Avibactam / Ceftazidine
Avibactam / Ceftaroline

Avibactam (NXL104)

Forest Laboratories began developing combination products of NXL104 with the anti-MRSA fifth-generation cephalosporin, ceftaroline fosamil, to treat Gram-positive pathogens and with ceftazidime for Gram-negative pathogens. Cerexa, Inc., a wholly-owned subsidiary of Forest Laboratories, recently acquired by Cubist was developing the ceftaroline fosamil-- avibactam combination, while AstraZeneca and Forest collaboratively develop the ceftazidime - avibactam (CAZ-AVI or CAZ104) combination.

Avibactam has a broad spectrum of activity against classes A and C serine b-lactamases [1], including ESBLs and class A carbapenemases
[2,3]. It inhibits selected class D b-lactamases including OXA-48, but apparently not other class D carbapenemases, as judged by the absence of synergy with imipenem against resistant strains of A. baumannii producing OXA-51 and OXA-58 [4] and does not inhibit class B MBLs.

Avibactam form a covalent bond with b-lactamases that is slowly reversible, reforming the avibactam molecule and the b-lactamase enzyme (Figure 1) [5].

Figure 1. Mechanism of action of Avibactam.

Avibactam can greatly lower MICs (4- to 1024-fold), restoring susceptibility of resistant Enterobacteriaceae, against several b-lactam antibiotics [1,3-4,6-10]. It  reduces the MICs of ceftazidime (2- to 16-fold) against AmpC derepressed mutants of P. aeruginosa and against P. aeruginosa mutants producing the class A PER-1 ESBL. This inhibitor is not effective against P. aeruginosa strains with OXA ESBLs or the VEB-1 enzyme [4,9-13]. Avibactam does not reduce the MICs of ceftazidime against carbapenem-resistant A. baumannii [4,10-11]. Avibactam demonstrated synergy with ceftaroline against selected b-lactamase-producing anaerobic strains, Bacteroides fragilis, Prevotella spp. and Finegoldia magna cultured from diabetic foot infections [14]. The antistaphylococcal cephalosporin ceftaroline is a good partner antibiotic, since S. aureus (including MRSA) is a dominant aerobic pathogen [15] in the, often mixed aerobic/anaerobic [16], diabetic foot infections.

AstraZeneca has patented a process for the preparation of DBOs, including avibactam [17]. A patent regarding the use of DBOs as diagnostic agents has appeared [18] as well as a patent of novel crystalline forms of avibactam [19]. Patents have appeared involving the preparation of chiral avibactam and chiral intermediates useful therein [20,21].

Clinical trials

A Phase I safety, tolerability and pharmacokinetic study of avibactam alone and a 4:1 combination of ceftazidime/avibactam has been completed [22]. A Phase I study of the effect of 2000 mg avibactam + 1500 mg ceftaroline combination and a 2000 mg avibactam +
3000 mg ceftazidime combination on QT/QTc interval has been completed [23]. A Phase I study to evaluate the concentrations of two different avibactam/ceftazidime mixtures on concentrations in epithelial lining fluid and plasma has been completed [24]. A Phase I pharmacokinetic and drug - drug interaction study of avibactam/ceftazidime mixtures has been completed [25].

A Phase I trial mass balance recovery, metabolite profile and metabolite identification of [14C]avibactam has been completed [26].



1. Bonnefoy A, Dupuis-Hamelin C, Steier V, et al. "In vitro activity of AVE1330A, an innovative broad-spectrum non-beta-lactam beta-lactamase inhibitor". J. Antimicrob. Chemother. 54: 410-17, 2004.

2. Stachyra T, Pechereau M-C, Bruneau J-M, et al. "Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor".
Antimicrob. Agents Chemother. 54: 5132-8, 2010.

3. Stachyra T, Levasseur P, Pechereau M-C, et al. "In vitro activity of the beta-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases". J. Antimicrob. Chemother. 64: 326-9, 2009.

4. Aktas Z, Kayacan C, Oncul O. "In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase producing Klebsiella pneumoniae. Int. J. Antimicrob. Agents 39: 86-9, 2012.

5. Ehmann DE, Jahic H, Ross PL, et al. "Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor". Proc. Natl. Acad. Sci. USA 109: 11663-8, 2012.

