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HAP/VAP
cUTI
cIAI
Paediatrics
Bacteraemia
With mortality rates significantly higher in patients with inappropriate empirical therapy than in those with appropriate treatment (47% and 20% respectively), there is an unmet need for new, more effective treatment.10
REPROVE Phase III trial:1
879 patients hospitalised adults with HAP/VAP were randomised in a controlled setting to show noninferiority, compared with a carbapenem, of an antimicrobial therapy targeting Gram-negative pathogens in HAP/VAP.
Baseline pathogens1
Predominantly K. pneumoniae and P. aeruginosa, including some ceftazidime-resistant strains.
100 patients (28%) had ≥1 ceftazidime-resistant isolate.
Trial design
REPROVE: International, non-inferiority, randomised, double-blind, Phase III trial1
Lung penetration PK/PD data
Complementary kinetic profile with proven penetration into the lung11
Concentration–time profiles following administration of 2 g of ceftazidime + 0.5 g of avibactam
Professor of Pulmonology and Respiratory Critical Care Medicine at University of Barcelona, Spain, talks about hospital-acquired pneumonia and ventilator-associated pneumonia, as well as the REPROVE study, a Phase III randomised clinical trial comparing ceftazidime-avibactam to meropenem.
ZAVICEFTA is as effective as a carbapenem in patients with HAP/VAP caused by Gram-negative pathogens.1
In cUTI the likelihood of initial antibiotic therapy failure and serious complications, particularly the development of antimicrobial resistance, is more common compared with uncomplicated UTI.15
RECAPTURE Phase III trial:
1033 hospitalised adults with cUTI were randomised in a controlled setting to show noninferiority, compared with a carbapenem, of an antimicrobial therapy targeting Gram-negative pathogens in cUTI.
Baseline pathogens
Predominantly E, coli and K. pneumoniae, including some ceftazidime-resistant strains.
Trial design
RECAPTURE: International, non-inferiority, randomised, double-blind, Phase III trial2
Infectious Diseases Consultant at Manchester University NHS Foundation Trust, sharing his view on the challenges of MDR Gram-negative infections. Learn about his clinical practice experience in a renal transplant patient and the role of ceftazidime-avibactam in patients with cUTI.
REPRISE Phase III trial:
333 hospitalised adults with cUTI or cIAI were randomised in a controlled setting. The REPRISE study is the first pathogen directed clinical trial for ceftazidime–avibactam examining its efficacy against ceftazidime resistant Gram-negative pathogens.
Baseline pathogens
Ceftazidime-resistant Enterobacterales (most commonly E. coli or K. pneumoniae) and P. aeruginosa.
Trial design
REPRISE: Pathogen-directed, international, randomised, open-label, Phase III trial3
Example
Consultant Microbiologist at Hampshire Hospitals, discuss the REPRISE study.
ZAVICEFTA is as effective as a carbapenem in patients with cUTI and as effective as best-available therapy in cUTI or cIAI patients caused by Gram-negative pathogens.2,3
Underlying medical conditions and inadequate early antibiotic therapy are among the factors consistently associated with poor outcomes in patients with cIAIs.4,17
RECLAIM Phase III trial:
1066 hospitalised adults with cIAI were randomised in a controlled setting to show noninferiority, compared with a carbapenem, of an antimicrobial therapy targeting Gram-negative pathogens in cIAI.
Baseline pathogens
E coli, K. pneumoniae and P. aeruginosa, including some ceftazidime-resistant strains. 417 patients (40%) had polymicrobial infection at baseline.
Trial design
RECLAIM: International, non-inferiority, randomised, double-blind, comparative, Phase III programme5
REPRISE Phase III trial:
333 hospitalised adults with cUTI or cIAI were randomised in a controlled setting. The REPRISE study is the first pathogen directed clinical trial for ceftazidime–avibactam examining its efficacy against ceftazidime resistant Gram-negative pathogens.
Baseline pathogens
Predominantly E. coli and K. pneumoniae, including some ceftazidime-resistant strains.
Trial design
REPRISE: Pathogen-directed, international, randomised, open-label, Phase III trial3
Example
Consultant Microbiologist at Hampshire Hospitals, discuss the REPRISE study.
ZAVICEFTA is as effective as a carbapenem in patients with cUTI and as effective as best-available therapy in cUTI or cIAI patients caused by Gram-negative pathogens.2,3
Safe, effective treatment options are urgently needed to address the growing threat of MDR Gram-negative infections in paediatric patients.7,20
Phase II trial:
95 hospitalised paediatric patients 3 months and older with cUTI. The first randomised controlled trial of ZAVICEFTA in paediatric patients with cUTI.
Baseline pathogens
Predominantly E coli (92%)
Trial design
cUTI paediatric trial: Multicentre, single-blind, randomised, actively-controlled, Phase II trial8
Phase II trial:
83 hospitalised paediatric patients 3 months and older with cIAI. The first time randomised controlled trial of ZAVICEFTA in paediatric patients with cIAI.
Baseline pathogens
Predominantly E coli (80%) and P. aeruginosa (33%)
Trial design
cIAI paediatric trial: Multicentre, single-blind, randomised, actively-controlled, Phase II trial7
Example
ZAVICEFTA achieved favourable clinical response rates in paediatric patients aged 3 months and older with cIAI¶¶¶¶¶¶ and cUTI, with similar effectiveness to comparator therapies when assessed in paediatric trials.7,8
With mortality rates as high as 48%, new effective treatment options are needed to address the increasing threat of MDR Gram-negative bacteraemia.23,26,27
Phase III clinical trial programme:
A post-hoc analysis******* of 101 adult patients in five Phase III international, randomised, non-inferiority trials in patients with bacteraemia††††††† associated with HAP/VAP, cIAI or cUTI.9,28
Baseline pathogens9
E coli (69%), K pneumoniae (21%), P aeruginosa (17%)
Baseline diagnoses9
Acute pyelonephritis (69%), VAP (21%)
ZAVICEFTA showed favourable clinical and microbiological response rates in adult patients with bacteraemia††††††† associated with HAP/VAP, cIAI or cUTI.9,28
Learn more about ZAVICEFTA’s safety and tolerability.
ZAVICEFTA’s pathogen coverage in comparison to competitor treatments.
†Use of ZAVICEFTA in paediatric patients aged 3 months and older is also supported by evidence from adequate and well-controlled studies in adults, and additional pharmacokinetic and safety data from paediatric trials. ZAVICEFTA has proven clinical efficacy across four Phase III, international, randomised, non-inferiority trials in 1423 adult patients with HAP/VAP, cIAI or cUTI.1–3,5,7,8
‡Five Phase III international, randomised, non-inferiority trials in patients with HAP/VAP, cIAI or cUTI.6,28
¶Non-inferiority was concluded if the lower limit of the 95% CI was greater than -12.5%.1
**cMITT population comprised patients with minimum disease criteria but excluded patients with only non-target pathogens.1
††The CE population comprised patients in the cMITT population who received an adequate course of treatment and had an assessable clinical outcome within the assessment window, no protocol deviations that could affect the assessment of efficacy, and no unacceptable previous or concomitant antibiotics.1
‡‡Clinical cure was defined as resolution of all signs and symptoms of pneumonia such that no antibacterial therapy for nosocomial pneumonia was taken between end of treatment and test of cure inclusive.1
§§n=6 for ELF median concentrations at 2 and 4 hours in the 2 g ceftazidime + 0.5 g avibactam group.11
***Non-inferiority was concluded if the lower limit of the 95% CI was greater than -12.5%.2
†††The mMITT population comprised all randomised patients with minimum disease criteria and eligible baseline pathogen(s).2
‡‡‡Formal statistical comparison not performed; corresponding CIs for the efficacy of best available therapy were used to provide context for descriptive estimates of ceftazidime–avibactam efficacy.3
§§§Patients in the mMITT population included all patients who had a diagnosis of cUTI or cIAI with at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug.3
¶¶¶Preferred best-available therapy options for cUTI and cIAI were 5–21 days of treatment with meropenem, imipenem, doripenem, colistin and (for cIAI) tigecycline, administered intravenously, but any therapy, including combination treatment, was permitted.3
****Clinical cure defined as complete resolution or substantial improvement of signs and symptoms of the index infection such that no further antibacterial therapy was necessary. For cIAI patients, cure also required no drainage or surgical intervention needed after 96 hours from randomisation.3
††††Non-inferiority was considered met if the lower limit of the 95% CI for between-group difference was greater than the prespecified non-inferiority margin of -12.5%.5
‡‡‡‡Patients in the MITT population are defined as patients who received study drug and met the clinical disease criteria.5
§§§§Clinical cure defined as complete resolution or substantial improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage or surgery intervention was necessary. Non-inferiority was considered met if the lower limit of the 95% CI for between-group difference was greater than the prespecified non-inferiority margin of -12.5%.5
¶¶¶¶Patients in the MITT population are defined as patients who received study drug and met the clinical disease criteria.5
*****Multicentre retrospective cohort study using data from 48 US children’s hospitals to determine the proportion of MDR-GNE diagnoses among patients aged 0 to <18 years who were diagnosed with an Enterobacterales-associated infection between 1 January 2007, and 31 March 2015.17
†††††The study was not powered for inferential statistical comparisons between treatment groups, so descriptive statistics were used to summarise safety and efficacy data. The primary objective was to evaluate safety and tolerability; evaluation of efficacy and pharmacokinetics was a secondary objective. Analysed in the micro-ITT population (all randomised patients with a study-qualifying baseline pathogen).8
‡‡‡‡‡A favourable clinical outcome was defined as clinical cure. A favourable per-patient microbiologic response was defined as eradication of the pathogen(s). If a patient had more than 1 pathogen, the outcome had to be favourable for each pathogen for it to be counted as a favourable response.7
§§§§§Dose adjusted depending on weight, age and renal status.7,8
¶¶¶¶¶Dose adjusted according to local prescribing information or as prescribed by the investigator.8
******All randomised patients who received ≥1 dose of IV study drug.8
††††††The study was not powered for inferential statistical comparisons between treatment groups, so descriptive statistics were used to summarise all variables. The primary objective was to evaluate safety and tolerability; evaluation of clinical and microbiologic outcomes to provide a descriptive estimate of efficacy was a secondary objective. A favourable clinical outcome was defined as clinical cure at the TOC visit. Safety and tolerability data included vital signs, physical examination, laboratory parameters, creatinine clearance and electrocardiogram data. The safety analysis set consisted of all randomised patients who received any amount of IV study drug.8
‡‡‡‡‡‡All randomised patients.8
§§§§§§All randomised patients with a baseline pathogen known to cause cIAI.8
¶¶¶¶¶¶ZAVICEFTA plus metronidazole for cIAI.28
*******Exploratory analysis of adult patients with Gram-negative bacteraemia.9
†††††††Defined as any patient with ≥1 bacteria identified from a blood culture at baseline for all studies, except for RECAPTURE, which also required the same pathogen to be identified in a urine sample at >105 CFUs/mL.28
‡‡‡‡‡‡‡Meropenem in HAP/VAP and cIAI; doripenem in cUTI.28
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