Mario Tumbarello

I nuovi antibiotici: Ceftazidime-avibactam

Istituto di Clinica delle Malattie Infettive

Disclosures (last 5 years)

• Advisor/consultant – Angelini, Astra Zeneca, Gilead, MSD, Nordic

Pharma, Roche.

• Speaker/chairman. – Astellas, Astra Zeneca, Gilead, MSD, Novartis,

Pfizer.

2009 2016

Klebsiella pneumoniae: percentage of invasive isolates with resistance to carbapenems

Mechanisms underlying resistance to carbapenems in Enterobacteriaceae

Beta-

lactamase

enzymes

Ambler class Type Enzymes Antibiotic targets

A Serine-

carbapenemase

KPC, IMI-1/2, SME,

NMC-A

penicillins,

cephalosporins,

carbapenems,

aztreonam

B Metallo-beta-

lactamases (MBL)

VIM, IMP, NDM-1 carbapenems, all

other beta-lactams

except aztreonam

D OXA beta-

lactamases

OXA-48 and other

OXA-type enzymes

penicillins,

oxacillins,

carbapenems,

cephalosporins

Decreased expression/loss of

outer membrane proteins (OMPs)

Porin lesion type:

ompK35, ompK36, ompC, ompF, ompK37

http://www.eurosurveillance.org/images/dynamic/ES/V18N04/V18N04.pdf

In vitro activity of ceftazidime-avibactam

Drawz SM Clin Microbiol Rev 2010;23:160–201.

Most enzymes inhibited by avibactam

KPCs

Older TEM & SHV, ESBLs: new TEM, SHV,

CTX-M

AmpC IMP, NDM-1 VIM-1

OXA

Class C Class D Class B

β-lactamases

Metallo-enzymes Serine enzymes

Class A

Variable inhibition by avibactam

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: 1) Resolution of UTI-

specific symptoms 2) Resolution/improvement

of flank pain 3) Per-patient microbiol

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

AVI, avibactam; CAZ, ceftazidime; CE, clinically evaluable; cIAI, complicated intra-abdominal infection; cMMIT, clinically modified intent-to-treat; cUTI, complicated urinary tract infection; DOR, doripenem; IV, intravenous; MER, meropenem; mMITT, microbiological modified intent-to-treat; q8h, every 8 h; TOC, test of cure; UTI, urinary tract infection; VAP, ventilator-associated pneumonia.

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)

Zavicefta EMA EPAR. April 2016. Accessed Nov 2017 ( www.ema.europa.eu, ceftazidime-avibactam PI)

http://www.ema.europa.eu/

REPRISE study efficacy results mMITT population

• Clinical cure rates at TOC were similar between treatment groups • Favourable per-patient microbiological response rates were numerically higher with

ceftazidime-avibactam than the best available therapy in the cUTI population • The number of cIAI patients in this study was small, although results were favourable

towards ceftazidime-avibactam

Clinical response rate (90% CI) at TOC Per-patient favourable microbiological response rate (95% CI) at TOC

Microbiological response rate (%) 0 20 30 40 50 60 70 100 80 90 10

126/154 (82%) 94/148 (64%)

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

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

Ceftazidime-avibactam BAT

cUTI+cIAI

cIAI

cUTI

Clinical response rate (%) 0 20 30 40 50 60 70 100 80 90 10

140/154 (91%) 135/148 (91%)

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

132/144 (92%) 129/137 (94%)

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

Carmeli Y et al. Lancet Infect Dis. 2016 Jun;16(6):661-73.

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.

Reprise Treatment in the BAT group (safety population)

cUTI, n (%) cIAI, n (%) Any preferred monotherapy 146 (95.4) 14 (93.3)

Any other monotherapy 6 (3.9) 0

BAT single therapy • Amikacin • Colistin • Doripenem • Ertapenem • Ertapenem sodium • Gentamicin • Imipenem • Meropenem • Piperacillin/tazobactan

1 (0.7) 2 (1.3)

11 (7.2) 1 (0.7) 2 (1.3) 1 (0.7)

76 (49.7) 57 (37.3)

1 (0.7)

0 0 0 0 0 0

5 (33.3) 9 (60.0)

0

Any combination therapy • Ciprofloxacin+meropenem • Colistin+imipenem

0

1 (0.7)

