Francesco G. De Rosa “Infectious Diseases 2”

City of Health and Science University of Turin, Italy

Ceftolozane Tazobactam

Disclosures

Consultant/Advisory Board/Speaker fees • Pfizer, MSD, AstraZeneca, Angelini • Astellas Pharma, Basilea, Sanofi Aventis • Thermo Fisher, Biomiereuix • BioTest, Nordic Pharma • Sofar, Gilead Sciences

• More stable against the AmpC b-lactamases • AmpC possesses a low catalytic efficiency for ceftolozane • Ceftolozane

– Active against some class D oxacillinases (eg, OXA-1) – Inhibits PBPs and inhibitor-resistant TEMs and SHVs as well as AmpC

• Tazobactam target – Class A serine b-lactamases (eg, TEM-1)

• Ceftolozane-tazobactam combination – Target class A, C, and some class D b-lactamases – Major exception is carbapenemase – Extended-spectrum beta-lactamases (ESBLs) (eg, CTX-M-15).

“Changing Beta-lactam Partner”: Ceftolozane Papp-Wallace & Bonomo, Inf Dis Clin North Am 2016

Takeda S et al Int H Antimicrob 2007

Chemical Structure of Ceftolozane Papp-Wallace & Bonomo, Inf Dis Clin North Am 2016

5

Ceftolozano/tazobactam Antibiotico composto da:

- ceftolozano solfato, nuovissima cefalosporina con spiccata attività

anti-Pseudomonas - tazobactam, inibitore

irreversibile delle β-lattamasi

Potente e rapida attività battericida tempo- dipendente contro batteri

Gram-negativi clinicamente rilevanti, quali:

- E. coli (inclusi ceppi produttori di ESBL Extended Spectrum Beta-

lactamases), - K. pneumoniae (compresi ceppi

ESBL-produttori) - P. aeruginosa (inclusi ceppi

MDR, Multi Drug Resistant ed XDR, extensively drug-

resistant) Bassetti M, Righi E. Future Microbiol. 2015;10(2):151-60. Zhanel et al. Drugs. 2014;74:31-51. Solomkin J. Et al CID 205; 60 (10): 1462-71 Wagenlehner FM et al. Lancet 2015; 385: 1949-1956

•5

•Anello aminotiazolico: potenzia l’attività verso i

Gram -

Il Gruppo Ossimico

conferisce stabilità verso le Beta-

lattamasi

Anello pirazolico fornisce stabilità contro le AmpC

Drawz SM, et al. AAC. 2014;58:1835. PP-ZVA-GLB-0061 Date of preparation: April 2017

Initial β-lactamase inhibitors

Drawz SM, et al. AAC. 2014;58:1835

Carbapenemase producers

Ceftolozane/Tazobactam Overview Zhanel et al. Drugs. 2014;74:31-51

8

Class Antipseudomonal cephalosporin +

β-lactamase inhibitor Fixed 2:1 ratio

Mechanism of action Rapidly bactericidal Inhibits cell wall synthesis Active against organisms with

porin deficiencies or mutations Inhibits β-lactamases, broadens

coverage to most ESBL-producing Enterobacteriaceae

In vitro activity Pseudomonas aeruginosa,

including drug-resistant strains Escherichia coli, including ESBL-

positive strains Klebsiella pneumoniae, including

ESBL-positive strains Minimal activity against Gram-

positive bacteria Limited activity against

anaerobes No activity against KPC, MBL

Development

cIAIs & cUTIs Phase 3 trial underway for

nosocomial pneumonia

In vivo efficacy Activity in mouse models of

sepsis, pneumonia, urinary tract infection, burn wound

infection, and thigh infection Positive outcomes and

adhered to an expected safety profile in Phase 2 and 3 trials

in adult patients with cUTI and cIAI

Pharmacokinetics

Linear PK Lung penetration Rapid tissue distribution Minimal accumulation Extensive renal excretion Low protein binding Minimal CYP450 drug-drug

interactions

+

ASPECT-cIAI

• Pooled analysis of 2 Phase 3, randomized, controlled, double-blind, multicenter trials in adult patients with cIAI

• Primary objective – To demonstrate the noninferiority of ceftolozane/tazobactam and metronidazole vs

meropenem based on the difference in clinical cure rates at the TOC visit (26-30 days after initiation of treatment) in the MITT population

