• Ceftazidime-avibactam is indicated in adults and paediatric patients aged 3 months and older for the treatment of the following infections:^*1
  • Complicated intra-abdominal infection (cIAI)¹
  • Complicated urinary tract infection (cUTI), including pyelonephritis¹
  • Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP)¹
• Treatment of adult patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above¹
• Ceftazidime–avibactam is also indicated for the treatment of infections due to aerobic Gram-negative organisms in adults and paediatric patients aged 3 months and older with limited treatment options^†

• RECLAIM 1 & 2 compared the use of ZAVICEFTA® plus metronidazole (for anaerobe coverage) with meropenem in patients with cIAIs¹
• RECLAIM 3 compared the use of ZAVICEFTA® plus metronidazole (for anaerobe coverage) with meropenem in patients with cIAIs from the Asia-Pacific region²
• RECAPTURE 1 & 2 compared the use of ZAVICEFTA® with doripenem in patients with cUTIs³
• REPRISE was the first pathogen-directed study that compared the use of ZAVICEFTA® with best-available therapy (mainly carbapenems) in patients with ceftazidime-resistant infections (cIAIs and cUTIs)⁴
• REPROVE compared the use of ZAVICEFTA® with meropenem in patients with HAP, including VAP^5,6

• Across three of the indications for ZAVICEFTA® (HAP/VAP, cUTI and cIAI), it has been compared with carbapenems, which are the standard-of-care treatment for resistant Gram-negative infections^1–3
• In all Phase III trials including patients with cUTIs and cIAIs, the dosing of ZAVICEFTA® in patients with CrCl >50 mL/min has been consistent^1,4–6
• The REPRISE trial was the first pathogen-directed study to examine the efficacy, safety and tolerability of ZAVICEFTA® in patients with cUTIs or cIAIs due to ceftazidime-resistant Gram-negative pathogens²
• In the RECAPTURE and REPRISE trials, the effectiveness of ZAVICEFTA®, including against ceftazidime-non-susceptible pathogens, highlights its potential clinical value as a carbapenem-sparing treatment in this setting^2,3
• REPROVE was a Phase III study of ZAVICEFTA® in adults with HAP, including VAP, and was the first randomised controlled study of a new antimicrobial therapy targeting Gram-negative pathogens in HAP/VAP to show non-inferiority to a carbapenem⁷
• At the time of the REPROVE trial, ZAVICEFTA® was the first Gram-negative antibiotic approved in the United States in over 15 years for the treatment of adults with HAP/VAP⁸
• Across the Phase III clinical trial programme, ZAVICEFTA® has demonstrated a consistent safety profile and has consistent dosing across all indications^1–3,7,8

• Based on the in vitro activity of ZAVICEFTA®, neither Stenotrophomonas spp. nor Acinetobacter spp. were expected to respond to either study drug; therefore, patients with these pathogens at baseline were excluded^1,2

• Ceftazidime-resistant pathogens were defined based on Clinical and Laboratory Standards Institute breakpoint-defined resistant and intermediate categories for ceftazidime, which are MIC ≥8 mg/L against Enterobacterales and ≥16 mg/L against P. aeruginosa^1,2

• ZAVICEFTA® plus metronidazole was shown to be non-inferior to meropenem in all populations and, thus, met the primary endpoint of clinical cure at TOC visit

• In both the ZAVICEFTA® plus metronidazole and meropenem groups, clinical cure was reported by >75% of patients with E. coli infections and >90% of those with P. aeruginosa infections
• ZAVICEFTA® plus metronidazole had a similar cure rate to meropenem for ceftazidime-resistant Gram-negative pathogens (83.0% vs 85.9%) and for ceftazidime-susceptible pathogens (82.0% vs 87.7%)

• In patients with moderate renal impairment at baseline, the overall clinical cure rate was 48.8% with ZAVICEFTA® plus metronidazole treatment and 74.4% with meropenem treatment¹
• As ZAVICEFTA® and meropenem are excreted through the kidneys, dosage adjustments were made for all patients with moderate renal impairment at baseline, with the aim of achieving adequate plasma levels while minimising the risk of overexposure due to impaired renal clearance¹
• The protocol-specified reduction in total daily dose in renal impairment for ZAVICEFTA® (−66%) was greater than that for meropenem (−33%), which increased the risk of underdosing in patients receiving ZAVICEFTA®¹
• Dosage adjustment is required in patients with moderate or severe renal impairment (CrCl 50 mL/min or less)²

