). In subgroup analyses of clinical and microbiological outcomes at test of cure, numerical differences were noted by age (ie, <65 years or ≥65 years), pathogen group (ie, Enterobacterales), region (ie, North America and South America), race (ie, white, other, etc), and APACHE II score (ie, ≤15; appendix p 22).

Nosocomial pneumonia Bloodstream infections or sepsis

Complicated urinary tract infections

Overall

Cefiderocol (n=40)


Cefiderocol (n=23)


Cefiderocol (n=17)


Cefiderocol (n=80)


Clinical outcomes

End of treatment

Clinical cure 24 (60%; 43·3–75·1)

12 (63%; 38·4–83·7)

16 (70%; 47·1–86·8)

7 (50%; 23·0–77·0)

13 (77%; 50·1–93·2)

3 (60%; 14·7–94·7)

53 (66%; 54·8–76·4)

22 (58%; 40·8–73·7)

Clinical failure 13 (33%) 7 (37%) 6 (26%) 7 (50%) 1 (6%) 1 (20%) 20 (25%) 15 (40%)

Indeterminate 3 (8%) 0 1 (4%) 0 3 (18%) 1 (20%) 7 (9%) 1 (3%)

Test of cure

Clinical cure* 20 (50%; 33·8–66·2)

10 (53%; 28·9–75·6)

10 (43%; 23·2–65·5)

6 (43%; 17·7–71·1)

12 (71%; 44·0–89·7)

3 (60%; 14·7–94·7)

42 (53%; 41·0–63·8)

19 (50%; 33·4–66·6)


Indeterminate 4 (10%) 3 (16%) 4 (17%) 1 (7%) 3 (18%) 1 (20%) 11 (14%) 5 (13%)

Follow-up

Sustained clinical cure

20 (50%; 33·8–66·2)

6 (32%; 12·6–56·6)

9 (39%; 19·7–61·5)

4 (29%; 8·4–58·1)

9 (53%; 27·8–77·0)

3 (60%; 14·7–94·7)

38 (48%; 36·2–59·0)

13 (34%; 19·6–51·4)

Relapse 0 3 (16%) 1 (4%) 1 (7%) 1 (6%) 0 2 (3%) 4 (11%)


Indeterminate 4 (10%) 4 (21%) 4 (17%) 2 (14%) 5 (29%) 1 (20%) 13† (16%) 7† (18%)

Microbiological outcomes

End of treatment

Eradication 12 (30%; 16·6–46·5)

5 (26%; 9·1–51·2)

14 (61%; 38·5–80·3)

4 (29%; 8·4–58·1)

12 (71%; 44·0–89·7)‡

1 (20%; 0·5–71·6)‡

38 (48%; 36·2–59·0)

10 (26%; 13·4–43·1)

Persistence 15 (38%) 9 (47%) 1 (4%) 1 (7%) 0 0 16 (20%) 10 (26%)

Indeterminate 13 (33%) 5 (26%) 8 (35%) 9 (64%) 5 (29%) 4 (80%) 26 (33%) 18 (47%)

Test of cure

Eradication§ 9 (23%; 10·8–38·5)

4 (21%; 6·1–45·6)

7 (30%; 13·2–52·9)

4 (29%; 8·4–58·1)

9 (53%; 27·8–77·0)‡

1 (20%; 0·5–71·6)‡

25 (31%; 21·3–42·6)

9 (24%; 11·4–40·2)

Persistence 8 (20%) 7 (37%) 3 (13%) 2 (14%) 5 (29%) 1 (20%) 16 (20%) 10 (26%)

Indeterminate 23 (58%) 8 (42%) 13 (57%) 8 (57%) 3 (18%) 3 (60%) 39 (49%) 19 (50%)

Follow-up

Sustained eradication

8 (20%; 9·1–35·6)

3 (16%; 3·4–39·6)

6 (26%; 10·2–48·4)

3 (21%; 4·7–50·8)

7 (41%; 18·4–67·1)‡

1 (20%; 0·5–71·6)‡

21 (26%; 17·0–37·3)

7 (18%; 7·7–34·3)

Recurrence 0 1 (5%) 0 0 0 0 0 1 (3%)

Persistence 8 (20%) 7 (37%) 3 (13%) 2 (14%) 5 (29%) 1 (20%) 16 (20%) 10 (26%)

Indeterminate 24 (60%) 8 (42%) 14 (61%) 9 (64%) 5 (29%) 3 (60%) 43¶ (54%) 20¶ (53%)

Data are n (%) or n (%, 95% CI), categorised by clinical diagnosis and visit. *Primary endpoint for patients with nosocomial pneumonia, or bloodstream infections or sepsis. †Indeterminate clinical responses were reported as either deaths (for seven patients assigned cefiderocol and three assigned best available therapy), or missing (for six patients assigned cefiderocol and four assigned best available therapy [definitions in the appendix, p 8]). ‡Eradication was defined as reduction of urine culture Gram-negative uropathogens from at least 105 colony forming units (CFU) per mL at baseline to less than 103 CFU per mL. §Primary endpoint for patients with complicated urinary tract infections. ¶Indeterminate microbiological responses were reported as deaths (21 patients assigned cefiderocol and six assigned best available therapy); additional therapy required (for ten patients assigned cefiderocol and seven assigned best available therapy); or missing (for 12 patients assigned cefiderocol and seven assigned best available therapy [definitions in the appendix, p 10]).

Table 3: Clinical and microbiological secondary outcomes in the carbapenem-resistant microbiological intention-to-treat population

• PN : Guérison clinique dans le groupe céfidérocol 50.0% (20/40) vs 52.6% (10/19)

• BSI/Sepsis : Guérison clinique dans le groupe céfidérocol 43.5% (10/23) vs 42.9% (6/14)

• IU : Eradication microbiologique dans le groupe céfidérocol 52.9% (9/17) vs 20.0% (1/5)

• Mortalité J28 (toute cause) : 33% (13/40) dans le groupe cefiderocol vs16% (3/19)


Articles

Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trialMatteo Bassetti, Roger Echols, Yuko Matsunaga, Mari Ariyasu, Yohei Doi, Ricard Ferrer, Thomas P Lodise, Thierry Naas, Yoshihito Niki, David L Paterson, Simon Portsmouth, Julian Torre-Cisneros, Kiichiro Toyoizumi, Richard G Wunderink, Tsutae D Nagata

SummaryBackground New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections.

Methods We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23).

Findings Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8–66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9–75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2–65·5) of 23 patients in the cefiderocol group and six (43%, 17·7–71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8–77·0) of 17 patients in the cefiderocol group and one (20%, 0·5–71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug.

Interpretation Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options.

Lancet Infect Dis 2020

Published Online October 12, 2020 https://doi.org/10.1016/ S1473-3099(20)30796-9

See Online/Comment https://doi.org/10.1016/ S1473-3099(20)30828-8

Infectious Diseases Clinic, Department of Health Sciences, University of Genoa, Genoa and Hospital Policlinico San Martino IRCCS, Genoa, Italy (Prof M Bassetti MD); Infectious Disease Drug Development Consulting, Easton, CT, USA (R Echols MD); Shionogi, Florham Park, NJ, USA (Y Matsunaga MD, S Portsmouth MD); Shionogi, Osaka, Japan (M Ariyasu BPharm, K Toyoizumi PhD, T D Nagata MD); Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA (Y Doi MD); Department of Intensive Care Medicine and SODIR-VHIR Research Group, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain (R Ferrer MD); Albany College of Pharmacy and Health Sciences, Albany, NY, USA (Prof T P Lodise PharmD); Department of Medical Microbiology, Bicêtre Hospital, Paris, France (Prof T Naas MD); Department of Clinical Infectious Diseases, Showa University School of Medicine, Tokyo, Japan (Prof Y Niki MD); UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, QLD, Australia (Prof D L Paterson MD); Maimonides Institute for Biomedical Research, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain

Infections à métallo-β-lactamases

*Incluant NDM, VIM, IMP; PN: pneumonie nosocomiale, IU: infection urinaire, MTD: meilleur traitement disponibleBassetti 2020 Lancet ID et rapport de l’étude CREDIBLE-CR

Céfidérocol MTD

Total 16 7

Bactériémie 4 1

PN 6 3

IU 6 3

Entérobactéries 10 4

P. aeruginosa 4 3

A. baumannii 2 0

Caractéristiques des infections à métallo-β-lactamases

0

10

20

30

40

50

60

70

80

Guérison clinique (TOC) Eradication microbiologique (TOC) Mortalité toutes causes confondues(J49)

Pouc

entag

e de p

atien

ts

Céfiderocol MTD

12/16

2/7

7/16

1/73/16

4/775%

29%

44%

14%19%

57%

Cefiderocoln/N (%)

(95%IC (%))

MTDn/N (%)

(95%IC (%))Tous les patients 34/101 (33,7)

(24,6- 43,8)10/49 (20,4)(10,2-34,3)

Patients avec une infection à Acinetobacter spp. 21/42 (50)(34,2- 65,8)

3/17 (17,6)(3,8-43,4)

Patients avec une infection sans Acinetobacter (comprenant entérobactéries ou P. aeruginosa…)

EntérobactériesP. aeruginosa

13/59 (22)(12,3-34,7)

6/28 (21,4)2/11 (18,2)

6/32 (18,8)(7,2- 36,4)

4/15 (26,7)2/11 (18,2)

Mortalité selon bactérie

*Parmi ces patients, 30% (16) avaient des souches ayant une CMI au méropénème supérieure à 64 mg/L. Bassetti 2020 Lancet ID et rapport de l’étude CREDIBLE-CR; 2: Wunderick 2020 Lancet ID

Acinetobacter spp.

