DAVID M LIVERMORE

New agents:

clinical use & testing

University of East Anglia

Antibiotics, licensed in the UK since 2015

Class License

Tedizolid (MSD) Oxazolidinone SSTI

Dalbavancin (Cardiome) Lipoglycopeptide SSTI

Oritavancin (Melinta) Lipoglycopeptide SSTI – not marketed

Ceftolozane/tazobactam

(MSD)

b-Lactam/BLI cIAI, cUTI

Ceftazidime/avibactam b-Lactam/BLI cIAI, cUTI, HAP,

MDR pathogens

Ceftobiprole Cephalosporin HAP (not VAP)

TedizolidLinezolid

Tedizolid MICs 4 – 8 x lower than linezolid

…. 0.25-0.5 mg/L vs. 1-4 mg/L for staph & enterococci

200 mg q24h instead of 600 mg q12h

EUCAST S <0.5, R >0.5 vs. linezolid S <4, R >4 mg/L

…. 0.5-1 mg/L for cfr isolates, 4-8 mg/L for rRNA mutation

Prokocimer et al., JAMA 2013;309:559; Livermore et al. JAC 2009;63:713

Shaw, Barbachyn Ann N Y Acad Sci 2011;1241:48-70

Tedizolid vs. linezolid

ESTABLISH – Tedizolid Phase III SSSI trials, pooled, 1333 patients

ESTABLISH 1 = oral

ESTABLISH 2 = iv/oral

Tedizolid

200 mg q24h,

6 days

Linezolid

600 mg q12h

10 days

Cure at end of therapy 87.0% 87.9%

2-3 day response 81.4% 79.4%

GI side effects 16.0% 23.0%*

Nausea 8.2% 12.2%*

Platelets <150,000/mm3 at

EOT

4.9% 10.8%*

* P <0.05 Shorr et al., AAC 2015; 59:864

Oxazolidinones & myelosuppression

Linezolid is myelosuppressive

Weekly blood counts advised; caution re. prolonged Rx

3 cases where platelet recovery followed switch to tedizolid:

1 parenchymal abscess: 23 days linezolid, platelets <83 x 109/L switch to

tedizolid, platelets normal in 10 days, continued 9 weeks

1 vascular graft infection: 58 days linezolid, platelets <83 x 109/L; 10 days

daptomycin, platelets normalised; then 88 days tedizolid

1 hip replacement: 30 days linezolid, haemoglobin 8.5 g/dL & reticulocytes

<10x109/L; switch to tedizolid for 10 days, levels/counts recovered

Khatchatourian et al. JAC 2017;72:2135

Lipoglycopeptides

Rapid cidality

Oritavancin, telavancin

Long (c. 10 day) T1/2

Oritavancin, dalbavancin

Activity vs. VanB

All except vancomycin

Activity vs. VanA

? Oritavancin

VISA, hetero-VISA and dalbavancin

7

Dalbavancin / S. aureus Range MIC50 MIC90

MRSA (15) <0.03-0.12 0.06 0.06

VISA (8) 0.5-2 Too few Too few

hVISA (10) 0. 12-0.25 0.25 0.15

Jones et al., DMID 2013;75:304 Citron et al. DMID 2014;79:438

Clinical response @48-72h: ITT popn.Dalbavancin 2-dose, Phase III

Boucher et al. NEJM. 2014;370:2169

8

DISCOVER 1 DISCOVER 2 Pooled

Pati

en

ts,

%

Response =

Stop of spread of infection erythema AND

Temperature <37.6C on 3 consecutive readings 6 h apart.

Dalbavancin

1g day 1

0.5g day 8

Vancomycin

1g q12h

10-14 days

(Linezolid

oral option

from day 4)

Dalbavancin, 1- & 2- dose trials: 1.5g (Day 1) or 1+0.5g (Days 1 & 8)

Dunne et al. CID 2016;62:545

Candidates for dalbavancin as OPAT for ABSSSI?

• Patients likely to comply poorly with oral regimens

• Patients unable to reach/bring to clinic daily

• Patients likely to abuse iv access

... but otherwise well enough to be outside hospital

... In single-dose trial, 379 /698 (54.3%) were outpatients

• Need to evaluate multi-dose regimens for chronic infections

• Ongoing Phase II trial in long bone osteomyelitis

Dunne et al. CID 2016;62:545

Mischlinger et al., Wien Klin Wochenchr 2017 Aug 3

http://www.clinicaltrials.gov NCT03091439

Ceftolozane (Merck)

Takeda et al. AAC 2007:51; 826–830

• Protected vs. ESBLs by combination with tazobactam

• Not stable to carbapenemanses

• Not stable to Enterobacter AmpC

Avibactam, a diazabicyclooctane

Combined with ceftazidime

Inhibits:

Class A, inc. KPC

Class C / AmpC

Some class D

NOT Class B

MICs ceftolozane-tazobactam: ESBL+ve: BSAC bacteraemia isolates 2011-5

http//:www.bsacsurv.org Livermore et al. JAC 2017; 72: 2278

0

20

40

60

80

100

120

140

160

0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 128 256 >256

MIC (mg/L)

E. coli Klebsiella spp.

E. coli 2% resistant - MIC >1 mg/L

Klebsiella 16% resistant - MIC >1 mg/L

Ceftazidime + avibactam (4 mg/L) Enterobacteria with CTX-M ESBLs

Livermore JAC 2008; 62:1053-6

Ceftolozane-tazobactam vs. ESBL isolates from all cUTI & cIAI trials

153 patients (11%) had ESBLs: 103 cUTI, 50 cIAI

More were older (31% vs 21% aged >65 & renally impaired

UTI comparator, levofloxacin; cIAI, meropenem

Ceftolozane-tazo Comparator

Clin Cure, cUTI 98.1 82.6 (levofloxacin)

Micro erad, cUTI 72.2 45.7 (levofloxacin)

Clin Cure, cIAI 95.8 88.5 (meropenem)

Micro erad, cIAI 95.8 88.5 (meropenem)

Popejoy ID Week 2014, Poster 260

REPRISE trial CAZ-AVI in ceftazidime-R infections

• 333 patients; open label randomised; 165 got CAZ-AVI &

168 ’best available’ Rx

97% ‘best available’ patients got carbapenems

Mostly (96%) as monotherapy

>90% Enterobacteriaceae, mostly E. coli/Klebsiella

‘mostly ESBL producers’

• 154 CAZ-AVI patients analysable (144 cUTI; 10 cIAI)

• 148 Best available Rx analysable (137 cUTI; 11 cIAI)

Carmeli et al. LID 2016;16:661 & 16:997

REPRISE trial outcomes

Carmeli et al. LID 2016;16:661

Ceftolozane-tazo vs. carbapenemase Enterobacteriaceae sent to AMRHAI- first year of testing from July 2015

MIC (mg/L)

0.25 0.5 1 2 4 8 16 >16

OXA-48

C’taz <4 28 57 42 23 4 1

OXA-48

C’taz >4 1 5 10 9 18 27 24 104

KPC 2 1 4 17 63 47 50 32

MBL 1 315

Livermore et al. JAC 2017; 72: 2278

Ceftazidime-avibactam, 207 referred KPC Enterobacteria, July ‘15 to July ‘16

0

10

20

30

40

50

60

70

80

90

Co

un

t

MIC (mg/L)

Ceftazidime CAZ-AVI

138 Klebsiella, 33 E. coli; 30 Enterobacter/Citrobacter; 6 others

CAZ-AVI, 343 referred OXA-48 Enterobacteriaceae, July 2015 to July ‘16

154 Klebsiella, 130 E. coli; 53 Enterobacter/Citrobacter; 6 others

0

10

20

30

40

50

60

70

80

90

100

Co

un

t

MIC (mg/L)

Ceftazidime

CAZ-AVI

CAZ-AVI compassionate use: 38 infections carbapenemase producers

• Salvage therapy, most-intra-abdominal infections

• 18 known bacteraemic

• 36 Carbapenemase-producing Enterobacteriaceae

• Microbiological cure predicted survival (p <0.01)

• OXA-48 (compared with KPC) predicted mortality (p = 0.07)

Temkin et al., AAC 2017;61: e01964

n Clinical cure Microbiological

cure

Survived to

discharge

KPC 23 17 18 17 (74%)

OXA-48 13 8 6 5 (38%)

109 bacteraemias with carbapenem-R Enterobacteria (106 KPC)….

0

5

10

15

20

25

30

35

40

45

30

-day c

lin

ical o

utc

om

e Failure

Success

Ceftazidime/

avibactam

Carbapeenem/

aminoglycoside

Carbapenem/

colistin

Other

CAZ/AVI better for:

Success, p 0.006

Survival p 0.01

Shields et al., AAC 2017; 61: e00883

Ceftazidime-avibactam vs. Carbapenem-R Enterobacteriaceae

University of Pittsburgh, consecutive CAZ-AVI patients

37 carbapenem-R; 31 with KPC; 31 Klebsiella

Various infection sites: 12 pneumonias, 10 bacteraemias

Clinical cure = 67%

90-day survival = 62%

Microbiological failure = 10 (27%)

