Susceptibility

Clinical efficacy against specific pathogens


Clinical efficacy has been established in clinical studies against the pathogens stated under its respective indication and that was susceptible to Zerbaxa in vitro:


Complicated Intra-abdominal Infections

Gramnegative pathogens

Enterobacter cloacae

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas aeruginosa


Grampositive pathogens

Streptococcus anginosus

Streptococcus constellatus

Streptococcus salivarius

Complicated Urinary Tract Infections, including pyelonephritis

Gramnegative pathogens

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Combines an Antipseudo­monal Cephalosporin with an Established Beta-lactamase Inhibitor1

Clinical efficacy in complicated urinary tract infections, including pyelonephritis, has not been established against the following pathogens, although in vitro studies suggest that they would be susceptible to ZERBAXA in the absence of acquired mechanisms of resistance1:

  • Citrobacter freundii
  • Citrobacter koseri
  • Enterobacter aerogenes
  • Morganella morganii
  • Serratia liquefacians
  • Serratia marcescens
  • Proteus vulgaris

The safety and effectiveness of ZERBAXA in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Minimum inhibitory concentration breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows1:

Pathogen MIC* (mg/L) Susceptible MIC* (mg/L) Resistant

Enterobacteriaceae

≤1

>1

Pseudomonas aeruginosa

≤4

>4

Culture and susceptibility information and local epidemiology should be considered when selecting or modifying antibacterial therapy.

*MIC=Minimum Inhibitory Concentrations

In vitro-data indicates that the following pahogens are not susceptible to ceftolozan/tazobaktam:


  • Staphylococcus aureus
  • Enterococcus faecalis
  • Enterococcus faecium

Referenser

  • 1.

    EU Summary of Product Characteristics for ZERBAXA, section 5.1. 2018/06.

Susceptibility testing

E-test bioMérieux

The pages below contains information regarding available resources for susceptibility testing for Zerbaxa, the list may not be complete, please consult your local vendor of such materials for current status

Ceftolozane and Tazobactam ETEST® C/T 256 Strip Available from bioMérieux

Ordering Information:

Description

µg/mL

Strip/Box

Ref.

ETEST® Ceftolozane-Tazobactam

Each strip contains:

• Ceftolozane MIC range: 0.016- 256 µg/mL

• Tazobactam: 4 µg/mL

Single pack: 30 test strips

414447

  • The ETEST® C/T 256 strip is an in vitro quantitative technique of Antimicrobial Susceptibility Testing (AST) for determining a Minimum Inhibitory Concentration (MIC) for ceftolozane/tazobactam.
  • For in vitro diagnostic use only. Observe approved biohazard precautions and aseptic techniques. This product is to be used only by adequately trained and qualified laboratory personnel. Sterilize all biohazard waste before disposal.

For more information, visit www.biomerieux-diagnostics.com

MIC breakpoints for defining interpretive categories approved by EUCAST should be used for interpreting ETEST® MIC values


EUCAST breakpoints

Organism

Interpretive criteria for Ceftolozane/Tazobactam (µg/mL)

Interpretive criteria for Ceftolozane/Tazobactam (µg/mL)

Interpretive criteria for Ceftolozane/Tazobactam (µg/mL)

Susceptible

Intermediate

Resistant

Enterobacteriaceae

≤1/4

Not Applicable

>1/4

Pseudomonas aeruginosa

≤4/4

Not Applicable

>4/4

Please consult the Summary of Product Characteristics before prescribing.

bioMérieux is a registered trademark of bioMérieux, SA. ETEST is a registered trademark of AB Biodisk.

Liofilchem

The pages below contains information regarding available resources for susceptibility testing for Zerbaxa, the list may not be complete, please consult your local vendor of such materials for current status

Ceftolozane and Tazobactam MIC Test Strip Available from Liofilchem

Ordering Information:

Description

µg/mL

Strips/Box

Ref.

Ceftolozane* - Tazobactam

0.016 - 256*

10

921461

Ceftolozane* - Tazobactam

0.016 - 256*

30

92146

Ceftolozane* - Tazobactam

0.016 - 256*

100

921460

  • For in vitro diagnostic use only. Observe approved biohazard precautions and aseptic techniques. This product is to be used only by adequately trained and qualified laboratory personnel. Sterilize all biohazard waste before disposal.

For more information, contact liofilchem@liofilchem.net.

