• Avibactam is semi-synthetic and produced via an enantioselective process; it is synthesised as a sodium salt that is water-soluble

• Avibactam is a first-in-class, broad-spectrum diazabicyclooctane. It is a non–β-lactam/β-lactamase inhibitor that has been designed to block many clinically important β-lactamases, including Ambler class A, class C and some class D, which protects ceftazidime from degradation, thus restoring its activity¹
• Avibactam restores the in vitro activity of ceftazidime against most Enterobacterales that express β-lactamases and against Pseudomonas aeruginosa, including:^2,3
  • ESBL (TEM, SHV and CTX-M)-, AmpC-, KPC-, plasmid-encoded class C- and certain OXA (e.g. OXA-48)-producing Enterobacterales
  • Stably derepressed AmpC-producing MDR P. aeruginosa 
• The combination of ceftazidime with avibactam improves in vitro activity against a number of different β-lactamase–producing aerobic Gram-negative pathogens^3,4

• Co-administration of an anti-anaerobic antibiotic such as metronidazole with ZAVICEFTA is required for anaerobic species⁵ (hence its inclusion within the Phase III intra-abdominal study programme, RECLAIM)

• Avibactam inactivates susceptible β-lactamases by covalent acylation of the β-lactamase active-site serine residue¹
• The binding is slowly reversible, as the five-membered urea ring of avibactam is less strained than the four-membered β-lactam ring and can close again after opening, restoring activity. This means that avibactam remains available to continue inactivating β-lactamases, whereas other β-lactamase inhibitors will not^1,2
• This makes avibactam a potent β-lactamase inhibitor.³ The MICs are much lower for the combination of ceftazidime and avibactam than for ceftazidime alone; for example, the modal MIC for KPC is 16 mg/L for ceftazidime alone and 0.5 mg/L for ZAVICEFTA⁴
• Avibactam has lower MIC50 values than the β-lactamase inhibitors clavulanic acid, tazobactam and sulbactam against a range of class A (e.g. TEM, KPC) and class C (e.g. AmpC) β-lactamases.³ It also has activity against some class D enzymes (e.g. OXA-48),¹ unlike clavulanic acid and tazobactam⁵

• Yes, ZAVICEFTA demonstrates in vitro activity against Ambler class A–producing isolates, including ESBLs, as well as class C and to a limited extent, class D β-lactamase–producing isolates¹
• Although ceftazidime alone (like other cephalosporins) is not active against ESBL-producing organisms, when used in combination with avibactam, degradation of ceftazidime by serine β-lactamase enzymes is inhibited, restoring the antibacterial activity of ceftazidime^1,2

ZAVICEFTA does not have activity against Acinetobacter baumannii.⁸
•Evidence of in vitro activity •Evidence of some in vitro activity •No evidence of in vitro activity

• Yes, ZAVICEFTA demonstrated activity against ceftazidime–non-susceptible pathogens, including ESBL-producing organisms, during the Phase III clinical trial programme^1* 
• In RECLAIM 1 & 2, 111 patients (13.5%) had a ceftazidime-resistant aerobic Gram-negative pathogen, the majority of which were Escherichia coli or Klebsiella pneumoniae, and approximately 80% of patients with ceftazidime-resistant pathogens had an ESBL-positive infection. ZAVICEFTA was effective in patients with ceftazidime-resistant Gram-negative pathogens, with clinical cure rates similar to those with meropenem (83.0% vs 85.9%) and to those seen in patients with ceftazidime-susceptible Gram-negative pathogens (82.0%)¹
• In RECAPTURE 1 & 2, ceftazidime–non-susceptible pathogens were identified in 159 patients (19.6%) and ESBL-positive Enterobacterales in 155 (19.1%). Clinical cure rates with ZAVICEFTA were 81.7% in patients with ceftazidime-susceptible pathogens and 64.0% for non-susceptible pathogens (rates with doripenem were 73.1% and 60.0%, respectively)²
• All patients in REPRISE had infections caused by ceftazidime-resistant pathogens. The clinical cure rate with ZAVICEFTA was 91% compared with 91% with best-available therapy³
• In REPROVE, 100 patients (28%) had infections with one or more ceftazidime–non-susceptible Gram-negative pathogens, including 79 with Enterobacterales and 25 with P. aeruginosa. Clinical cure rates in the CE population were 80.6% for ceftazidime-non-susceptible pathogens and 75.0% for ceftazidime-susceptible pathogens with ZAVICEFTA compared with 78.0% and 78.4%, respectively, with meropenem⁴