3 KPC cases with selection of resistance (MICs 64-128 mg/L)

Asp179Tyr substitution alone or in combination

Shields et al. CID 2016;63:1615 & AAC 2017; 61: e02097

Routes to raised b-lactam MICs for P. aeruginosa

Carben-

icillin

Pip-

tazo

Ceftaz-

idime

Aztreo-

nam

Imi-

penem

Mero-

penem

Loss of OprD

Raised efflux

Derepressed AmpC

Acquired MBL

Acquired ESBL

Acq’d penicillinase

Resistance MICs raised, may or may not exceed bpt

Small MIC rise or none No effect Livermore CID 2002;34:634

Ceftazidime, CAZ-AVI & ceftolozane tazo vs. P. aeruginosa groups

Mech

(hard & soft)

N* % Susceptible

Ceftazidime <8 CAZ-AVI <8+4 Ceftol-tazo <4+4

AmpC 149 20.8 94.6 96.6

Efflux defic Carb <16 75 100 100 100

Efflux Carb 32-128 303 100 99.7 100

Efflux Carb 256-512 398 65.3 86.0 99.7

Efflux Carb >512 152 27.4 41.7 94.7

ESBL 31 0 6.5 3.2

GES 19 73.7 89.5 84.2

MBL 125 0.8 0.8 0

Unass. CAZ low 79 100 92.4 100

Unass. CAZ mid 40 0 30.0 67.5

Unass. CAZ high 44 0 9.3 16.3

* 30 isolates not tested with ceftazidime avibactamLivermore et al., JAC 2017;72:2278;

Livermore et al., JAC 2017 epub

Ceftolozane-tazo vs. P. aeruginosa non-susceptible to ALL other b-lactams

Ceftolozane/

tazobactam

MIC (mg/L)

%S<0.25 0.5 1 2 4 8 16 >16

All (422) 0 20 90 72 37 23 15 165 51.9

Carbapenemase/E

SBL –ve (267) 20 90 71 35 21 12 18 80.9

Ceftazidime/

avibactam

All (411) 2 7 38 71 98 195 28.7

Carbapenemase/E

SBL –ve (267)2 6 36 69 90 58 43.3

ALL : imipenem >4; meropenem >2; ceftazidime >8; pip-tazo >16; carbenicillin

>128; EUCAST Criteria

Livermore et al., JAC 2017;72:2278; Livermore et al., JAC 2017 epub

Testing issues…

Tedizolid testing

• Breakpoints (S <0.5, R >0.5) for staphylococci, bHS

• Breakpoint (S <0.5, R >0.5) for S. anginosus

• Linezolid-S isolates can be assumed S

• No bpts for enterococci or S. pneumoniae

www.eucast.org

Dalbavancin testing

• Large sticky molecule….

• Not suitable for disc testing

• Broth MIC need polysorbate (Tween) 80 added @ 0.002%

• Agar MICs read higher (sticks to agar?)

• S. aureus susceptible to vanco/teico reliably susceptible

Lin et al. AAC 2005; 49: 770

www.eucast.org

Ceftolozane/tazobactam testing

• Fixed 4 mg/L tazobactam; 30+10 mg disc

• Criteria for Enterobacteriaceae and P. aeruginosa

• No major issues reported / apparent

www.eucast.org

Ceftazidime/avibactam testing issues

P. aeruginosa Enterobacteriaceae

MIC bpt

(mg/L)

Zone bpt

(mm)

MIC bpt

(mg/L)

Zone bpt

(mm)

Ceftazidime alone

(10 mg disc)<8, >8 >17, <17 <1, >4 >22, <19

CAZ-AVI

(10+4 mg disc)<8, >8 >17, <17 <8, >8 >13, <13

www.eucast.org

Ceftazidime alone, Enterobacteriaceae

CAZ-AVI Enterobacteriaceae

• Validation looks good

• But CAZ-AVI zone bpt small cf. CAZ alone

• May reflect different dynamics zone zone formation

• But needs watching!

Ceftobiprole

Staphylococci

• MICs mostly 0.5-2 mg/L for MRSA vs. ceftaroline, 0.25-1 mg/L

Enterobacteriaceae

• Widely active… more than ceftaroline... except if ESBL or K1

• Bpts S <0.25, R >0.25 very low

P. aeruginosa

• MICs mostly 1-4 mg/L, including for some with AmpC++

• EUCAST, insufficient evidence, no pK/pD bpt of S <4, R >4

http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Rationale_documents/Ceftobiprole

_Rational_Document_1.0_20160331f.pdf

In the days of empirical cefuroxime & MRSA we’d

have thought this wonderful

Now?

Perhaps we don’t sufficiently consider this….. or

ceftaroline…… vs. MRSA infections

Vancomycin vs. β-lactams for MSSA bacteraemia

Kim et al. AAC 2008;52:192–7

Cohort, 7 years

all cases

Case control matched for

underlying status

Vanco β-Lactam Vanco β-Lactam

No. cases 27 267 27 54

No. deaths 10 47 10 6

Deaths, % 37 18 37 11

p 0.02 <0.001