6. Endimiani A, Choudhary Y, Bonomo RA. "In vitro activity of NXL104 in combination with beta-lactams against Klebsiella pneumoniae isolates producing KPC carbapenemases". Antimicrob. Agents Chemother. 53: 3599-601, 2009.

7. Livermore DM, Mushtaq S, Warner M, et al. "NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum beta-lactamases and carbapenemases.
J. Antimicrob. Chemother. 62: 1053-6, 2008.

8. Mushtaq S, Warner M, Williams G, et al. "Activity of chequerboard combinations of ceftaroline and NXL104 versus beta-lactamase-producing Enterobacteriaceae". J. Antimicrob. Chemother. 65: 1428-32, 2010.

9. Sader HS, Flamm RK, Jones RN. "Antimicrobial activity of ceftaroline-avibactam tested against recent clinical isolates from USA medical centers (2010-2011)". Antimicrob. Agents Chemother. 57: 1982-8, 2013.

10. Castanheira M, Sader HS, Farrell DJ, et al. "Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more beta-lactamases and methicillin-resistant Staphylococcus aureus carrying various Staphylococcal cassette chromosome mec types. Antimicrob. Agents Chemother. 56: 4779-85, 2012.

11. Mushtaq S, Warner M, Livermore DM. "In vitro activity of ceftazidime +NXL104 against Pseudomonas aeruginosa and other non-fermenters". J. Antimicrob. Chemother. 65: 2376-81, 2010.

12. Walkty A, DeCorby M, Lagace-Wiens PRS, et al. "In vitro activity of ceftazidime combined with NXL104 versus Pseudomonas aeruginosa isolates obtained from patients in
Canadian hospitals (CANWARD 2009 Study). Antimicrob. Agents Chemother. 55: 2992-4, 2011.

13. Levasseur P, Girard A-M, Claudon M, et al. "In vitro antibacterial activity of the ceftazidime-avibactam (NXL104) combination against Pseudomonas aeruginosa clinical isolates". Antimicrob. Agents Chemother. 56: 1606-8, 2012.

14. Goldstein EJC, Citron DM, Merriam C, et al. "Comparative in vitro activity of ceftaroline, ceftaroline-avibactam, and other antimicrobial agents against aerobic
and anaerobic bacteria cultured from infected diabetic foot wounds". Diagn. Microbiol. Infect. Dis. 76, (3): 347-51, 2013.

15. Eleftheriadou I, Tentolouris N, Argiana V, et al. "Methicillin-resistant Staphylococcus aureus in diabetic foot infections". Drugs 70: 1785-97, 2010.

16. Citron DM, Goldstein EJC, Merriam CV, et al. "Bacteriology of moderate-to-severe diabetic foot infections and in vitro activity of antimicrobial agents". J. Clin. Microbiol. 45: 2819-28, 2007.

17. Boyd JA, Cherryman JH, Golden M, et al. "Process for the preparation of heterocyclic compounds including trans7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide, its salts and synthetic intermediates". WO2012172368; 2012.

18. Shlaes D, Levasseur P. "Use of (1R,2S,5R)-1,6-diazabicyclo[3.2.1]octane2-carboxamide, 7-oxo-6-(sulfooxy)-,monosodium salt as a diagnostic reagent for detecting serine beta-lactamases". EP2135959; 2009.

19. Dedhiya MG, Bhattacharya S, Ducandas V, et al. "Novel crystalline forms of trans-7-oxo-6-(sulfooxy)-1,6diazabicyclo[3,2,1]octane-2-carboxamide sodium salt". CA2716914; 2011.

20. Abe T, Okue M, Sakamaki Y. "Optically active diazabicyclooctane derivatives as beta-lactamase inhibitors and process for preparing them". US20120165533; 2012.

21. Abe T, Okue M, Sakamaki Y. "Preparation of optically-active diazabicyclooctane derivative and method for manufacturing same". WO2012086241; 2012.

22. ClinicalTrials.gov Identifier: NCT01291602.

23. ClinicalTrials.gov Identifier: NCT01290900.

24. ClinicalTrials.gov Identifier: NCT01395420.

25. ClinicalTrials.gov Identifier: NCT01430910.

26. ClinicalTrials.gov Identifier: NCT01448395.



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