Antimicrobial health technology evaluation guidance Published: 17 August 2022
Evidence-based recommendations on ceftazidime with avibactam for treating severe drug-resistant gram-negative bacterial infections
Guidance development process
This guidance is part of a project with NHS England to test a new health technology evaluation process and payment model for 2 antimicrobial products (cefiderocol and ceftazidime-avibactam).
The recommendations in this guidance represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, health professionals are expected to take this guidance fully into account, alongside the individual needs, preferences and values of their patients.
The application of the recommendations in this guidance is at the discretion of health professionals and their individual patients and do not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
All problems (adverse events) related to a medicine or medical device used for treatment or in a procedure should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme.
1.1 Ceftazidime–avibactam is recommended, within its marketing authorisation, as an option for treating severe drug-resistant infections caused by gram-negative bacteria. This includes, but is not limited to, infections caused by OXA‑48 carbapenemase-producing Enterobacterales. Clinicians should follow advice from specialists in microbiology or infectious disease and offer ceftazidime–avibactam only if there are no suitable alternative treatment options.
The decision to offer ceftazidime–avibactam should be guided by results from tests for microbiological susceptibility and mechanisms of resistance that confirm that the infection is susceptible to ceftazidime–avibactam, and not susceptible to other suitable antibiotics. If these results are not yet available, ceftazidime–avibactam may be offered, but only if the infection:
- needs urgent treatment, and
- is expected to be susceptible to ceftazidime–avibactam and not to other suitable antibiotics.
As well as considering susceptibility, judgements about whether an alternative treatment is suitable may take account of concerns about its toxicity, availability or interactions with other drugs, and its spectrum of activity.
Prescribers should follow the recommendations on new antimicrobials in the NICE guideline on antimicrobial stewardship.
1.2 Because of the uncertainty in the estimates of the value of ceftazidime–avibactam to the NHS in England, NICE encourages research to further develop best practice in the health economic evaluation of antimicrobials (see sections 5 and 6).
2. Commercial arrangement
2.1 Under its contract with NHS England, the company will receive quarterly payments that are not linked to the volume of ceftazidime–avibactam supplied to the NHS. The value of the payments was informed by the NICE committee’s estimate of the benefits of ceftazidime–avibactam, measured in quality-adjusted life years (QALYs) (see section 4.25 of the committee discussion). It has been agreed for a 3-year period, with an option to extend up to 10 years.
2.2 Purchasing authorities will acquire ceftazidime–avibactam using an agreed confidential invoice price. NHS England will subtract the costs of these purchases from its quarterly payments to the company.
2.4 The contract between the company and NHS England also stipulates conditions relating to good antimicrobial stewardship, manufacturing and environmental practices; monitoring for emerging resistance; and ensuring supply of ceftazidime–avibactam.
3. Information about ceftazidime with avibactam
3.1 Ceftazidime–avibactam is a combination of ceftazidime, which is a third-generation cephalosporin, and avibactam, which is a next generation non-beta-lactam beta-lactamase inhibitor. Ceftazidime binds to a variety of bacterial penicillin-binding proteins, and avibactam inactivates a range of carbapenemase enzymes. Ceftazidime–avibactam is administered as an intravenous infusion over 2 hours, and given every 8 hours. Dosage adjustment is needed for people with renal impairment.
Marketing authorisation indication
3.2 Ceftazidime–avibactam (Zavicefta, Pfizer) is indicated in:
- adults and children aged 3 months and older for treating complicated intra-abdominal infection, complicated urinary tract infection including pyelonephritis, and hospital-acquired pneumonia including ventilator-associated pneumonia
- adults with bacteraemia in association with, or that is suspected to be associated with, any of the infections listed above
- adults and children aged 3 months and older with infections caused by aerobic gram-negative organisms, when there are few treatment options.
Dosage in the marketing authorisation
3.3 The dosage schedule is available in ceftazidime–avibactam's summary of product characteristics.
4. Committee discussion
The antimicrobials evaluation committee considered the evidence submitted by Pfizer (the company that manufactures ceftazidime–avibactam) and other stakeholders, the assessment report from the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions (EEPRU), and consultation comments on EEPRU’s report from stakeholders. See the committee papers for full details of the evidence.
5. Recommendations for research
5.1 NICE recommends further research to develop best practice in the health economic evaluation of antimicrobials in the UK, Europe and globally, as detailed in sections 5.2, 5.3 and 5.4.
5.2 Develop methods to model and quantify the additional elements of benefit of new antimicrobials, including, but not limited to, spectrum, transmission, enablement, diversity and insurance value.
5.3 Determine the relationship between a pathogen’s in vitro susceptibility to an antimicrobial treatment and relevant outcomes in people with multi-drug-resistant bacterial infections. Data should include patient identification to allow linkage. It should reflect the site from which the sample was taken, state the probable site of infection, identify the pathogen, identify the mechanism of antimicrobial resistance, and record antimicrobial treatment. Relevant clinical outcomes may include, but are not limited to, mortality (including all-cause mortality and mortality attributable to the infection), clinical cure (signs and symptoms of infection resolved, and no further antimicrobial therapy needed) and microbiological eradication. Relevant safety outcomes include acute kidney injury, renal replacement therapy, colonisation with multi-drug-resistant pathogen after treatment, and Clostridioides difficile infection. Relevant resource-use outcomes include length of hospital stay by ward type and duration of treatment. Ideally, a range of different antimicrobial treatments would be included in a single study, to ensure consistent laboratory methods and clinical breakpoints.
