Pooled analysis from seven clinical studies demonstrates consistent efficacy for ceftazidime-avibactam in the treatment of multi-drug resistant gram-negative bacteria

AstraZeneca has presented positive data  demonstrating the efficacy of the investigational antibiotic, ceftazidime-avibactam (CAZ-AVI), in treating patients with ceftazidime-resistant Gram-negative infections,(1)  which are increasingly resistant to most available antibiotics, often precipitating the need for clinicians to reach for agents previously reserved for last-line use.

The data, from a pooled analysis of seven clinical trials of patients with either complicated Intra-Abdominal Infections (cIAI) or complicated Urinary Tract Infections (cUTI), demonstrated that ceftazidime-avibactam was effective at treating patients with ceftazidime-resistant Gram-negative pathogens caused by Enterobacteriaceae and Pseudomonas aeruginosa. CAZ-AVI was equally effective at treating patients with ceftazidime-resistant or ceftazidime-susceptible Gram-negative pathogens, regardless of underlying infection.(1) In addition, response rates were similar to carbapenem comparators. Alongside cIAI and cUTI, CAZ-AVI is also being studied for the treatment of Nosocomial Pneumonia including Hospital Acquired Pneumonia and Ventilator Associated Pneumonia.(2)

Hans Sijbesma, Managing Director, Antibiotics Business Unit, AstraZeneca, said: “We are encouraged by the data which highlight the potential for CAZ-AVI to address the challenges of treating patients with life-threatening infections where the lack of effective treatment options has a critical impact on mortality, morbidity and associated healthcare costs.”

In Europe, it is estimated that Gram-negative bacteria are responsible for two thirds of the 25,000 deaths resulting from antimicrobial resistance reported annually.3 Resistance to carbapenems is particularly troubling as they are one of the last lines of defence in severe hospital-treated Gram-negative infections.(4)

In addition to the CAZ-AVI data being presented at this year’s ECCMID, there are also five abstracts featuring new Zinforo™ (ceftaroline fosamil) data, an antibiotic approved for the treatment of adult patients with complicated skin and soft tissue infections (cSSTI) or community-acquired pneumonia (CAP), as well as two abstracts for ATM-AVI, an investigational antibiotic being developed for the treatment of targeted serious bacterial infections. CAZ-AVI, Zinforo™ and ATM-AVI are key antibiotics within AstraZeneca’s recently established Antibiotic Business Unit.

CAZ-AVI combines a cephalosporin (ceftazidime) with a next generation non-beta lactam β-lactamase inhibitor (avibactam). The addition of avibactam protects ceftazidime from being broken down by β-lactamases that are produced by these resistant bacteria. It is being developed to treat a broad range of Gram-negative bacterial infections which are becoming increasingly resistant to antibiotics and pose a threat to public health, including multi-drug resistant P. aeruginosa, carbapenem-resistant Gram-negative pathogens, & ESBL-producing Enterobacteriaceae.

Pooled analysis results: Efficacy of CAZ-AVI against ceftazidime-resistant Gram-negative pathogens

The data analyzed for the pooled analysis included one Phase 2 and three Phase 3 randomized, double-blind trials of hospitalised patients with complicated Intra-Abdominal Infections (cIAI), two Phase 3 double-blind trials in patients with complicated urinary tract infections (cUTI), including pyelonephritis, and an open-label study of patients with either cIAI or cUTI caused by ceftazidime-resistant pathogens.1 In the trials, CAZ-AVI 2000-500 mg given every 8 hours was compared in cIAI with meropenem 1 g plus metrionidazole 500 mg, both every 8 hours and in cUTI with doripenem 500 mg every 8 hours.(1) For the open label study in patients with ceftazidime-resistant pathogens, the comparator was investigator-determined best available therapy. Efficacy was measured in terms of per-pathogen microbiogical responses at test-of-cure visit, and a weighted meta-analysis was used to pool the responses for all studies:(1)