EUCAST breakpoints

Organism

Interpretive criteria for Ceftolozane/Tazobactam (µg/mL)

Interpretive criteria for Ceftolozane/Tazobactam (µg/mL)

Interpretive criteria for Ceftolozane/Tazobactam (µg/mL)

Susceptible

Intermediate

Resistant

Enterobacteriaceae

≤1/4

Not Applicable

≤1/4

Pseudomonas aeruginosa

≤4/4

Not Applicable

≤4/4

Vid införande av nytt antibiotikum i ert laboratorium rekommenderas att utföra kvalitetskontroll enligt EUCASTs rekommendationer
samt att testa kliniska isolat och jämföra distributionen med den i EUCASTs databas.

Please consult the Summary of Product Characteristics before prescribing.

Liofilchem® and the Liofilchem company logo are registered trademarks of LIOFILCHEM s.r.l.

Mast Group Ltd

The pages below contains information regarding available resources for susceptibility testing for Zerbaxa, the list may not be complete, please consult your local vendor of such materials for current status

Ceftolozane and Tazobactam Susceptibility Disk Available From Mast Group Ltd (www.mastgrp.com)

Ordering Information:

Description

Catalog Number

Ceftolozane / Tazobactam 5x50 cartridge (30µg/10µg) 

C/T40C

  • For in vitro diagnostic use only. Observe approved biohazard precautions and aseptic techniques. This product is to be used only by adequately trained and qualified laboratory personnel. Sterilize all biohazard waste before disposal.

Disk Interpretive Criteria Available for Pseudomonas aeruginosa and Enterobacteriaceae EUCAST breakpoints

Organism

Minimum Inhibitory Concentrations (mcg/mL)

Minimum Inhibitory Concentrations (mcg/mL)

Disk Diffusion Zone Diameter (mm)

Disk Diffusion Zone Diameter (mm)

S

R

S

R

Enterobacteriaceae

≤1/4

>1/4

≥23

<23

Pseudomonas aeruginosa

≤4/4

>4/4

≥24

<24

Vid införande av nytt antibiotikum i ert laboratorium rekommenderas att utföra kvalitetskontroll enligt EUCASTs rekommendationer
samt att testa kliniska isolat och jämföra distributionen med den i EUCASTs databas.

Please consult the Summary of Product Characteristics before prescribing.

Efficacy

In the ASPECT-cUTI trial

Clinical Efficacy in Complicated Urinary Tract Infections

In a non-inferiority trial, a statistically significant difference was observed in the ZERBAXA®  (ceftolozane and tazobactam) arm compared to the levofloxacin arm with respect to the composite microbiological and clinical cure rates (treatment difference: 8.5 %; 95 % CI: 2.3−14.6 in the mMITT population)1*

Study design

  • A multinational, double-blind randomised Phase 3 study with 1068 patients hospitalised with cUTI (including 82% of the mMITT population who were diagnosed with pyelonephritis) who received either ZERBAXA 1.5 g (1 g/0.5 g) every 8 hours or levofloxacin 750 mg once daily for 7 days.
  • Primary endpoint: a composite cure, defined as achieving clinical cure and microbiological eradication of all baseline uropathogens.
  • Participants: 800 mMITT patients (mean age: 49.1 years in the ZERBAXA group, 48.1 in the levofloxacin group) with cUTI including 656 (82%) with pyelonephritis. The mMITT population included all patients who received study medication and had at least one baseline uropathogen.
  • Secondary efficacy endpoint: the composite microbiological and clinical cure response at the TOC visit in the microbiologically evaluable population, which included protocol-adherent mMITT patients with a urine culture at the TOC visit.1

Composite microbiological + clinical cure rates and microbiological eradication rates at TOC visit1,a

a   The 95% CI was based on the stratified Newcombe method.1

*   The difference in the primary composite outcome favouring ZERBAXA was likely attributable to the 212/800 (26.5%) of patients with organisms non-susceptible to levofloxacin at baseline.1

ASPECT=Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam; CI=Confidence interval; ESBL=Extended-spectrum beta-lactamase; ME=Microbiologically evaluable; mMITT=Microbiologically modified intent-to-treat; TOC=Test-of-cure; cUTI=Complicated urinary-tract infections; cLUTI=Complicated lower-urinary-tract infections.

Composite cure rates by subgroups:

Composite cure rates were significantly higher for ZERBAXA than for levofloxacin among patients aged 65 years or older, those with cLUTI (complicated lower urinary tract infections), and those with levofloxacin-resistant or ESBL-producing uropathogens at diagnosis (mITT population)1†

  • Patients ≥65 years: 70.0% (70/100) versus 53.5% (53/99; treatment difference: 16.5% [95% CI: 3.0−29.2])1
  • Patients with cLUTI: 67.1% (47/70) versus 47.3% (35/74; treatment difference: 19.8% [95% CI: 3.7−34.6])1
  • Patients ESBL-positive †: 62.3% (38/61) versus 35.1% (20/57; treatment difference: 27.2% [95% CI: 9.2−42.9])1

†   Includes isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Enterobacter aerogenes, and Serratia marcescens.

Referenser

  • 1.

    Wagenlehner FM, Umeh O, Steenbergen J, et al. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet 2015;385:1949-56.

In the ASPECT-cIAI trial

Clinical Efficacy in Complicated Intra-abdominal Infections

In a non-inferiority trial, ZERBAXA® (ceftolozane and tazobactam), in combination with metronidazole, demonstrated comparable clinical cure rates to those of meropenem1

Study design1

  • A multinational, double-blind randomised Phase 3 study with 993 adults hospitalised with cIAI who received either ZERBAXA 1.5 g (1 g/0.5 g) every 8 hours plus metronidazole 500 mg every 8 hours or meropenem 1g IV every 8 hours for 4–14 days.1
  • Primary efficacy endpoint: a clinical response, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the TOC visit, which occurred 24 to 32 days after the first dose of study drug.
  • Primary efficacy analysis population: the MITT population, including all patients who received study medication (patients with missing clinical outcome data or indeterminate responses were considered to have failed treatment).
  • Diagnoses: included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, perforation of the intestine, and other causes of intra-abdominal abscesses and peritonitis.1
  • Key secondary efficacy endpoint: a clinical response at the TOC visit in the ME population, which included all protocol-adherent MITT patients.1

Clinical cure rates in a Phase 3 study of cIAIs at TOC visit1*

The MITT population comprised 806 patients; mean age was 50.8 years in the ZERBAXA plus metronidazole arm and 50.4 years in the meropenem arm1

*    The weighted difference in cure rates and the 95% CI around the difference in cure rates between study treatments were calculated using a stratified Newcombe CI with minimum risk weights.

†    Weighted difference.

CrCl=Creatinine clearance; MITT=Microbiological intent-to-treat; CE=Clinically evaluable; ME=Medically evaluable; CI=Confidence interval; NR=Not reported; ESBL=Extended-spectrum beta-lactamase; APACHE II=Acute Physiology and Chronic Health Evaluation II.

Composite cure rates by subgroups

  • In elderly (age 65 years and older) patients in the ZERBAXA plus metronidazole arm, clinical cure rates were 86.8% (53/61) compared with 93.2% (55/59) in the meropenem arm (medically evaluable population)1
  • In patients with moderate renal impairment (CrCl 30 to <50 mL/min) clinical cure rates in the ZERBAXA plus metronidazole arm were 72.7% (8/11) compared with 71.4% (5/7) in the meropenem arm (medically evaluable population)1

Per pathogen clinical cure rates in a Phase 3 study of cIAIs (ME population)1

No statistical analysis performed Figure adapted from Solomkin et al. 2015, supplementary Table 2.1

Results
In infections caused by ESBL-producing E. coli, K. pneumoniae and P. aeruginosa, cure rates were similar to those of the overall trial results1

Referenser

  • 1.

    Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: Results from a randomized, double-blind, Phase 3 trial (ASPECTcIAI). Clin Infect Dis 2015;60:1462-71.

Dosing

The recommended dose regimen of ZERBAXA® (ceftolozane and tazobactam) is 1.5 g (1 g/0.5 g) administered every 8 hours by IV infusion over 1 hour in patients 18 years or older1

Dose of ZERBAXA by infection in patients with creatinine clearance (CrCl) greater than 50 mL/min1

Infection Dose Frequency Infusion time Duration of treatment

Complicated intra-abdominal infectionsa

1 g / 0.5 g

Every 8 hours

1 hour

4–14 days

Complicated urinary tract infections, including acute pyelonephritis

1 g / 0.5 g

Every 8 hours

1 hour

7 days

a    To be used in combination with metronidazole when anaerobic pathogenus are suspected.

