December Horizon Scanning Research & 2016 Intelligence Centre

Meropenem/vaborbactam (Carbavance) for treatment resistant gram-negative bacterial infections – first line

NIHR HSRIC ID: 10693

Lay summary

Hospital acquired infections, such as pneumonia, complicated urinary tract infections and bloodstream infections, are serious infections and a huge problem for the NHS. They prolong patients’ stay in hospital and increase healthcare costs. These infections are frequently caused by types of bacteria that are becoming resistant to commonly prescribed antibiotics. Resistance to antibiotics is a serious global concern. If licensed, Carbavance could offer a treatment option for patients in hospital who have acquired a serious bacterial infection that is resistant to certain antibiotics.

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

• Gram-negative bacterial infections: serious; treatment resistant; in a hospital setting – first line.

TECHNOLOGY

DESCRIPTION

Carbavance is a fixed-dose combination of meropenem (RPX-2003; biapenem) and vaborbactam (RPX-7009). Meropenem is a beta-lactam carbapenem antibiotic, while vaborbactam is a beta-lactamase inhibitor that inhibits the major mediators of bacterial resistance, specifically the Klebsiella pneumoniae carbapenemase (KPC) enzyme, which is the primary resistance mechanism to carbapenems. In the phase III clinical trial, Carbavance is administered by intravenous (IV) infusion at meropenem 2g plus vaborbactam 2g every 8 hours for up to 14 days1.

Carbavance does not currently have Marketing Authorisation in the EU for any indication; similarly vaborbactam is also not licensed in the EU. Meropenem is licensed in the EU for: severe pneumonia, including hospital and ventilator-associated pneumonia; broncho- pulmonary infections in cystic fibrosis; complicated urinary tract infections; complicated intra- abdominal infections; intra- and post-partum infections; complicated skin and soft tissue infections; acute bacterial meningitis; treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above; and the management of neutropenic patients with fever that is suspected to be due to a bacterial infection2.

Common (≥ 1/100 to <1/10) adverse reactions related to meropenem include: thrombocythaemia; headache; diarrhoea; vomiting; nausea; abdominal pain; increased transaminases, blood alkaline phosphatase or blood lactate dehydrogenase; rash; pruritus; inflammation and pain.

Carbavance is also in phase III clinical trials for Klebsiella infections; complicated urinary tract infection; hospital-acquired pneumonia and sepsis.

INNOVATION and/or ADVANTAGES

If licensed, Carbavance will offer an additional treatment option for hospitalised patients with treatment resistant gram-negative bacterial infections.

DEVELOPER

The Medicines Company Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

Horizon Scanning Research & Intelligence Centre

PATIENT GROUP

BACKGROUND

Gram-negative bacteria do not retain the crystal violet stain used in bacterial differentiation and are characterised by their cell envelopes which is made of a thin peptidoglycan cell wall. Increasing resistance in gram-negative bacteria is a particular and growing public health concern because of the limited treatment options for infections caused by these bacteria, especially those that are resistant to carbapenem antibiotics, which are last-line drugs used to treat those infections3.

Hospital acquired pneumonia (HAP) occurs after a hospital stay of at least 48 hours. These infections can be very severe and life-threatening due to the patients’ underlying illness and frailty, and the treatment-resistant nature of the pathogens4.

Ventilator associated pneumonia (VAP) is a hospital associated pneumonia that occurs 48 hours or more after tracheal intubation. Early onset VAP occurs within four days of intubation and mechanical ventilation, and is often caused by bacteria that remain sensitive to first line antibiotic therapy, whereas late onset VAP develops after four days and is often caused by multi-drug resistant pathogens4.

Complicated urinary tract infections (cUTI) are a frequent cause of hospital admissions and healthcare associated complications. The most common pathogen encountered in cUTI are the gram-negative bacteria Escherichia coli, other common Enterobacteriaceae (i.e. Klebsiella spp. or Citrobacter spp.) and Pseudomonas spp. Successful treatment remains a challenge due to the majority of pathogens in cUTI showing multi-drug resistance5.

CLINICAL NEED and BURDEN OF DISEASE

Approximately 99,000 cases of bacteraemia were reported in adults aged over 18 in the UK between April 2011 and March 2012, and just over half of these infections (53%) were caused by gram-negative bacteria. Resistance was common, with resistance to third- generation cephalosporins seen in 9-11% of Escherichia coli and Klebsiella spp. Resistance to carbapenems is also now being seen, with resistance reported in 9% of Pseudomonas and 1% of Enterobacter spp6. The consequences of antimicrobial resistance include increased treatment failure for common infections and decreased treatment options where antibiotics are vital, such as during certain cancer treatments7.