Bassetti 2020 Lancet ID et rapport de l’étude CREDIBLE-CR

Paramètre à l’inclusion

Patients avec une infection à Acinetobacter

Patients avec une infection sans Acinetobacter (comprenant entérobactéries

ou P. aeruginosa)

Cefiderocol MTD Cefiderocol MTD

Age≥ 65 ans, n (%) 26 (62) 7 (41) 38 (64) 15 (47)

Total APACHE II≥ 16, n (%) 24 (57) 8 (47) 22 (37) 14 (44)

Choc dans le mois précédent l’inclusion, n (%) 11 (26) 1 (6) 8 (14) 5 (16)

Hospitalisation en USI à la randomisation 34 (81) 8 (47) 23 (39) 13 (41)

• 10 patients en soins critiques : bactériémies ou PAVM due à ABRI, S. maltophilia, ou NDM-K. pneumoniae

• Guérison à J30 : 70% • Survie à J30 : 90%• 2 échecs microbiologiques

Falcone M et al. Clin Infect Dis, 2021

• 13 patients traités du 1er Septembre 2020 au 31 Mars 2021

• 5/13 (38%) USI• 4/13 (31%) infections post-chirurgicales• 4/13 (31%) patients ID (2/4: transplantés

d’organe; 2/4: hémopathie)

Bavaro DF, et al. Antibiotics 2021

• Eradication microbiologique : 100%• Survie J30 : 10/13; 2 décès dus au SARS-CoV-2 • 1 décès due à une infection intercurrente• Pas de récidive à J30

Bavaro DF, et al. Antibiotics 2021

0102030405060708090

CRAB CR-P. aeruginosa KPC-Kp

%

M A J O R A R T I C L E

Cefiderocol Resistance • OFID • 1

Open Forum Infectious Diseases

Received 11 March 2021; editorial decision 8 June 2021; accepted 10 June 2021.Correspondence: Pranita D. Tamma, MD, MHS, Division of Pediatric Infectious Diseases,

Department of Pediatrics, Johns Hopkins University School of Medicine, 200 North Wolfe Street, Suite 3149, Baltimore, MD 21287 ([email protected]).

Open Forum Infectious Diseases®2021© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact [email protected]: 10.1093/ofid/ofab311

Ce!derocol Activity Against Clinical Pseudomonas aeruginosa Isolates Exhibiting Ce"olozane-Tazobactam ResistancePatricia J. Simner,1 Stephan Beisken,2 Yehudit Bergman,1 Andreas E. Posch,2 Sara E. Cosgrove,3, and Pranita D. Tamma4,

1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, 2Ares Genetics, Vienna, Austria, 3Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, and 4Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Background. Mutations in the AmpC-AmpR region are associated with treatment-emergent ce"olozane-tazobactam (TOL-TAZ) and ce"azidime-avibactam (CAZ-AVI) resistance. We sought to determine if these mutations impact susceptibility to the novel cephalosporin-siderophore compound ce!derocol.

Methods. #irty-two paired isolates from 16 patients with index P. aeruginosa isolates susceptible to TOL-TAZ and subse-quent P. aeruginosa isolates available a"er TOL-TAZ exposure from January 2019 to December 2020 were included. TOL-TAZ, CAZ-AVI, imipenem-relebactam (IMI-REL), and ce!derocol minimum inhibitory concentrations (MICs) were determined using broth microdilution. Whole-genome sequencing of paired isolates was used to identify mechanisms of resistance to ce!derocol that emerged, focusing on putative mechanisms of resistance to ce!derocol or earlier siderophore-antibiotic conjugates based on the pre-viously published literature.

Results. Analyzing the 16 pairs of P. aeruginosa isolates, ≥4-fold increases in ce!derocol MICs occurred in 4 of 16 isolates. Ce!derocol nonsusceptibility criteria were met for only 1 of the 4 isolates, using Clinical and Laboratory Standards Institute criteria. Speci!c mechanisms identi!ed included the following: AmpC E247K (2 isolates), MexR A66V and L57D (1 isolate each), and AmpD G116D (1 isolate) substitutions. For both isolates with AmpC E247K mutations, ≥4-fold MIC increases occurred for both TOL-TAZ and CAZ-AVI, while a ≥4-fold reduction in IMI-REL MICs was observed.

Conclusions. Our !ndings suggest that alterations in the target binding sites of P. aeruginosa–derived AmpC β-lactamases have the potential to reduce the activity of 3 of 4 novel β-lactams (ie, ce"olozane-tazobactam, ce"azidime-avibactam, and ce!derocol) and potentially increase susceptibility to imipenem-relebactam. #ese !ndings are in need of validation in a larger cohort.

Keywords. AmpC; antimicrobial resistance; ce"azidime-avibactam; omega loop.

Pseudomonas aeruginosa with difficult-to-treat resistance (DTR; ie, P. aeruginosa resistant to all traditional β-lactams and fluoroquinolones) poses significant clinical challenges [1]. Several novel β-lactam agents have become Food and Drug Administration (FDA) approved with activity against DTR P. aeruginosa, including ceftolozane-tazobactam (TOL-TAZ), ceftazidime-avibactam (CAZ-AVI), imipenem-cilastatin-relebactam (IMI-REL), and cefiderocol. Unreliable baseline susceptibility of DTR P. aeruginosa to the novel agents, as well

as reports of resistance emerging during therapy, has tempered enthusiasm for several of these agents [2].

TOL-TAZ remains a preferred agent for the treatment of DTR P. aeruginosa infections [1]. We previously reported that in a cohort of 28 patients infected with DTR P. aeruginosa and paired clinical isolates before and a"er receipt of TOL-TAZ, half of patients had isolates that developed ≥4-fold increases in TOL-TAZ minimum inhibitory concentrations (MICs) a"er exposure to this agent [3].

Before the clinical use of ce!derocol, there was widespread belief that resistance would primarily result from mutations in TonB-dependent receptors (TBDRs), a series of bacterial outer membrane proteins that mediate siderophore–iron com-plex transport [4-6]. While such mutations have been identi-!ed [7, 8], there have also been isolated reports of changes in the ampC region contributing to ce!derocol resistance among the Enterobacterales [9, 10]. #is may occur a"er exposure to oxyminocephalosporins, such as CAZ-AVI or cefepime, in the absence of exposure to ce!derocol. It is unknown what role exposure to TOL-TAZ, also an oxyminocephalosporin, has

applyparastyle “!g//caption/p[1]” parastyle “FigCapt”

Dow

nloaded from https://academ

ic.oup.com/ofid/article/8/7/ofab311/6297178 by guest on 21 August 2021

4 • OFID • Simner et al

Table 1.

Continued

Isolateb

Clinical S

ummaryc

TOL-TAZ MIC

, mcg

/mL

CAZ-AVI MIC

, mcg

/mL

IMI-REL MIC,

mcg/ mL

Cefideroc

ol MIC

, mcg/

mLPote

ntial Res

istance Ta

rgets for S

iderophor

e–Antibio

tic Conju

gates Ide

ntified in

Subseque

nt Isolate

s but NO

T Index Is

olatesd

PDCa

ba

ba

ba

bAmp

CAmp

RAmp

DMex

ROprD

TBDR

PBP3

PvdS

12a-b

16 yo M,

ventilato

r-depende

nt with P.

aerugino

sa pneu-

monia. R

eceived T

OL-TAZ 3

g q8h × 6

d (no HD)

; other

β-lactams

: merope

nem (7d)

. Alive at

day 30: y

es.

423

24

88

0.250.25

----

----

----

----

PDC- 34

13a-b

53 yo M,

60% bod

y surface

area burn

s with P.

aerugino

sa pneu

monia. R

eceived T

OL-TAZ 3

g q8h × 6

d (no HD)

; othe

r β-lactam

s: merop

enem (10d

). Alive a

t day 30:

no.

10.5

164

44

0.50.5

----

----

----

----

PDC-8

14a-b

55 yo F, a

noxic bra

in injury

with P. ae

ruginosa

pneu-

monia. R

eceived T

OL-TAZ 3

g q8h × 7

d (no HD)

; other

β-lactams

: merope

nem (3d)

. Alive at

day 30: y

es.

281

616

84

0.51

----

----

----

PBP3 E466

K--

PDC-5

15a-b

74 yo M, v

entilator-

dependen

t with P. a

eruginos

a pneu-

monia. R

eceived T

OL-TAZ 3

g q8h × 6

d (HD); o

ther β-lac

tams: non

e. Alive a

t day 30:

yes.

1256

2256

432

0.120.25

----

AmpD G148

A--OprD

stop

mutation

E384

----

--PDC

- 19a

16a-b

65 yo M,

ventricu

lar assist

device w

ith P. aeru

ginosa b

ac-terem

ia and de

vice-asso

ciated inf

ection, de

vice not

removed.

