# Oral β-lactam combinations are effective in vitro against Mycobacterium avium, regardless of clarithromycin susceptibility

## TL;DR

Oral beta-lactam antibiotic combinations work well against Mycobacterium avium in lab tests, even when resistance to clarithromycin is present.

## Contribution

This study shows that oral beta-lactam combinations are effective against Mycobacterium avium regardless of clarithromycin resistance.

## Key findings

- Five oral beta-lactam combinations showed synergistic effects against Mycobacterium avium type strain.
- Faropenem combined with cefuroxime had the highest synergistic effect among clinical isolates.
- Mycobacterium intracellulare showed lower susceptibility to beta-lactams compared to Mycobacterium avium.

## Abstract

The global incidence and prevalence of pulmonary disease caused by the
Mycobacterium avium complex (MAC), mainly comprising
M. avium and Mycobacterium
intracellulare, is increasing. However, treating MAC pulmonary
disease is challenging in cases of clarithromycin (CLR)-resistant MAC or
where the patients experience adverse effects or drug interactions with the
few available antibiotics. Therefore, developing novel and highly effective
antibiotics against MAC is crucial. Although the efficacy of dual
β-lactams against Mycobacterium abscessus has been
receiving attention, the efficacy of dual β-lactams against MAC
remains unclear. Here, we used MAC type strains and clinical isolates to
determine whether dual β-lactams were effective against MAC and which
combinations synergistically inhibited bacterial growth using a broth
microdilution checkerboard assay with 6 oral and 22 intravenous antibiotics.
The combination effect and antibacterial activity differed between
M. avium and M. intracellulare. Five
combinations of oral β-lactams and 78 combinations of intravenous
β-lactams showed a synergistic effect against the M.
avium type strain. Among the M. avium clinical
isolates, faropenem combined with cefuroxime showed the highest synergistic
effect, and amoxicillin combined with tebipenem showed the lowest minimum
inhibitory concentration. There was no significant difference in the
combination effects between the CLR-susceptible and CLR-resistant M.
avium clinical isolates in these pairs. In conclusion,
regardless of CLR susceptibility, the oral β-lactam combinations were
effective against M. avium. Thus, when treating MAC
pulmonary disease, it is crucial to determine whether M.
avium or M. intracellulare is the cause.

Mycobacterium avium complex causes chronic respiratory
infections, but treatment is often limited by drug resistance,
intolerance, or interactions. As new therapeutic strategies are urgently
needed, we focused on β-lactam antibiotics, which are widely used
and well tolerated. Although dual β-lactams are effective against
Mycobacterium abscessus, their utility against
Mycobacterium avium complex has remained largely
unexplored. Our in vitro study revealed that several
β-lactam combinations are effective against Mycobacterium
avium, regardless of drug resistance, indicating potential
for clinical use. In contrast, Mycobacterium
intracellulare showed lower susceptibility to
β-lactams. Given this difference in drug susceptibility, we
emphasize the clinical need to distinguish Mycobacterium
avium and Mycobacterium intracellulare to
optimize treatment of Mycobacterium avium complex
pulmonary disease.