Because ZERBAXA is eliminated primarily by the kidneys, a dose adjustment is required for patients whose CrCl is 50 mL/min or less, as shown below1

Patients with renal impairment should be monitored frequently for any changes in renal function during treatment, and the dose of ZERBAXA should be adjusted as necessary.

Estimated CrCI (mL/min)b

Recommended dose regimen for ZERBAXAC

30-50

500 mg ceftolozane / 250 mg tazobactam intravenously every 8 hours

15-29

250 mg ceftolozane / 125 mg tazobactam intravenously every 8 hours

End-stage renal disease (ESRD) on haemodialysis days (HD)

A single loading dose of 500 mg ceftolozane / 250 mg tazobactam followed after 8 hours by a 100 mg ceftolozane / 50 mg tazobactam maintenance dose administered every 8 hours for the remainder of the treatment period (on haemodialysis days, the dose should be administered at the earliest possible time following completion of haemodialysis)

b    CrCl estimated using Cockcroft-Gault formula. c    All doses of ZERBAXA are administered over 1 hour.

Referenser

  • 1.

    EU Summary of Product Characteristics. Zerbaxa, section 4.2. 2018/06.

Safety Profile

Adverse reactions identified during clinical trials in patients receiving ZERBAXA® (ceftolozane and tazobactam) (N=1,015)a1

System Organ Class

Common (≥1/100 to <1/10)

Uncommon (≥1/1000 to <1/100)

Infections and infestations

Candidiasis including oropharyngeal and vulvovaginal candidiasis, clostridium difficile colitis, fungal urinary tract infection

Blood and the lymphatic system disorders

 Thrombocytosis

Anaemia

Metabolism and nutrition disorders

Hypokalaemia

Hyperglycaemia, hypomagnesaemia, hypophosphataemia

Psychiatric disorders

Insomnia, anxiety

Nervous system disorders

Headache, dizziness

 

Ischemic stroke

Cardiac disorders

Atrial fibrillation, tachycardia, angina pectoris

Vascular disorders

Hypotension

Phlebitis, veneous thrombosis

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Nausea, diarrhoea, constipation, vomiting, abdominal pain

Gastritis, abdominal distension, dyspepsia, flatulence, ileus paralytic

Skin and subcutaneous tissue disorders

Rash

Urticaria

Renal and urinary disorders

Renal impairment, renal failure

General disorders and administration site conditions

Pyrexia, infusion site reactions

Investigations

Alanine aminotransferase increased, aspartate aminotransferase increased

Coombs test positive, increased serum gamma-glutamyl transpeptidase (GGT), increased serum alkaline phosphatase

The most common adverse reactions (occurring in ≥3 % of patients in pooled Phase III trials) included nausea, constipation, diarrhoea, headache and pyrexia, and were generally mild or moderate in severity1

a    The ZERBAXA dose was 1 g/0.5 g intravenously every 8 hours, adjusted to match renal function where appropriate, for up to 14 days.

Referenser

  • 1.

    EU Summary of Product Characteristics. ZERBAXA, section 4.8. 2018/06.

SSI

ZERBAXA® (Ceftolozan/Tazobaktam) Antibakteriella medel för systemiskt bruk, övriga cefalosporiner och penemer. Rx; EF; SPC juni 2018. 1 g/0,5 g pulver till koncentrat till infusionsvätska, lösning.

▼ Detta läkemedel är föremål för utökad övervakning. Detta kommer att göra det möjligt att snabbt identifiera ny säkerhetsinformation. Hälso- och sjukvårdspersonal uppmanas att rapportera varje misstänkt biverkning.

Indikationer

Zerbaxa är avsett för behandling av följande infektioner hos vuxna; Komplicerade intraabdominella infektioner, akut pyelonefrit och komplicerade urinvägsinfektioner.

Kontraindikationer

Överkänslighet mot de aktiva substanserna eller mot något hjälpämne. Överkänslighet mot någon antibiotika av typen cefalosporiner. Svår överkänslighet (t.ex. anafylaktisk reaktion, svår hudreaktion) mot någon annan typ av betalaktamantibiotika (t.ex. penicilliner eller karbapenemer).

Varningar och försiktighet

Allvarliga och ibland dödliga överkänslighetsreaktioner (anafylaktiska reaktioner) kan förekomma. Om en allvarlig allergisk reaktion uppkommer under behandlingen med ceftolozan/tazobaktam ska läkemedlet sättas ut och lämpliga åtgärder vidtas. Patienter med anamnes på överkänslighet mot cefalosporiner, penicilliner eller andra betalaktamantibiotika kan också vara överkänsliga mot ceftolozan/tazobaktam.

Nedsatt Njurfunktion: Försämrad njurfunktion har observerats hos patienter som fått ceftolozan/tazobaktam. Dosen ceftolozan/tazobaktam ska justeras med hänsyn till njurfunktionen.

Patienter med neutropeni: Patienter med nedsatt immunförsvar och patienter med svår neutropeni exkluderades från kliniska studier.

Clostridium difficile-associerad diarré: Antibiotikaassocierad kolit och pseudomembranös kolit har rapporterats med ceftolozan/tazobaktam. I dessa fall bör man överväga att sätta ut behandlingen med ceftolozan/tazobaktam och att sätta in understödjande behandling tillsammans med specifik behandling mot Clostridium difficile.

Serokonversion vid direkt antiglobulintest (Coombs test) och potentiell risk för hemolytisk anemi: Utveckling av ett positivt direkt antiglobulintest (DAGT) kan ske under behandling med ceftolozan/tazobaktam.

Innehåller natrium.

Graviditet: Det finns inga data från användning av ceftolozan/tazobaktam hos gravida kvinnor. Tazobaktam passerar över placenta. Det är inte känt om ceftolozan passerar över placenta. Zerbaxa ska endast användas under graviditet om den förväntade nyttan uppväger den potentiella risken för kvinnan och fostret.

Amning: Det är okänt om ceftolozan och tazobaktam utsöndras i bröstmjölk. En risk för det nyfödda barnet/spädbarnet kan inte uteslutas.

Fertilitet: Effekterna av ceftolozan och tazobaktam på fertiliteten hos människor har inte studerats.

Förmågan att framföra fordon och använda maskiner: Zerbaxa kan ha en mindre effekt på förmågan att framföra fordon och använda maskiner. Yrsel kan förekomma efter administrering av Zerbaxa.

Säkerhetsprofil

Zerbaxa utvärderades i jämförande, kontrollerade kliniska fas 3-studier av komplicerade intraabdominella infektioner och komplicerade urinvägsinfektioner (inklusive pyelonefrit), som omfattade totalt 1 015 patienter behandlade med Zerbaxa (1 g/0,5 g intravenöst var 8:e timme, justerat för att i förekommande fall vara anpassat till njurfunktionen) under upp till 14 dagar.

De vanligaste biverkningarna (≥ 3 % i sammanlagda fas 3-studier) som förekom hos patienter som fick Zerbaxa var illamående, huvudvärk, förstoppning, diarré och feber och de var i allmänhet lindriga eller måttliga.

Vanliga biverkningar (≥1/100, <1/10): trombocytos, hypokalemi, sömnlöshet, ångest, huvudvärk, yrsel, hypotoni, illamående, diarré, förstoppning, kräkning, buksmärta, hudutslag, feber, reaktioner vid injektionsstället, förhöjt alaninaminotransferas, förhöjt aspartataminotransferas.

Interaktioner

Inga signifikanta läkemedelsinteraktioner förväntas mellan ceftolozan/tazobaktam och substrat, hämmare och inducerare av cytokrom P450-enzymer (CYP-enzymer) baserat på in vitro- och in vivo-studier.

Aktiva substanser som hämmar OAT1 eller OAT3 (t.ex. probenecid) kan öka plasmakoncentrationerna av tazobaktam.

Dosering

Intravenös dos av Zerbaxa till patienter med kreatininclearance >50 ml/min. 1g ceftolozan/0,5g tazobactam var 8:e timme. Infusionstiden är 1 timme.

Särskilda populationer

I en populationsfarmakokinetisk analys av ceftolozan/tazobaktam sågs ingen kliniskt relevant trend för exponeringen med avseende på ålder. Ingen dosjustering av ceftolozan/tazobaktam enbart baserat på ålder rekommenderas. Ingen dosjustering rekommenderas baserat på kön. Ingen dosjustering behövs till patienter med nedsatt leverfunktion.

För fullständig information, förpackningar och priser se fass.se

SE-ZER-00002