Professional Documents
Culture Documents
Caz Avi Aztreoanm Aac.01426-19
Caz Avi Aztreoanm Aac.01426-19
Caz Avi Aztreoanm Aac.01426-19
crossm
a
College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
December 2019 Volume 63 Issue 12 e01426-19 Antimicrobial Agents and Chemotherapy aac.asm.org 1
Biagi et al. Antimicrobial Agents and Chemotherapy
TABLE 1 Genotypic and phenotypic susceptibility of tested serine and NDM-producing E. coli and K. pneumoniae isolatesa
MIC (mg/liter)b
Isolate Genotypic profile ATM ATMⴙAVI ATMⴙVBR CAZ CAZ-AVI MER MER-VBR
EC-1 NDM, CMY-2/FOX, CTX-M-1, TEM ⱖ256 16 64 ⱖ256 ⱖ256 64 128
EC-2 NDM, TEM 16 0.25 1 ⱖ256 ⱖ256 64 64
EC-3 NDM-1, CMY-6, CTX-M-15, TEM-1 ⱖ256 4 32 ⱖ256 ⱖ256 64 128
EC-4 NDM-5, OXA-1 0.25 0.25 0.25 ⱖ256 ⱖ256 ⱖ256 ⱖ256
KP-1 NDM-1, CMY-6, CTX-M-15, OXA-1, SHV-11, TEM-1B 128 0.125 2 ⱖ256 ⱖ256 ⱖ256 ⱖ256
KP-2 NDM-1, CTX-M-15, OXA-232, SHV, TEM ⱖ256 0.5 128 ⱖ256 ⱖ256 ⱖ256 ⱖ256
KP-3 NDM, SHV 128 ⱕ0.03 0.125 ⱖ256 ⱖ256 ⱖ256 ⱖ256
KP-4 NDM, CTX-M-1 group, SHV, TEM ⱖ256 0.125 2 ⱖ256 ⱖ256 ⱖ256 ⱖ256
aAvibactam and vaborbactam were tested at fixed concentrations of 4 and 8 mg/liter, respectively.
bATM, aztreonam; AVI, avibactam; VBR, vaborbactam; CAZ, ceftazidime; MER, meropenem.
nation (8) and their ability to hydrolyze all available -lactam antibiotics, with the
exception of aztreonam (9). Despite its activity against MBLs, aztreonam is readily
hydrolyzed by most serine -lactamases which are often coharbored with the MBL
enzyme (10), making it ineffective as monotherapy against these pathogens. As the
fixed-dose combination of aztreonam-avibactam is not yet available for clinical use (11),
data have emerged supporting the use of aztreonam in combination with ceftazidime-
avibactam. These are primarily limited to anecdotal clinical reports (12, 13) and in vitro
data (14–16). Importantly, there are no data evaluating aztreonam in combination with
meropenem-vaborbactam against pathogens coharboring serine and MBL enzymes.
While the theory behind combining aztreonam with either ceftazidime-avibactam or
meropenem-vaborbactam is the same, notable differences between these combina-
tions are present upon comparison of the penicillin-binding protein (PBP) targets of the
-lactams (ceftazidime and meropenem) and the -lactamase affinity of the inhibitors
(avibactam and vaborbactam) (17). The impact of these important differences on the
activity of aztreonam-based combinations has yet to be explored.
As there is an urgent need to identify optimal treatment regimens against serine
and MBL-producing CROs, the objective of this study was to evaluate and compare
the in vitro activity of aztreonam plus ceftazidime-avibactam and aztreonam plus
meropenem-vaborbactam against clinical Escherichia coli and Klebsiella pneumoniae
strains coproducing NDM and one or more serine -lactamases.
(Results of this study were presented in part at IDWeek 2018 San Francisco, CA, USA,
as abstract 2443 [18] and at ECCMID 2019 Amsterdam, Netherlands as abstract 6204
[19].)
RESULTS
Genotypic and phenotypic susceptibility profiles are displayed in Table 1. All strains
were resistant to ceftazidime, ceftazidime-avibactam, meropenem, and meropenem-
vaborbactam. Likewise, all strains were resistant to aztreonam except for EC-4 (MIC,
0.25 mg/liter). For the seven aztreonam-resistant strains, the addition of either avibac-
tam or vaborbactam to aztreonam reduced the MIC by 4-log2 to 12-log2 or 1-log2 to
10-log2 dilutions, respectively (Table 1).