9 Eckmann et al. ECCMID 2014. Poster P0266a.

Ceftolozane/tazobactam 1.5 g IV q8h

plus metronidazole 0.5 g IV q8h

Meropenem 1 g IV q8h

988 total patients with cIAI Randomized (1:1)

Duration of treatment: 4-10 days of IV study drug (no oral switch)

CXA-cIAI-10-08 N = 494

(planned sample)

CXA-cIAI-10-09 N = 494

(planned sample)

ASPECT-cIAI Demographic and Baseline Characteristics (ITT)

Ceftolozane/tazobactam + metronidazole

(n = 476)

Meropenem (n = 494)

Sex, male, n (%) 266 (55.9) 300 (60.7) Race, white, n (%) 448 (94.1) 459 (92.9) Age, y, mean (SD) 50.9 (17.9) 50.7 (16.8) Age ≥ 65 y, n (%) 116 (24.4) 105 (21.3) Body mass index, kg/m², mean (SD) 26.8 (5.5) 27.0 (5.1) Baseline APACHE II category, n (%) <10 387 (81.3) 409 (82.8) ≥10 88 (18.5) 82 (16.6) Creatinine clearance, mL/min, n (%) Normal (≥80) 333 (70.0) 350 (70.9) Mild renal impairment (>50-<80) 116 (24.4) 125 (25.3) Moderate renal impairment (≥30-≤50) 27 (5.7) 16 (3.2) Severe renal impairment (<30) 0 1 (0.2)

Peritonitis present, n (%) 398 (83.6) 396 (80.2) Anatomical site of infection, n (%) Appendix 209 (43.9) 219 (44.3) Colon 59 (12.4) 70 (14.2)

10 Eckmann et al. ECCMID 2014. Poster P0266a.

Baseline characteristics were similar between the 2 arms

ASPECT-cIAI Per-pathogen Microbiological Eradication (ME at TOC)

96 100

86

100 98 93

100 95 88

100 100 98 95 94

0102030405060708090

100

E. coli(n = 426)

K. pneumoniae(n = 53)

E. cloacae(n = 43)

P. aeruginosa(n = 53)

Gram-negativeanaerobes(n = 246)

Gram-positiveaerobes(n = 308)

Gram-positiveanaerobes

(n = 83)

Ceftolozane/tazobactam+metronidazoleMeropenem

Gram-negative aerobes

11 cIAI, complicated intra-abdominal infection; ME, microbiologically evaluable; TOC, test of cure.

Era

dica

tion

(%

)

Eckmann et al. ECCMID 2014. Poster P0266a.

ASPECT-cIAI

Clinical Response by ESBL Status (ME at TOC) 100 100 100 100 100 100

88,5

72,7

90

77,8 75

0 0

102030405060708090

100

EnterobacteriaceaeESBL+

EnterobacteriaceaeCTX-M-14/15

E. coli ESBL+ E. coli CTX-M-14/15 K. pneumoniae ESBL+ K. pneumoniae CTX-M-14/15

Ceftolozane/tazobactam+metronidazole Meropenem

4/4

K. pneumoniae

12

• CTX-M-14/15 is a subset of ESBL-producers • Eckmann et al. ECCMID 2 2014. Poster P0266a

Clin

ical

cur

e (%

)

22/22 23/26 12/12 14/14 8/11

E. coli K. pneumoniae E. coli

18/20 9/9 7/9 6/6 3/4

ASPECT-cIAI

Clinical Response at TOC Visit by Infection Site

13 Eckmann et al. ECCMID 2014. Poster P0266a.

95% CI for the difference of ceftolozane/tazobactam [TOL/TAZ] + metronidazole – meropenem are calculated as Wilson score CIs. A patient can have more than 1 anatomical site of infection. Data as-observed approach used for calculation of Wilson score CIs.

Subgroup in CE population Subgroup in ME population Primary site of infection

15

Favors TOL/TAZ

30 45 60 75 0 -15 -30 -45 -60 -75

Favors meropenem

Anatomical site of infection

Bowel (small or large)

Other site of IAI

Appendix

Biliary-cholecystitis

Colon

Other

Parenchymal (liver)

Parenchymal (spleen)

Small bowel

Stomach/duodenum

Primary site of infection

15

Favors TOL/

30 45 60 75 0 -15 -30 -45 -60 -75

Favors meropenem

Anatomical site of infection

Bowel (small or large)

Other site of IAI

Appendix

Biliary-cholecystitis

Colon

Other

Parenchymal (liver)

Parenchymal (spleen)

Small bowel

Stomach/duodenum

ASPECT-cUTI • Primary

– FDA: Demonstrate noninferiority (NI) of ceftolozane/tazobactam versus levofloxacin based on the difference in composite microbiological and clinical cure rates in the mMITT population at TOC visit 7 days after EOT (NI margin 10%, 95% CI)

– EMA: Demonstrate NI of ceftolozane/tazobactam versus levofloxacin based on the difference in microbiological eradication rates in the ME population at the TOC visit (NI margin 10%, 99% CI)

• Secondary – Clinical and microbiological responses at EOT, TOC, and last follow-up visits (mMITT and

ME populations) – Safety of ceftolozane/tazobactam in cUTI

14 Wagenlehner et al. ECCMID 2014. Poster eP449.

Ceftolozane/ tazobactam 1.5 g IV q8h

Levofloxacin 750 mg IV daily

Approx. 954 patients with cUTI

Randomized (1:1)

CXA-cUTI-10-04 477 planned patients

CXA-cUTI-10-05 477 planned patients Duration of treatment:

7 days of IV study drug (no oral switch)

ASPECT-cUTI Demographic and Baseline Characteristics (mMITT)

15 1. Wagenlehner et al. ECCMID 2014. Poster eP449. 2. Data on file, Cubist Pharmaceuticals.

aNo antibiotics permitted within 48 h prior to obtaining the baseline urine culture. bUrinary catheter was removed before end of treatment in all but 3 patients in the ceftolozane/tazobactam group and 1 patient in the levofloxacin

group.

Ceftolozane/tazobactam (n = 398)

Levofloxacin (n = 402)

Age, y, mean (range) 49.1 (18-90) 48.1 (18-87)

Sex, n (%)

Male 105 (26.4) 103 (25.6)

Female 293 (73.6) 299 (74.4)

Diagnosis, n (%)

Pyelonephritis 328 (82.4) 328 (81.6)

cLUTI 70 (17.6) 74 (18.4)

Baseline creatinine clearance (mL/min), n (%)

>80 (normal) 247 (62.1) 274 (68.2)

50-79 (mild renal impairment) 116 (29.1) 100 (24.9)

30-49 (moderate renal impairment) 31 (7.8) 27 (6.7)

Prior antibiotics (within 14 days of 1st dose)a, n (%)2 14 (3.5) 6 (1.5)

Urinary catheter at baselineb, n (%) 11 (2.8) 10 (2.5)

Diabetes, n (%) 42 (10.6) 40 (10.0)

Hypertension, n (%) 125 (31.4) 119 (29.6)

Bacteremia, n (%) 29 (7.3) 33 (8.2)

ASPECT-cUTI Outcomes in Key Subgroups (mMITT at TOC)

16

Ceftolozane/ Tazobactam Levofloxacin 95% CI

Composite cure 38/61 (62.3%) 20/57 (35.1%) 9.2 to 42.9

Clinical cure 55/61 (90.2%) 42/57 (73.7%) 2.6 to 30.2

62,3

90,2

35,1

73,7

0

20

40

60

80

100

Composite cure Clinical cure

Ceftolozane/tazobactam Levofloxacin

Patie

nts w

ith c

ure

(%)

Ceftolozane/ Tazobactam Levofloxacin 95% CI

Composite cure 60/100 (60.0%) 44/112 (39.3%) 7.2 to 33.2

Clinical cure 90/100 (90.0%) 86/112 (76.8%) 3.1 to 22.9

60

90

39,3

76,8

0

20

40

60

80

100

Composite cure Clinical cure

Ceftolozane/tazobactam Levofloxacin

Patie

nts w

ith c

ure

(%)

Wagenlehner et al. ECCMID 2014. Poster eP449.

Levofloxacin-resistant pathogens ESBL-producing pathogens

ASPECT-cUTI Key Primary and Secondary Analysis Endpoints at TOC Visit

17

NI m

argi

n

Ceftolozane/ tazobactam

n/N (%)

Levofloxacin n/N (%)

Percentage difference (95% CI)

Percentage difference (99% CI)

306/398 (76.9) 275/402 (68.4) 8.5 (2.3 to 14.6) 8.5 (0.4-16.5)

284/341 (83.3) 266/353 (75.4) 8.0 (2.0 to 14.0) 8.0 (0.01-15.8)

95% CI

ME population

mMITT population

Ceftolozane/tazobactam – levofloxacin (difference [%])

n/N (%) n/N (%) (95% CI)

320/398 (80.4) 290/402 (72.1) 8.3 (2.4 to 14.1)

294/341 (86.2) 274/353 (77.6) 8.6 (2.9 to 14.3)

-10 -5 5 10 15 0

ME population

mMITT population

20

-10 -5 5 10 15 0 20 Microbiological eradication

-10 -5 5 10 15 0

ME population

mMITT population

20

Clinical cure n/N (%) n/N (%) (95% CI)

366/398 (92.0) 356/402 (88.6) 3.4 (-0.7 to 7.6)

327/341 (95.9) 329/353 (93.2) 2.7 (-0.8 to 6.2)

Composite cure

Wagenlehner et al. ECCMID 2014. Poster eP449.

Primary end point

Utilizzo

• Infezioni complicate intraddominali • Infezioni complicate delle vie urinarie • Carbapenem-sparing strategy • Inoltre…. • ESBL • HAP – VAP

– 3g q8h ev • Infezioni da P. aeruginosa MDR

Pip-Tazo vs Meropenem Effect on 30-Day Mortality E. coli or K. pneumoniae Bloodstream Infection & Ceftriaxone Resistance:

A Randomized Clinical Trial Harris PNA et al, MERINO Trial JAMA 2018;320:984-994

• Noninferiority, parallel group, randomized 1:1 clinical trial – Hospitalized patients from 26 sites in 9 countries – February 2014 to July 2017 – At least 1 positive blood culture with E. coli or Klebsiella spp – Nonsusceptible to ceftriaxone but susceptible to pip-tazo

• 1646 patients screened: 391 included in the study – Pip-tazo, 4.5 g, every 6 hours (n = 188 participants) – Meropenem, 1 g, every 8 hours (n = 191 participants) – Minimum of 4 days, up to a maximum of 14 days – Total duration decided by the treating clinician

• Primary outcome: – All-cause mortality at 30 days after randomization – Noninferiority margin of 5%

Pip-Tazo vs Meropenem Effect on 30-Day Mortality E. coli or K. pneumoniae Bloodstream Infection & Ceftriaxone Resistance:

A Randomized Clinical Trial Harris PNA et al, MERINO Trial JAMA 2018;320:984-994

• 379 patients (mean age, 66.5 years; 47.8% women) randomized, treated with least 1 dose of study drug – 378 (99.7%) completed the trial

• Primary outcome for Pip/Tazo: – 23 of 187 patients = 12.3%

• Primary outcome for Meropenem: – 7 of 191 patients = 3.7% – Risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority

• Other results: – Effects were consistent in an analysis – Nonfatal serious adverse events: 2.7% Vs. 1.6%, respectively

• Definitive treatment with pip-tazo compared with meropenem did not result in a noninferior 30-day mortality

• These findings do not support use of pip-tazo in this setting

Carbapenem-sparing Strategy?

ASPECT-cIAI

Clinical Response by ESBL Status (ME at TOC) 100 100 100 100 100 100

88,5

72,7

90

77,8 75

0 0

102030405060708090

100

EnterobacteriaceaeESBL+

EnterobacteriaceaeCTX-M-14/15

E. coli ESBL+ E. coli CTX-M-14/15 K. pneumoniae ESBL+ K. pneumoniae CTX-M-14/15

Ceftolozane/tazobactam+metronidazole Meropenem

4/4

K. pneumoniae

22

• CTX-M-14/15 is a subset of ESBL-producers • Eckmann et al. ECCMID 2 2014. Poster P0266a

Clin

ical

cur

e (%

)

22/22 23/26 12/12 14/14 8/11

E. coli K. pneumoniae E. coli

18/20 9/9 7/9 6/6 3/4

Increased relative abundance of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae within the gut microbiota is associated with risk of

bloodstream infection in long-term acute care hospital patients Shimasaki T et al Clin Infect Dis 2018 Sep 18

• Relative abundance of specific bacterial taxa in the intestinal microbiota and bacteremia has been reported in some high-risk patient populations – Collection of weekly rectal swab samples from patients in one LTCCF in Chicago – Samples tested for KPC-Kp by PCR and culture – Positive samples underwent 16S rRNA gene sequence analysis – Relative abundance of the operational taxonomic unit containing KPC-Kp

• ROC curves were constructed – Using results from analysis of the sample with highest relative abundance of

KPC-Kp from each patient admission, excluding samples collected after KPC-Kp bacteremia