• These were identical Phase III, prospective, randomised, multicentre, double-dummy, double-blind, comparative global studies and, with a prespecified agreement with the FDA and EMA, were combined into a single inferential database

Abbreviation:

• No clinically significant differences were observed between the two treatment groups in the key baseline demographics

• The proportion of patients who received prior systemic antimicrobial therapy in the 72 hours before randomisation was 62.3% in the ZAVICEFTA® plus metronidazole group and 62.1% in the meropenem group; however, patients were only enrolled if they had a new infection or were considered to have failed previous treatment

• The pathogens isolated from blood and intra-abdominal sites were ‘typical of those found in patients with cIAIs and similar between treatment groups’
• Ceftazidime-resistant aerobic Gram-negative pathogens, mainly E. coli and K. pneumoniae, were found in 111 patients (47 in the ZAVICEFTA® plus metronidazole group and 64 in the meropenem group). Of the patients with ceftazidime-resistant pathogens, approximately 80% had ESBL-positive infections and approximately 3% had MBL-positive infections

Abbreviation:

• The antibacterial spectrum of ceftazidime is primarily Gram-negative; therefore, to supplement ceftazidime in situations where Gram-positive pathogens such as MRSA or Enterococcus were identified or suspected, the addition of vancomycin or linezolid was permitted. Neither of these agents has activity against Gram-negative organisms, so the assessment of clinical efficacy of ZAVICEFTA® was not confounded

Abbreviation:

• No, in RECLAIM 1 & 2, patients with moderate renal impairment at baseline received a reduced dose of ZAVICEFTA® (ceftazidime 1000 mg and avibactam 250 mg in a 2-hour infusion q12h) or meropenem (1000 mg in a 30-minute infusion q12h)*

Abbreviation:

• The lower limit of the two-sided 95% CI for the treatment difference for the EMA primary endpoint was >0%, showing significantly greater efficacy of ZAVICEFTA® versus doripenem at the 5% significance level
• ZAVICEFTA® was shown to be non-inferior to doripenem for both FDA co-primary endpoints

Abbreviation:

• The choice of doripenem as the comparator was based on its efficacy in cUTI, expected activity against ceftazidime-resistant pathogens, dosing schedule and recommended use in severe UTI, as well as its availability
• Doripenem is recognised as a highly effective agent in the treatment of cUTI, despite no longer being a commercialised product in most international markets

Abbreviation:

• The EMA primary endpoint of microbiological eradication at TOC was achieved by 77.4% in the ZAVICEFTA® group compared with 71.0% in the doripenem group (difference 6.4% [95% CI: 0.33, 12.36])
• The FDA co-primary endpoint of patient-reported symptomatic resolution at Day 5 was achieved by 70.2% in the ZAVICEFTA® group compared with 66.2% in the doripenem group (difference 4.0% [95% CI: –2.39, 10.42])
• The FDA co-primary endpoint of symptomatic resolution combined with microbiological eradication at TOC was achieved by 71.2% in the ZAVICEFTA® group versus 64.5% in the doripenem group (difference 6.7% [95% CI: 0.30, 13.12])

Abbreviation:

• The primary endpoints and non-inferiority margins used in the RECAPTURE trials were designed to meet the regulatory criteria of both the EMA and FDA

Abbreviation:

• The pathogens isolated from urine and blood were those commonly found in cUTIs; >95% of patients had Enterobacterales, of which almost 75% were E. coli
• Ceftazidime-non-susceptible pathogens were isolated in 159 patients (19.6%): 75 in the ZAVICEFTA® group and 84 in the doripenem group
• Baseline pathogens potentially non-susceptible to ZAVICEFTA® or doripenem were isolated from 27 patients: 19 non-susceptible to doripenem, 5 non-susceptible to doripenem and ZAVICEFTA® and 1 non-susceptible to ZAVICEFTA®; 7 had either missing susceptibility data or an undefined breakpoint

Abbreviation:

• In the REPRISE trial, best-available therapy was based on the investigator’s standard of care and the local label recommendations, which were documented prior to randomisation. The preferred best-available therapy options, as stated in the protocol, were meropenem, imipenem, doripenem, tigecycline (cIAIs only) and colistin, but any therapy, including combination treatment, was permitted
• In the best-available therapy group, 97% of patients received a carbapenem antibiotic; the majority received this as monotherapy, with the most frequently prescribed being imipenem and meropenem

Abbreviation:

