Ceftazidime-avibactam combined with aztreonam successful for NDM producers
NDM is a metallo-beta-lactamase and provides a bigger treatment challenge than KPC. This is because avibactam (and vaborbactam and relebactam) does not inhibit it. Therefore, NDM producers are resistant to ceftazidime-avibactam.
However, avibactam may still play a role in the treatment of infections with NDM producers. This is when it is combined with aztreonam.
Aztreonam is a curious antibiotic because it is not inactivated by NDM. However, most NDM producing bacteria produce other beta-lactamases as well, some of which will inactivate aztreonam. So aztreonam alone will rarely be a useful option for NDM producers. Several years ago, David Livermore from the UK, hypothesized that combining avibactam with aztreonam would provide a useful treatment option for NDM producers. This is because the avibactam will inactivate all of the "other" beta-lactamases, allowing aztreonam to kill the bacteria because it is not destroyed by NDM.
Development of the aztreonam-avibactam combination is being supported by 2 pharmaceutical companies, the US government's Biomedical Advanced Research and Development Authority (BARDA) and the European COMBACTE-CARE project.
See: https://www.imi.europa.eu/content/combacte-care
One of the key missions in the aztreonam-avibactam development project must surely be the appropriate dosing of this combination. There may well be subtleties in use of the combination which will be needed to optimize its use. Development of aztreonam-avibactam has been extraordinarily slow, so don't expect it to be available as a package anytime soon.
In the meantime, Robert Bonomo and others, have been working on a more readily available combination of ceftazidime-avibactam with aztreonam. Marshall and colleagues from the Bonomo lab in Cleveland have described a patient with a prosthetic joint infection due to an NDM producing Enterobacter isolate, successfully treated with ceftazidime-avibactam with aztreonam. Colistin was also used in this case. As an illustration of the synergy between ceftazidime-avibactam and aztreonam, the inhibition zone of the ceftazidime-avibactam disk increased from 18mm to 28 mm on the addition of aztreonam.
The reference for this paper is:
More recently, Aurelien Dinh from Paris has described two patients with NDM producers successfully treated with the ceftazidime-avibactam-aztreonam combination. The first patient, who had 26 days of constant bacteremia due to an NDM producing Klebsiella pneumoniae isolate. The bloodstream was sterilized within a day of the ceftazidime-avibactam-aztreonam combination being commenced. Their second patient, with lung abscesses due to NDM producing Pseudomonas aeruginosa, was also successfully treated with this combination.
Dinh and colleagues used ceftazidime-avibactam at a dose of 2/0.5 grams every 8 hours and aztreonam at 2 grams every 8 hours. The duration of each infusion was not mentioned. Neither was the relative timing of the antibiotics, as this may prove to be important. It remains to be seen whether ceftazidime-avibactam-aztreonam has some unique advantages over the avibactam-aztreonam combination.
The siderophore cephalosporins (eg, cefiderocol) also have activity against most NDM producing strains, although clinical studies are awaited.
The reference for this paper is:
However, avibactam may still play a role in the treatment of infections with NDM producers. This is when it is combined with aztreonam.
Aztreonam is a curious antibiotic because it is not inactivated by NDM. However, most NDM producing bacteria produce other beta-lactamases as well, some of which will inactivate aztreonam. So aztreonam alone will rarely be a useful option for NDM producers. Several years ago, David Livermore from the UK, hypothesized that combining avibactam with aztreonam would provide a useful treatment option for NDM producers. This is because the avibactam will inactivate all of the "other" beta-lactamases, allowing aztreonam to kill the bacteria because it is not destroyed by NDM.
Development of the aztreonam-avibactam combination is being supported by 2 pharmaceutical companies, the US government's Biomedical Advanced Research and Development Authority (BARDA) and the European COMBACTE-CARE project.
See: https://www.imi.europa.eu/content/combacte-care
One of the key missions in the aztreonam-avibactam development project must surely be the appropriate dosing of this combination. There may well be subtleties in use of the combination which will be needed to optimize its use. Development of aztreonam-avibactam has been extraordinarily slow, so don't expect it to be available as a package anytime soon.
In the meantime, Robert Bonomo and others, have been working on a more readily available combination of ceftazidime-avibactam with aztreonam. Marshall and colleagues from the Bonomo lab in Cleveland have described a patient with a prosthetic joint infection due to an NDM producing Enterobacter isolate, successfully treated with ceftazidime-avibactam with aztreonam. Colistin was also used in this case. As an illustration of the synergy between ceftazidime-avibactam and aztreonam, the inhibition zone of the ceftazidime-avibactam disk increased from 18mm to 28 mm on the addition of aztreonam.
The reference for this paper is:
Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, Humphries RM, Spellberg
B, Hujer KM, Marshall EK, Rudin SD, Perez F, Wilson BM, Wasserman RB, Chikowski
L, Paterson DL, Vila AJ, van Duin D, Kreiswirth BN, Chambers HF, Fowler VG Jr,
Jacobs MR, Pulse ME, Weiss WJ, Bonomo RA.
Antimicrob Agents Chemother.
2017 Mar 24More recently, Aurelien Dinh from Paris has described two patients with NDM producers successfully treated with the ceftazidime-avibactam-aztreonam combination. The first patient, who had 26 days of constant bacteremia due to an NDM producing Klebsiella pneumoniae isolate. The bloodstream was sterilized within a day of the ceftazidime-avibactam-aztreonam combination being commenced. Their second patient, with lung abscesses due to NDM producing Pseudomonas aeruginosa, was also successfully treated with this combination.
Dinh and colleagues used ceftazidime-avibactam at a dose of 2/0.5 grams every 8 hours and aztreonam at 2 grams every 8 hours. The duration of each infusion was not mentioned. Neither was the relative timing of the antibiotics, as this may prove to be important. It remains to be seen whether ceftazidime-avibactam-aztreonam has some unique advantages over the avibactam-aztreonam combination.
The siderophore cephalosporins (eg, cefiderocol) also have activity against most NDM producing strains, although clinical studies are awaited.
The reference for this paper is:
Davido B, Fellous L, Lawrence C, Maxime V, Rottman M, Dinh A.
Antimicrob Agents
Chemother. 2017 Jun 19. [Epub ahead of print]
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