5.4 Establish better methods to synthesise evidence from in vitro antimicrobial susceptibility studies. This could include:
- Establishing whether the different laboratory methods and clinical breakpoints used to assess antimicrobial susceptibility, which are set by different organisations (for example, European Committee on Antimicrobial Susceptibility Testing [EUCAST] and Clinical and Laboratory Standards Institute [CLSI]), are interchangeable.
- Establishing whether it is preferable to use clinical breakpoints at the same time as sample collection, or whether it is acceptable to apply newly published breakpoints to historical data.
- Developing a tool to assess the quality of in vitro antimicrobial susceptibility studies.
- Establishing if and how changes to laboratory methods used to assess susceptibility affect synthesising data from different antimicrobial susceptibility studies.
- Developing reporting guidelines (similar to those provided by PRISMA and CONSORT) to ensure studies of antimicrobial susceptibility are reported clearly and comprehensively.
6. Recommendations for data collection and antimicrobial surveillance
6.1 The contract between the company and NHS England requires the company to participate in the UK Antimicrobial Registry (UKAR), developed by the British Society for Antimicrobial Chemotherapy (BSAC) in partnership with the University of Aberdeen. This registry will provide information on the relationship between patterns of antimicrobial usage and emergence of resistance in the UK, and will provide quantitative data on clinical and safety outcomes. The UKAR registry and other surveillance and monitoring programmes in England for antimicrobials, for example Blueteq, should capture the following information:
- Anatomical site of clinical infection.
- Type of sample, for example, sputum, tracheal, bronchial wash, pleural aspirate.
- Pathogen and mechanism of antimicrobial resistance:
- When the results of microbiological or gene tests are available: record the confirmed pathogen, confirmed resistance mechanism and the antimicrobial agents the pathogen is susceptible to.
- If the antimicrobial is used empirically when results of microbiological or gene tests are not yet available, record the suspected pathogen and resistance mechanism.
- Data should capture whether the confirmed pathogen and resistance mechanism differed from that suspected in the empirical setting.
- Clinical outcomes including, but not limited to, mortality (including all-cause mortality and mortality attributable to the infection), clinical cure (resolution of signs or symptoms of infection and no further antimicrobial therapy needed) and microbiological eradication.
- Safety outcomes including acute kidney injury, renal replacement therapy, colonisation with a multi-drug-resistant pathogen after treatment and Clostridium difficile
- Resource use outcomes including length of hospital stay by ward type and duration of treatment with antimicrobials.
6.2 NICE recommends that as the UK further develops its infrastructure for health data, such as hospital electronic health records and the UKHSA’s surveillance systems for antimicrobial resistance, consideration is given to new data fields relating to clinically significant infections including those outlined above (see section 6.1). This data would help address uncertainties in the future when estimating the health benefits of new antimicrobial therapies in the UK.
Chair, antimicrobials evaluation committee
7. Antimicrobials evaluation committee members and NICE project team
Antimicrobials evaluation committee members
The antimicrobials evaluation committee was convened to test a new process for health technology evaluation on 2 antimicrobial drugs. The committee has 18 members, including 12 members from other NICE committees and 6 members with specialist expertise in infectious disease.
Committee members are asked to declare any interests in the technology to be evaluated. NICE manages these conflicts of interest.
The minutes of the committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.
NICE project team
NICE assigned the antimicrobial evaluation to a team consisting of a technical lead, a technical adviser, several senior advisers and a project manager.
- Caroline Bregman: technical lead
- Sophie Cooper: technical adviser
- Jacoline Bouvy, Nick Crabb, Colm Leonard: senior advisers
- Charlotte Downing: project manager
Information for the public
Ceftazidime-avibactam is available on the NHS. It is a possible treatment for severe drug-resistant infections caused by gram-negative bacteria. Clinicians should follow advice from specialists in microbiology or infectious disease and offer ceftazidime-avibactam only if there are no suitable alternative treatment options.
Is this treatment right for me?
Your healthcare professionals should give you clear information, talk with you about your options and listen carefully to your views and concerns. Your family can be involved too, if you wish. Read more about making decisions about your care.
Questions to think about
- How well does it work compared with other treatments?
- What are the risks or side effects? How likely are they?
- How will the treatment affect my day-to-day life?
- What happens if the treatment does not work?
- What happens if I do not want to have treatment? Are there other treatments available?
The approach is set out in:
- Evaluation Framework (PDF).
- The 2018 report from the Policy Research Unit in Economic Evaluation of Health and Care Interventions (EEPRU): Rothery et al. ‘Framework for value assessment of new antimicrobials. Implications of alternative funding arrangements for NICE Appraisal.
- Antimicrobials evaluation committee: membership (Word).
Invitation to participate
- Final scope (Word).
- Final stakeholder list (Word).
- NICE's response to comments on the draft scope and provisional stakeholder list (Word).
- Equality impact assessment (Word).
- Addendum to protocol - updated PICO table (Word).
- Protocol (Word).