• In the REPRISE trial of patients with ceftazidime-resistant Gram-negative bacterial infections, the clinical cure rates at TOC were¹:
  • 91% (140/154) for ZAVICEFTA® versus 91% (135/148) for best-available therapy in all patients
  • 92% (132/144) for ZAVICEFTA® versus 94% (129/137) for best-available therapy in patients with cUTIs
  • 91% (52/57) for ZAVICEFTA® versus 90% (63/70) for best-available therapy in patients with acute pyelonephritis
  • 92% (80/87) for ZAVICEFTA® versus 99% (66/67) for best-available therapy in patients with cUTIs but without acute pyelonephritis
  • 80% (8/10) for ZAVICEFTA® plus metronidazole versus 55% (6/11) for best-available therapy in patients with cIAIs
  • In addition, the per-patient favourable microbiological response rates at TOC in patients with cUTIs were:
    • 82% (118/144; 95% CI: 75.1, 87.6) for ZAVICEFTA® versus 64% (88/137; 95% CI: 56.0, 71.9) for best-available therapy
• In the RECLAIM trial of patients with cIAIs, the clinical cure rates were²:
  • 83.0% (39/47) for ZAVICEFTA® plus metronidazole versus 85.9% (55/64) for meropenem in patients with ceftazidime-resistant pathogens
  • 82.0% (237/289) for ZAVICEFTA® plus metronidazole versus 87.7% (256/292) for meropenem in patients with ceftazidime-susceptible pathogens

Abbreviation:

• In patients with cUTIs, the median (range) duration of treatment was 10 (2–21) days in both treatment groups
• In patients with cIAIs, the median (range) duration of treatment was 10.5 (6–21) days in the ZAVICEFTA® group and 12 (4–23) days in the best-available therapy group

Abbreviation:

• Most of the infections were caused by Enterobacterales, most commonly E. coli and K. pneumoniae
• ZAVICEFTA®-non-susceptible Enterobacterales (MIC ≤8 mg/L was considered provisionally susceptible and MIC >8 mg/L as provisionally resistant) were isolated in 2% (2/132) and 1% (2/134) of the ZAVICEFTA® and best-available therapy groups, respectively
• For P. aeruginosa, 9 of 14 isolates from urine samples in patients with cUTIs in the ZAVICEFTA® group were considered to be provisionally resistant (MIC >8 mg/L) to ZAVICEFTA®
• In the best-available therapy group, 95% of patients (130/137) with cUTIs had MIC values that were considered to be susceptible to the relevant best-available therapy
• In the cIAI population, 21 (95%) of 22 Enterobacterales isolated from the intra-abdominal site were resistant to ceftazidime (MIC ≥8 mg/L) and 22 (100%) had ZAVICEFTA® MICs within the provisional range of susceptibility
  • One patient with cIAI had a P. aeruginosa isolate that was considered to be provisionally resistant to ZAVICEFTA® (MIC >8 mg/L)

Abbreviation:

• The small number of patients with cIAIs enrolled in the REPRISE study meant that study results only allowed for general descriptions of treatment-related trends for this population¹
• The RECLAIM 1 & 2 studies included 1,066 patients with cIAIs and demonstrated non-inferiority of ZAVICEFTA® plus metronidazole versus meropenem²

Abbreviation:

• REPROVE was the first randomised controlled study of a new antimicrobial therapy targeting Gram-negative pathogens in HAP/VAP to show non-inferiority to a carbapenem¹
• REPROVE was a large trial (n=726 in MITT population), with wide geographical coverage, and included a large number of patients with VAP (246; 34%)¹
• It was unique in that the primary endpoint was assessed in both the MITT and CE populations¹
• The comparator in REPROVE was meropenem 1000 mg q8h¹
• 625 patients (86%) had an APACHE II score of 10 to 19, and 99 (13.5 %) had a score of 20 to 30; 36 (5%) had moderate or severe renal impairment¹
• 100 patients (28%) in REPROVE had one or more ceftazidime–non-susceptible Gram-negative pathogens, including 79 with Enterobacterales and 25 with P. aeruginosa¹
• There was no difference in clinical cure rates with ZAVICEFTA® between subgroups according to baseline characteristics such as VAP/non-VAP, APACHE II score of 10 to 19/20 to 30, normal/impaired renal function or ceftazidime-susceptible/non-susceptible pathogens¹
• Although AEs were reported in 75% of patients in the ZAVICEFTA® group and 74% in the meropenem group, they were judged to be treatment-related in only 16% and 13%, respectively. Four patients (1%) had a serious AE that was considered by investigators as possibly related to ZAVICEFTA®¹
• The overall type and distribution of AEs were consistent with what is expected for patients with HAP/VAP and/or the known safety profiles of ZAVICEFTA® and meropenem²
• AEs resulted in discontinuation of study drug in 3.7% of patients in the ZAVICEFTA® arm and 3.0% of patients in the meropenem arm²
• Serious AEs were reported in 18.1% of patients in the ZAVICEFTA® arm and 13.6% of patients in the meropenem arm; the most common serious AEs (reported in ≥1% of patients in either treatment arm) were pneumonia, respiratory failure and sepsis²
• REPROVE was the first randomised controlled trial to show non-inferiority, compared with a carbapenem, of a new antimicrobial therapy targeting Gram-negative pathogens, and ZAVICEFTA® was the first new Gram-negative antibiotic approved in the United States for this indication in over 15 years^1,2

