AIM: The objective of this study was to assess if avibactam, a new β-lactamase inhibitor, can restore the potency of carbapenems, a sub-class of β-lactams, against Mycobacterium abscessus clinical isolates. MATERIALS & METHODS: Twenty-eight M. abscessus clinical isolates that are resistant to multiple drugs currently used to treat its infection were included. MIC of carbapenems alone and in combination with avibactam against these strains were determined. RESULTS: Tebipenem, an oral carbapenem, and ertapenem and panipenem exhibited the greatest shift in MIC when supplemented with avibactam. CONCLUSION: Avibactam restores MICs of tebipenem, ertapenem and panipenem against M. abscessus to therapeutically achievable concentrations and raises the possibility of usefulness of these carbapenems to treat drug-resistant M. abscessus infections.

1. Amit Kaushik, PhD

2. Introduction
M. abscessus
Why carbapenems?
Why β-lactamase inhibitors (BLI)?
Why drug resistant M. abscessus clinical strains?

3. Introduction
Soroka D, et al. J Antimicrob Chemother. 2014 Mar;69(3):691-6.
Dubée V, et al. J Antimicrob Chemother. 2015 Apr;70(4):1051-8.

4. Materials & Methods
Carbapenems
Ertapenem
Meropenem
Imipenem
Doripenem
Biapenem
Faropenem
Tebipenem
&
Panipenem
β-lactamase inhibitors
Clavulanate
Sulbactam
Tazobactam
&
Avibactam

5. Results:
Kaushik A, et al. Future Microbiology, accepted and posted online on 24 Feb 2017.

6. CLA SXT CIP MXF FOX AMI TGC LZD IMI TOB Susc
1N R R R R R R 4 R R R 1
2N R R R R R 16 0.5 R R R 2
4N R R R R R R 1 R R R 1
5N R R R R R R 1 R R R 1
201 R R R R R R 4 R R R 1
7N R R R R R R 4 R R R 1
11N R R R R R R 4 R R R 1
12N R "1/19 R R 8 16 0.25 R 4 R 5
13N 1 R R R R 16 1 R R R 3
14N R R R R R 16 4 R R R 2
19N R R R R R 16 1 R 4 R 3
201 R R R R R R 4 R R R 1
202 R R R R 16 R 1 R R R 2
203 R R R R R R 2 R R R 1
204 R R R R R 16 4 R R R 2
206 R R R R R 16 0.5 R R R 2
208 R R R R R R 0.5 R R R 1
210 R R R R R R 1 R R R 1
211 R R R R R R 0.5 R R R 1
212 R R R R R R 0.5 R R R 1
214 2 R R R R R 1 R R R 2
215 R R R R R R 2 R R R 1
216 R R R R R R 1 R R R 1
218 R R 1 R R 16 1 R 4 R 4
Test Ranges0.06-16 0.25/4.75-8/1520.12-4 0.25-8 4-128 1.0-64 0.015-4 1.0-32 2.0-64 1.0-16
Susceptible Breakpoint2 2.0/38 1 1 16 16 NI 8 4 4
Twenty eight drug resistant clinical isolates of M.
abscessus (Courtesy Dr. Nicole M Parrish)