Results of time-kill experiments of each commercially available agent alone at the
highest concentration tested against each E. coli and K. pneumoniae strain are displayed
in Fig. 1 and 2, respectively. Neither ceftazidime (with or without avibactam) nor
meropenem (with or without vaborbactam) was bactericidal alone at 24 h regardless of
the concentration tested (Fig. 1 and 2). Against the E. coli strains, aztreonam was not
bactericidal against strains EC-1 and EC-3 (Fig. 1A and C) but was bactericidal against
EC-2 at ⱖ2⫻ MIC and EC-4 at ⱖ0.5⫻ MIC (Fig. 1B and D). Aztreonam was not
bactericidal against any K. pneumoniae strain at any concentration tested (Fig. 2A to D).
Based on results from individual time-kill experiments, a concentration of 1⫻ MIC or
0.25⫻ MIC of aztreonam was combined with ceftazidime-avibactam at the maximum
concentration of free, unbound drug in serum (fCmax) or meropenem-vaborbactam at
fCmax for strains EC-2 and EC-4, respectively (Fig. 3B and D). For the remaining strains
FIG 1 Mean log10 CFU/ml versus time profiles for each drug at the highest concentration tested against the four E. coli strains. Aztreonam is shown at fCmax
(A and C) and at 4⫻ MIC (B and D). Ceftazidime and meropenem are shown at fCmax in all panels. Curves represent average concentrations from triplicate
experiments.
(EC-1 and EC-3) and all K. pneumoniae strains, aztreonam at fCmax was combined with
either ceftazidime-avibactam or meropenem-vaborbactam at fCmax (Fig. 3A and C and
4A to D). Dual -lactam combinations of aztreonam plus either ceftazidime or mero-
penem were synergistic against 0/8 (0%) and 1/8 (12.5%) strains, respectively (see Fig.
S1 and S2 in the supplemental material). The triple-drug combinations (aztreonam
plus either ceftazidime-avibactam or meropenem-vaborbactam) were synergistic
against all aztreonam-resistant strains, based on the known -lactamases present,
regardless of the species (Fig. 3 and 4). The triple-drug combination of aztreonam plus
ceftazidime-avibactam was synergistic against 3/4 (75%) E. coli strains (all except the
aztreonam-susceptible strain [EC-4]) and was synergistic against 4/4 (100%) K. pneu-
moniae strains. The combination of aztreonam plus meropenem-vaborbactam was also
synergistic against 3/4 (75%) E. coli strains (all except the aztreonam-susceptible strain
[EC-4]) and was synergistic against 3/4 (75%) K. pneumoniae strains (all except the
OXA-232-producing strain [KP-2]). Tables S1 to S4 display means ⫾ standard deviations
(SDs) of the 24-h bacterial densities (log10 CFU/ml) for each drug alone and in
combination against each isolate at each concentration tested.
FIG 2 Mean log10 CFU/ml versus time profiles for each drug at the highest concentration tested against the four K. pneumoniae strains. (A to D) All drugs are
shown at fCmax. Curves represent average concentrations from triplicate experiments.
DISCUSSION
Despite the recent therapeutic advancements in the treatment of CROs, MBL-
producing pathogens remain a significant challenge. While aztreonam is capable of
evading MBL-mediated hydrolysis, the frequent presence of coharbored serine
-lactamases renders aztreonam ineffective, necessitating the need for combination
therapy. To date, the only data available have evaluated aztreonam in combination
with ceftazidime-avibactam. It is imperative that potential alternatives are evaluated in
order to provide clinicians with options against this significant unmet medical need.
In this study, combining aztreonam with ceftazidime-avibactam or meropenem-
vaborbactam produced synergistic interactions against 7/8 (87.5%) and 6/8 (75%)
clinical Enterobacteriaceae strains coproducing NDM and at least one serine
-lactamase. The only difference in synergy observed between the two triple-drug
combinations was against strain KP-2, where synergy was observed when aztreonam
was combined with ceftazidime-avibactam but not with meropenem-vaborbactam.
This discordance is likely attributable the inhibitory activity of avibactam (20), but not
vaborbactam, against the OXA-48-like variant OXA-232 produced by this strain. Addi-
tionally, synergy was not observed with either triple combination against EC-4 (which
FIG 3 Mean log10 CFU/ml versus time profiles for each individual drug at the highest concentration tested that demonstrated no activity and triple-drug
combinations against the four E. coli strains. (A to D) Ceftazidime-avibactam and meropenem-vaborbactam are shown at fCmax alone and in combination. (A
and C) Aztreonam is shown at fCmax alone and in combination. Aztreonam is shown at 1⫻ MIC (B) and at 0.25⫻ MIC (D) alone and in combination. Curves
represent average concentrations from triplicate experiments.