Receive

d TOL-TAZ

3g q8h ×

16d (HD

); other

β-lactams

: merope

nem (1d)

. Alive at

day 30: y

es.

1256

832

324

0.121

AmpC E247

K--

----

----

----

PDC-3

Abbreviat

ions: CA

Z-AVI, ce

ftazidime

-avibacta

m; HD, he

modialys

is; IMI-RE

L, imipen

em-releb

actam; M

IC, minim

um inhib

itory con

centratio

n; PDC, Ps

eudomon

as-derive

d cephal

osporinas

e; TBDR,

TonB-dep

endent re

ceptor; T

OL-TAZ, c

eftolozan

e-tazobac

tam.a Gree

n represe

nts antibi

otic MIC

in susce

ptible ran

ge. Red re

presents

antibioti

c MIC no

t in susce

ptible ran

ge.b Bold

isolate nu

mbers in

dicate ≥4

-fold chan

ge in cefi

derocol M

IC against

index to

subseque

nt paired

P. aerugin

osa isola

tes.c “Oth

er β-lacta

ms” inclu

des β-lac

tam agen

ts admini

stered wi

thin 7 da

ys before

the inde

x isolate

was colle

cted up t

o the time

the subs

equent is

olate was

collected

. As all in

dex isola

tes were r

esistant t

o ceftazi

dime, cef

epime, pi

peracillin

-tazobact

am, and

meropene

m, there w

as limited

use of “t

raditiona

l” β-lacta

ms.d As o

nly chang

es from i

ndex to s

ubsequen

t isolates

are inclu

ded, mut

ations pre

sent in b

oth index

and sub

sequent i

solates a

re not inc

luded. As

an exam

ple, 9 of

13 index

isolates n

ot suscep

tible to im

ipenem-r

elebacta

m contain

ed oprD

mutants

.

Downloaded from https://academic.oup.com/ofid/article/8/7/ofab311/6297178 by guest on 21 August 2021

• Mutations dans région AmpC-AmpRassociées à résistance à ceftolozane-tazobactam (TOL-TAZ ) et ceftazidime-avibactam (CAZ-AVI)

• 32 paires d'isolats de 16 patients § isolats index de P. aeruginosa sensibles à

TOL-TAZ § isolats après traitement par TOL-TAZ

• 4/16 paires : ì ≥4x CMI au cefiderocol • Mutations AmpC E247K : ì ≥4x CMI à

TOL-TAZ et CAZ-AVI + î ≥4x CMI à IMI-REL

• Altérations sites de liaison d'AmpC β-lactamases dérivées de P. aeruginosa : § Peuvent réduire l'activité de 3 sur 4

nouveaux β-lactamines (ie, ceftolozane-tazobactam, ceftazidime-avibactam, et cefiderocol)

§ Peuvent augmenter susceptibilité à imipenem-relebactam

OFID 2021

Comparaison entre molécules

R E V I E W A R T I C L E

Meta-analysis of Treatments for MDRGNO • OFID • 1


Received 7 October 2020; editorial decision 22 December 2020; accepted 4 January 2021.Correspondence: Geneva Wilson, MPH, PhD, 5000 S. 5th Ave, (151H) Bldg, 1, D304, Hines, IL

60141 ([email protected]).

Open Forum Infectious Diseases®2021Published by Oxford University Press on behalf of Infectious Diseases Society of America 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.DOI: 10.1093/ofid/ofaa651

Meta-analysis of Clinical Outcomes Using Ce"azidime/Avibactam, Ce"olozane/Tazobactam, and Meropenem/Vaborbactam for the Treatment of Multidrug-Resistant Gram-Negative InfectionsGeneva M. Wilson,1, Margaret Fitzpatrick,1,2 Kyle Walding,2 Beverly Gonzalez,1 Marin L. Schweizer,3,4 Katie J. Suda,5,6 and Charlesnika T. Evans1,7

1Center of Innovation for Complex Chronic Healthcare (CINCCH), Edward Hines Jr. Veterans Affairs Hospital, Hines, Illinois, USA, 2Loyola Medical Center, Maywood, Illinois, USA, 3College of Public Health, University of Iowa, Iowa City, Iowa, USA, 4Center for Access and Delivery Research and Evaluation (CADRE), Iowa City VA Health Care System, Iowa City, Iowa, USA, 5Center for Health Equity Research and Promotion, VA Pittsburgh Heath Care System, Pittsburgh, Pennsylvania, USA, 6Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA, and 7Department of Preventive Medicine, Center for Health Services and Outcomes Research, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Ce"olozane-tazobactam (C/T), ce"azidime-avibactam (C/A), and meropenem/vaborbactam (M/V) are new beta-lactam/beta-lactamase combination antibiotics commonly used to treat multidrug-resistant Pseudomonas aeruginosa (MDRPA) and carbapenem-resistant Enterobacteriaceae (CRE) infections. #is review reports the clinical success rates for C/T, C/A, and M/V. PubMed and EMBASE were searched from January 1, 2012, through September 2, 2020, for publications detailing the use of C/T, C/A, and M/V. A meta-analysis determined the pooled e$ectiveness of C/T, C/A, and M/V. #e literature search returned 1950 publications; 29 publications representing 1620 patients were retained. Pneumonia was the predominant infection type (49.8%). MDRPA was the major pathogen treated (65.3%). #e pooled clinical success rate was 73.3% (95% CI, 68.9%–77.5%). C/T, C/A, or M/V resistance was reported in 8.9% of the population. #ese antibiotics had a high clinical success rate in patients with complicated infections and limited treatment options. Larger studies comparing C/T, C/A, and M/V against other antibiotic regimens are needed.

Keywords. antimicrobial resistance; epidemiology; meta-analysis; multidrug-resistant infections.

Carbapenem-resistant Enterobacteriaceae (CRE) have been identified as an urgent antibiotic-resistant threat by the Centers for Disease Control and Prevention (CDC) [1]. Infections caused by CRE are difficult to treat due to the limited number of antibiotic options available. In 2017, the CDC reported 13 100 hospital-based cases of CRE in the United States, 1100 estimated deaths (8.4% mortality rate), and costs of ~$130 mil-lion dollars annually [1]. Multidrug-resistant Pseudomonas aeruginosa (MDRPA) has been classified as a serious threat by the CDC. It infects ~32 600 people each year and contributes to 2700 deaths. Treating MDRPA costs ~$767 million annually [1]. Risk factors for CRE and MDRPA include previous antibiotic exposure, frequent contact with health care facilities, older age, and use of indwelling devices [2–7].

Ce"olozane/tazobactam (C/T) is a combination fourth-generation cephalosporin and β-lactamase inhibitor that was approved for use by the Food and Drug Administration in 2014. Ce"olozane is a potent antibiotic with activity against many

gram-negative bacteria, including Pseudomonas aeruginosa. Tazobactam irreversibly binds to serine β-lactamases, thus pro-tecting against hydrolysis by β-lactamase enzymes produced by bacteria. C/T is primarily used for the treatment of multidrug-resistant Pseudomonas aeruginosa infections (MDRPA) but can also be used to treat infections caused by extended-spectrum beta-lactamase (ESBL)–producing organisms [8, 9].

Ce"azidime/avibactam (C/A) is a combination of a third-generation cephalosporin and a novel β-lactamase inhibitor and was approved for use in 2015. Ce"azidime has increased a&nity for the penicillin-binding protein (PBP)–3 that is com-monly found in gram-negative organisms and inhibits bacterial cell wall synthesis. Avibactam is a non-β-lactam β-lactamase in-hibitor that reduces the availability of active enzymes that can inactivate β-lactam antibiotics. C/A is primarily used for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) but is also used to treat infections caused by other multidrug-resistant gram-negative organisms (MDRGNOs) [8, 10].

Meropenem/vaborbactam (M/V) is a combination carbapenem and beta-lactamase inhibitor that was approved for use in the United States in 2017 [11]. Meropenem acts by inhibiting the cell wall synthesis of gram-positive and -nega-tive bacteria. Vaborbactam is a cyclic boronic acid–based beta-lactamase that was designed to augment the performance of carbapenem antibiotics against carbapenemase-producing

applyparastyle “'g//caption/p[1]” parastyle “FigCapt”


Table 1. De

mographics

of Included S

tudies (n = 2

9 Studies)

Author, Year

Study Desi

gn Locat

ionDurat

ion of

Study, mo

Duration of

Treatm

ent Samp

le Size

Age, y

SOT, %

Kidney

Disease , %

Cancer Pn

eumonia

%MDRPA

%CRE

Alosaimy, 2

020Obs.

studyUSA

20 ≥72 h

MV40

58 (34–69)a

NR37.5

NR32.5

N/A84.6

Bassetti, 20

19Obs.

studyItaly

21≥96 h

C/T 101

67 (49–74)a

10.930.7

29.731.7

69.0N/A

Bosaeed, 20

20Obs.

study

Saudi Arab

ia 24

≥96 h C/T

2457 (36

–71)a8.3

20.820.8

31.6100

N/ACasto

n, 2017

Obs. study

Spain9

NR 12

67 (54–75)b

NR25.0

16.750.0

100N/A

De la Calle

, 2019Obs.

