Francesco G. De Rosa “Infectious Diseases 2” City of ... · Poster P0266a. Baseline...
Transcript of Francesco G. De Rosa “Infectious Diseases 2” City of ... · Poster P0266a. Baseline...
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
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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
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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
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• 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
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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
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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)
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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
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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
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-10 -5 5 10 15 0 20 Microbiological eradication
-10 -5 5 10 15 0
ME population
mMITT population
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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
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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