• Cox regression analysis was performed – To evaluate risk factors associated with time to achieve KPC-Kp relative

abundance thresholds calculated by ROC curve analysis

Increased relative abundance of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae within the gut microbiota is associated with risk of

bloodstream infection in long-term acute care hospital patients Shimasaki T et al Clin Infect Dis 2018 Sep 18

• 2,319 samples from 562 admissions (506 patients) – 255 (45.4%) were colonized with KPC-Kp – 11 (4.3%) had KPC-Kp bacteremia

• ROC curve analysis – Relative abundance cutoff of 22% predicted KPC-Kp bacteremia with sensitivity

73%, specificity 72%, and relative risk 4.2 (P=0.01)

• Multivariable Cox regression model – Adjusted for age, Charlson comorbidity index and medical devices – Carbapenem receipt was associated with achieving the 22% relative abundance

threshold (P=0.044).

• Conclusions: – In adult LTACH patients, carbapenem receipt was associated with increased hazard

for high relative abundance of KPC-Kp in the gut microbiota – Increased relative abundance of KPC-Kp was associated with KPC-Kp bacteremia

25

Ceftolozane/Tazobactam Ongoing Adult Program: Design of Phase 3 Pneumonia Study (ASPECT-NP) • Rationale: Demonstrates value of C/T in critically ill patients, especially

those with Pseudomonas infections

• Study Design:

• C/T vs. meropenem in double-blind, Phase III RCT in adults with VABP or ventilated HABP (together known as ventilated nosocomial pneumonia [VNP])

• Treatment duration for 8-14 days • Empirical linezolid IV 600 mg q12h for MRSA is required for all

patients • Primary outcome (FDA, CFDA): all-cause mortality at 28 days • Secondary outcome (primary outcome for EMA, PMDA):

investigator’s assessment of clinical response

Ceftolozane/tazobactam 3 g IV q8h*

Meropenem 1 g IV q8h

726 patients with VNP

Randomized (1:1) Stratified by

VNP diagnosis (VABP and Ventilated HABP) and age

(≥65 and <65 y)

Duration of treatment: 8-14 days of IV study drug (no oral switch)

https://clinicaltrials.gov

27

Activity of Ceftolozane-Tazobactam and Ceftazidime-avibactam

against Beta-Lactam-Resistant P. aeruginosa Isolates Humphries RM et al. AAC 2017;61(12)

Activity of Ceftolozane-Tazobactam and Ceftazidime-avibactam

against Beta-Lactam-Resistant P. aeruginosa Isolates Humphries RM et al. AAC 2017;61(12)

• Ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) • MICs study of 309 beta-lactam-resistant isolates of P. aeruginosa

– Three institutions in the area of Los Angeles, CA

• Overall susceptibilities: – Imi- and meropenem: 12.0% and 16% – Pip/tazo: 20.7% – Ceftazidime & Cefepime: 24.6% and 26% – C/T 72.5% – CZA 61.8%

• C/T-resistant isolates 9% were CZA susceptible • CZA-resistant isolates 36% were C/T susceptible

Ceftolozane/Tazobactam Proposed Dosing Based on Pharmacokinetic Studies

cIAI cUTI NP/VAP

CrCL >50 mL/min 1.5 g q8h 1.5 g q8h 3 g q8h

CrCL 30-50 mL/min 750 mg q8h 750 mg q8h 1.5 g q8h

CrCL 15-30 mL/min 375 mg q8h 375 mg q8h 750 mg q8h

Hemodialysis 750 mg loading dose, 150 mg q8h

750 mg loading dose, 150 mg q8h

ND

30 CrCL, creatinine clearance; cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; NaCl, sodium chloride; NP, nosocomial pneumonia, q8h, every 8 hours; VAP, ventilator-associated pneumonia. Data on file, Cubist Pharmaceuticals.

Current Formulation Ceftolozane 1000 mg active

Tazobactam sodium 500 mg active Citric acid 21 mg L-Arginine 615.4 mg

NaCl 484.2 mg

Reconstituted with 10 mL 0.9% NaCl or sterile water for injection (SWFI) and further diluted in 100 mL 0.9% NaCl or SWFI and infused over 1 h

Utilizzo

• Infezioni complicate intraddominali • Infezioni complicate delle vie urinarie • Carbapenem-sparing strategy • Inoltre…. • ESBL • HAP – VAP

– 3g q8h ev • Infezioni da P. aeruginosa MDR