studySpain

26≥72 h

C/A23

58.8 (16.03

)c21.7

43.521.7

21.7N/A

100.0Diaz-C

anestro, 20

18Obs.

studySpain

28

C/T for ≥48

h58

60.8 (14.5)c

1.725.9

32.760.3

97N/A

Dinh, 2017

Obs. study

France

9≥1 do

se of C/T

1548.3 (

3–73)d

33.320.0

26.746.7

100N/A

Escola-Verg

e, 2018

Obs. study

Spain

20≥72 h

of C/T

3859.5 (

19–85)b

28.921.1

28.936.8

100N/A

Gallagher, 2

018Obs.

studyUSA

38≥24 h

of C/T

20560 (48

–70)a17.1

26.316.1

59.0100

N/AGuim

araes, 2019

Case series

Brazil

21

≥48 h of C/

A 29

50.5e24.1

48.3NR

10.3N/A

100.0Haida

r, 2017

Obs. study

USA 9

NR 21

58 (23–91)b

38.123.8

9.576.2

100N/A

Hart, 2019

Case series

USA

41≥24 h

C/T 70

57 (14)c

67.1NR

NR55.7

100N/A

Jorgensen,

2019Obs.

study

USA 48

≥72 h of C/

A 203

62 (49–72)a

NR32.0

13.337.4

3158

Jorgensen,

2020Obs.

study

USA 48

≥72 h of C/

T 259

62 (52–72)a

NRNR

9.362.9

87N/A

King, 2017

Chart revie

w USA

13≥24 h

of C/A

6060 (51

–69)a25.0

31.7NR

26.7N/A

83.3Mollo

y, 2020

Case series

USA

Not reporte

d Not re

ported

133 mo

– 19 yf

NRNR

7.776.9

100N/A

Molnar, 20

17Obs.

studyUSA

Not reporte

d ≥24 h

C/T 34

57 (42–66)a

44.1NR

NR64.7

100N/A

Munita, 20

17Obs.

studyUSA

Not reporte

d Not re

ported

3552.9 (

16–89)d

NR11.4

25.742.9

77.0N/A

Nambiar, 20

19Case

series

USA 22

Not reporte

d 32

C/A = 61 (1

1)c C/T =

48 (19)c

100.012.5

NR46.9

13.087.5

Nathan, 201

6Case

series

USA 14

NR 28

57 (18–64)d

0.0NR

39.328.6

50.025.0

Rodriguez-

Nunez, 202

0Obs. stud

y USA, U

K, France, S

pain 24

≥72 h of C/

T, 90

64 (16.2)c

3314.4

18.9100

77.0N/A

Sacha, 2017

Case series

USA

10≥1 do

se of C/T

4965 (51

–71)a34.7

NR14.3

69.469

N/ASante

vecchi, 201

8Case

series

USA 12

≥1 dose of

C/A 10

53 (32–75)d

20.0NR

10.060.0

70N/A

Shields, 201

6Case

series

USA 10

≥72 h of C/

T 37

64 (26–78)b

29.7NR

0.032.4

N/A100.0

Shields, 202

0Obs.

study

USA 16

MV for ≥48

h 20

56 (31–83)a

NRNR

NR 35.0

NR70.0

Sousa, 2018

Obs. study

Spain20

≥48 h of C/

A 57

64 (26–86)d

NR21.05

24.5626.3

N/A100.0

Temkin, 20

17Case

series E

urope and A

ustralia

36≥1 do

se of C/A

3861 (47

–67)a13.2

18.42NR

NRN/A

89.5Vena,

2020Obs.

studyItaly

24 ≥72 h

of C/A

4161.6 (

13.0)cNR

26.0917.39

48.893

N/AXipell

, 2018Case

series

Spain

12≥72 h

of C/T

2362 (41

–70)a19.5

21.926.8

34.8100

N/A

Abbreviatio

ns: C/A, ce

ftazidime/a

vibactam;

C/T, ceftolo

zane/tazob

actam; CRE

, carbapene

m-resistant

Enterobac

teriaceae; M

DRPA, mul

tidrug-resis

tant Pseudo

monas aeru

ginosa; Ob

s., observa

tional; SOT

, solid orga

n transplan

t; XDRPA,

extensively

drug-

resistant Ps

eudomonas

aeruginosa

. a Medi

an (interqu

artile range

). b Medi

an (range).

c Mean (SD).

d Mean

(range).

e Mean only.

f Rang

e only.

• 29 études >> 1620 patients• Pneumonie : 49.8% • Pseudomonas aeruginosa

MDR : 65.3%

OFID 2021

6 • OFID • Wilson et al

14 studies; this is comparable to the AE rates found for older antibiotic therapies [10, 41].

In this systematic review and meta-analysis of 29 studies that included 1620 patients primarily treated with C/T, C/A, or M/V for MDRO infections or salvage therapy, we found a high pooled clinical success rate of 73.3%. "ere was a moder-ately high amount of heterogeneity among the articles (72.6%). Clinical success rates for C/T and C/A were similar. "e most

common infection site reported in these studies was either HAP or VAP (44%). HAP/VAP caused by MDROs is o#en associated with greater clinical severity than other infection types (eg, cUTI), making infection resolution more di$cult [42]. "erefore, the success rates for these drugs in treating HAP/VAP are particularly encouraging. Another %nding of in-terest was that the studies that focused on C/T, C/A, and M/V as salvage therapy showed a higher clinical success rate than

All Studies Forest Plot

All Studies

Bosaeed, 2020Caston, 2017

Alosaimy, 2020Bassetti, 2019

De la Calle, 2019Diaz-Canestro, 2018

Dinh, 2017Escola-Verge, 2018

Gallagher, 2018Guimaraes, 2019

Haidar, 2017Hart, 2019

Jorgensen, 2019Jorgensen, 2020

King, 2017Molloy, 2020Molnar, 2017Munita, 2017

Nambiar, 2019Nathan, 2016

Rodriguez-Nunez, 2020

Incl

uded

Stu

dies

Sacha, 2017Santevechi, 2018

Shields, 2016Shields, 2020Sousa, 2018

Temkin, 2017Vena, 2020

Xipell, 2018

0.25 0.50 0.75 1.00Clinical Success Rate

1.25

Figure 2. Forest plot of clinical success rate among studies meeting inclusion criteria (n = 29). The mean and SD of the clinical success rates for each study are represented. The pooled mean and SD are presented as the total.

Table 2. Stratified Analyses and Subanalyses of Included Studies

Included Studies Pooled Rate (CI), % I2 Value, %

Outcomes Clinical success 29 73.3 (68.9–77.5) 72.6Microbiological success 19 67.9 (58.8–77.4) 87.9Recurrence rate 14 33.9 (28.2–39.7) 47.3Clinical success among subset analyses C/T-only studies 18 73.8 (67.8–79.7) 78.5C/A-only studies 12 73.0 (67.7–78.4) 51.9Salvage therapy patients 12 80.7 (78.0–83.4) 0.0Studies with low risk of bias 16 72.7 (66.8–78.6) 80.0Studies with moderate risk of bias 13 73.9 (67.7–80.1) 55.4

R E V I E W A R T I C L E



Received 7 October 2020; editorial decision 22 December 2020; accepted 4 January 2021.Correspondence: Geneva Wilson, MPH, PhD, 5000 S. 5th Ave, (151H) Bldg, 1, D304, Hines, IL

60141 ([email protected]).

Open Forum Infectious Diseases®2021Published by Oxford University Press on behalf of Infectious Diseases Society of America 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.DOI: 10.1093/ofid/ofaa651

Meta-analysis of Clinical Outcomes Using Ce"azidime/Avibactam, Ce"olozane/Tazobactam, and Meropenem/Vaborbactam for the Treatment of Multidrug-Resistant Gram-Negative InfectionsGeneva M. Wilson,1, Margaret Fitzpatrick,1,2 Kyle Walding,2 Beverly Gonzalez,1 Marin L. Schweizer,3,4 Katie J. Suda,5,6 and Charlesnika T. Evans1,7

1Center of Innovation for Complex Chronic Healthcare (CINCCH), Edward Hines Jr. Veterans Affairs Hospital, Hines, Illinois, USA, 2Loyola Medical Center, Maywood, Illinois, USA, 3College of Public Health, University of Iowa, Iowa City, Iowa, USA, 4Center for Access and Delivery Research and Evaluation (CADRE), Iowa City VA Health Care System, Iowa City, Iowa, USA, 5Center for Health Equity Research and Promotion, VA Pittsburgh Heath Care System, Pittsburgh, Pennsylvania, USA, 6Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA, and 7Department of Preventive Medicine, Center for Health Services and Outcomes Research, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Ce"olozane-tazobactam (C/T), ce"azidime-avibactam (C/A), and meropenem/vaborbactam (M/V) are new beta-lactam/beta-lactamase combination antibiotics commonly used to treat multidrug-resistant Pseudomonas aeruginosa (MDRPA) and carbapenem-resistant Enterobacteriaceae (CRE) infections. #is review reports the clinical success rates for C/T, C/A, and M/V. PubMed and EMBASE were searched from January 1, 2012, through September 2, 2020, for publications detailing the use of C/T, C/A, and M/V. A meta-analysis determined the pooled e$ectiveness of C/T, C/A, and M/V. #e literature search returned 1950 publications; 29 publications representing 1620 patients were retained. Pneumonia was the predominant infection type (49.8%). MDRPA was the major pathogen treated (65.3%). #e pooled clinical success rate was 73.3% (95% CI, 68.9%–77.5%). C/T, C/A, or M/V resistance was reported in 8.9% of the population. #ese antibiotics had a high clinical success rate in patients with complicated infections and limited treatment options. Larger studies comparing C/T, C/A, and M/V against other antibiotic regimens are needed.