Overall, 79.3% (n=308) of patients with ceftazidime-resistant Enterobacteriaceae demonstrated a favourable response to CAZ-AVI compared with 82.4% (n=719) of patients with ceftazidime-susceptible pathogens. Although the numbers are small, 76.6% (n=25) of patients with ceftazidime-resistant P. aeruginosa responded to CAZ-AVI compared with 85.6% (n=57) of patients with ceftazidime-susceptible pathogens. CAZ-AVI showed similar efficacy to the comparator.(1)

About CAZ-AVI
CAZ-AVI (ceftazidime-avibactam) is an investigational antibiotic being developed to treat serious Gram-negative bacterial infections. CAZ-AVI is a combination of avibactam and ceftazidime - a third generation antipseudomonal cephalosporin with a well-established efficacy and safety profile. Avibactam is a first-in-class broad-spectrum β-lactamase inhibitor, which protects ceftazidime against degradation by Class A, C and some D, β-lactamases.(5)

CAZ-AVI offers a differentiated profile versus existing treatment options in serious Gram-negative infections through its activity against a broad range of isolates of carbapenem-resistant Enterobacteriaceae and difficult to treat P. aeruginosa combined with robust coverage of extended spectrum β-lactamase-expressing pathogens.(5)

CAZ-AVI is being jointly developed by AstraZeneca and Allergan. AstraZeneca holds the global rights to commercialise CAZ-AVI, with the exception of North America where the rights are held by Allergan. In the U.S., CAZ-AVI is marketed under the brand name AVYCAZ® (ceftazidime-avibactam) for injection.

About ZINFORO™
ZINFORO™ (ceftaroline fosamil) is an intravenous cephalosporin antibiotic intended for use as a monotherapy in the treatment of adult patients with complicated skin and soft tissue infections (cSSTI) or community-acquired pneumonia (CAP).6 ZINFORO™ is a bactericidal and works by binding to and inhibiting penicillin-binding proteins (PBPs). PBPs are involved in bacterial cell wall synthesis and repair and their inhibition leads to reduced bacterial cell replication and/or cell death.6-8

ZINFORO™ was granted Marketing Authorisation by the European Commission (EC) for the treatment of adult patients with cSSTI or CAP on 23 August, 2012. Ceftaroline fosamil is marketed as TEFLARO™ in the U.S.

About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com

References

1. Gasink L, Stone G, Armstrong J, Broadhurst H, Newell P, Wardman A. Efficacy of ceftazidime-avibactam against ceftazidime-resistant Gram-negative pathogens: a pooled analysis from the ceftazidime-avibactam clinical trial programme. Oral presentation at 26th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Amsterdam, Netherlands; 9-12 April 2016.
2. ClinicalTrials.gov. A study comparing ceftazidime-avibactam versus meropenem in hospitalized adults with nosocomial pneumonia. Available at: https://clinicaltrials.gov/ct2/show/NCT01808092 Last accessed  April 2016.
3. European Centre for Disease Prevention and Control (ECDC). Technical Report: the bacterial challenge: time to react. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2009/11/WC500008770.pdf Last accessed April 2016.
4. Bryan J. Carbapenems have stood the test of time so far but resistance is emerging. Pharm J. 2014;292:online DOI: 10.1211/PJ.2014.20065329
5. Lagace-Wiens P, Walkty A, Karlowsky JA. Ceftazidime–avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evidence. 2014;9:13-25.
6. Zinforo summary of product characteristics April 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002252/WC500132586.pdf Last accessed March 2016.
7. Laudano JB. Ceftaroline fosamil: a new broad-spectrum cephalosporin. J Antimicrob Chemother. 2011;66(Suppl 3):iii11-iii18.

Biek D, Critchley IA, Riccobene TA, Thye DA. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity. J Antimicrob Chemother. 2010;65(Suppl 4):iv9-iv16.