• An observational real-world study of 109 patients with carbapenem-resistant K. pneumoniae bacteraemia treated at University of Pittsburgh Medical Center included 13 patients who received ZAVICEFTA¹
  • Survival rates at 30 and 90 days were 92% (12/13) among patients receiving ZAVICEFTA regimens versus 69% (66/96) and 55% (53/96), respectively, among patients receiving any other regimen 
  • Survival rates were 87.5% (7/8) and 100% (5/5) among patients receiving ZAVICEFTA alone or in combination with gentamicin, respectively
  • Clinical success and survival have shown a trend of improvement for patients with carbapenem-resistant K. pneumoniae bacteraemia who received ZAVICEFTA
• In a recent US real-world prospective observational study,* treatment with ZAVICEFTA showed a trend towards lower all-cause 30-day hospital mortality compared with colistin for the treatment of CRE infections (9% vs 32%^†)²
  • ZAVICEFTA was associated with a trend of improved clinical outcomes, and a trend towards decreased all-cause hospital mortality and improved benefit–risk outcomes, compared with colistin for the treatment of CRE infections
  • ZAVICEFTA is a reasonable alternative to colistin in the treatment of CRE infections^‡
• In a real-world retrospective observational study, outcomes with ZAVICEFTA were evaluated in a large cohort of patients with severe KPC-Kp infections³
  • Retrospective multicentre study was conducted in 17 Italian hospitals in patients with documented KPC-Kp infections (n=138)^§
  • All patients received ZAVICEFTA as salvage therapy
  • Salvage therapy was given only after first-line antibacterial treatment regimens had failed or could not be continued
  • Treatment with ZAVICEFTA suggested a trend towards lower 30-day mortality compared with other treatment regimens
  • The overall 30-day mortality rate was 34.1%; the highest rate (36.5%) was among patients with bacteraemic KPC-Kp infections, and the lowest rate (16.7%) was observed in those with UTIs
  • The 30-day mortality rate among KPC-Kp bacteraemia patients was lower with ZAVICEFTA than in a matched cohort treated with other second-line regimens (controls; 36.5% vs 55.8%)
• In a recent, real-world retrospective multicentre study, treatment with ZAVICEFTA was evaluated in patients with serious KPC-Kp infections⁴
  • The study was performed in 22 Italian hospitals in 577 patients with BSIs (n=391), or non-bacteraemia infections, such as urinary tract, lower respiratory tract, and intra-abdominal structure infections
  • The 30-day mortality rate after infection onset was 25.3% (146/577)
  • There was no statistical difference in mortality between patients managed with ZAVICEFTA alone or those treated with combination regiments (26.1% vs. 25%)
  • ZAVICEFTA therapy was associated with a low rate of adverse reactions, which required drug discontinuation in only a few cases
  • Mortality was negatively associated with ZAVICEFTA administration by prolonged infusion
  • The in vitro resistance only developed during therapy in 20 patients (3.5%)
  • ZAVICEFTA was described as an important option for treating serious KPC-Kp infections, even when used alone
• The recently published IDSA guidance recommends ZAVICEFTA as a preferred treatment option^¶ for KPC-producing infections^5\\

• Class D β-lactamases are diverse and are referred to as oxacillinases¹
• Avibactam is active only against particular class D enzymes, including OXA-10 and -48^2,3
• ZAVICEFTA has shown in vitro activity against OXA-48–producing E. coli and K. pneumoniae^4,5
• In a real-world prospective observational study, outcomes with ZAVICEFTA were evaluated in patients with severe infections due to OXA-48–producing Enterobacterales⁶
  • Single-centre study was conducted in a Spanish hospital of a large cohort of patients with carbapenem-resistant infections caused by OXA-48–producing Enterobacterales who were treated with ZAVICEFTA as salvage therapy (n=57)*
  • ZAVICEFTA was started because of previous treatment failure, absence of adequate treatment options or toxicity of previous antibiotic treatment
  • The majority of patients (81%) received ZAVICEFTA as monotherapy
  • Treatment with ZAVICEFTA showed a trend of promising results for OXA-48–producing Enterobacterales infections for which treatment options are limited
  • All-cause mortality was 14% at 14 days and 22% at 30 days
  • The recurrence rate of infection was 10% at 90 days
  • Resistance to ZAVICEFTA was not detected in any case, and only two patients developed AEs related to treatment 
• In a real-world multicentre and retrospective study, treatment of ZAVICEFTA was evaluated in patients with haematologic malignancies who had CPE bacteraemia⁷
  • Of 31 patients, 8 (25.8%) were treated with ZAVICEFTA
  • OXA-48–type CPE were the most frequent in both treatment groups
  • No significant differences in crude mortality were found between the study and comparator groups
  • Patients in the ZAVICEFTA group showed a trend of higher clinical cure rates than those in the comparator group
  • The results suggest that ZAVICEFTA is an effective alternative treatment option for haematologic patients with OXA-48–type CPE
• The recently published IDSA guidance recommends ZAVICEFTA as the only preferred treatment option for OXA-48-producing CRE infections⁸