Keywords. antimicrobial resistance; epidemiology; meta-analysis; multidrug-resistant infections.

Carbapenem-resistant Enterobacteriaceae (CRE) have been identified as an urgent antibiotic-resistant threat by the Centers for Disease Control and Prevention (CDC) [1]. Infections caused by CRE are difficult to treat due to the limited number of antibiotic options available. In 2017, the CDC reported 13 100 hospital-based cases of CRE in the United States, 1100 estimated deaths (8.4% mortality rate), and costs of ~$130 mil-lion dollars annually [1]. Multidrug-resistant Pseudomonas aeruginosa (MDRPA) has been classified as a serious threat by the CDC. It infects ~32 600 people each year and contributes to 2700 deaths. Treating MDRPA costs ~$767 million annually [1]. Risk factors for CRE and MDRPA include previous antibiotic exposure, frequent contact with health care facilities, older age, and use of indwelling devices [2–7].

Ce"olozane/tazobactam (C/T) is a combination fourth-generation cephalosporin and β-lactamase inhibitor that was approved for use by the Food and Drug Administration in 2014. Ce"olozane is a potent antibiotic with activity against many

gram-negative bacteria, including Pseudomonas aeruginosa. Tazobactam irreversibly binds to serine β-lactamases, thus pro-tecting against hydrolysis by β-lactamase enzymes produced by bacteria. C/T is primarily used for the treatment of multidrug-resistant Pseudomonas aeruginosa infections (MDRPA) but can also be used to treat infections caused by extended-spectrum beta-lactamase (ESBL)–producing organisms [8, 9].

Ce"azidime/avibactam (C/A) is a combination of a third-generation cephalosporin and a novel β-lactamase inhibitor and was approved for use in 2015. Ce"azidime has increased a&nity for the penicillin-binding protein (PBP)–3 that is com-monly found in gram-negative organisms and inhibits bacterial cell wall synthesis. Avibactam is a non-β-lactam β-lactamase in-hibitor that reduces the availability of active enzymes that can inactivate β-lactam antibiotics. C/A is primarily used for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) but is also used to treat infections caused by other multidrug-resistant gram-negative organisms (MDRGNOs) [8, 10].

Meropenem/vaborbactam (M/V) is a combination carbapenem and beta-lactamase inhibitor that was approved for use in the United States in 2017 [11]. Meropenem acts by inhibiting the cell wall synthesis of gram-positive and -nega-tive bacteria. Vaborbactam is a cyclic boronic acid–based beta-lactamase that was designed to augment the performance of carbapenem antibiotics against carbapenemase-producing

applyparastyle “'g//caption/p[1]” parastyle “FigCapt”

OFID 2021

Ceftolozane tazobactam

Timsit et al. Crit Care (2021) 25:290 https://doi.org/10.1186/s13054-021-03694-3

RESEARCH

Ceftolozane/tazobactam versus meropenem in patients with ventilated hospital-acquired bacterial pneumonia: subset analysis of the ASPECT-NP randomized, controlled phase 3 trialJean-François Timsit1, Jennifer A. Huntington2, Richard G. Wunderink3, Nobuaki Shime4, Marin H. Kollef5, Ülo Kivistik6, Martin Nováček7, Álvaro Réa-Neto8, Ignacio Martin-Loeches9,10, Brian Yu2, Erin H. Jensen2, Joan R. Butterton2, Dominik J. Wolf2, Elizabeth G. Rhee2 and Christopher J. Bruno2*

Abstract Background: Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other infection sites. Among nosocomial pneumonia sub-types, ventilated HABP (vHABP) is associated with the lowest survival. In the ASPECT-NP randomized, controlled trial, participants with vHABP treated with ceftolozane/tazobactam had lower 28-day all-cause mortality (ACM) than those receiving meropenem. We conducted a series of post hoc analyses to explore the clinical significance of this finding.

Methods: ASPECT-NP was a multinational, phase 3, noninferiority trial comparing ceftolozane/tazobactam with meropenem for treating vHABP and VABP; study design, efficacy, and safety results have been reported previously. The primary endpoint was 28-day ACM. The key secondary endpoint was clinical response at test-of-cure. Participants with vHABP were a prospectively defined subgroup, but subgroup analyses were not powered for noninferiority test-ing. We compared baseline and treatment factors, efficacy, and safety between ceftolozane/tazobactam and mero-penem in participants with vHABP. We also conducted a retrospective multivariable logistic regression analysis in this subgroup to determine the impact of treatment arm on mortality when adjusted for significant prognostic factors.

Results: Overall, 99 participants in the ceftolozane/tazobactam and 108 in the meropenem arm had vHABP. 28-day ACM was 24.2% and 37.0%, respectively, in the intention-to-treat population (95% confidence interval [CI] for dif-ference: 0.2, 24.8) and 18.2% and 36.6%, respectively, in the microbiologic intention-to-treat population (95% CI 2.5, 32.5). Clinical cure rates in the intention-to-treat population were 50.5% and 44.4%, respectively (95% CI − 7.4, 19.3). Baseline clinical, baseline microbiologic, and treatment factors were comparable between treatment arms. Multivari-able regression identified concomitant vasopressor use and baseline bacteremia as significantly impacting ACM in ASPECT-NP; adjusting for these two factors, the odds of dying by day 28 were 2.3-fold greater when participants received meropenem instead of ceftolozane/tazobactam.

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Open Access

*Correspondence: [email protected] MRL, Merck & Co., Inc., Kenilworth, NJ, USAFull list of author information is available at the end of the article

Page 9 of 14Timsit et al. Crit Care (2021) 25:290

gain in ROC was obtained when additional variables were included. The initial, variable selection step of this multivariable analysis therefore showed that the

four most important factors influencing 28-day ACM in the vHABP subgroup were: concomitant vasopres-sor use (categorical variable), baseline age (continuous variable), baseline bacteremia (categorical variable), and baseline PaO2/FiO2 (continuous variable) (Addi-tional file 1: Figure S1).

"e four factors, in combination with treatment (i.e., ceftolozane/tazobactam vs meropenem), were fur-ther evaluated in a backward elimination logistic main effects regression model. Treatment, bacteremia, and vasopressor use remained significant (p < 0.05) in the final regression model, while age and baseline PaO2/FiO2 were removed from the model due to lack of sig-nificant impact on 28-day all-cause mortality. Since this was a main effects model, no interaction terms were included. "e final model had an area under the ROC curve of 0.74, indicating that successful classification of mortality is achieved with this fitted model. ORs for death by day 28 (Table 5) were 5.4 for vasopressor use (adjusting for treatment and bacteremia) and 2.7 for bacteremia (adjusting for treatment and vasopressor use). Treatment was also significantly associated with mortality (adjusting for vasopressor use and bactere-mia): the OR with meropenem treatment (vs ceftolo-zane/tazobactam) was 2.3 (95% CI 1.2, 4.5). Results of the sensitivity analysis were fully consistent with those of the main multivariable analysis, with treatment, vasopressor use, and bacteremia as the only factors sig-nificantly associated with mortality (Additional file 1: Table S7).

Table 3 Primary and secondary efficacy outcomes in ASPECT-NP participants with ventilated hospital-acquired bacterial pneumonia by treatment arm

CE, clinically evaluable. CI, con"dence interval. C/T, ceftolozane/tazobactam. ITT, intent-to-treat. ME, microbiologically evaluable. mITT, microbiological intent-to-treat. TOC, test-of-cure

*Patients with missing/indeterminate data are reported as deceased or as failures, depending on the endpoint‡ Not all ITT patients had con"rmed baseline pathogens and susceptibility data available§ Data reported as observed, i.e., patients with missing/indeterminate responses excluded from analysis¶ Per-patient microbiologic eradication

**Unstrati"ed Newcombe CIs; positive di#erences are in favor of ceftolozane/tazobactam, negative di#erences are in favor of meropenem

Endpoint C/Tn/N (%)

Meropenemn/N (%)

% Di!erence (95% CI)**

28-day all-cause mortality (ITT)* 24/99 (24.2%) 40/108 (37.0%) 12.8% (0.2, 24.8)

All LRT pathogens susceptible to randomized study drug‡ 7/38 (18.4%) 20/55 (36.4%) 17.9% (− 0.9, 34.0)

≥ 1 LRT pathogen non-susceptible to randomized study drug‡ 10/37 (27.0%) 11/26 (42.3%) 15.3% (− 7.9, 37.3)

28-day all-cause mortality (mITT)* 10/55 (18.2%) 26/71 (36.6%) 18.4% (2.5, 32.5)