The population likely to be eligible to receive Carbavance could not easily be estimated from available routine published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE guidelines in development. Antimicrobial stewardship-changing risk-related behaviours in the general population (GID-PHG89). Expected January 2017.

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• NICE guidelines. Antimicrobial stewardship: systems and processes for effective antimicrobial medicine use (NG15). August 2015. • NICE clinical guideline. Pneumonia in adults: diagnosis and management (CG191). December 2014. • NICE clinical guideline. Healthcare-associated infections: prevention and control in primary and community care (CG139). March 2012. • NICE quality standard. Antimicrobial stewardship (QS121). April 2016. • NICE quality standard. Medicines optimisation (QS120). March 2016. • NICE quality standard. Healthcare-associated infections (QS113). February 2016. • NICE quality standard. Urinary tract infections in adults (QS90). June 2015. • NICE quality standard. Infection prevention and control (QS61). April 2014. • NICE quality standard. Urinary tract infection in children and young people (QS36). July 2013. • NICE public health guidance. Healthcare-associated infections: prevention and control (PH36). November 2011. • NICE key therapeutic topics. Antibiotic prescribing – especially broad spectrum antibiotics (KTT9). February 2016.

NHS England Policies and Guidance

• NHS England. 2013/14 NHS Standard Contract for Specialised Services for Infectious Diseases (Adult). B07/S/a. • NHS England. 2013/14 NHS Standard Contract for High Security Infectious Disease Unit (All ages). B07/S/b.

Other Guidance

• Department of Health England. Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infection (5th Annual Report). 20158.

CURRENT TREATMENT OPTIONS

It is important to initiate antibiotics as soon as possible after diagnosis, and the choice should be guided by careful consideration of patient specific factors, such as severity of illness and previous antibiotic exposure. In addition, local epidemiology should be considered in line with good antimicrobial surveillance4. Infections caused by highly resistant pathogens need treatment with broad-spectrum antibiotics (such as: extended-spectrum penicillins, third-generation cephalosporins, aminoglycosides, carbapenems, linezolid, vancomycin, teicoplanin, or colistin), as recommended by British Society of Antimicrobial Chemotherapy guidance9.

There are many different types of antibiotics, most of which can be broadly classified into six groups10: • Penicillins – such as penicillin and amoxicillin. • Cephalosporins – such as cephalexin. • Aminoglycosides – such as gentamicin and tobramycin. • Tetracyclines – such as tetracyclin and doxycycline. • Macrolides – such as erythromycin and clarithomycin. • Fluoroquinolones – such as ciprofloxacin and levofloxacin.

Current treatment options for HAP or VAP may include antibiotic therapy, oxygen, and 4,9,11 ventilator support . The choice of agent for initial antibiotic therapy will depend on the likelihood of infection with multi-drug resistant pathogens12. Late onset pneumonia (>5 days

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stay in hospital) has a significantly greater risk for being caused by multi-drug resistant bacteria and therefore requires combination antibiotic therapy. This may include an anti- pseudomonal cephalosporin, carbapenem or penicillin administered in combination with an anti-pseudomonal fluoroquinolone, aminoglycoside, or a beta-lactamase inhibitor. In contrast, for early onset pneumonia (<5 days stay in hospital), antibiotic monotherapy may be adequate using an appropriate cephalosporin, quinolone, or extended-spectrum penicillin. Generally, with effective treatment, improvements will be seen within 42 to 72 hours. Antibiotics can be safely discontinued after seven days if signs and symptoms improve (such as a reduction in C-reactive protein, white cell count and temperature, alongside a clinical improvement and an improvement in oxygenation)4.

The major goals of VAP management are early, appropriate antibiotics in adequate doses followed by de-escalation based on microbiological culture results and the clinical response of the patient13. There is no clear consensus, but many experts will continue antibiotic treatment for 14-21 days, although seven days of antibiotic therapy may be adequate in many cases9. The management of cUTIs includes the removal of indwelling catheters, if possible, and antibiotic therapy. These infections (including acute pyelonephritis) are frequently caused by gram-negative bacteria and according to European Association of Urology Guidelines, second or third generation cephalosporins, beta-lactam antibiotics (e.g. penicillins) in combination with beta-lactamase inhibitors and quinolones should be used for treatment5.