• The EUCAST MIC breakpoint for ZAVICEFTA is ≤8 mg/L for P. aeruginosa–susceptible strains and >8 mg/L for resistant strains¹
• In a US microbiological surveillance study, 97.0% of P. aeruginosa strains (n=7,452) were found to be susceptible (MIC ≤8 mg/L) to ZAVICEFTA, and in MDR P. aeruginosa strains, the susceptibility rate was 82.1%²
• In 2018, a real-world observational study by Rodríguez-Núñez et al. evaluated the outcomes of eight patients with infections due to MDR or XDR P. aeruginosa treated with ZAVICEFTA (including four strains resistant to ceftolozane–tazobactam)³
  • Patients were predominantly male (87.5%), with a median age of 64.5 years, and all had comorbidities (Charlson index ≥3). In 6 patients (75%), the infection was hospital-acquired, and in the remaining 2 patients, it was healthcare-related. Five patients had a hospital-acquired lower respiratory tract infection; in the other three patients, the sources of infection were osteomyelitis, meningitis and catheter-related bacteraemia
  • Four patients (50%) achieved clinical cure, and the 30- and 90-day mortality rates were 12.5% and 37.5%, respectively
  • One patient (12.5%) discontinued treatment with ZAVICEFTA due to the development of encephalopathy
  • The authors concluded that ZAVICEFTA may be a valuable option for serious infections due to resistant P. aeruginosa
• ZAVICEFTA was shown to be highly potent in vitro against clinical isolates of P. aeruginosa collected in European countries from 2012 to 2015⁴
  • Susceptibility to ZAVICEFTA was 92.4% (MIC90 8 mg/L) among 5,716 isolates of P. aeruginosa⁴
  • Susceptibility to ZAVICEFTA increased to 95.9% among the subset of MBL-negative isolates; ZAVICEFTA was not active against MBL-positive isolates (2.8% susceptible)⁴
  • Overall, 74% of meropenem–non-susceptible and 85.1% of MBL-negative, meropenem–non-susceptible isolates remained susceptible to ZAVICEFTA⁴
  • ZAVICEFTA was the most active agent tested against 14 isolates of colistin-resistant P. aeruginosa (92.9% susceptible) compared to susceptibilities of <65% for the other tested agents⁴
  • Susceptibility to ZAVICEFTA was 75.5% for P. aeruginosa in VAP patients⁵
• ZAVICEFTA was shown to be highly active in vitro against clinical isolates of P. aeruginosa collected in the United States from 2017 to 2018⁶
  • ZAVICEFTA expressed 96% susceptibility against P. aeruginosa⁶
  • ZAVICEFTA showed activity against MDR, XDR and β-lactam–non-susceptible P. aeruginosa isolates⁶
• ZAVICEFTA was shown to be highly active in vitro against clinical isolates of P. aeruginosa collected in Latin America from 2012 to 2015⁷
  • Susceptibility to ZAVICEFTA was 87.4% among all P. aeruginosa isolates⁷
  • ZAVICEFTA inhibited 89.5% of carbapenem–non-susceptible P. aeruginosa isolates in which no acquired β-lactamase was detected⁷
• Clinical isolates of P. aeruginosa collected in China were shown to be susceptible to ZAVICEFTA in 2017⁸
  • ZAVICEFTA showed 86.5% susceptibility against P. aeruginosa⁸
  • The rate of susceptibility of the carbapenem-resistant P. aeruginosa isolates to ZAVICEFTA was 65.7%⁸
• Jorgensen et al. reported on a real-world observational study — the largest clinical study of patients treated with ZAVICEFTA for Pseudomonas spp.⁹
  • ZAVICEFTA was used to treat 63 patients with Pseudomonas spp. infections, and the majority of those infections had a respiratory tract source (n=38, 60.3%)⁹
  • Among the P. aeruginosa isolates tested, ZAVICEFTA susceptibility was high (92.6%)⁹
  • Overall, receipt of ZAVICEFTA within 48 hours of infection onset was protective, showing that ZAVICEFTA can be an effective therapy for MDR Pseudomonas spp.⁹

• In vitro data suggest that the following species are not susceptible to ZAVICEFTA: Staphylococcus aureus (methicillin-susceptible and methicillin-resistant), anaerobes, Enterococcus spp., Stenotrophomonas maltophilia and Acinetobacter spp.¹
• ZAVICEFTA possesses a limited spectrum of activity against Gram-positive pathogens, with poor in vitro activity against S. aureus (MIC90 >32 mg/L) but consistent activity against β-haemolytic streptococci (MIC90 0.5 mg/L)²