Abbreviation:

• ZAVICEFTA® was shown to be non-inferior to meropenem for the primary endpoint of clinical cure at the TOC visit in both the MITT and CE populations^1,2

Abbreviation:

• In the MITT population, clinical cure rates were 68.8% (245/356) for ZAVICEFTA® versus 73.0% (270/370) for meropenem (difference –4.2 [95% CI: –10.76, 2.46])
• In the CE population, clinical cure rates were 77.4% (199/257) for ZAVICEFTA® versus 78.1% (211/270) for meropenem (difference –0.7 [95% CI: –7.86, 6.39])
• ZAVICEFTA® was therefore shown to be non-inferior to meropenem for the primary endpoint of clinical cure at the TOC visit in both the MITT and CE populations

Abbreviation:

• The pathogens isolated were similar between groups and consistent with those commonly observed in HAP, including VAP¹
• Prominent Gram-negative pathogens isolated from a respiratory site or blood were predominantly Enterobacterales (259/355; 73.0%), including 36.6% (n=130) K. pneumoniae; another 29.6% (n=105) were P. aeruginosa^1,2
• 100 patients (28%) had at least one ceftazidime–non-susceptible Gram-negative pathogen¹

Abbreviation:

• The efficacy of ZAVICEFTA® against ceftazidime-non-susceptible pathogens was similar to that against ceftazidime-susceptible pathogens and was also comparable to meropenem
• Clinical cure rates in the CE population were 80.6% (29/36) for ceftazidime-non-susceptible pathogens and 75.0% (63/84) for ceftazidime-susceptible pathogens with ZAVICEFTA® compared with 78.0% (32/41) and 78.4% (69/88), respectively, with meropenem

Abbreviation:

• In the extended ME population, clinical cure rates against K. pneumoniae were 78.4% (29/37) for ZAVICEFTA® versus 79.6% (39/49) for meropenem (difference –1.2 [95% CI: –19.60, 15.96])
• Clinical cure rates against P. aeruginosa in the same population were 42.9% (18/42) for ZAVICEFTA® versus 40.0% (14/35) for meropenem (difference 2.9 [95% CI: –19.13, 24.32])

Abbreviation:

• The efficacy of ZAVICEFTA® in VAP patients was similar to that in non-VAP patients and was also comparable to meropenem
• Clinical cure rates in the MITT population were 70.3% (83/118) for VAP patients and 68.1% (162/238) for non-VAP patients with ZAVICEFTA® compared with 74.2% (95/128) and 72.3% (175/242), respectively, with meropenem
• Clinical cure rates in the CE population were 77.5% (62/80) for VAP patients and 77.4% (137/177) for non-VAP patients with ZAVICEFTA® compared with 75.9% (63/83) and 79.1% (148/187), respectively, with meropenem

Abbreviation:

• All-cause mortality at the TOC visit and Day 28 did not differ between the groups in either the clinically MITT (ZAVICEFTA® 8.1% [29/356] vs meropenem 6.8% [25/370] at TOC; 8.4% [30/356] vs 7.3% [27/370] at Day 28) or CE population (4.3% [11/257] vs 3.0% [8/270] at TOC; 4.7% [12/257] vs 3.3% [9/270] at Day 28)

Abbreviation:

• Yes. During the early stages of REPROVE, results from RECLAIM 1 and 2 became available, suggesting the potential that the per-protocol regimen of ZAVICEFTA® could be an underdose in patients with moderate or severe renal impairment. Thus, the REPROVE protocol was amended to increase the ZAVICEFTA® dose in such patients, and patients with moderate or severe renal impairment who received the original dosing regimen were excluded from the main analyses (ceftazidime 1000 mg and avibactam 250 mg q8h for CrCl 31–50 mL/min; 750 mg and 187.5 mg q12h for CrCl 16–30 mL/min) or meropenem (1000 mg q12h)^1,2
• The statistical analysis plan for REPROVE was updated to exclude patients with moderate or severe renal impairment at baseline who were randomly assigned before the protocol amendment from the main analyses to ensure that the main efficacy and safety results reflected the approved ZAVICEFTA® dosage regimens¹

Abbreviation:

• No, bacteraemia was not a prespecified requirement for randomisation and/or stratification; however, the clinical development programme for ZAVICEFTA® included patients with bacteraemia in all five (RECLAIM 1 & 2, RECLAIM 3, RECAPTURE 1 & 2, REPRISE, REPROVE) of the completed Phase III clinical trials conducted to support the indications of cIAI, cUTI and HAP/VAP 
• Efficacy and safety data for the bacteraemia subsets (n=54 and n=99 in the efficacy and safety subsets, respectively) were evaluated against the overall set, which included all patients enrolled in the Phase III studies, regardless of bacteraemia
• Due to the relatively small numbers of patients in the bacteraemia subset, it is expected that results in the overall set would closely approximate those in the non-bacteraemia subset 
• In total, 24 completed clinical studies in adults have contributed to the overall ZAVICEFTA® safety database and have established the safety profile of ZAVICEFTA®

Abbreviation:

• The efficacy of ZAVICEFTA® for the treatment of bacteraemia is supported by data from a subset of 101 patients across the Phase III trial programme* in adults with HAP/VAP, cIAI and cUTI^1,2
• In this post-hoc analysis,† ZAVICEFTA® showed favourable clinical and microbiological response rates in patients with bacteraemia‡ associated with HAP/VAP, cIAI or cUTI^2,3
  • Overall clinical cure rates were 87% (47/54) in patients treated with ZAVICEFTA® versus 83% (39/47) for comparators² 
  • The proportion of patients with a favourable microbiological response was 79.6% (43/54) with ZAVICEFTA® versus 68.1% (32/47) for comparators²
  • The most common primary diagnoses among patients with bacteraemia were acute pyelonephritis (47%) and VAP (15%)²
  • The most frequently isolated pathogens (E. coli [69%], K. pneumoniae [21%] and P. aeruginosa [17%]) were consistent with the overall Phase III pool²

Abbreviation:

• Use of ZAVICEFTA in paediatric patients aged 3 months and older is supported by evidence from three adequate and well-controlled studies in adults, and additional PK and safety data from paediatric trials^1–5 
• PK properties, safety and tolerability of a single dose of ZAVICEFTA have been assessed in a Phase 1, multicentre, open-label PK study in paediatric patients (N=32) aged 3 months to <18 years, hospitalised with an infection and receiving systemic antibiotic therapy. The single-dose PK of ZAVICEFTA was broadly similar to that previously observed in adults with normal renal function and no new safety concerns were identified^1,6 
• ZAVICEFTA has been evaluated in paediatric patients aged 3 months to <18 years in two Phase 2, single-blind, randomised, comparative clinical studies, one in patients with cIAI and one in patients with cUTI (N=128). In the cIAI trial, patients received ZAVICEFTA plus metronidazole, and in the cUTI trial, patients received ZAVICEFTA alone. The primary objective in each study was to assess safety and tolerability of ZAVICEFTA (+/- metronidazole). Secondary objectives included assessment of PK properties and efficacy; efficacy was a descriptive endpoint in both studies^7,8 
  • ZAVICEFTA achieved favourable clinical response rates in paediatric patients aged 3 months and older with cIAI and cUTI, with similar effectiveness to comparator therapies (meropenem or cefepime)^7,8 
  • In the cIAI study, favourable clinical/microbiologic responses were observed in ≥90% of patients in both ZAVICEFTA and meropenem groups at end-of-intravenous treatment and test-of-cure visits⁷ 
  • In the cUTI study, favourable clinical response rates >90% were observed for both treatment groups early during treatment at 72 hours (90.7% for ZAVICEFTA and 95.7% for cefepime) and remained >81% for both groups at the late follow-up (LFU) visit⁸

Abbreviation: