M. AntonelliDept of Anesthesiology and Intensive Care

Universita’ Cattolica del Sacro CuoreFondazione Policlinico Universitario A. Gemelli

Ceftazidime–Αvibactam combination:  clinical trial data and…a bit more

DisclosuresDisclosures

•

Research grants : Toray, Pfizer, Maquet, Orion, GE,  Fisher and Paykel

•

Advisor/consultant:  Orion, MSD, Bayer, Basileah

Speaker/chairman:  Fisher and Paykel, Orion, Maquet, 

Pfizer

The opinions expressed in this presentation belong to the presenter and do not necessarily reflect the views of the company. 

For all medicinal products mentioned, please refer to the approved Summaries of Product Characteristics

Ceftazidime–avibactam Phase III clinical trial programme

Seven prospective, international, multicentre, randomised Phase III studies

•

Double-blind randomisation (1:1)

–

CAZ 2000 mg + AVI 500

mg + metronidazole 500 mg IV q8h or

–

MER 1000 mg IV + placebo q8h

•

Primary objective –

RECLAIM 1 and 2:–

Assess non-inferiority of CAZ–AVI re: clinical cure at TOC visit in patients with ≥1 identified pathogen (mMITT populations)

–

RECLAIM 3:–

Proportion of patients with clinical cure at TOC visit (CE populations)

•

Open-label randomisation (1:1)

–

CAZ 2000 mg + AVI 500 mg + metronidazole 500 mg q8h IV or

–

Best available therapy•

Primary objective–

Estimate per-patient clinical response to CAZ–AVI and best available therapy at TOC visit in cUTI and cIAI caused by CAZ-resistant Gram-negative pathogens

•

Double-blind randomisation (1:1)

–

CAZ 2000 mg + AVI 500 mg q8h IV or

–

DOR 500 mg + placebo q8h IV

•

Primary objective –

Assess non-inferiority of CAZ–AVI on co-primary endpoints in mMITT analysis set:

–

Resolution of UTI-

specific symptoms

–

Resolution/improvement of flank pain

–

Per-patient microbiological eradication and symptomatic resolution

•

Double-blind randomisation (1:1)

–

CAZ 2000 mg + AVI 500 mg q8h IV or

–

MER 1000 mg + placebo q8h IV

–

Plus open-label empiric linezolid + aminoglycoside

•

Primary objective–

Assess non-inferiority of CAZ–AVI on clinical cure rate at TOC visit in cMITT and CE populations

RECLAIM 1, 2 and 3: Adults with cIAI

REPRISE Adults with CAZ-resistant

pathogens

REPROVE Adults with nosocomial

pneumonia (including VAP)

RECAPTURE 1 and 2: Adults with cUTI (including acute

pyelonephritis)

AVI, avibactam; CAZ, ceftazidime; CE, clinically evaluable; cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; DOR, doripenem; IV, intravenous; MER, meropenem; mMITT, microbiological modified intent-to-treat; TOC, test of cure; VAP, ventilator-associated pneumonia.

RECAPTURE 1 & 2 Phase III studies in cUTI

Study design

•

Two identically designed, double-blind, double-dummy, randomized, multicenter, parallel-group, non inferiority trials comparing the efficacy and safety of ceftazidime–avibactam with doripenem

•

All data collected from the two trials were combined and analysed as a single pooled dataset EOT

(within 24 h last IV

infusion & before oral)

Doripenem 500mg, 30 min IV infusion, q8h

+ optional oral switch

CAZ–AVI(2000–500 mg, q8h)

+ optional oral switchHospitalized patients aged ≥18

years with cUTI or acute pyelonephritis (min 5 days IV, 10–14*

days IV + oral therapy)

1:1 randomization

Late Follow Up45–52 days

after randomization

21–25 days

after

randomization

Test Of Cure

*Therapy could be extended up to 14 days for bacteremic patients.

cUTI,

complicated urinary tract infection; CAZ–AVI, ceftazidime–avibactam; q8h, every 8 h; EOT, end of treatment; IV, intravenous; TOC, test of cure; LFU, late follow-up. Wagenlehner F, et al. Clin Infect Dis 2016;63:754-62.

RECAPTURE 1 & 2 Study endpoints

Primary endpoints–

FDA co-primary endpoints •

The proportion of patients with symptomatic resolution†

(or return to premorbid state) at Day 5 visit (based on PSAQ)

•

The proportion of patients with both a favorable microbiological response and symptomatic

resolution (or return to premorbid state) at TOC

in the mMITT population –

EMA primary endpoint•

The proportion of patients with a favourable per-patient microbiological response (i.e. eradication) at TOC in the mMITT population

•

The sponsor pre-specified non-inferiority margin was –12.5%. The FDA required a non-

inferiority margin of –10%

Key secondary endpoints–

Per-patient microbiological response at EOT (IV) and LFU–

Per-patient and per-pathogen microbiological

response at TOC

and LFU in patients with ≥1 ceftazidime-non-susceptible or only ceftazidime-susceptible pathogens isolated at baseline

–

Investigator-determined clinical cure

at EOT (IV), TOC and LFU –

Sustained clinical cure at LFU–

Safety

assessed by monitoring AEs†

Symptomatic resolution of UTI-specific symptoms, except flank pain, with resolution or improvement in flank pain from baseline at Day 5 visit.

AEs, adverse events; EMA, European Medicines Agency; EOT, end of

treatment; FDA, Food and Drug Administration; IV, intravenous; LFU, late follow-up; mMITT, microbiologically modified intent-to-treat; PSAQ, patient-reported symptom assessment questionnaire; TOC, test of cure.Wagenlehner F, et al. Clin Infect Dis 2016;63:754-62.

RECAPTURE 1 & 2 Study design and participants

•

Diagnosis based on +ve urine cultures within 48 h of enrollment showing 1–2 Gram-positive uropathogens and pyuria

•

cUTI without pyelonephritis was defined as presence of >2 symptoms with one UTI-specific symptom as well as one complicating factor

•

Patients were enroled before cultures were obtained if–

Positive results were expected

–

Appropriate antibiotic was considered–

Urine Gram stain showed Gram-negative bacilli

•

Indwelling catheters for >24 h were removed or replaced before baseline urine collection

cUTI,

complicated urinary tract infection; UTI,

urinary tract infection.Wagenlehner F, et al. Clin Infect Dis 2016;63:754–62.

RECAPTURE 1 & 2 Study flow

Patients randomized

n=1033

CAZ–AVI n=516

Doripenem n=517

Safety population n=511 (did not receive

treatment n=5)

mMITT population n=393

Safety population n=509(did not receive

treatment n=8)

mMITT population n=417

Completed TOC visit n=490Completed study n=473

Discontinued n=43 (subject decision n=12, eligibility criteria not fulfilled n=1, lost to follow-up

n=20, other reason=10)

Completed TOC visit n=492 Completed study n=476

Discontinued n=41 (subject decision n=12, eligibility criteria not fulfilled n=6 lost to follow-up

n=20, other reason 3)

CAZ–AVI, ceftazidime–avibactam; mMITT, microbiological modified intent to treat; TOC,

test of cure.Wagenlehner F, et al. Clin Infect Dis 2016;63:754–62.

RECAPTURE 1 & 2 Baseline characteristics (mMITT)

ParameterCAZ–AVI

(n=393)

Doripenem

(n=417)

Age, years, mean (SD) 54.1 (20.2) 53.3 (18.6)Gender, male, n (%) 121 (30.8) 124 (29.7)Body mass index kg/m2, mean (SD) 26.2 (5.9) 26.3 (5.6)Renal status, n (%)

•

Normal renal function/mild impairment (CrCL >50

mL/min) 350 (89.1) 379 (90.9)•

Moderate impairment (CrCL >31 to ≤50

mL/min) 42 (10.7) 35 (8.4)•

Severe impairment (CrCL <31

mL/min) 1 (0.3) 3 (0.7)White blood cell count, 109/mL, median (range) 8.5 (3.3, 27.8) 7.9 (3.1, 35.4)Bacteremia, n (%) 38 (9.7) 33 (7.9)Diagnosis, n (%)•

cUTI without pyelonephritis 106 (27.0) 121 (29.0)•

Pyelonephritis 287 (73.0) 296 (71.0)–

With ≥1 complicating factor 41 (10.4) 39 (9.4)–

Meeting symptom criteria for cUTI 33 (8.4) 31 (7.4)Baseline pathogen in urine, n(%)1

•

Enterobacteriaceae 376 (95.7) 396 (95.0)–

Escherichia coli 292 (74.3) 306 (73.4)–

Klebsiella pneumoniae 44 (11.2) 56 (13.4)–

Proteus mirabilis 17 (4.3) 13 (3.1)•

Other Gram-negative bacteria 18 (4.6) 21 (5.0)–

Pseudomonas aeruginosa 18 (4.6) 20 (4.8)Prior systemic antibiotic use, n (%) 28 (7.1) 27 (6.5)

19.6% of all baseline pathogens were ceftazidime-non-susceptible 1. Includes pathogens reported with a combined frequency of ≥10 patients. Patients could have >1 pathogen. Multiple isolates of the same species from the same patient are counted only once.

CAZ–AVI, ceftazidime–avibactam; CrCL,

creatinine clearance; cUTI, complicated urinary tract infection;

mMITT,

microbiological modified intent-to-treat; SD, standard deviation.Wagenlehner F, et al. Clin Infect Dis 2016;63:754–62.

RECAPTURE 1 & 2 Primary efficacy results (mMITT)

Patients, N (%)

CAZ–AVI

(n=393)

Doripenem

(n=417)

Difference, %

(95% CI)

FDA co-primary endpoints

•

Patient-assessed symptomatic resolution at Day 5 276 (70.2) 276 (66.2) 4.0 (–2.39, 10.42)

•

Combined patient-assessed symptomatic resolution and favourable per-patient microbiological response at TOC

280 (71.2) 269 (64.5) 6.7 (0.30, 13.12)

–

Per-patient favourable microbiological response at TOC 304 (77.4) 296 (71.0) 6.4 (0.33, 12.36)

–

Patient-reported symptomatic resolution at TOC 332 (84.5) 360 (86.3) –1.9 (–6.78, 3.02)

EMA primary endpoint

•

Per-patient favourable microbiological response at TOC 304 (77.4) 296 (71.0) 6.4 (0.33, 12.36)

The sponsor concluded non-inferiority if the lower limit if the 95% at TOC was greater than –12.5%. The FDA inferiority margin was a lower limit of the 95% CI greater than –10.0%. The mMITT population was all randomised patients with a minimum disease criteria and eligible baseline pathogen(s).

CAZ–AVI, ceftazidime–avibactam; CI, confidence interval; EMA, European Medicines Agency; EOT, end of treatment; FDA, Food and Drug Administration; mMITT, microbiological modified intent-to-treat; TOC, test of cure.Wagenlehner F, et al. Clin Infect Dis 2016;63:754–62.