FIG 4 Mean log10 CFU/ml versus time profiles for each individual drug at the highest concentration tested that demonstrated no activity and triple drug
combinations against the four K. pneumoniae strains. (A to D) All drugs are shown alone and in combination at fCmax. Curves represent average concentrations
from triplicate experiments.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at https://doi.org/10.1128/AAC
.01426-19.
SUPPLEMENTAL FILE 1, PDF file, 0.8 MB.
ACKNOWLEDGMENTS
There was no external financial support for this work.
E.W. serves on the speaker’s bureaus for Melinta Therapeutics and Astellas Pharma
and on the advisory boards for GenMark Diagnostics and Shionogi. All other authors
certify no potential conflicts of interest.
REFERENCES
1. Nordmann P, Naas T, Poirel L. 2011. Global spread of carbapenemase- Antimicrob Agents Chemother 61:e00486-17. https://doi.org/10.1128/
producing Enterobacteriaceae. Emerg Infect Dis 17:1791–1798. https:// AAC.00486-17.
doi.org/10.3201/eid1710.110655. 15. Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, Humphries RM, Spell-
2. Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. 2011. berg B, Hujer KM, Marshall EK, Rudin SD, Perez F, Wilson BM, Wasserman
Carbapenems: past, present, and future. Antimicrob Agents Chemother RB, Chikowski L, Paterson DL, Vila AJ, van Duin D, Kreiswirth BN, Cham-
55:4943– 4960. https://doi.org/10.1128/AAC.00296-11. bers HF, Fowler VG, Jr, Jacobs MR, Pulse ME, Weiss WJ, Bonomo RA. 2017.
3. Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. 2014. Can ceftazidime-avibactam and aztreonam overcome beta-lactam resis-
Antibiotic treatment of infections due to carbapenem-resistant tance conferred by metallo-beta-lactamases in Enterobacteriaceae? An-
Enterobacteriaceae: systematic evaluation of the available evidence. An- timicrob Agents Chemother 61:e02243-16. https://doi.org/10.1128/AAC
timicrob Agents Chemother 58:654 – 663. https://doi.org/10.1128/AAC .02243-16.
.01222-13. 16. Wenzler E, Deraedt MF, Harrington AT, Danizger LH. 2017. Synergistic
4. Livermore DM, British Society for Antimicrobial Chemotherapy Working activity of ceftazidime-avibactam and aztreonam against serine and
Party on The Urgent Need: Regenerating Antibacterial Drug Discovery metallo-beta-lactamase-producing Gram-negative pathogens. Diagn Micro-
and Development. 2011. Discovery research: the scientific challenge of biol Infect Dis 88:352–354. https://doi.org/10.1016/j.diagmicrobio.2017.05
finding new antibiotics. J Antimicrob Chemother 66:1941–1944. https:// .009.
doi.org/10.1093/jac/dkr262. 17. Davies TA, Shang W, Bush K, Flamm RK. 2008. Affinity of doripenem and
5. Spellberg B, Bartlett JG, Gilbert DN. 2013. The future of antibiotics comparators to penicillin-binding proteins in Escherichia coli and Pseu-
and resistance. N Engl J Med 368:299 –302. https://doi.org/10.1056/ domonas aeruginosa. Antimicrob Agents Chemother 52:1510 –1512.
NEJMp1215093. https://doi.org/10.1128/AAC.01529-07.
6. Zasowski EJ, Rybak JM, Rybak MJ. 2015. The beta-lactams strike back: 18. Biagi M, Wenzler E. 2018. Searching for the optimal treatment regimen
ceftazidime-avibactam. Pharmacotherapy 35:755–770. https://doi.org/10 for metallo-ß-lactamase producing Enterobacteriaceae: aztreonam plus
.1002/phar.1622. ceftazidime-avibactam vs. aztreonam plus meropenem-vaborbactam.
7. Cluck D, Lewis P, Stayer B, Spivey J, Moorman J. 2015. Ceftolozane- Abstr IDWeek 2018 San Francisco, CA, USA, abstr 2443.
tazobactam: a new-generation cephalosporin. Am J Health Syst Pharm
19. Biagi M, Wenzler E. 2019. Abstr ECCMID 2019 Amsterdam, Netherland,
72:2135–2146. https://doi.org/10.2146/ajhp150049.
abstr 6204.
8. Wailan AM, Paterson DL. 2014. The spread and acquisition of NDM-1: a
20. Kazmierczak KM, Bradford PA, Stone GG, de Jonge BLM, Sahm DF. 2018.
multifactorial problem. Expert Rev Anti Infect Ther 12:91–115. https://
In vitro activity of ceftazidime-avibactam and aztreonam-avibactam
doi.org/10.1586/14787210.2014.856756.
against OXA-48-carrying Enterobacteriaceae isolated as part of the Inter-
9. Dortet L, Poirel L, Nordmann P. 2014. Worldwide dissemination of the
national Network for Optimal Resistance Monitoring (INFORM) Global
NDM-type carbapenemases in Gram-negative bacteria. Biomed Res Int
Surveillance Program from 2012 to 2015. Antimicrob Agents Chemother
2014:249856. https://doi.org/10.1155/2014/249856.
62:e00592-18. https://doi.org/10.1128/AAC.00592-18.
10. Biedenbach D, Bouchillon S, Hackel M, Hoban D, Kazmierczak K, Hawser
21. CLSI. 2018. Performance standards for antimicrobial susceptibility
S, Badal R. 2015. Dissemination of NDM metallo-beta-lactamase genes
among clinical isolates of Enterobacteriaceae collected during the SMART testing: approved 28th ed. Document M100-S28. CLSI, Wayne, PA.
global surveillance study from 2008 to 2012. Antimicrob Agents Che- 22. CLSI. 1999. Methods for determining bactericidal activity of antimicro-
mother 59:826 – 830. https://doi.org/10.1128/AAC.03938-14. bial agents. CLSI document M26-A. CLSI, Wayne, PA.
11. Sy SK, Beaudoin ME, Zhuang L, Loblein KI, Lux C, Kissel M, Tremmel R, 23. Scully BE, Swabb EA, Neu HC. 1983. Pharmacology of aztreonam after
Frank C, Strasser S, Heuberger JA, Mulder MB, Schuck VJ, Derendorf H. intravenous infusion. Antimicrob Agents Chemother 24:18 –22. https://
2016. In vitro pharmacokinetics/pharmacodynamics of the combination doi.org/10.1128/aac.24.1.18.
of avibactam and aztreonam against MDR organisms. J Antimicrob 24. Swabb EA, Singhvi SM, Leitz MA, Frantz M, Sugerman A. 1983.
Chemother 71:1866 –1880. https://doi.org/10.1093/jac/dkw082. Metabolism and pharmacokinetics of aztreonam in healthy subjects.
12. Davido B, Fellous L, Lawrence C, Maxime V, Rottman M, Dinh A. 2017. Antimicrob Agents Chemother 24:394 – 400. https://doi.org/10.1128/
Ceftazidime-avibactam and aztreonam, an interesting strategy to over- aac.24.3.394.
come beta-lactam resistance conferred by metallo-beta-lactamases in 25. Das S, Li J, Armstrong J, Learoyd M, Edeki T. 2015. Randomized phar-
Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents macokinetic and drug-drug interaction studies of ceftazidime, avibac-
Chemother 61:e01008-17. https://doi.org/10.1128/AAC.01008-17. tam, and metronidazole in healthy subjects. Pharmacol Res Perspect
13. Shaw E, Rombauts A, Tubau F, Padullés A, Càmara J, Lozano T, Cobo- 3:e00172. https://doi.org/10.1002/prp2.172.
Sacristán S, Sabe N, Grau I, Rigo-Bonnin R, Dominguez MA, Carratalà J. 26. O’Callaghan CH, Acred P, Harper PB, Ryan DM, Kirby SM, Harding SM.
2018. Clinical outcomes after combination treatment with ceftazidime/ 1980. GR 20263, a new broad-spectrum cephalosporin with anti-
avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing pseudomonal activity. Antimicrob Agents Chemother 17:876 – 883.
Klebsiella pneumoniae infection. J Antimicrob Chemother 73:1104 –1106. https://doi.org/10.1128/aac.17.5.876.
https://doi.org/10.1093/jac/dkx496. 27. Rubino CM, Bhavnani SM, Loutit JS, Morgan EE, White D, Dudley MN,
14. Monogue ML, Abbo LM, Rosa R, Camargo JF, Martinez O, Bonomo RA, Griffith DC. 2018. Phase 1 study of the safety, tolerability, and phar-
Nicolau DP. 2017. In vitro discordance with in vivo activity: humanized macokinetics of vaborbactam and meropenem alone and in combi-
exposures of ceftazidime-avibactam, aztreonam, and tigecycline alone nation following single and multiple doses in healthy adult subjects.
and in combination against New Delhi metallo-beta-lactamase- Antimicrob Agents Chemother 62:e02228-17. https://doi.org/10
producing Klebsiella pneumoniae in a murine lung infection model. .1128/AAC.02228-17.