The role of a new Cephalosporin with a beta …...The role of a new Cephalosporin with a...

The role of a new Cephalosporin with a beta-lactamase inhibitor in complicated Intra-Abdominal (cIAI) and

complicated Urinary Tract Infections (cUTI)

Nikolaos V. Sipsas, MD, FIDSA Associate Professor

Internal Medicine – Infectious Diseases General Hospital of Athens “Laiko”,

Medical School, National and kapodistrian University of Athens

Circular ΕΟΦ 81867/19.11.2012 Conflict of Interest (2012-2016)

•  Speakershonoraria,researchandtravelgrantsfrom:•  AbbVie•  Astellas•  Gilead•  GSK•  Janssen•  MSD•  Pfizer

Ce#olozane/Tazobactam

3

NewCephalosporin&Oldinhibitor

Class Ø  Antipseudomonal Cephalosporin + β-lactamase inhibitor Ø  Fixed 2:1 ratio

Mode of Action Ø  Rapidly Bactericidal Ø  Inhibits cell wall synthesis Ø  Active against P. aeruginosa with porin

deficiencies or mutations Ø  Inhibits β-lactamases Ø  Broad spectrum to most ESBL-producing

Enterobacteriaceae

Zhanel et al. Drugs. 2014;74:31-51. Ceftolozane/Tazobactam, SmPC 2017

+

Selec;veMechanismofAc;onvs.P.aeruginosa

4

Ce#olozaneisaCephalosporinwithpotentpenicillin-bindingprotein(PBP)inhibitorac;vityandhasahighaffinityforallPseudomonasaeruginosaPBPsessen;alforcellwallsynthesis

Ce#olozane

5

NotaffectedbyCommonResistanceMechanismsofP.aeruginosa

1. Takeda et al. Antimicrob Agents Chemother. 2007;51:826-30. 2. Crandon et al. Antimicrob Agents Chemother. 2012;56:6137-46. 3. Davies et al. J Antimicrob Chemother. 2011;66:2298-2307. 4. Livermore. Clin Infect Dis. 2002;34:634-40. 5. Riera et al. J Antimicrob Chemother. 2011;66:2022-7. 6. Zhanel et al. Drugs. 2007;67:1027-52.

Outermembrane

porinlossβ-lactamaseenzyme Effluxpump Effluxpump

OprD AmpC MexXY MexAB

CeGolozane1 0 + 0 0

CeGazidime2 0 ++++ 0 ++

Imipenem3-6 ++++ 0/+ 0 0

Meropenem3-6 +++ 0/+ 0 ++

Piperacillin/tazobactam4 0 ++++ 0 +++

Cefepime4 0 +++ ++ ++

Aztreonam4 0 ++ 0 +++

0:NoimpactonMICrelaPvetoparentstrain.+:2-foldincreaseinMICrelaPvetoparentstrain.++:4-foldincreaseinMICrelaPvetoparentstrain.+++:8-foldincreaseinMICrelaPvetoparentstrain.++++:>8-foldincreaseinMICrelaPvetoparentstrain.

Tazobactam

6

InvitrocoverageagainstESBLs

Inhibitoryac;vityofβ-lactamaseinhibitorsagainstvariousβ-lactamases

1. Livermore et al. J Antimicrob Chemother. 2010;65:1972-4. 2. Titelman et al. Diag Microbiol Infect Dis. 2011;70:137-41. 3. Drawz and Bonomo. Clin Microbiol Rev. 2010;23:160-201. 4. Jacoby and Munoz-Price. N Engl J Med. 2005;352:380-91. 5. Shadid et al. Crit Rev Microbiol. 2009;35:81-108. 6. Ceftolozane/Tazobactam SmPC 2017. 7. Zhanel et al. Drugs. 2013;73:159-77.

