Aztreonam PLUS Avibactam – A New Bright Star in the Night Sky

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Looking at the molecular structure of ceftazidime (CTAZ) and aztreonam (ATM), the differences are clear, and so are the similarities: ATM does not have the cephem ring structure of CTAZ, only the 4-member beta-lactam ring.  However, the side chains are identical in both CTAZ and ATM which explains the overlapping gram-negative spectrum of both drugs.CTAZ and AZT

With so little difference between the 2 molecules one would assume an augmented but otherwise identical Gram-negative activity spectrum when either drug is combined with avibactam (AVI).  Avibactam, formerly known as NVX-104, is a novel non-beta-lactam beta-lactamase inhibitor (BLI). The combination with CTAZ was recently approved for cUTI and cIAI; it is on the market as Avycaz.  A registration study for HAP/VAP is ongoing, a logical next indication.  So what could possibly be the rationale for developing an Aztreonam / Avibactam combination?  What does it have over Avycaz?

A recent publication by Vasoo et al. provides some helpful side-by-side comparison data.[1]  In this study of 177 carbapenemase-producing Gram-negatives, the combination of CTAZ/AVI and ATM/AVI had similar activity against isolates expressing Class A, C and D beta-lactamases, however only ATM/AVI had reliable activity against the NDM pathogens which are Class B metallo-beta-lactamase producers.

Table:  Comparison of Aztreonam and Ceftazidime with and without Avibactam [1][2], [3][4]

Table with Construction Sign
Note: Corrections / comments / differentiating data are appreciated – will update based on your feed-back. Thank you!

That is no minor differentiating factor as only colistin, tigecycline and fosfomycin provide fairly reliable coverage against these dreaded pathogens. As we know, reports of colistin resistance have recently sprung up more frequently. Colistin is a favorite drug in pig farms in Southern China; it will soon lose the aura of impregnable activity against MDR pathogens. Unfortunately, the tetracycline class of drugs does not seem to be quite as potent as other antibiotics even for pathogens in the susceptible MIC range, and resistance is also on the increase. For fosfomycin, there is just not enough data to determine whether it will hold up against CPEs. In addition, fosfomycin has a track record of resistance developing rather quickly. [5]

Both Avycaz and the combination ATM/AVI were active against ESBLs, KPC and OXA-48 group isolates, demonstrating the superior potency of both drugs over carbapenem antibiotics.

From a marketing perspective, it will be interesting to see how CTAZ/AVI and ATM/AVI will be positioned in the market.  As it turns out, AstraZeneca has both combos in its portfolio.  Well, with such outstanding potency ATM/AVI should be an easy pitch:

May The A+A Force Be With You!

Btw, the combination of ceftaroline plus avibactam seems to have been abandoned by Actavis/Allergan.

Abbreviations:
ATM       aztreonam
AVI         avibactam
BLI         beta-lactamase inhibitor
cIAI        complicated intra-abdominal infection
CPE       carbapenemase-producing enterobacteriaceae
CTAZ     ceftazidime
cUTI       complicated urinary tract infection
ESBL     extended-spectrum beta-lactamase
HAP       hospital-acquired pneumonia
NDM      New Delhi Metallo-beta-lactamase
VAP       ventilator-associated pneumonia

References:
[1] Vasoo, S.  In Vitro Activities of Ceftazidime-Avibactam, Aztreonam-Avibactam, and a Panel of Older and Contemporary Antimicrobial Agents against Carbapenemase-Producing Gram-Negative Bacilli.  AAC 2015; 59: 7842
[2] Bush, K. Other B-lactam antibiotics. Finch, R.: Antibiotic and Chemotherapy, Chapter 15; 9th ed, Elsevier, 2010
[3] Craig, W. Chapter 21: Cephalosporins. In: Mandell: PPID 2015
[4] Doi, Y.  Chapter 22: Other Betalactam Antibiotics.  In: Mandell: PPID 2015
[5] Morrill,  Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. Open Forum Infect Dis (Spring 2015) 2 (2):doi: 10.1093/ofid/ofv050

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