1 (6.7)

0

97% of patients in the BAT group received a carbapenem (mainly as monotherapy), with imipenem and meropenem most frequently prescribed

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

REPROVE study Primary endpoint efficacy: Clinical cure rates at TOC

(CE and cMITT populations)

• Ceftazidime-avibactam was non-inferior to meropenem for the treatment of HAP/VAP in this setting

CE, clinically evaluable; CI, confidence interval; cMITT, clinically modified intention-to-treat; HAP, hospital-acquired pneumonia; TOC, test of cure; VAP, ventilator-associated pneumonia. Torres A, et al. Lancet Infect Dis 2017; doi 10.1016/S1473–3099(17)30747–8 [Epub ahead of print].

CE population cMITT population

(n=199/257) (n=211/270) (n=270/370) (n=245/356)

Grafico1

Difference (95% CI): −0.7%(−7.86, 6.39)Difference (95% CI): −0.7%(−7.86, 6.39)

Difference (95% CI): −4.2%(−10.76, 2.46)Difference (95% CI): −4.2%(−10.76, 2.46)

Ceftazidime-avibactam

Meropenem

Patients with favourable clinical response (%)

Clinical cure rate at test of cure

77.4

78.1

68.8

73

Sheet1

Ceftazidime-avibactamMeropenem

Difference (95% CI): −0.7%(−7.86, 6.39)77.478.1

Difference (95% CI): −4.2%(−10.76, 2.46)68.873.0

• In the pooled microbiologically modified ITT population, 1051 patients with MDR Enterobacteriaceae and 95 patients with MDR P. aeruginosa isolates were identified.

• Favourable microbiological response rates at TOC for all MDR Enterobacteriaceae and MDR P. aeruginosa were 78.4%and 57.1%, respectively, for ceftazidime/avibactam and 71.6% and 53.8%, respectively, for comparators

Data from 5 Phase III randomized controlled trials of ceftazidime/avibactam versus predominantly carbapenem comparators in patients with: cIAI (RECLAIM 1 and 2; NCT01499290 and RECLAIM 3; NCT01726023), cUTI (RECAPTURE 1 and 2; NCT01595438 and NCT01599806), NP including VAP

• Infections included 12 pneumonia, 14 bacteremia, and others. • Ceftazidime-avibactam was administered as monotherapy or in combination regimens in

70% (26/37) and 30% (11/37), respectively. • Combinations included intravenous (n=7) or inhaled (n=1) gentamicin, intravenous (n=1) or

intrathecal (n=1) colistin, and tigecycline (n=1). • Survival rates at 30-days was 76% (28/37). Clinical success was 59% (22/37) and did not

differ for patients receiving monotherapy (58% [15/26]) or combination therapy (64% [7/11]).

• The emergence of ceftazidime-avibactam resistance (MIC >8 μg/mL) was detected in 8% (3/37) patients following a median of 15 days (range, 10 – 19) of ceftazidime-avibactam therapy.

• Ceftazidime-avibactam is an important addition to the limited antimicrobial armamentarium against CRE infections, which is at least as efficacious as alternative regimens and likely to be better-tolerated.

http://0-cid.oxfordjournals.org.sbda-opac.unicatt.it/content/current

The mechanisms by which blaKPC-3 mutations mediate ceftazidime-avibactam resistance and reversion to carbapenem susceptibility are not defined..

• Meropenem at clinically achievable concentrations was bactericidal against ceftazidime-avibactam-resistant K pneumoniae in vitro, and it eradicated isolate 4-C from our patient’s bloodstream.

• However, meropenem resistance has emerged in ceftazidime-avibactam-resistant isolates from our patients during in vitro passage at subinhibitory meropenem concentrations.

Chart review for 60 patients who received CAZ-AVI for a CRE infection. In-hospital mortality was 32% 53% of patients had microbiological cure 65% had clinical success

There were no statistically significant differences between monotherapy with CAZ-AVI and combination therapy for any of the outcomes.

38 patients with infections caused by CRE (36) or P. aeruginosa (2) who were treated in Europe and Australia with ceftazidime-avibactam. The most common infections were intra-abdominal. 68.4% of patients had primary or secondary BSI; 65.8% of patients concurrently received other antibiotics to which their pathogen was non-resistant in vitro, 73.7% experienced clinical and/or microbiological cure, and 20.8% with documented microbiological cure vs. 71.4% with no documented microbiological cure died.

31 patients (8 in ceftazidime-avibactam group and 23 in the comparator group)

No significant differences in crude mortality were found between study and comparator

groups (p = 0.19)

Patients in study group had higher clinical cure rates than the comparator group within

14 days of initiating treatment (85.7% vs. 34.8%, respectively, p = 0.031)

• Ceftazidime-avibactam treatment of carbapenem-resistant K. pneumoniae bacteremia was associated with higher rates of clinical success (P=0.006) and survival (P=0.01) than other regimens.

• Aminoglycoside- and colistin-containing regimens were associated with increased rates of nephrotoxicity (P=0.002).

Thirty-day mortality rates was 28% (31/109). Treatment regimens included C-A (n=13), CB+AG (n=25), CB+COL (n=30), and others (n=41); the corresponding clinical success rates by regimen were 85% (11/13), 48% (12/25), 40% (12/30), and 37% (15/41), respectively. C-A was administered as monotherapy (n=8) or in combination with gentamicin (n=5); corresponding success rates were 75% (6/8) and 100% (5/5), respectively.

Thirty-eight patients were treated first with CAZ-AVI and 99 with colistin. Most patients received additional anti-CRE agents as part of their treatment. BSI (n = 63; 46%) and respiratory (n = 30; 22%) infections were most common. In patients treated with CAZ-AVI versus colistin, hospital mortality 30 days after starting treatment was 9% versus 32%, respectively (P = .001).

CAZ-AVI Colistin

Four strains were assessed in an in vitro, one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for 96 h. Against susceptible isolates, amikacin displayed similar activity compared with caz/avi. Polymyxin B produced comparable activity to caz/avi against two strains. Neither meropenem nor tigecycline produced effective killing.

Roma Milano Torino Udine Modena Pisa Genova

Bologna Palermo Napoli Pescara Perugia Verona Ferrara

Apr 2016 – Dec 2017

Variable All infections

(n=138) Bacteremic infections (n=104)

Nonbacteremic infections

(n=34) P value

Ward submitting index culture

Medical (all) 60 (43.5) 42 (40.4) 18 (52.9) 0.20 Hematology 9 (6.5) 6 (5.7) 3 (8.8) 0.53

Surgical (all) 32 (23.2) 23 (22.1) 9 (26.5) 0.60 Transplants 7 (5.1) 5 (4.8) 2 (5.9) 0.80

ICU 46 (33.3) 39 (37.5) 7 (20.6) 0.07 Days before CAZ-AVI treatment median (IQR)

7 (3-10) 7 (3-9) 7 (4-10) 0.23

CAZ-AVI combined with: 109 (78.9) 82 (78.8) 27 (79.4) 0.94

non-carbapenem drugsd 88/109 (80.7) 63/82 (76.8) 25/27 (92.6) 0.07

carbapenemsd 21/109 (19.3) 19/82 (23.17) 2/27 (7.4) 0.07

Days of CAV-AVI treatment - median (IQR)

14 (4-41) 14 (3-28) 15 (6-55) 0.18

30-day mortality 47 (34.1) 38 (36.5) 9 (26.5) 0.28 Infection relapsee 12 (8.7) 10 (9.6) 2 (5.8) 0.50

S R

• Three patients (2.2%) (2 with bacteremia, 1 with pneumonia) had persistently positive cultures after starting CAZ-AVI treatment, and their isolates eventually developed in vitro resistance to the drug.

• Two of the three were treated with CAZ-AVI monotherapy, and one of the two received chronic renal replacement therapy.

Thirty-day survival rates of CAZ-AVI treated bacteremic patients according to concomitant drugs used as combitation therapy or to CAZ-AVI monotherapy.