-:NoinhibitoryacPvity+:InhibitoryacPvity

β-lactamaseenzyme

AmpC CTX-M SHV TEM KPC MBLSulbactam3 -/+a + + + - -Clavulanicacid4,5 - + + + - -Tazobactam3,6 - + + + - -Avibactam7 + + + + + -


7

Invitroac;vityagainstMDRP.aeruginosa

Farrell et al. Antimicrob Agents Chemother. 2013;57:6305-10.

Species(n)

Ce#olozane/tazobactam Ce#azidime Meropenem Piperacillin/

tazobactam Levofloxacin

MIC50/90(mg/L)

%S≤8mg/La %Sb %Sb %Sb %Sb

Enterobacteriaceae(7071)–MDR(601)

0.25/14/>32

96.162.7

88.122.0

98.077.0

90.934.6

81.917.8

Escherichiacoli(2691) 0.25/0.5 99.3 91.7 99.7 95.0 72.6–ESBLphenotype(327) 0.5/4 31.8 97.6 77.4 22.6Klebsiellapneumoniae(1298) 0.25/32 89.1 82.2 92.2 84.7 82.9–ESBLphenotype(244) 32/>32 5.3 59.0 25.4 20.1Enterobacterspp.(1029) 0.25/8 93.5 75.6 98.6 81.5 94.7Citrobacterspp.(381) 0.25/8 91.6 84.8 97.9 87.1 91.9Serra5aspp.(573) 0.5/1 99.5 97.7 99.1 96.9 96.5Pseudomonasaeruginosa(1971) 0.5/2 98.5 82.9 80.3 76.8 74.9–MDR(310) 2/8 90.3 22.6 19.4 11.0 15.2–XDR(175) 4/16 85.7 9.1 7.4 2.3 2.9

Ce#olozane/Tazobactamvs.Pip/Tazo

8

LowerMIC90againstESBLsActivity against Escherichia coli and Klebsiella pneumoniae producing ESBLs

Isolates E. coli (n = 149) and K. pneumoniae (n = 20) (most were CTX-M-14 ή M-15)

Titelman et al. Diagn Microbiol Infect Dis. 2011;70:137-41.

8

93

1

58

0

20

40

60

80

100

CeGolozane CeGolozane/tazobactam Piperacillin Piperacillin/tazobactam

Suscep

;bility(%

)

An;bio;c MIC(mg/L) MIC50 MIC90 Range

CeGolozane 64 >64 <0.25->64 CeGolozane/tazobactam <0.25 2 <0.25->64 Piperacillin >128 >128 <0.5->128 Piperacillin/tazobactam 8 64 <1->128

Ce#olozane/Tazobactamvs.Ce#azidime/AvibactamPotentan;pseudomonalac;vity

Buerhle et al. (2016): doi:10.1128/AAC.02969-15

¢  Morecef-aviisolatesexhibitedMICsaboveorattosuscepPbilitybreakpoint(p=0.003).

•  Ce#olozane/Tazobactam:13%(5/38)•  Ce#azidime-avibactam47%(18/38)

¢  “WeanPcipatethatceGolozane-tazobactamwillbemostusefulatourcenteragainstinfecPonsthatarecausedbyP.aeruginosaresistanttoandallβ-lactams,astheagentislikelytobemoreac;vethance#azidime-avibactamandlesstoxicthancolis;norgentamicin.

¢  WeanPcipatethatceGazidime-avibactamwillbemostusefulagainstinfecPonscausedbyCRE,forwhichβ-lactamasesandcarbapenemasesarepredominantresistancedeterminants.”

¢  StudyconductedinUS

LowratesofResistancetoCe#olozanebyP.aeruginosainvitro

Highresistance:inisolateswithmultiplemutationsthatleadto

modificationofAmpC

Cabot et al. Antimicrob Agents Chemother. 2014;58:3091-9.