Monomicrobial 5/33 (15.2%) 16/40 (40.0%) 24.8% (4.0, 42.4)

Polymicrobial 5/22 (22.7%) 10/31 (32.3%) 9.5% (− 15.3, 31.2)

Clinical cure at TOC (ITT)* 50/99 (50.5%) 48/108 (44.4%) 6.1% (− 7.4, 19.3)

Clinical cure at TOC (CE)§ 34/59 (57.6%) 32/49 (65.3%) − 7.7% (− 25.0, 10.6)

Microbiologic eradication at TOC (mITT)*,¶ 43/55 (78.2%) 44/71 (62.0%) 16.2% (− 0.1, 30.8)

Microbiologic eradication at TOC (ME)*,¶ 15/21 (71.4%) 16/25 (64.0%) 7.4% (− 19.1, 31.9)

0

10

20

30

40

50

0 4 8 12 16 20 24 28

99C/TPatients at risk

95 89 89 83 79 75 74108Meropenem 95 89 84 78 74 69 67

Cum

ulat

ive

perc

enta

ge o

f dea

ths

Time (days)

MeropenemC/T

43 (39.8)31 (31.3)Number of deaths (%)10899Number of participants

MeropenemC/T

Fig. 2 Time to death in participants with vHABP (ITT population). C/T, ceftolozane/tazobactam. ITT, intention to treat population (all randomized patients). vHABP, ventilated hospital-acquired bacterial pneumonia

• Sous groupe d’ASPECT-NP : PAVM• 99 patients sous ceftolozane/tazobactam vs 108

sous méropénem

• Analyse ajustée sur facteurs confondants : mortalité 2 X plus élevée avec méropénem vs ceftolozanetazobactam

• Facteurs de mauvais pronostic en analyse multivariée : vasopresseur et bactériémie

Critical Care 2021

M A J O R A R T I C L E

C/T Outcomes in Immunocompromised Patients • OFID • 1


Received 11 February 2021; editorial decision 15 February 2021; accepted 4 March 2021.Correspondence: Elizabeth B. Hirsch, PharmD, Department of Experimental and Clinical

Pharmacology, University of Minnesota College of Pharmacy, 4–212 MTRF, 2001 6th St. SE, Minneapolis, MN 55455 ([email protected]).

Open Forum Infectious Diseases®2021© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.DOI: 10.1093/ofid/ofab089

A Multicenter Evaluation of Ce!olozane/Tazobactam Treatment Outcomes in Immunocompromised Patients With Multidrug-Resistant Pseudomonas aeruginosa InfectionsDelaney E. Hart,1 Jason C. Gallagher,2 Laura A. Puzniak,3 and Elizabeth B. Hirsch1; for the C/T Alliance to deliver Real-world Evidence (CARE)1University of Minnesota College of Pharmacy, Minneapolis, Minnesota, USA, 2Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA, and 3Merck & Co., Inc., Kenilworth, New Jersey, USA

Background. Real-world data assessing outcomes of immunocompromised patients treated with ce!olozane/tazobactam (C/T) are limited. "is study evaluated treatment and clinical outcomes of immunocompromised patients receiving C/T for multidrug-resistant (MDR) Pseudomonas aeruginosa.

Methods. "is was a 14-center retrospective cohort study of adult immunocompromised inpatients treated for ≥24 hours with C/T for MDR P. aeruginosa infections. Patients were de#ned as immunocompromised if they had a history of previous solid organ transplant (SOT), disease that increased susceptibility to infection, or received immunosuppressive therapies. "e primary outcomes were all-cause 30-day mortality and clinical cure.

Results. Sixty-nine patients were included; 84% received immunosuppressive agents, 68% had a history of SOT, and 29% had diseases increasing susceptibility to infection. "e mean patient age was 57 ± 14 years, and the median (interquartile range) patient Acute Physiology and Chronic Health Evaluation II and Charlson Comorbidity Index scores were 18 (13) and 5 (4), respectively, with 46% receiving intensive care unit care at C/T initiation. "e most frequent infection sources were respiratory (56%) and wound (11%). All-cause 30-day mortality was 19% (n = 13), with clinical cure achieved in 47 (68%) patients. Clinical cure was numerically higher (75% vs 30%) in pneumonia patients who received 3-g pneumonia regimens vs 1.5-g regimens.

Conclusions. Of 69 immunocompromised patients treated with C/T for MDR P. aeruginosa, clinical cure was achieved in 68% and mortality was 19%, consistent with other reports on a cross-section of patient populations. C/T represents a promising agent for treatment of P. aeruginosa resistant to traditional antipseudomonal agents in this high-risk population.

Keywords. ce!olozane/tazobactam; immunocompromised; multidrug-resistant; P. aeruginosa; pneumonia.

Ceftolozane/tazobactam (C/T) was approved for use in the United States in 2014 [1]. C/T is approved for treatment of complicated urinary tract infections (cUTIs) including pye-lonephritis using a 1.5-g-based regimen and for complicated intra-abdominal infections in combination with metronida-zole. In 2019, C/T was also approved for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) at an increased 3-g-based regimen [1–3]. C/T has demonstrated activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and ESBL-producing Enterobacterales via nu-merous in vitro studies [4–7].

Complex patient populations are o!en excluded from phase 3 clinical trials to ensure homogeneity of the patient population.

A large subset of patients that are o!en at higher risk of MDR infections includes immunocompromised patients; however, the outcomes of this patient population with novel agents are o!en not studied or reported in registration trials. In particular, pa-tients with hematologic malignancies and transplant recipients have a particularly high risk of gram-negative bacteremia due to gastrointestinal mucositis, neutropenia for prolonged periods, and frequent health care exposure [8, 9]. Data analyzing the use of C/T among immunocompromised patient populations are still very limited, despite this agent being in clinical use since 2014. Notably, most of the publications include small sample sizes, case reports, and case reviews [10–15]. A recent review of 7 adult pa-tients with hematologic malignancies or hematopoietic cell trans-plant recipients treated with C/T demonstrated a 100% 30-day survival and 71.4% clinical cure rate [10]. Several of the larger re-cent cohort studies evaluating outcomes of patients treated with C/T for MDR P. aeruginosa infections included limited patients (21% or less) with immunocompromising conditions.

In light of the limited data available for this patient popu-lation, we aimed to evaluate treatment patterns and clinical outcomes of immunocompromised patients treated with C/T for multidrug-resistant P. aeruginosa infections in an e%ort to

applyparastyle “#g//caption/p[1]” parastyle “FigCapt”

Dow



4 • OFID • Hart et al

upon C/T initiation. The CART analysis identifying the 30-day mortality split at APACHE II score >25 demonstrates that the most critically ill patients with a high APACHE II score were at greatest risk for mortality. Furthermore, these patients had prolonged hospital stays, as demonstrated by a median hospital length of stay of 38 days, although many factors can confound hospital length of stay in immunocompromised patients.

In the present study of 69 immunocompromised patients, morbidity and clinical cure rates were similar to previous, larger studies conducted within nonimmunocompromised patient populations. Patients receiving 1.5-g C/T dosing plus metro-nidazole in the ASPECT-cIAI trial had a clinical cure rate of 76.9% in patients receiving C/T, and patients treated with the 3-g C/T dose in the phase 3 ASPECT-NP clinical trial had a 28-day all-cause mortality rate of 24.0% and clinical cure rate of 54% [3, 19]. In addition to the phase 3 trials evaluating C/T, 1 of the largest studies evaluating use of C/T speci"cally for MDR P. aeruginosa reported clinical success in 73.7% of patients and 30-day mortality in 19% of patients [20]. #is study included 205 patients, with a median age (IQR) of 60 (48–70) years and the most frequent infection source being pneumonia (59%). #e median CCI (IQR) was 4 (3–6), and the median APACHE II score (IQR) was 19 (11–24), which was similar to the comor-bidity and severity of illness of patients in the present study. Of the 205 patients, 35 (17.1%) had a history of organ transplanta-tion and 33 (16.1%) had a history of cancer, although outcomes were not reported speci"c to disease states. A recent observa-tional cohort study of C/T use for MDR or XDR P. aeruginosa in comparison with aminoglycoside or polymyxin included 100 patients treated with C/T. Clinical cure was observed in 81% of C/T-treated patients; of these, only 14 patients were noted

to be immunosuppressed [13]. A third observational study of C/T use for treatment of MDR and XDR P. aeruginosa evaluated 58 patients, noting a 63.8% clinical cure rate and 27.6% 30-day mortality; however, only 7 (12%) of the included patients were reported to be immunosuppressed [13, 21]. In comparison to these larger studies, immunocompromised individuals in the present study had very similar clinical success (68%) and all-cause 30-day mortality (19%) rates.