Characteristics of patient groups whose KPC Kp bacteremic infections were treated with CAZ-AVI-containing salvage regimens (cases) or alternative salvage regimens

Cases

(n=104) Controls (n=104) P value

Age - median (IQR) 60 (27-79) 72 (53-85)

Percentages of 30 day survival in patients with BSI across treatment regimens

% s

urvi

val

53/82 64,6 %

40/77 51,9 %

13/22 59,1 %

6/27 22,2 %

Grafico1

CAZ AVI combi

combi w/o CAZ AVI

CAZ AVI mono

mono w/o CAZ AVI

Colonna1

0.646

0.519

0.591

0.222

Foglio1

Colonna1

CAZ AVI combi64.60%

combi w/o CAZ AVI51.90%

CAZ AVI mono59.10%

mono w/o CAZ AVI22.20%

Per ridimensionare l'intervallo di dati del grafico, trascinare l'angolo inferiore destro dell'intervallo.

Multivariate analysis of factors associated with 30-day mortality in the 208 patients with KPC-Kp bacteremia.

Without propensity score

adjustment

Adjusted for the propensity

score for therapy with CAZ-AVI

Variables P value OR (95% CI) P value OR (95% CI)

Mechanical ventilation

Kaplan-Meier survival analyses in the cohorts with KPC Kp bloodstream infections (BSIs)

after adjustment for the presence of septic shock at the start of salvage treatment

P

• Ceftazidime-avibactam was used to treat 77 patients with CRE infections.

• 33 (43%) infections were pneumonia (26, 79% VAP), 20 (26%) were bacteremia, 8 (10%) UTI, 7 (9%) intra-abdominal infections, 6 (8%) skin/soft tissue infection, and 3 other infections.

• Thirty-day survival rate was 81%. • Success rates were lowest for pneumonia (36%) and

higher for bacteremia (75%) and urinary tract infections (88%).

• Ceftazidime-avibactam resistance emerged in 10% of patients

Colistin does not potentiate the in vitro killing activity of ceftazidime-avibactam in static time-kill models. The combination did not suppress ceftazidime-avibactam resistance

• 57 patients were treated with CAZ/AVI. The median age was 64 years, 77% were male and the median Charlson index was 3.

• The most frequent sources of infection were intra-abdominal (28%), followed by respiratory (26%) and urinary (25%). Thirty-one (54%) patients had a severe infection (defined as presence of sepsis or septic shock).

• Most patients received ceftazidime/avibactam as monotherapy (81%) and the median duration of treatment was 13 days.

• Mortality at 14 days was 14%. • There was no association between mortality and monotherapy with

ceftazidime/avibactam. • The recurrence rate at 90 days was 10%. • Ceftazidime/avibactam resistance was not detected.

OXA-48

CAZ/AVI shows promising results, even in monotherapy, for the treatment of patients with severe infections due to OXA-48-producing CRE and limited therapeutic options. The emergence of resistance to ceftazidime/avibactam was not observed.

OXA-48

MBL

Diapositiva numero 1Disclosures (last 5 years)Diapositiva numero 3Mechanisms underlying resistance to carbapenems in EnterobacteriaceaeDiapositiva numero 5In vitro activity of ceftazidime-avibactamCeftazidime-avibactam Phase III �clinical trial programmeREPRISE study efficacy results �mMITT populationReprise�Treatment in the BAT group (safety population)REPROVE study �Primary endpoint efficacy: Clinical cure rates at TOC�(CE and cMITT populations)Diapositiva numero 11Diapositiva numero 12Diapositiva numero 13Diapositiva numero 14Diapositiva numero 15Diapositiva numero 16Diapositiva numero 17Diapositiva numero 18Diapositiva numero 19Diapositiva numero 20Diapositiva numero 21Diapositiva numero 22Diapositiva numero 23Diapositiva numero 24Diapositiva numero 25S RThirty-day survival rates of CAZ-AVI treated bacteremic patients according to concomitant drugs used as combitation therapy or to CAZ-AVI monotherapy.�Characteristics of patient groups whose KPC Kp bacteremic infections were treated with CAZ-AVI-containing salvage regimens (cases) or alternative salvage regimensPercentages of 30 day survival in patients with BSI across treatment regimensMultivariate analysis of factors associated with 30-day mortality in the 208 patients with KPC-Kp bacteremia.�Kaplan-Meier survival analyses in the cohorts with KPC Kp bloodstream infections (BSIs)Diapositiva numero 32Diapositiva numero 33Diapositiva numero 34Diapositiva numero 35Diapositiva numero 36Diapositiva numero 37Diapositiva numero 38Diapositiva numero 39Diapositiva numero 40