In vitro dynamics of resistance development in PAO1 In vitro dynamics of resistance development in PAOMS

0 1 2 3 40

64

Days

An;b

io;c

concen

tra;

on(xMIC)32

168421

0.55 6 7

CeGazidimeMeropenemCiprofloxacinCeGolozane/tazobactam

0 1 2 3 40

64

Days

An;b

io;c

concen

tra;

on(xMIC)

32168421

0.55 6 7

The development of resistance of P. Aeruginosa in Ceftolozane/ tazobactam is slower compared to ceftazidime, meropenem and ciprofloxacin

11

Ceftolozane/tazobactam dose (mg)

8

4

0

0 250 125

-4

500 250

750 375

1000 500

1250 625

1500 750

Δ L

og10

CFU

/mL

of th

e dr

ug-r

esis

tant

su

bpop

ulat

ion

at 1

0 da

ys

ESBL-producingEscherichiacoli1

Ceftolozane dose (mg)

Pseudomonasaeruginosa2

0 -1 -2

-4 -5

-3

0

5 4

2 1

3

62.5 31.25

125 62.5

250 125

500 250

750 375

1000 500

2000 1000

§  Inthe10-dayhollow-fibermodel,resistancewasnotselectedatclinicallyrelevantdosesusedinpaPentswithnormalrenalfuncPon1,2

§  Thehigherce#olozane/tazobactamdoseregimensnotonlypreventedresistanceemergencebutalsosterilizedthemodelsystem1

1.  VanScoy et al. Antimicrob Agents Chemother. 2013;57:4134-8. 2.  VanScoy et al. Antimicrob Agents Chemother. 2014;58:6024-31.

ClinicallyRelevantDosingRegimensofCe#olozane/TazobactamPreventResistanceAmplifica;onforbothE.coliandP.aeruginosa

Pharmacokine;c

•  Dose-independent linear kinetics1

•  Mean t1/2 ̴ 2.7 h after multiple dosing1

•  No relevant drug accumulation with q8h dosing1

•  Extensive renal excretion1

–  High urine recovery rate (100% ceftolozane)

•  ~21% protein binding2

•  No drug-drug interactions between: –  Ceftolozane and tazobactam1

–  Ceftolozane/tazobactam and any OAT1/OAT3, CYP1A2, and CYP3A4 substrates that were tested 2

Ceftolozane

Tazobactam

q8h/q12h,every8/12hours;PK,pharmacokine;cs;t1/2,elimina;onhalf-life.1. Miller et al. Antimicrob Agents Chemother. 2012;56:3086-91. Ceftolozane/Tazobactam, SmPC 2017.

Semilogconcentra;on-;meprofilea#ersingle-doseadministra;onof1.5gce#olozane/tazobactam1

0 4 8 12 16 20 24 Time (h)

0.1

1

10

100

500

Mea

n Pl

asm

a C

once

ntra

tion

(µg/

mL)

0.01

¢  Peak plasma [c]: 69.1 / 18.4 mg/L ¢  AUC: 172 / 24.4 mg•h/L ¢  Protein bound: 16-21 / 30% ¢  Vd: 13.5 / 18.2 L ¢  Metabolism: Not to any appreciable extent ¢  Half-life: 2.77 / 0.91 hr ¢  Excretion: >95% / >80% excreted unchanged

in urine

Dosing,administra;onandadjustmentsinRenalInsufficiency

13

Ceftolozane/Tazobactam, SmPC 2017

Infec;on Dose FrequencyInfusion;me(h)

Dura;onoftreatment

cIAIs 1.5g(1g/0.5g) q8h 1 4-14days

cUTIs,includingpyelonephri;s 1.5g(1g/0.5g) q8h 1 7days

CrCL(mL/min)α Dose

30to50 Ce#olozane/tazobactam750mg(500mg/250mg)IVq8h

15to29 Ce#olozane/tazobactam375mg(250mg/125mg)IVq8h

Endstagerenaldiseaseonhaemodialysis

Asingleloadingdoseof500mgCe#olozane/250mgTazobactamfolloweda#er8hoursbya100mgCe#olozane/50mgTazobactammaintenancedoseadministeredevery8hoursfortheremainderofthetreatmentperiod(onhaemodialysisdays,thedoseshouldbeadministeredattheearliestpossible;mefollowingcomple;onofhaemodialysis)

Registra;onTrials

14

ASPECTcIAI&cUTI

ASPECT-cIAIΣχεδιασμόςΜελέτης

•  Συγκεντρωτικήανάλυση2τυχαιοποιημένων,ελεγχόμενων,διπλάτυφλών,πολυκεντρικώνδοκιμώνΦάσης3σεενηλίκουςασθενείςμεcIAI

•  Κύριοςαντικειμενικόςσκοπός–  Ηκατάδειξητηςμηκατωτερότηταςτουσυνδυασμούκεφτολοζάνης/ταζομπακτάμηςκαι

μετρονιδαζόληςέναντιτηςμεροπενέμηςμεβάσητηδιαφοράσταποσοστάκλινικήςίασηςκατάτηνεπίσκεψηTOC(26-30ημέρεςμετάτηνέναρξητηςθεραπείας)στονπληθυσμόMITT(FDA)ήτονπληθυσμόCE(EMA)

Eckmannetal.ECCMID2014.PosterP0266a.

Κεφτολοζάνη/ταζοµπακτάµη1,5 g IV q8h

+ µετρονιδαζόλη 500 mg IV q8h

Μεροπενέµη 1 g IV q8h

Συνολικά 988 ασθενείς µε cIAI Τυχαιοποίηση (1:1)

Διάρκειατηςθεραπείας:4-14ημέρεςενδοφλέβιουφαρμάκουτηςμελέτης(χωρίςαλλαγήσεαπότουστόματοςθεραπεία)

CXA-cIAI-10-08 N = 494

(προγραµµατισµένο δείγµα)

CXA-cIAI-10-09 N = 494

(προγραµµατισµένο δείγµα)

Ce#olozane/Tazobactamvs.Meropenem

16

Non-inferior

Ce#olozane/Tazobactam+metronidazole

n/N(%)

Meropenemn/N(%)

Percentagedifference(99%CI)

323/389(83,0) 364/417(87,3) -4,2(-8,9έως0,5)

259/275(94,2) 304/321(94,7) -1,0(-4,5έως2,6)

Ce#olozane/Tazobactam+metronidazole

n/N(%)

Meropenemn/N(%)


353/375(94,1) 375/399(94,0) 0,0(-4,2έως4,3)

399/476(83,8) 424/494(85,8) -2,2(-8,0έως3,4)

FDA95%CI

-10 -5 5 10 150

PopulaPonME

PopulaPonMITT

CeGolozane/Tazobactam–Meropenem (difference[%])

NI

EMA99%CI

-12,5 -5 5 15

PopulaPonCEPopulaPonITT

0

NI

-10 10

ClinicalCureattheTestofCurevisit

Solomkin et al. Clin Infect Dis. 2015;60(10):1462-71.


17

ClinicalCureperpathogen

95 9386

10095

919488

10093

9692

0

20

40

60

80

100

E.coli(n=439)

K.pneumoniae(n=55)

E.cloacae(n=44)

P.aeruginosa(n=55)

Gram-veanaerobe(n=246)

Gram+veaerobe(n=353)

CeGolozane/Tazobactam+metronidazole

Meropenem

Clin

ical

Cur

e (

%)



18

EfficacyagainstESBLs

100 100 100 100 100 100

88.5

72.7

90

77.875

00

20

40

60

80

100

EnterobacteriaceaeESBL+

EnterobacteriaceaeCTX-M-14/15

E.coliESBL+ E.coliCTX-M-14/15 K.pneumoniaeESBL+ K.pneumoniaeCTX-M-14/15

CeGolozane/Tazobactam+metronidazole Meropenem

4/422/22 23/26 12/12 14/148/11 18/20 9/9 7/9 6/6 3/4

Clin

ical

Cur

e (%

)


ASPECT-cUTIΑντικειμενικοίΣκοποί•  Κύριος

–  FDA:Κατάδειξητηςμηκατωτερότητας(NI)τουσυνδυασμούκεφτολοζάνης/ταζομπακτάμηςέναντιτηςλεβοφλοξασίνηςμεβάσητηδιαφοράστασύνθεταποσοστάμικροβιολογικήςεκρίζωσηςκαικλινικήςίασηςστονπληθυσμόmMITTκατάτηνεπίσκεψηTOC(7ημέρεςμετάτηνολοκλήρωσητηςθεραπείας)(όριοNI10%,95%CI)1

–  EMA:ΚατάδειξητηςNIτουσυνδυασμούκεφτολοζάνης/ταζομπακτάμηςέναντιτηςλεβοφλοξασίνηςμεβάσητηδιαφοράσταποσοστάμικροβιολογικήςεκρίζωσηςστονπληθυσμόMEκατάτηνεπίσκεψηTOC(όριοNI10%,99%CI)

•  Δευτερεύοντες1–  ΚλινικέςκαιμικροβιολογικέςανταποκρίσειςκατάτηνεπίσκεψηEOT,τηνεπίσκεψηTOCκαιτιςτελευταίες

επισκέψειςπαρακολούθησης(πληθυσμοίmMITTκαιME)–  Ασφάλειατουσυνδυασμούκεφτολοζάνης/ταζομπακτάμηςστηcUTI

1.Wagenlehneretal.ECCMID2014.PostereP449.

Κεφτολοζάνη/ταζομπακτάμη1,5gIVq8h

Λεβοφλοξασίνη750mgIVημερησίως

1083ασθενείςμεcUTI Τυχαιοποίηση(1:1)

CXA-cUTI-10-04N=558

CXA-cUTI-10-05N=525 Διάρκειατηςθεραπείας:

7ημέρεςενδοφλέβιουφαρμάκουτηςμελέτης(χωρίςαλλαγήσεαπότουστόματοςθεραπεία)

Ce#olozane/Tazobactamvs.Levofloxacin

20

Non-Inferior

ΌριοΝΙ

95%CI

PopulaPonME

PopulaPonmMITT

99%CI

CeGolozane/Tazobactam–Levofloxacin(difference[%])

-10 -5 5 10 150

PopulaPonmMITT

PopulaPonME

20

-10 -5 5 10 150 20

PrimaryObjecPvesFDA:CompositecureinpopulaPonmMITT

EMA:MicrobiologicaleradicaPoninpopulaPonME

Wagenlehner F, et al. Lancet. 2015;385(9981);1949-56.



Levofloxacinn/N(%)

Ce#olozane/Tazobactamn/N(%)

ClinicalCureandMicrobiologicalEradica;on

21

Superiorityvs.Levofloxacin*


Levofloxacinn/N(%) 95%CI

Compositecure 38/61(62.3) 20/57(35.1) 9.2to42.9

Clinicalcure 55/61(90.2) 42/57(73.7) 2.6to30.2

62.3

90.2

35.1

73.7

0

20

40

60

80

100

Compositecure Clinicalcure

Ce#olozane/tazobactam Levofloxacin

Pa;e

ntsw

ithcure(%

)

60

90

39.3

76.8

0

20

40

60

80

100

Composite cure Clinical cure

Ceftolozane/tazobactam Levofloxacin

Pa;e

ntsw

ithcure(%

)

Levofloxacin-resistantpathogensESBL-producingpathogensa


Levofloxacinn/N(%) 95%CI

Compositecure 60/100(60.0) 44/112(39.3) 7.2to33.2

Clinicalcure 90/100(90.0) 86/112(76.8) 3.1to22.9

*In patients: - ≥65 years old - Infection at the lower urinary tract system - Pathogens resistant to Levofloxacin or pathogens producing ESBLs



22

EfficacyagainstESBLs

87.891.7

74.4

62.5

0

20

40

60

80

100

Escherichiacoli Klebsiellapneumoniae

Compo

sitecure(%

)

11/12 5/836/41 32/43



23

MicrobiologicalEradica;onperPathogen

88.9 90.5

75

84

70

100

33.3

85.7

78 79.6

50

60.9

28.6

72.7

85.7

58.3

0

20

40

60

80

100

Enterobacteriaceae(643)

E.coli(546) E.coliESBL(72) K.pneumoniae(48) K.pneumoniaeESBL(17)

P.mirabilis(21) E.cloacae(13) P.aeruginosa(19)

MicrobiologicalEradica;o

n(%

)

Key Gram-negative PathogensCeGolozane/tazobactam Levofloxacin


Ce#olozane/TazobactamHighratesofsuscep;bilityagainstESBLs

Ce#olozane/TazobactamLowMICagainstESBLs


26

SafetyProfileagainstMeropenem&Levofloxacin

Solomkin et al. Clin Infect Dis. 2015;60(10):1462-71. Wagenlehner F, et al. Lancet. 2015;385(9981);1949-56.

Conclusion

27

Ø  Invitroac;vityagainstESBLsandMDRP.aeruginosa3

Ø  Non-InferiortoMeropenemincomplicatedIntra-AbdominalInfecPons2

Ø  Non-InferiortoLevofloxacinincomplicatedUrinaryTractInfecPons1

Ø  Superiorityvs.LevofloxacinininfecPonsoflowerUrinaryTractSystem1

1. Wagenlehner FM et al. Lancet. 2015;385:1949-1956. 2. Solomkin JS et al. Clin Infect Dis. 2015;60(10):1462-1471. 3. Ceftolozane/tazobactam, SmPC 2017 4. VanScoy B et al. Antimicrob Agents Chemother. 2013;57(8):4134-4138. 5. VanScoy B et al. Antimicrob Agents Chemother. 2014;58(10):6024-6031.

WhentoconsiderceGo/tazo•  Asacarbapenem-sparingdefiniPvetherapyforthe

treatmentofinfecPonscausedby:–  ESBL-producingEnterobacteriaceae–  MDRP.aeruginosa.

•  IncombinaPonwithmetronidazoleforempirictherapyof:–  healthcare-associatedcIAIs–  inpaPentswithriskfactorsforMDRs–  inareaswheretheprevalenceofMDRpathogensishigh

•  PhaseIIItrialforthetreatmentofvenPlatednosocomialpneumonia

28

PaPentProfile

§  History(last6mo)oftreatmentwithbroad-spectruman;bio;cs

§  Admissiontoahospitalfor>5days

§  PrioradmissiontoICU

§  Long-termhealth-carefacili;es

§  Hospitaliza;onclosetoknownMDRcarrier

§  Dialysis

§  Immunosuppression

§  Healthcareassociatedinfec;ons

Akovaetal.ClinMicrobiolInfect2012;18:439

Healthcare-associatedinfecPons,intheUSA,peryear

•  ESBL-producingEnterobacteriaceae, ~26,000

•  Carbapenem-resistantEnterobacteriaceae,

~9,000

•  MDRP.aeruginosa ~6,700

•  EspeciallyaffectedbyMDRsGram-ves

–  cUTIs

–  cIAIs30

HamptonT.JAMA.2013;310:1661–1663.ZilberbergMD,etal.InfectControlHospEpidemiol.2013;34:940–946.

CARBAPENEM–SPARINGREGIMENSINTHECONTEXTOFABSPROGRAMS

Thankyou

The role of a new Cephalosporin with a beta …...The role of a new Cephalosporin with a...

Documents

Transcript of The role of a new Cephalosporin with a beta …...The role of a new Cephalosporin with a...