• There are numerous mechanisms for developing resistance, including:^1,2
• Inherent resistance: the ability of a bacterium to resist the action of a specific antibiotic due to inherent structural or functional properties¹
• Acquired resistance: a change in genetic composition of a microorganism so that an antibiotic agent that was once effective against the organism is no longer effective²
• Resistance mechanisms that may affect ZAVICEFTA include:³
• Mutant or acquired penicillin-binding proteins
• Decreased outer membrane permeability and active efflux to either compound
• Mutated or acquired β-lactamase enzymes that are able to hydrolyse ceftazidime but are refractory to avibactam
• The most common mechanism of resistance to ZAVICEFTA is the presence or acquisition of a β-lactamase that is not inhibited by avibactam, such as all MBLs⁴
• There are limited studies on the selection of resistance to avibactam in combination with cephalosporins^5–8
• Of the many papers published since the launch of ZAVICEFTA in 2015, several studies have reported resistance 
• In 2015, the first case of a ZAVICEFTA-resistant KPC-3–producing K. pneumoniae (MIC for ceftazidime–avibactam of 32 μg/mL) was reported in a patient with no history of ZAVICEFTA therapy and with initial susceptibility to ZAVICEFTA (MIC of 4 μg/mL). It was hypothesised that a combination of mutations to avibactam’s target site could result in resistance both to avibactam and to ceftazidime as a result of ceftazidime hydrolysis. Efflux and porin mutations have been associated with ZAVICEFTA resistant in P. aeruginosa and Enterobacter cloacae⁶
• In 2016, Shields et al. conducted a small retrospective study of 37 patients, which reported the emergence of ZAVICEFTA resistance among 3 patients with CRE infections, including pneumonia and bacteraemia plus kidney infections, IAIs, SSTIs and mediastinal infections. Approximately one-third of patients were solid organ or haematopoietic transplant recipients. Microbiological failure (defined as isolation of CRE after ≥7 days of treatment) occurred in 10 patients (27%), with ZAVICEFTA resistance being detected in 3 of these patients (30%; 8% of the total study population). Reasons for microbiological failure were recurrent infections within 30 (n=5) and 90 (n=4) days and urinary colonisation (n=1) with CRE. Treatment failures were associated with higher SOFA scores, indicating that host factors in addition to antimicrobial activity against CRE are important determinants of outcomes⁷
• In 2017, detailed case reports of the three patients in whom resistant isolates developed were provided by Shields et al. Whole-genome sequencing identified mutations in plasmid-borne blaKPC-3, resulting in variant KPC-3 enzymes, as the mechanism of resistance to ZAVICEFTA in these patients. In addition, in some of the isolates, emergence of ZAVICEFTA resistance restored susceptibility to meropenem⁹
• In 2018, Shields et al. conducted a larger study, which included 77 patients with CRE infections who were treated with ZAVICEFTA.10 This study included the patients previously reported from this centre.7,9 ZAVICEFTA resistance was detected in 8 patients (10%), exclusively among K. pneumoniae isolates harbouring KPC-3 enzymes. Phylogenetic analysis of the genome sequences showed that in seven of the eight patients, the resistant isolates clustered within a previously defined sequence type (ST258), whereas resistant isolates from one patient clustered independently from other ST258 isolates. Further analysis showed that renal replacement therapy was found to be an independent risk factor for both clinical failure of ZAVICEFTA treatment and emergence of resistance, suggesting that it may lead to inadequate drug exposures¹⁰
• In 2019, Gaibani et al. evaluated ZAVICEFTA resistance and the mechanisms of resistance among KPC-Kp strains isolated from patients with bloodstream infections. Of 105 KPC producers (out of a total of 120 CPE strains collected), 102 (97.1%) KPC-Kp strains were susceptible to ZAVICEFTA, with 3 (2.9%) being resistant. Resistance was associated with porin ompK35–ompK37 deficiency associated with an ompK36 variant in two ZAVICEFTA-resistant KPC-Kp strains. Only one ZAVICEFTA-resistant KPC-Kp strain exhibited a specific mutation within the blaKPC gene (D179Y). Findings have shown that the incidence of ZAVICEFTA resistance emerged in KPC-Kp strains independent of previous antimicrobial exposure¹¹
• Resistance can develop for any antibiotic. Following the principles of good antibiotic stewardship (i.e. the appropriate use of an agent, at the right dose, for the right length of time and in the right patient) is one of the strongest safeguards against further growth of resistance¹²
  • Overall, according to a rapid risk assessment from the ECDC in 2018, surveillance studies continue to report very low rates of ZAVICEFTA resistance in CRE¹³
  • In 2021, Tumbarello et al. investigated ZAVICEFTA activity against KPC-Kp infections in a large cohort study (n=577) and the in vitro resistance developed during ZAVICEFTA therapy in 20 patients (3.5%)¹⁴  

• ZAVICEFTA is included in the following guidelines and recommendations: