The discovery of ceftazidime/avibactam as an anti-Mycobacterium avium agent.
J Antimicrob Chemother
; 72(suppl_2): i36-i42, 2017 Sep 01.
Article
in En
| MEDLINE
| ID: mdl-28922808
ABSTRACT
OBJECTIVES:
To determine if ceftaroline and ceftazidime combined with avibactam are efficacious against pulmonary Mycobacterium avium complex (MAC) disease.METHODS:
First, we performed a concentration-effect study of ceftaroline and ceftaroline/avibactam against extracellular MAC in test tubes. Given the difficulty of obtaining avibactam at the time of experimentation, we used a single concentration of commercial ceftazidime/avibactam, and two sets of non-treated controls, one with ceftazidime/avibactam and the other without. After finding antimicrobial activity with the ceftazidime/avibactam 'control', we performed ceftazidime/avibactam dose-effect studies in test tubes against extracellular MAC and in 24-well plates against intracellular MAC. We then performed a ceftazidime/avibactam exposure-effect and dose-fractionation studies in the hollow-fibre system model of intracellular pulmonary MAC (HFS-MAC). In each experiment, we repetitively sampled each HFS-MAC at specified times to validate ceftazidime/avibactam pharmacokinetics and to quantify bacterial burden.RESULTS:
Ceftaroline killed extracellular MAC with maximal microbial kill (Emax) of 4.87â±â0.26 log10 cfu/mL. However, the ceftazidime/avibactam 'control' also killed MAC compared with the non-treated control. Ceftazidime/avibactam Emax was 3.8 log10 cfu/mL against extracellular bacilli and 3.6 log10 cfu/mL against intracellular MAC. In the HFS-MAC, ceftazidime/avibactam achieved a half-life of 2.5-3.3 h and killed MAC 0.61-2.40 log10 cfu/mL below the starting bacterial burden. The ceftazidime/avibactam efficacy was linked to the proportion of the dosing interval for which the concentration persists above the MIC (fT>MIC), with optimal efficacy at free-drug fT>MIC of 52% (r2 = 0.95).CONCLUSIONS:
Ceftazidime/avibactam effectively kills MAC at exposures easily achieved in the lung by clinical doses. Efficacy was higher than with clinically achievable doses of azithromycin and ethambutol.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ceftazidime
/
Cephalosporins
/
Azabicyclo Compounds
/
Anti-Bacterial Agents
/
Mycobacterium avium
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
J Antimicrob Chemother
Year:
2017
Document type:
Article
Affiliation country:
Estados Unidos