7. Strains ID E EA FC M MA FC I IA FC D DA FC B BA FC F FA FC T TA FC P PA FC
1N 128 16 8 16 4 4 8 8 1 16 4 4 16 4 4 64 32 2 256 4 64 128 16 8
2N 256 8 32 8 4 2 8 8 1 16 8 2 16 4 4 128 32 4 256 8 32 64 8 8
3N 128 16 8 16 4 4 8 8 1 32 4 8 16 4 4 64 32 2 256 4 64 64 16 4
4N 64 16 4 16 8 2 16 16 1 16 8 2 16 8 2 64 16 4 256 4 64 32 16 2
5N 64 16 4 16 4 4 32 32 1 16 4 4 16 8 2 64 16 4 256 8 32 128 32 4
6N 128 16 8 16 4 4 8 8 1 16 4 4 16 4 4 128 32 4 256 4 64 128 8 16
11N >256 32 8 128 8 16 32 32 1 128 8 16 128 8 16 128 64 2 >256 16 16 128 64 2
12N >256 16 16 16 4 4 16 8 2 32 4 8 16 4 4 128 32 4 >256 4 64 128 16 8
13N 256 8 32 32 8 4 32 16 2 16 8 2 16 8 2 64 32 2 128 8 16 64 16 4
14N >256 32 8 128 8 16 32 8 4 32 8 4 64 8 8 128 64 2 >256 16 16 256 32 8
19N 256 8 32 16 4 4 4 4 1 16 4 4 16 4 4 128 32 4 128 4 32 64 4 16
201 256 16 16 32 4 8 16 8 2 32 4 8 32 8 4 256 64 4 >256 4 64 128 8 16
202 >256 32 8 128 8 16 32 8 4 64 8 8 128 8 16 128 64 2 >256 8 32 256 16 16
203 >256 32 8 64 8 8 16 16 1 64 8 8 64 8 8 128 32 4 128 8 16 64 16 4
204 >256 32 8 128 8 16 32 16 2 128 8 16 64 16 4 256 64 4 >256 8 32 256 16 16
206 >256 16 16 32 4 8 16 8 2 32 8 4 32 8 4 128 32 4 256 4 64 128 8 16
208 256 16 16 16 4 4 16 8 2 32 8 4 16 8 2 64 32 2 256 4 64 64 8 8
210 256 8 32 16 8 2 8 8 1 32 4 8 32 8 4 128 32 4 256 8 32 64 8 8
211 >256 16 16 32 4 8 16 8 2 32 4 8 16 4 4 128 64 2 >256 4 64 64 16 4
212 >256 32 8 16 8 2 16 8 2 16 8 2 16 8 2 64 32 2 256 8 32 64 16 4
214 64 16 4 16 8 2 32 32 1 8 4 2 16 8 2 64 16 4 128 8 16 64 32 2
215 64 8 8 16 8 2 32 32 1 16 8 2 16 8 2 64 16 4 256 16 16 64 32 2
216 128 16 8 16 8 2 16 16 1 16 8 2 32 8 4 128 64 2 256 16 16 64 16 4
218 128 16 8 16 4 4 8 8 1 8 4 2 16 8 2 64 32 2 256 8 32 32 16 2
JHH2 >256 32 8 128 8 16 16 16 1 32 8 4 32 8 4 256 64 4 >256 16 16 256 16 16
JHH4 128 16 8 16 4 4 16 8 2 16 4 4 16 8 2 64 32 2 256 8 32 64 16 4
JHH9 128 8 16 16 4 4 16 8 2 16 4 4 16 4 4 64 32 2 256 4 64 64 16 4
JHHKB >256 64 4 128 16 8 32 16 2 128 8 16 128 16 8 64 32 2 128 16 8 256 32 8
Results:
E=Ertapenem, M=Meropenem, I=Imipenem, D=Doripenem, B=Biapenem, F=Faropenem, T=Tebipenem,
P=Panipenem, A=Avibactam and FC=Fold change. Avibactam at a fixed conc. of 4 ug/ml

9. Figure: Susceptibility trends for M. abscessus clinical isolates (n=28) against carbapenems with or without
4 µg/mL avibactam (Avi). The data labels in each plot represent the number of isolates. Tebipenem (Tebi),
ertapenem (Erta), panipenem (Pani), doripenem (Dori), biapenem (Bia), meropenem (Mero), faropenem
(Faro) and imipenem (Imi).

10. Peak plasma levels:
Drug Dose
(mg)
Cmax
(µg/mL)
PMID
Tebipenem 500 7.92 19673356
Ertapenem 1000 155 18154543
Panipenem 500 28 18154543
Avibactam 250 11.88 25813217

11. Conclusions
 Maximum restoration observed with:
Tebi, Erta and Pani
 Least restoration observed with:
Imi and Faro
 Most effective carbapenems in combination with avibactam against DR
strains are:
Dori, Bia, Mero and Tebi
Further study of combinations of avibactam and tebipenem or ertapenem or
panipenem, in a clinical setting, would be a step toward the possibility of
adding new options for treatment of drug-resistant M. abscessus.

12. 12