When evaluating clinical outcomes by infection source in this cohort, clinical cure was achieved most o$en in patients with UTI, bloodstream infections, and intra-abdominal in-fections. #irty-day all-cause mortality rates ranged from 0% to 25% overall and were lowest in patients with bone/joint in-fections and CNS infections; however, these groups were very small, making the data di%cult to extrapolate. A primary source of pneumonia encompassed slightly over half (n = 39; 56%) of the patient cohort. Clinical cure was achieved in only 62% of these patients; however, upon analysis of clinical cure strati"ed by FDA-approved 3-g pneumonia dosing of C/T, clinical cure was numerically higher in those who received the appropriate pneumonia dose (75% vs 30%), and 30-day mortality was nu-merically lower (18% vs 30%) in the pneumonia patients re-ceiving pneumonia dosing. #is higher 3-g dose/indication was approved in 2019 while data from this retrospective cohort date back to 2015, so it is reasonable that the higher 3-g pneu-monia dosing was not universally used o&-indication. While this cohort is small, these results demonstrate the importance of utilizing the FDA-approved dosing of 3 g for patients with pneumonia.

Other smaller studies examining the outcomes of C/T use ex-clusively among immunocompromised patients have consisted

Bone/joint (n = 4)PNA (n = 39)

62%

21%

50%

25%

83%

100%

Clinical cure All-cause 30-day mortality

17% 17%

100%

17%

75%

67%

0%

Wound (n = 8) IAI (n = 6) BSI (n = 6) UTI (n = 6) CNS (n = 3)

0%

Figure 1. Clinical outcomes by source of infection. Abbreviations: BSI, primary bloodstream infection; CNS, central nervous system; IAI, intra-abdominal infection; PNA, pneumonia; UTI, urinary tract infection.

Dow



C/T Outcomes in Immunocompromised Patients • OFID • 3

most frequent infection sources were respiratory (57%) and wound (12%). Four patients had multiple infection sources: 1 had a CNS, bone/joint, and wound infection; 1 had pneu-monia and wound infection; 2 had concurrent CNS and bone/joint infections.

Treatment Characteristics

Overall, 36% of patients had a polymicrobial culture, with 45% of patients receiving combination antimicrobial therapy. The most commonly used concurrent antibiotics were aminoglycosides in 15 patients (48% of concurrent antibiotics), followed by

fluoroquinolones in 9 patients (29%), polymyxins in 7 patients (23%), and beta-lactams in 2 patients (6%). Of the 39 patients with pneumonia, 28 (71.8%) received 3-g pneumonia dosing, 10 (25.6%) received 1.5-gram (nonpneumonia) dosing, and 1 patient had incomplete dosing data.

Outcomes

All-cause 30-day mortality among all patients was 19% (13/69), with clinical cure achieved in 68% (47/69) of patients (Table 2). Clinical cure and all-cause 30-day mortality rates varied by in-fection source, with the highest rates of clinical cure in patients with UTI (100%; 6/6) and bloodstream infections (100%; 6/6) and the lowest all-cause 30-day mortality rates in patients with central nervous system and bone/joint infections (both 0%) (Figure 1). In patients with pneumonia, clinical cure was 75% (21/28) in the 3-g pneumonia dosing group vs 30% (3/10) in the nonpneumonia dosing group, and 30-day mortality was 18% (5/28) in those who received the pneumonia-dose C/T vs 30% (3/10) in those who did not. The mean length of C/T therapy was 13 ± 10.8 days, and the median (IQR) length of hospital stay was 38 (55) days. CART analysis identified the 30-day mortality split at APACHE II score >25 (76% vs 24%; P = 0.002).

DISCUSSION

This 14-center study aimed to evaluate real-world treatment pat-terns and clinical outcomes of immunocompromised patients treated with C/T for multidrug-resistant P. aeruginosa infec-tions. As a majority of current clinical data exclude immuno-compromised patients or these patients make up a small subset of the studied patient population, it is pertinent to describe out-comes in this high-risk group. Patients in our cohort were char-acterized as immunocompromised for a variety of conditions. A majority of patients were taking immunosuppressive agents (84%), a subset had a history of SOT (68%), and a smaller subset of patients had diseases conferring susceptibility to in-fection such as active malignancies (29%). In addition to an im-munocompromised status of all included patients, many were considered critically ill, demonstrated by a median APACHE II score of 18, with 46% of patients receiving ICU-level care

Table 1. Baseline Characteristics of the Patients

Characteristic Total (n = 69)

Age, mean ± SD, y 57 ± 14In ICU on day 1, No. (%) 32 (46)APACHE II score, median (IQR) 18 (13)Charlson comorbidity index, median (IQR) 5 (4)Immunocompromised type,a No. (%) Receiving immunosuppressive agents 58 (84) Solid organ transplant recipient 47 (68) Immunocompromising disease stateb 20 (29) Leukemia 6 (9) Lymphoma 3 (4) Diffuse metastatic cancer 9 (13)Comorbidities, No. (%) Chronic pulmonary disease 32 (46) Chronic kidney disease 28 (41) Diabetes 17 (25) Myocardial infarction 10 (14) Heart failure 10 (14) Peptic ulcer disease 9 (13) Liver dysfunction 9 (13) Peripheral vascular disease 8 (12) Cerebrovascular disease 5 (7) Metastatic solid tumor 5 (7) Cystic fibrosis 4 (6) Hemiplegia/paraplegia 2 (3)Infection source,c No. (%) Pneumonia 39 (57) Wound 8 (12) Intra-abdominal 6 (10) Primary bloodstream infection 6 (10) Urinary tract 6 (10) Bone/joint 4 (6) Central nervous system 3 (4)Concurrent antibiotics, No. (%) 31 (45) Aminoglycoside 15 (48) Fluoroquinolone 9 (29) Polymyxin 7 (23) Beta-lactam 2 (6)

Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; ICU, intensive care unit; IQR, interquartile range.aPatients could have multiple reasons for immunocompromised classification.bTwo patients with unspecified disease characterized as sufficiently advanced to suppress resistance to infection, for example, leukemia, lymphoma, diffuse metastatic cancer.cPatients could have multiple sources of infection.

Table 2. Clinical Outcomes

Outcome

Clinical cure, all infection sources (n = 69), No. (%) 47 (68) Pneumonia, receiving pneumonia dosing (n = 28) 21 (75) Pneumonia, receiving nonpneumonia dosing (n = 10) 3 (30)30-d all-cause mortality, all infection sources (n = 69), No. (%) 13 (19) Pneumonia, receiving pneumonia dosing (n = 28) 5 (18) Pneumonia, receiving nonpneumonia dosing (n = 10) 3 (30)Length of C/T therapy, mean ± SD, d 13 ± 11Length of hospital stay, median (IQR), d 38 (54)

Abbreviations: C/T, ceftolozane/tazobactam; IQR, interquartile range.

Dow



• Etude rétrospective multicentrique (n=14)• Patients immunodéprimés traités ≥24 avec C/T• P. aeruginosa MDR • 66 patients • USI : 46% • Infection respiratoire : 56% • Mortalité J30 : 19%

OFID 2021

Ceftazidime avibactam

• Etude prospective observationelle• Multicentrique : 3 hôpitaux (Italie et Grêce)• 82 infections à NDM• 20 infections à VIM• Mortalité J30 : 19,2% avec CAZ-AVI + ATM vs 44%

autre traitement actif

CID 2021

Méropénem-vaborbactam

• Etude rétrospective observationnelle multicentrique (n=13 centres) aux USA (octobre 2017-juin 2020).

• Exclusion infection concomitante • Critère principal : mortalité J30; • 126 patients (20,5% ID)• Infection respiratoire (38,1%), IIA (19,0%)• CRE 78,6%

OFID 2020

Tebipénem

• Essai randomisé (1:1) double aveugle ADAPT-PO • TBP (600mgX3/j) vs Erta (1g/j) pour IU compliquées et PNA

(durée 7à 10j)

Tebipénème

IDSA 2020

Anticorps anti-staphylocoque

B. François et al. Lancet ID 2021

• Cefiderocol (In) CREDIBLE• Ceftolozane tazobactam >> Pseudomonas aeruginosa• Ceftazidime avibactam >> MBL• Mero vaborbactam : KPC mais pas que ….• Tebipenem : « attention aux urologues »• Anticorps : pas encore

Conclusion

• Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens

• https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00194-8/fulltext

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00194-8/fulltext

• Cross-resistance to cefiderocol and ceftazidime–avibactam in KPC β-lactamase mutants and the inoculum effect

• Claire Amaris HobsonAurélie CointeHervé JacquierAlakshChoudhuryMélanie MagnanCéline CourrouxOlivierTenaillonStéphane BonacorsiAndré Birgy

• https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00199-3/fulltext

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00199-3/fulltext










Research note

Cross-resistance to cefiderocol and ceftazidimeeavibactam in KPCb-lactamase mutants and the inoculum effect

Claire Amaris Hobson 1, Aur!elie Cointe 1, 2, Herv!e Jacquier 1, 3, Alaksh Choudhury 1,M!elanie Magnan 1, C!eline Courroux 2, Olivier Tenaillon 1, St!ephane Bonacorsi 1, 2,Andr!e Birgy 1, 2, *

1) IAME, UMR 1137, INSERM, Universit!e de Paris, AP-HP, France2) Laboratoire de Microbiologie, Hopital Robert Debr!e, AP-HP, 75019 Paris, France3) Laboratoire de Microbiologie, D!epartement des Agents Infectieux, Hopital Saint Louis-Lariboisi"ere-Fernand Widal, AP-HP, Paris, France

a r t i c l e i n f o

Article history:Received 28 January 2021Received in revised form18 March 2021Accepted 13 April 2021Available online 26 April 2021