EFFICACY and SAFETY

Trial NCT02168946, Rempex 506; Carbavance vs best available therapy with IV antibiotics; phase III. Sponsor Rempex Pharmaceuticals (a wholly owned subsidiary of The Medicines Company). Status Ongoing. Source of Trial registry1. information Location EU (incl UK), USA, and other countries. Design Randomised, active-controlled. Participants n=150 (planned); hospitalised; weight ≤185kg; a serious infection and/or bacteraemia, requiring administration of IV antibacterial therapy; a known or suspected carbapenem-resistant Enterobacteriaceae infection. Schedule Randomised to Carbavance (meropenem 2g plus vaborbactam 2g) IV once every 8 hrs for up to 14 days; or best available therapy with IV antibiotics. Follow-up Follow-up 30 days. Primary Efficacy measured by successful response (no alteration in antimicrobials required); outcomes microbiological eradication in cUTI/acute pyelonephritis defined as the demonstration that the bacterial pathogen(s) found at baseline reduced to <103 CFU/mL urine; microbiological eradication in bacteraemia defined as the demonstration that bacterial pathogen(s) found at baseline absent with repeat culture. Clinical cure defined as complete resolution or significant improvement of the baseline signs and symptoms, and no further antimicrobial warranted. Secondary All-cause mortality; response of overall success; clinical outcome of cure; outcomes microbiological outcome of eradication; relapse/recurrence; total ventilator days for pts with pneumonia; partial pressure arterial oxygen to fraction of inspired oxygen in pts with pneumonia; time to extubation in pts who are on ventilator at baseline; time to bacterial clearance in pts with bacteraemia. No quality of life measurement included in trial outcomes. Expected Study completion date reported as December 2016. reporting date

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ESTIMATED COST and IMPACT

COST

The cost of Carbavance is not yet known. Meropenem is already marketed in the UK; a 10 vial pack of 500mg powder for solution for injection costs £7714.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs

 Other: expert opinion states it is very hard to  None identified know how to advise clinicians on when to suspect that patients may be suffering from infections with relevant resistant pathogens. In addition, when there is a microbiological diagnosis of a resistant bacterium, it takes time to find out what the exact mechanism may be, and if this agent is used empirically then it may be used unnecessarily and would incur additional costsa.

Other Issues

 Clinical uncertainty or other research question  None identified identified: expert opinion states there are a number of competitor agents either available or in development which work on the same principle and it will be difficult for clinicians to decide which one to useb.

REFERENCES

1 ClinicalTrials.gov. A phase 3, multi-center, randomized, open-label study of carbavance (meropenem/vaborbactam) versus best available therapy in subjects with selected serious infections due to carbapenem-resistant enterobacteriaceae. www.clinicaltrials.gov/show/NCT02168946 Accessed 2 December 2016. 2 eMC. electronic Medicines Compendium. www.medicines.org.uk

a Expert personal communication.

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3 Department of Health. UK Five Year Antimicrobial Resistance (AMR) Strategy 2013 to 2018. September 2013. 4 Hunter JD. Ventilator associated pneumonia. British Medical Journal 2012;344:e3325. 5 National Institute for Health and Care Excellence. Complicated urinary tract infections: ceftolozane/tazobactam. Advice ESNM74. London: NICE; June 2016. 6 Health Protection Agency. English National Point Prevalence Survey on Healthcare Associated Infections and Antimicrobial Use, 2011: Preliminary data. London: Health Protection Agency; 2012. 7 Davies S. Annual Report of the Chief Medical Officer 2011: Volume Two. Infections and the Rise of Antimicrobial Resistance (2013). www.gov.uk/government/publications/chief-medical-officer- annualreport-volume-2 Accessed 2 December 2016. 8 Public Health England. Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infection 5th Annual Report. London: Department of Health; February 2015. 9 National Institute for Health and Care Excellence. Pneumonia in adults: diagnosis and management. Clinical guideline CG191. London: NICE; December 2014. 10 NHS Choices. Antibiotics. www.nhs.uk/conditions/Antibiotics-penicillins/Pages/Introduction.aspx Accessed 5 December 2016. 11 File T. Recommendations for treatment of hospital-acquired and ventilator-associated pneumonia: review of recent international guidelines. Clinical Infectious Diseases 2010;51(S1):S42–S47. 12 Medscape. Hospital acquired pneumonia. www.medscape.com/viewarticle/506080_4 Accessed 5 December 2016. 13 Kalanuria AA, Zai W and Mirski M. Ventilator-associated pneumonia in the ICU. Critical Care 2014;18:208. 14 Joint Formulary Committee. British National Formulary. BNF November 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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