RECAPTURE 1 & 2 Secondary efficacy results (mMITT) 

Patients, N (%)CAZ–AVI

(n=393)

Doripenem

(n=417)

Difference, %

(95% CI)

Microbiological

•

Per-patient favourable microbiological response at EOT (IV)

374 (95.2) 395 (94.7) 0.4 (–2.7, 3.56)

•

Per-patient favourable microbiological response at LFU 268 (68.2) 254 (60.9) 7.3 (0.68, 13.81)

•

Per-patient favourable microbiological response at TOC in patients with a ceftazidime-non-susceptible pathogen*

47/75 (62.7) 51/84**

(60.7) 2.0 (–13.18, 16.89)

•

Per-patient favourable microbiological response at LFU in patients with a ceftazidime-non-susceptible pathogen*

46/75 (61.3) 38/84 (45.2) 16.1 (0.50, 30.89)

•

Per-patient favourable microbiological response at TOC in patients with a ceftazidime-susceptible pathogen*

256/316 (81.0) 238/326 (73.0)

8.0 (1.50, 14.48)

•

Per-patient favourable microbiological response at LFU in patients with a ceftazidime-susceptible pathogen*

221/316 (69.9) 209/326 (64.1)

5.8 (–1.46, 13.05)

*Ceftazidime resistance non-susceptibility was defined as a central microbiology reference laboratory MIC ≥8 μg/mL for Enterobacteriaceae or ≥16 μg/mL for P. aeruginosa, or local laboratory disk diffusion diameter (from a 30 μg ceftazidime disk) of ≤20 mm for Enterobacteriaceae and ≤17 mm for P. aeruginosa. Nine patients were not included in either subset (ceftazidime-non-susceptible or ceftazidime-susceptible) because no susceptibility tests were performed (6 patients) or baseline blood or urine susceptibility results were missing (3 bacteraemic patients).**One patient in the doripenem group had 2 ceftazidime-nonsusceptible pathogens isolated at baseline.CAZ–AVI, ceftazidime–avibactam; CI, confidence interval; EOT, end of treatment; IV, intravenous; LFU, late follow-up; mMITT, microbiological modified intent-to-treat; TOC, test of cure.Wagenlehner F, et al. Clin Infect Dis 2016;63:754–62.

Microbiological response rates were higher in CAZ–AVI at all study visits

Favourable response rate, n/N (%)

Secondary endpointCAZ–AVI

(n=393)

Doripenem

(n=417)

Difference, %

(95% CI)

All baseline pathogens

Overall 311/400 (77.8) 297/419 (70.9) 6.9 (0.88, 12.81)

•

Enterobacteriaceae 299/382 (78.3) 281/398 (70.6) 7.7 (1.054, 13.75)

•

P. aeruginosa 12/18 (66.7) 15/20 (75.0) –8.3 (–36.77, 20.66)

Ceftazidime-non-susceptible pathogens

Overall 48/75 (64.0) 51/85 (60.0)* 4.0 (–11.11, 18.81)

•

Enterobacteriaceae 43/68 (63.2) 46/79 (58.2) 5.0 (–10.87, 20.50)

•

P. aeruginosa 5/7 (71.4) 5/6 (83.3) –11.9 (–54.78, 37.60)

Ceftazidime-susceptible pathogens

Overall 254/311 (81.7) 228/312 (73.1) 8.6 (2.03, 15.14)

•

Enterobacteriaceae 247/301 (82.1) 217/297 (73.1) 9.0 (2.32, 16.66)

•

P. aeruginosa 7/10 (70.0) 10/14 (71.4) –1.4 (–38.84, 33.69)

RECAPTURE 1 & 2  Per‐pathogen favourable microbiological response rates at TOC (mMITT)

The sponsor concluded non-inferiority if the lower limit if the 95% at TOC was greater than –12.5%. The FDA inferiority margin was a lower limit of the 95% CI greater than –10.0%.

*One patient in the doripenem group had 2 ceftazidime-nonsusceptible pathogens isolated at baseline

CAZ–AVI, ceftazidime–avibactam; CI, confidence interval; mMITT, microbiological modified intent-to-treat; TOC, test of cure.Wagenlehner F, et al. Clin Infect Dis 2016;63:754–62.

RECAPTURE 1 & 2 Summary of AEs up to LFU (safety

population)

n (%)CAZ–AVI

(n=511)Doripenem

(n=509)Any AE 185 (36.2) 158 (31.0)Any AE leading to death 0 (0.0) 0 (0.0)Any serious AE 21 (4.1) 12 (2.4)Any AE leading to discontinuation 7 (1.4) 6 (1.2)Any AE of severe intensity 10 (2.0) 7 (1.4)

•

Headache was the most frequently reported AE with both ceftazidime–avibactam (7.4%) and doripenem (7.9%)

•

No new safety concerns were identified

AE, adverse event; CAZ–AVI, ceftazidime–avibactam; LFU, late follow-up.Wagenlehner F, et al. Clin Infect Dis 2016;63:754–62.

RECAPTURE 1 & 2 Summary and conclusions

•

Non-inferiority of ceftazidime–avibactam versus doripenem for the treatment of hospitalized patients with cUTI, including acute pyelonephritis

•

Investigator-determined clinical cure rates were 90% across groups, and similar for patients with ceftazidime-non-susceptible and ceftazidime-susceptible pathogens

•

Per-pathogen eradication rates at TOC numerically favored ceftazidime–avibactam over doripenem for all Enterobacteriaceae including the most common ones such as E. coli, Klebsiella and Proteus

•

Ceftazidime–avibactam was generally well-tolerated, and demonstrated a safety profile consistent with that of ceftazidime alone

cUTI, complicated urinary tract infection; TOC, test of cure.Wagenlehner F, et al. Clin Infect Dis 2016;63:754–62.

RECLAIM studies Phase III studies in cIAI

•

RECLAIM 1* (NCT01499290) –

performed in various countries in Asia, Europe, South America, India, Israel, South Africa and USA1

•

RECLAIM 2* (NCT01500239) –

performed in various countries in Europe, South America, Canada, India, Israel, Thailand and USA1

•

RECLAIM 3 (NCT01726023) –

performed in China, Republic of Korea and

Vietnam2

Study designs and objectives of the three RECLAIM studies were similar

*Because of similar timelines, designs and country enrolment, data from RECLAIM 1 and 2 were combined to form a single publication.

cIAI, complicated intra-abdominal infection.

1. Mazuski JE, et al. Clin Infect Dis. 2016;62:1380–9. 2. Qin X, et al. Int J Antimicrob Agents. 2017;49:579-588.

RECLAIM 1 & 2 Study design

•

Two identically designed, prospective, randomised, multicentre, double-blind studies comparing the efficacy and safety of ceftazidime–avibactam + metronidazole with meropenem

•

It was pre-specified, with agreement from the FDA and the EMA, for data from the two studies to be combined and analysed as a single pooled dataset

EOT

within 24 h last IV infusion

Meropenem

1000 mg, 30 min IV infusion, q8h

Ceftazidime–avibactam(2000–500 mg, 2 h IV infusion)

+ metronidazole

(500 mg, 60 min IV infusion)

q8hHospitalised patients aged ≥18

years with cIAI requiring hospitalisation (5–14 days of therapy)

1:1 randomisation

42–49 days

after randomisation

28–35 days

after

randomisation

12.5% NI margin(powered for 10.0% NI margin as

required by FDA)

cIAI, complicated intra-abdominal infection; EMA, European Medicines Agency; EOT, end-of-treatment; FDA, Food and Drug Administration; IV, intravenous; LFU, late follow-up; NI, non-inferiority; TOC, test-of-cure.

Mazuski JE, et al. Clin Infect Dis. 2016;62:1380–9.

Late Follow UpTest Of Cure

RECLAIM 1 & 2 Study objectives

•

Primary objective–

To assess non-inferiority of ceftazidime–avibactam + metronidazole compared with meropenem

on clinical cure* rate at TOC visit (28–35 days after randomisation) in the mMITT primary analysis population, as required by the FDA, and in the MITT and Clinically evaluabe co-primary analysis populations, as required by the EMA

•

The sponsor pre-specified non-inferiority margin was –12.5%. The FDA required a non-

inferiority margin of –10% for the mMITT population

•

Key secondary objectives–

Clinical response at EOT (up to 24 h after last infusion) and LFU

(42–49 days after randomisation) visits; microbiological responses at each

time point; and efficacy of ceftazidime–avibactam + metronidazole or meropenem against ceftazidime-resistant pathogens

–

Safety and tolerability assessed by monitoring AEs and laboratory

parameters

*Complete resolution or significant improvement of signs and symptoms (no further antimicrobial therapy, drainage or surgical intervention necessary)AE, adverse event; CE, clinically evaluable; EMA, European Medicines Agency; EOT, end-of-treatment; FDA, Food and Drug Administration; LFU, late follow-up; MITT, modified intent-to-treat; mMITT, microbiologically modified intent-to-treat; TOC, test-of-cure.

Mazuski JE, et al. Clin Infect Dis. 2016;62:1380–9.

RECLAIM 1 & 2 Analysis populations

1066 patients randomised

Safety population1058 patients

mMITT population Met clinical disease criteria and

≥1 pathogen identified at study entry

823 patientsCeftazidime–avibactam + metronidazole n=413

Meropenem n=410

MITT populationMet clinical disease criteria and received study drug

1043 patientsCeftazidime–avibactam + metronidazole n=520

Meropenem n=523

CE at TOC population Met all evaluability criteria*

826 patientsCeftazidime–avibactam + metronidazole n=410

Meropenem n=416

Primary analysis set required by the FDA

Co-primary analysis sets required by the EMA

Mazuski JE, et al. Clin Infect Dis. 2016;62:1380‐9CE, clinically evaluable; EMA, European Medicines Agency; FDA, Food and Drug Administration; MITT, modified intention-to-treat; mMITT, microbiologically modified intention-to-treat; TOC, test-of-cure.

Mazuski JE, et al. Clin Infect Dis. 2016;62:1380–9.

RECLAIM 1 & 2 Baseline patient and disease characteristicsParameter CAZ–AVI + MTZ MER

Patient characteristics (mMITT population) n=520 n=523Age, years, mean (SD) 49.8 (17.5) 50.3 (18.3)

Gender, male, n (%) 326 (62.7) 332 (63.5)Renal status, moderate impairment (CrCL >30–≤50

mL/min), n (%)41 (7.9) 43 (8.2)

APACHE II score, n (%)≤10 437 (84.0) 434 (83.0)>10–≤30 78 (15.0) 80 (15.3)>30 1 (0.2) 0Primary diagnosis, n (%)Cholecystitis 87 (16.7) 77 (14.7)Diverticular disease 35 (6.7) 52 (9.9)Appendiceal perforation or peri-appendiceal abscess 218 (41.9) 213 (40.7)Acute gastric and duodenal perforations 96 (18.5) 99 (18.9)Traumatic perforations 9 (1.7) 8 (1.5)Secondary peritonitis 36 (6.9) 33 (6.3)Intra-abdominal abscess 39 (7.5) 41 (7.8)Single abscess 32 (6.2) 35 (6.7)Bacteraemia, n (%) 22 (4.2) 14 (2.7)Disease characteristics (mMITT population) n=413 n=410CAZ-resistant, n (%) 47 (11.4) 64 (15.6)

APACHE, Acute Physiology and Chronic Health Evaluation; AVI, avibactam; CAZ, ceftazidime; CrCL, creatinine clearance; MER, meropenem; mMITT, microbiological modified intent-to-treat; MTZ, metronidazole; SD, standard deviation.

Mazuski JE, et al. Clin Infect Dis. 2016;62:1380–9.

RECLAIM 1 & 2 Primary efficacy results: Clinical cure at TOC

Analysis population n

Clinical cure rate n/N (%) Between group difference, %

(95% CI)CAZ–AVI

+ MTZ MER

MITT(EMA co-primary analysis population)

1043 429/520 (82.5) 444/523 (84.9) –2.4 (–6.90, 2.10)

CE at TOC(EMA co-primary

analysis population)

826 376/410 (91.7) 385/416 (92.5) –0.8 (–4.61, 2.89)

mMITT(FDA primary

analysis population)

823 337/413 (81.6) 349/410 (85.1) –3.5 (–8.64, 1.58)

% difference in clinical cure rate (95% CI)

Primary efficacy endpoints: CAZ–AVI was non-inferior to MER in all populations

Solid line represents sponsor pre-specified NI margin of –12.5% for the lower limit of the 95% CI. Dashed line represents FDA requirement of –10%AVI, avibactam; CAZ, ceftazidime; CE, clinically evaluable; CI, confidence interval; EMA, European Medicines Agency; EOT, end of

treatment; FDA, Food and Drug Administration; LFU, late follow-up; MER, meropenem; MITT, modified intent-to-treat; mMITT, microbiological modified intent-to-treat; MTZ,

metronidazole; NI, non-inferiority; TOC, test of cure.

Mazuski JE, et al. Clin Infect Dis. 2016;62:1380–9.

RECLAIM 1 & 2 Clinical cure at TOC by pathogen (mMITT)CAZ–AVI + MTZ

(n=413)MER

(n=410) Comparison

Pathogen nClinical cure

n (%) n

Clinical cure

n (%)

Difference, %

(95% CI)

All CAZ-R 47 39 (83.0) 64 55 (85.9) –3.0 (–17.89, 10.60)

All CAZ-S 289 237 (82.0) 292 256 (87.7) –5.7 (–11.57, 0.17)

Enterobacteriaceae (CAZ-R) 44 36 (81.8) 62 53 (85.5) –3.7 (–19.31, 10.44)

Enterobacteriaceae (CAZ-S) 279 229 (82.1) 280 245 (87.5) –5.4 (–11.45, 0.54)

Escherichia coli (CAZ-R) 24 19 (79.2) 37 31 (83.8) –4.6 (–26.77, 14.86)

Escherichia coli (CAZ-S) 236 192 (81.4) 239 210 (87.9) –6.5 (–13.09, –0.02)

Klebsiella pneumoniae (CAZ-R) 13 10 (76.9) 13 9 (69.2) 7.7 (–27.10, 40.96)

Klebsiella pneumoniae (CAZ-S) 34 28 (82.4) 35 27 (77.1) 5.5 (–14.43, 24.56)

Non-Enterobacteriaceae

(CAZ-R) 4 4 (100.0) 4 4 (100.0) 0.0 (–52.33, 52.33)

Non-Enterobacteriaceae (CAZ-S) 35 31 (88.6) 43 41 (95.3) –6.8 (–22.10, 5.99)

Pseudomonas aeruginosa (CAZ-R) 2 2 (100.0) 4 4 (100.0) 0.0 (–69.74, 53.54)

Pseudomonas aeruginosa (CAZ-S) 30 27 (90.0) 32 30 (93.8) –3.8 (–20.55, 11.90)

These data suggest AVI restores the efficacy of CAZ against CAZ-resistant pathogens

AVI, avibactam; CAZ, ceftazidime; CAZ-R, ceftazidime-resistant; CAZ-S, ceftazidime-susceptible; CI, confidence interval; MER, meropenem; mMITT, microbiological modified intent-to-treat; MTZ,

metronidazole; TOC, test of cure.

Mazuski JE, et al. Clin Infect Dis. 2016;62:1380–9.

RECLAIM 1 & 2 Summary of AEs (safety population)

n (%) CAZ–AVI + MTZ (n=529)

MER (n=529)

Any AE 243 (45.9) 227 (42.9)Any AE leading to death 13 (2.5) 8 (1.5)Any SAE 42 (7.9) 40 (7.6)Any AE leading to discontinuation 14 (2.6) 7 (1.3)

Any AE of severe intensity 30 (5.7) 36 (6.8)

There were no new safety signals and the safety profile of CAZ–AVI + MTZ was comparable with that of CAZ, MTZ and MER alone

AE, adverse event; AVI, avibactam; CAZ, ceftazidime; LFU, late follow-up; MER, meropenem; MTZ,

metronidazole; SAE, serious adverse event.

Mazuski JE, et al. Clin Infect Dis. 2016;62:1380–9.

RECLAIM 1 & 2 Conclusions

•

The primary endpoint was met; ceftazidime–avibactam + metronidazole was non-

inferior to meropenem in hospitalized adults with cIAIs

•

Ceftazidime–avibactam + metronidazole was effective against ceftazidime-resistant pathogens

•

The safety and tolerability profile of ceftazidime–avibactam + metronidazole was broadly similar to the known profiles of ceftazidime and metronidazole alone

•

These results support the utilization of ceftazidime–avibactam + metronidazole as a potential alternative to carbapenems in the treatment of cIAI

cIAI, complicated intra-abdominal infection.

Mazuski JE, et al. Clin Infect Dis. 2016;62:1380–9.

REPROVE study Phase III study in HAP/VAP

•

Background: The randomised, double-blind, multicenter, Phase III REPROVE study (NCT01808092) compared the efficacy, safety and tolerability of ceftazidime–avibactam versus meropenem in the treatment of adults with nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP)

•

Material/methods: Adults (18–90 years) with NP, including VAP, were randomised 1:1 to receive ceftazidime–avibactam 2000–500 mg 2-h intravenous (IV) infusions every 8 h (q8h) or meropenem 1000 mg 30-min IV infusions q8h for 7–14 days (doses adjusted for renal function)

NP, nosocomial pneumonia; VAP, ventilator-associated pneumonia. Torres A, et al. OS0603: abstract presented at ECCMID 2017. Vienna, Austria. 22–25 April 2017.

REPROVE study Endpoints

•

The primary endpoint was assessment of non‐inferiority of  ceftazidime–avibactam compared with meropenem in clinical cure at 

TOC visit, 21–25 days from randomisation, in the clinically modified  intent‐to‐treat (cMITT) population (minimal disease criteria excluding 

patients with only  non‐target pathogens) and the clinically evaluable  (CE) subset of the cMITT, based on a 12.5% non‐inferiority margin

•

Secondary endpoints included clinical cure at TOC by ceftazidime  susceptibility of baseline isolates (mMITT and CE populations), per‐ pathogen favourable microbiological response at TOC (mMITT and  eME populations) and 

all‐cause mortality at Day 28 (cMITT and CE populations)

CE, clinically evaluable; cMITT, clinically modified intention to treat; eME, extended microbiologically evaluable; EOT, end of treatment; MDR, multi-drug resistant; TOC, test of cure; VAP, ventilator-associated pneumonia. mMITT microbiologically modified intention

to treat; Torres A, et al. OS0603: abstract presented at ECCMID 2017. Vienna, Austria. 22–25 April 2017.

REPROVE study Baseline characteristics

•

April 2013 ‐December 2015, 879 patients randomised in 23 countries,  excluding 62 patients with moderate/severe renal impairment (CrCL 16–50 

mL/min) recruited prior to a protocol amendment to the dose regimen  for patients with moderate/severe renal impairment

•

405 patients received ceftazidime–avibactam and  403 meropenem  (9 patients received no study treatment)

•

Baseline characteristics were well‐matched between treatment arms •

107/808 (13.2%) patients had an APACHE score ≥20 and 280/808 

(34.7%) had VAP•

Predominant Gram‐negative pathogens isolated at baseline in the 

microbiologically MITT population were Klebsiella pneumoniae  (36.6%) and Pseudomonas aeruginosa (29.6%): 100/355 (28.2%) 

patients had ≥1 ceftazidime non‐susceptible isolate

APACHE, Acute Physiology and Chronic Health Evaluation; CrCL, creatinine clearance level; VAP, ventilator-associated pneumonia.

Torres A, et al. OS0603: abstract presented at ECCMID 2017. Vienna, Austria. 22–25 April 2017.

REPROVE study Primary efficacy endpoint*

Patients, n/N (%)Ceftazidime–

avibactam Meropenem Difference, %

(95% CI)Clinical cure at TOCcMITT population 245/356 (68.8) 270/370 (73.0) –4.2 (–10.76,2.46)

VAP 83/118 (70.3) 95/128 (74.2) –3.9 (–15.11,7.31)Non-VAP 162/238 (68.1) 175/242 (72.3) –4.2 (–12.41,3.95)

CE population 199/257 (77.4) 211/270 (78.1) –0.7 (–7.86,6.39)VAP 62/80 (77.5) 63/83 (75.9) 1.6 (–11.55,14.63)Non-VAP 131/177 (77.4) 148/187 (79.1) –1.7 (–10.30,6.75)

*No formal statistical analysis was performed on subgroups or secondary endpoints CE, clinically evaluable; CI, confidence interval; cMITT, clinically modified intention to treat; TOC, test of cure; VAP, ventilator-associated pneumonia. Torres A, et al. OS0603: abstract presented at ECCMID 2017. Vienna, Austria. 22–25 April 2017.

REPROVE study Secondary efficacy endpoints*

Patients, n/N (%)Ceftazidime–avibactam Meropenem Difference, % (95% CI)

Clinical cure at TOC by ceftazidime susceptibility of baseline isolates**

mMITT population

Ceftazidime-non-susceptible 35/45 (77.8) 40/54 (74.1) 3.7 (–13.73,20.38)

Ceftazidime-susceptible 80/119 (67.2) 96/126 (76.2) –9.0 (–20.17,2.33)

CE population

Ceftazidime-non-susceptible 29/36 (80.6) 32/41 (78.0) 2.5 (–16.42,20.74)

Ceftazidime-susceptible 63/84 (75.0) 69/88 (78.4) –3.4 (–16.18,9.30)

Per-pathogen favourable microbiological response at TOCmMITT population

K. pneumoniae 37/59 (62.7) 53/71 (74.6) –11.9 (–27.76,4.03)

P. aeruginosa 22/58 (37.9) 18/47 (38.3) –0.4 (–19.01,17.98)

eME population

K. pneumoniae 29/37 (78.4) 39/49 (79.6) –1.2 (–19.60,15.96)

P. aeruginosa 18/42 (42.9) 14/35 (40.0) 2.9 (–19.13, 24.32)

All-cause mortality at Day 28

cMITT population 30/356 (8.4) 27/370 (7.3) 1.1 (–2.84,5.18)

CE population 12/257 (4.7) 9/270 (3.3) 1.3 (–2.14,5.04)

*No formal statistical analysis was performed on subgroups or secondary endpoints. **Ceftazidime-non-susceptible includes both the CLSI-breakpoint-defined ceftazidime resistant and intermediate categories (i.e., MIC ≥8 mg/L for Enterobacteriaceae and ≥16 mg/L for P. aeruginosa or disk diffusion diameters ≤20 mm for Enterobacteriaceae and ≤17 mm for P. aeruginosa from local laboratory )

CE, clinically evaluable; CI, confidence interval; eME, extended

microbiologically evaluable; cMITT, clinically modified intention to treat; mMITT, microbiologically modified intention to treat; MIC, minimal inhibitory concentration; TOC, test of cure.

Torres A, et al. OS0603: abstract presented at ECCMID 2017. Vienna, Austria. 22–25 April 2017.

REPROVE study Results

•

Ceftazidime–avibactam was non-inferior to meropenem for the primary endpoint of clinical cure at test-of-cure in the cMITT (p=0.007) and CE (p<0.001) populations

•

Subgroup analyses in non-VAP and VAP patients were consistent with the primary analysis

•

Efficacy of ceftazidime-avibactam against ceftazidime-non- susceptible pathogens was similar to that against ceftazidime- susceptible pathogens and was also comparable

to meropenem•

The adverse event rate with ceftazidime-avibactam was 74.6%

versus 74.2% with meropenem; serious adverse event rates were 18.5% and 13.4%, respectively. The most frequent adverse event in both treatment arms was diarrhea

CE, clinically evaluable; cMITT, clinically modified intention to treat; EOT, end of treatment; MDR, multi-drug resistant; mMITT, microbiologically modified intention to treat; TOC, test of cure; VAP, ventilator-associated pneumonia.

Torres A, et al. OS0603: abstract presented at ECCMID 2017. Vienna, Austria. 22–25 April 2017.

REPROVE Conclusions

•

Ceftazidime–avibactam was effective in the treatment of NP, including VAP, as demonstrated by non-inferiority to meropenem in both co-primary cMITT and CE populations

•

Safety and tolerability observations were consistent with the known profile of ceftazidime–avibactam

CE, clinically evaluable; cMITT, clinically modified intention to treat; NP, nosocomial pneumonia; VAP, ventilator-associated pneumonia. Torres A, et al. OS0603: abstract presented at ECCMID 2017. Vienna, Austria. 22–25 April 2017.

REPRISE

Phase III study in ceftazidime-resistant pathogen infections Study design

•

Pathogen-directed, prospective, open-label, randomized, multicenter study•

333 patients ≥18 years of age with a definitive diagnosis of cUTI or cIAI caused by a ceftazidime-resistant, Gram-negative pathogen

•

Patients randomized 1:1 (stratified by entry diagnosis [cIAI or cUTI] and region) to receive either:–

Ceftazidime 2000 mg + avibactam 500 mg (+ metronidazole 500 mg for cIAI) IV q8h, or–

BAT (meropenem, imipenem, doripenem, tigecycline or colistin) based on the investigator’s standard of care and local resistance panel

EOT

(within 24 h of last IV infusion)

Best Available Therapy(as specified and

documented

beforerandomization)

Ceftazidime–avibactam (+ metronidazole if cIAI)

(2000 mg ceftazidime–500 mg avibactam)Hospitalized patients

aged ≥18 years with cIAI or cUTI caused by a

ceftazidime-resistant Gram-negative pathogen

(5–21 days of IV therapy)

1:1 randomization

Test Of Cure

28–35 days

7–10 days

after last infusion

Follow-up 1

cUTI:

cIAI:

Follow-up 1

21–25 days

after randomized28–32 days

Follow-up 2

Choice of BAT documented

by investigator

BAT, best available therapy; cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; EOT, end of treatment.Carmeli Y, et al. Lancet Infect Dis. 2016;16:661–73.

REPRISE Baseline characteristics (mMITT)

cUTI cIAI

Ceftazidime–

avibactam (n=144)

BAT

(n=137)

Ceftazidime–

avibactam

+ metronidazole

(n=10)

BAT

(n=11)

Age, years; mean (SD) 64.3 (14.6) 61.3 (15.3) 49.9 (16.1) 68.4 (11.1)

Female, n (%) 64 (44.4) 63 (46.0) 6 (60.0) 4 (36.4)

Race, n (%)

•

White 136 (94.4) 131 (95.6) 9 (90.0) 11 (100)

•

Other* 8 (5.6) 6 (4.4) 1 (10.0) 0

Body mass index, kg/m2; mean

(SD) 28.1 (5.5) 28.0 (5.8) 25.2 (6.3) 28.6 (4.6)

Renal status, CrCL; mL/min, n (%)

•

>50 118 (81.9) 113 (82.5) 10 (100) 6 (54.5)

•

31–50 19 (13.2) 18 (13.1) 0 3 (27.3)

•

16–30 4 (2.8) 5 (3.6) 0 2 (18.2)

•

6–15 3 (2.1) 1 (0.7) 0 0

*Black or African American, Asian, or other.

BAT, best available therapy; cIAI, complicated intra-abdominal infection; CrCL,

creatinine clearance; cUTI, complicated urinary tract infection;

mMITT,

microbiological modified intent-to-treat; SD, standard deviation.Carmeli Y, et al. Lancet Infect Dis. 2016;16:661–73.

Susceptibilities of 314 Enterobacteriaceae isolates from the REPRISE study

MIC, minimum inhibitory concentration.

Stone GG, et al. Antimicrob Agents Chemother. 2017;61.pii: e01820-16.

cUTI diagnosisOpen‐label Phase III study of ceftazidime–avibactam and best ‐available‐therapy 

(97% carbapenems) in patients with cIAI or cUTI caused by ceftazidime‐resistant  Gram‐negative pathogens

BAT, best available therapy; cIAI, complicated intra-abdominal infection; cUTI,

complicated urinary tract infection; SD, standard deviation. Carmeli Y, et al. Lancet Infect Dis. 2016;16:661–73.

cUTI

Ceftazidime–avibactam (n=144)

BAT

(n=137)

Age, years; mean (SD) 64.3 (14.6) 61.3 (15.3)

Female, n (%) 64 (44.4) 63 (46.0)

cUTI diagnosis

Acute pyelonephritis 57 (40) 70 (51)

cUTI without pyelonephritis 87 (60) 67 (49)

Complicating factors

Partial obstructive uropathy 45 (31) 21 (15)

Abnormality of urogenital tract 39 (27) 38 (28)

Male with urinary retention 33 (23) 24 (18)

Catheterization 30 (21) 25 (18)

Urogenital procedure within 7 days 27 (19) 21 (15)

REPRISE: ceftazidime-resistant pathogens study

Open‐label Phase III study of ceftazidime–avibactam and best ‐

available‐therapy (97%  carbapenems) 

in 

patients 

with 

cIAI 

or 

cUTI 

caused 

by 

ceftazidime‐resistant 

Gram‐

negative pathogens

Microbiological response rate (%)

126/154 (82%) 94/148

(64%)

118/144 (82%)

88/137 (64%)

cUTI+cIAI

cUTI

140/154 (91%)

135/148 (91%)

132/144 (92%)

129/137

(94%)

n/N (%) n/N (%)

cIAI

Clinical response rate (%)0 20 30 40 50 60 70 10080 9010

8/10 (80%)

6/11 (55%)

0 20 30 40 50 60 70 10080 9010

8/10 (80%) 6/11 (55%)

Clinical response rate (90% CI) at TOCPer-patient favourable microbiological response

rate* (95% CI) at TOC

Ceftazidime–avibactam BAT

*Presumed from clinical response.

BAT, best available therapy; CI, confidence interval; cIAI, complicated intra-abdominal infection; cUTI, complicated intra-abdominal infection; mMITT, microbiological modified intent-to-treat; TOC, test of cure.Carmeli Y, et al. Lancet Infect Dis. 2016;16:661–73.

REPRISE Per-pathogen microbiological response at TOC

(in cUTI in mMITT population)

Favourable microbiological response rate (%) with 95% CI0 20 10040 60 80

OverallEnterobacteriaceae

Citrobacter freundii complexEnterobacter aerogenes

Enterobacter cloacaeEscherichia coli

Klebsiella oxytocaKlebsiella ozaenae

Klebsiella pneumoniaeMorganella morganii

Proteus mirabilisProteus rettgeri

Providencia stuartiiRaoultella terrigena

Serratia marcescensOther than Enterobacteriaceae

Ochrobactrum anthropiPseudomonas aeruginosa

0 20 10040 60 80

(118/144) 82% vs (88/137) 64%

(2/3) 67% vs (0/2) 0%

(5/8) 63% vs (5/6) 83%(52/59) 88% vs (38/57) 67%(0/0) NC vs (1/2) 50% (0/0) NC vs (1/1) 100%(46/55) 84% vs (43/65) 66% (1/1) 100% vs (0/0) NC(2/5) 40% vs (0/1) 0%(0/0) NC vs (0/1) 0%(1/1) 100% vs (0/0) NC(0/0) NC vs (1/1) 100%(0/0) NC vs (1/2) 50%

(1/1) 100% vs (0/0) NC(11/14) 79% vs (3/5) 60%

CAZ–AVI BAT

(1/1) 100% vs (0/0) NC

CAZ–AVI: BAT

Favourable microbiological response rates for the most common pathogens isolated in cUTI patients were higher in the ceftazidime–avibactam group than in the best available

therapy group (88% vs 67%, respectively for E. coli, and 84% vs 66% for K. pneumoniae)

BAT, best available therapy; CAZ–AVI, ceftazidime–avibactam; cUTI, complicated intra-abdominal infection; mMITT, microbiological modified intent-to-treat; NC, not calculated; TOC, test of cure.

Carmeli Y, et al. Lancet Infect Dis. 2016;16:661–73.

REPRISE Summary of AEs up to the late follow-up visit (safety

population)

n (%) CAZ–AVI (n=164) BAT (n=168)Any AE 51 (31.1) 66 (39.3)Any AE considered related to study drug 14 (8.5) 11 (6.5)Any AE leading to death 3 (1.8) 4 (2.4)Deaths considered related to study drug 0 (0.0) 0 (0.0)Any SAE 9 (5.5) 10 (6.5)Any AE leading to discontinuation 1 (0.6) 2 (1.2)

•

Gastrointestinal disorders were the most frequently reported AEs

with both ceftazidime–avibactam (12.8%) and BAT (17.9%)

•

No new, significant or unexpected safety concerns were identified

AE, adverse events; BAT, best available therapy; CAZ–AVI, ceftazidime–avibactam; SAE, serious adverse event.

Carmeli Y, et al. Lancet Infect Dis. 2016;16:661–73.

REPRISE Summary and conclusions

•

Treatment of serious ceftazidime-resistant Gram-negative cUTI with ceftazidime–avibactam achieved

–

Similar clinical cure rates to treatment with BAT–

Numerically higher per-patient microbiological response rates than BAT

•

In cIAI, clinical and microbiological response rates were high for ceftazidime–avibactam and similar to BAT

–

Interpretation of the findings is limited by the small number of patients•

Safety and tolerability profile of ceftazidime–avibactam was broadly similar to ceftazidime alone

•

The REPRISE study is the first pathogen-directed clinical trial for ceftazidime–avibactam examining its efficacy against ceftazidime-resistant Gram-negative pathogens

•

These results support the use of ceftazidime–avibactam as a potential alternative to carbapenems in patients with resistant Gram-negative infections

BAT, best available therapy; cIAI, complicated intra-abdominal infection; cUTI,

complicated intra-abdominal infection.Carmeli Y, et al. Lancet Infect Dis. 2016;16:661–73.

A difficult case…

•

Male, Age 47•

Calculous cholecystitis 

•

Necrotic haemorrhagic pancreatitis•

4 episodes of septic shock

•

Multiple vascular thrombosis•

Bleeding from multiple 

pseudoaneurysm of left hepatic artery•

Multiple abdominal abscesses 

•

KPC Klebsiella pneumoniae isolation  from abdominal infected collections

Positive blood cultures

ID/ AST

Sub cultures

Gram staining

Direct MALDI-TOF MS

Eazyplex Amplex for resistance genes

detection

FilmArray if polymicrobial

Treating physician

Day

2

Microbiology Lab Blood cultures workflow

Day

1

Last episode of  septic shock solved