Editor: P.T. Tassios

Keywords:Cefiderocol resistanceCeftazidimeeavibactam resistanceCross-resistanceInoculum effectKPC b-lactamasesKPC-2KPC-3KPC-31

a b s t r a c t

Objectives: Ceftazidimeeavibactam (CZA) and cefiderocol are recently commercialized molecules activeagainst highly drug-resistant bacteria, including carbapenem-resistant members of the Enterobacteri-aceae. Mutants resistant to CZA have been described, notably in Klebsiella pneumoniae carbapenemase(KPC) producers. Considering the structural similarities between ceftazidime and cefiderocol, we hy-pothesized that resistance to CZA in KPC-producing members of the Enterobacterales may lead to cross-resistance to cefiderocol.Methods: CZA-resistant mutants from three clinical isolates of the Enterobacterales carrying eitherblaKPC-2 or blaKPC-3 were selected in vitro. Mutants with increased MIC to CZA compared to the ancestralallele were cloned in a pBR322 plasmid and expressed in Escherichia coli TOP10. We evaluated the impactof these mutations on cefiderocol MICs and minimal bactericidal concentrations (MBCs), and we assessedthe impact of bacterial inoculum size on cefiderocol MICs.Results: We used 37 KPC mutants with increased CZA MICs. Of these, six have been described previouslyin clinical isolates. Compared to the wild-type alleles, increases in the cefiderocol MICs of 4- to 32-foldwere observed for 75.6% of tested mutants (28/37), MICs reaching up to 4 mg/L in E. coli TOP10 for KPC-31 (D179YeH274Y mutations). MBCs and MICs of cefiderocol were similar, confirming the bactericidalactivity of this drug. Finally, when using higher inocula (107 CFU/mL), a large increase in cefiderocol MICwas observed, and all isolates were categorized as resistant.Conclusion: We observed that most of the CZA-resistant KPC variants have a possible impact on cefi-derocol by increasing the cefiderocol MICs. In addition, cefiderocol is greatly impacted by the inoculumeffect, suggesting that precautions should be taken when treating infections with a suspected highinoculum. Claire Amaris Hobson, Clin Microbiol Infect 2021;27:1172.e7e1172.e10© 2021 The Authors. Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and

Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Antimicrobial resistance in Gram-negative bacteria is a majorpublic health concern, with predictions of catastrophic de-velopments in the coming years [1]. Ceftazidimeeavibactam (CZA)and cefiderocol are two of the most recently commercialized b-lac-tammolecules. Theyare active against highly drug-resistant bacteria,

including carbapenem-resistantmembers of theEnterobacteriaceae.Avibactam inhibits Ambler class A, class C and some class D b-lacta-mases. Cefiderocol is a siderophore cephalosporin sharing sidechains similar to those of both cefepime and ceftazidime. It also has achlorocatechol group which confers a siderophore-like structureacting as a decoy for the bacteria. The cefiderocol structure allowsrapid penetration into bacteria and resistance to hydrolysis by mostb-lactamases regardless of their class [2].

Soon after the commercialization of CZA in 2015, resistant mu-tants were described both in vitro and in vivo, notably Klebsiellapneumoniae carbapenemase (KPC) producers [3,4]. KPC b-lactamasehas spread worldwide, challenging the therapeutic management of

* Corresponding author. Andr!e Birgy, Hopital Robert-Debr!e (APHP), 48 BoulevardS!erurier 75019 Paris, France.

E-mail address: [email protected] (A. Birgy).

Contents lists available at ScienceDirect

Clinical Microbiology and Infection

journal homepage: www.cl in icalmicrobiologyandinfect ion.com

https://doi.org/10.1016/j.cmi.2021.04.0161198-743X/© 2021 The Authors. Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article underthe CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Clinical Microbiology and Infection 27 (2021) 1172.e7e1172.e10

Table1

Klebsiella

pneu

mon

iaecarbap

enem

ase-prod

ucing(K

PC)b-lactam

asemutan

tsan

dim

pact

onMIC

tocefide

roco

land

ceftazidim

eeav

ibactam

KPC

gene

sclon

edin

pBR3

22an

dex

pressedin

E.coliTO

P10

Clinical

alleles

Mutations

Anc

estral

allele

aCe

fide

roco

lCe

ftazidim

eeav

ibactam

Ertape

nem

Imipen

emMerop

enem

MIC

(mg/L)

Times

increa

seof

MIC

compa

redto

ancestrala

llele

MIC

(mg/L)

athigh

inoc

ulum

(107

CFU/m

L)

MIC

(mg/L)

Times

increa

seof

MIC

compa

red

toan

cestrala

llele

MIC

(mg/L)

MIC

(mg/L)

MIC

(mg/L)

KPC

-2an

cestrala

llele

ee

0.25

e32

0.5

e1.5

24

KPC

-3(H

274Y

)an

cestral

allele

ee

0.12

e16

1e

12

4

E.coliATC

C259

22e

e0.25

e8

0.12

5e

0.00

8<0.5

<1

E.coliTO

P10

ee

0.06

e4

0.19

e0.01

2<0.5

<1

Insertions

D2

eins1

65_E

LKPC

-30.5

4>32

1616

0.01

6<0.5

<1

E2KPC

e25

ins1

65_E

LKPC

-20.25

1>32

48

0.02

3<0.5

<1

D6

eins1

68_LK

KPC

-21

4>32

3264

0.02

3<0.5

<1

D8

eins1

68_LKþ

A18

5TKPC

-30.06

e>32

22

0.25

1<1

mut-6

eins1

75_S

AIPG

KPC

-30.5

4>32

2424

0.12

5<0.5

<1

2¼

C11

KPC

e44

ins2

61_A

VYT

RAPN

KDDKHSE

KPC

-20.5

2>32

6412

80.19

1<1

mut-1

¼D1

KPC

e29

ins2

69_K

DD

KPC

-30.5

4>32

3232

0.09

42

<1

C8e

ins2

74_S

EAVIþ

G14

7RKPC

-30.5

4>32

3232

0.03

2<0.5

<1

Deletions

C1e

del165

-175

_WEL

ELNSA

IPG

KPC

-30.25

232

2424

0.00

8<0.5

<1

C2e

del166

-171

_ELE

LNSþ

A17

2DKPC

-30.5

432

3232

0.01

2<0.5

<1

C6e

del168

-171

_ELN

SKPC

-30.5

4>32

>25

6>25

60.01

2<0.5

<1

C7e

del168

-169

_EL

KPC

-20.5

2>32

1.5

30.01

2<0.5

<1

E1e

del167

-170

_LEL

Nþ

S171

PKPC

-21

4>32

2448

0.02

3<0.5

<1

C4e

del176

-178

_DA

KPC

-30.12

132

88

0.00

6<0.5

<1

mut-7

ede

l_17

6-17

9_DAR

KPC

-30.5

4>32

3232

0.09

41

<1

mut-11

ede

l239

-240

_GV

KPC

-31

8>32

3232

0.01

2<0.5

<1

5e

del240

-241

_VYþ

G23

9DKPC

-21

4>32

4896

0.02

3<0.5

<1

Non

-syn

onym

ousmutation

sE7

P67L

KPC

-20.25

132

1224

0.02

3<0,5

<1

E8R1

64G

KPC

-30.5

2>32

1616

0.19

1<1

A4

R164

PKPC

-30.5

432

3232

0.00

8<0,5

<1

E11

S171

PKPC

-30.5

4>32

2424

0.04

7<0,5

<1

A1

A17

2DKPC

-31

8>32

2424

0.00

8<0,5

<1

A3

A17

2PKPC

-30.5

4>32

1616

0.02

31

<1

A5

KPC

-39

A17

2TKPC

-31

8>32

1616

0.09

41

<1

A6

A17

2TKPC

-21

4>32

1632

0.12

52

<1

A8

A17

2VKPC

-30.5

4>32

1212

0.09

42

<1

E10

D17

6NKPC

-30.5

4>32

1212

0.09

41

<1

A10

D17

6Nþ

Q29

5Sþ

ins2

95_

NCQ

TKFT

HIYFR

LIKPC

-30.5

44

1212

0.12

5<0,5

<1

A11

D17

6YKPC

-30.5

4>32

1616

0.02

3<0,5

<1

A9

D17

6GKPC

-31

8>32

1616

0.04

7<0,5

<1

B1D17

9AKPC

-31

8>32

2424

0.00

8<0,5

<1

B10

KPC

-33

D17

9YKPC

-22

8>32

2448

0.03

2<0,5

<1

10KPC

-31

D17

9YKPC

-34

32>32

4848

0.02

3<0,5

<1

B2D17

9EKPC

-30.5

432

1616

0.01

2<0,5

<1

B5D17

9GKPC

-31

8>32

1616

0.03

2<0,5

<1

D3

T243

PKPC

-30.25

232

1616

0.03

21

<1

D4

V11

9Mþ

T243

Pþ

V25

0AKPC

-21

416

816

0.00

8<0,5

<1

aKPC

mutan

tsde

rive

dfrom

KPC

-3ha

vetheH27

4Ymutation.

C.A. Hobson et al. / Clinical Microbiology and Infection 27 (2021) 1172.e7e1172.e101172.e9

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