Ceftaroline pharmacokinetics/pharmacodynamics in the hollow-fibre model of Mycobacterium abscessus lung disease

Guideline-based therapy (GBT) of Mycobacterium abscessus (MAB) lung disease (LD) achieves a sputum culture conversion rate in ∼35% of patients. The β-lactam antibiotics, imipenem and cefoxitin, are the cornerstone of GBT. However, a 1-h half-life means multiple infusions per day, which is difficult for months-long therapy.

As an alternative, we tested ceftaroline-avibactam, with a 3-h half-life, in the hollow-fibre model system of MAB-LD (HFS-MAB). Eight ceftaroline-avibactam exposures were administered twice daily based on human intrapulmonary pharmacokinetics. Next, we compared GBT (cefoxitin-clarithromycin-amikacin) to standard-dose and to high-dose ceftaroline-avibactam-tigecycline-moxifloxacin regimens, in the HFS-MAB, mimicking the intrapulmonary pharmacokinetics of all drugs.

Ceftaroline-avibactam maximal microbial kill was 0.72 log₁₀ colony-forming units (CFUs) per millilitre below day 0 burden (stasis). The ceftaroline pharmacokinetic-pharmacodynamic parameter linked to microbial kill and anti-microbial resistance was 0-24-h area under the concentration-time curve (AUC_0-24) to minimum inhibitory concentration. GBT killed 1.21 ± 0.25 log₁₀ CFU/mL versus 0.45 ± 0.42 log₁₀ CFU/mL below stasis for high-dose ceftaroline combination (P = 0.20). In combination regimens, proportion of the ceftaroline-resistant subpopulation was 41.22 ± 13.11 times lower than the cefoxitin-resistant subpopulation (P = 0.002).

Ceftaroline-avibactam administered twice a day would be an adequate replacement for the four-times-a-day cefoxitin treatments for MAB-LD.