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However, treating MAC pulmonary\n                        disease is challenging in cases of clarithromycin (CLR)-resistant MAC or\n                        where the patients experience adverse effects or drug interactions with the\n                        few available antibiotics. Therefore, developing novel and highly effective\n                        antibiotics against MAC is crucial. Although the efficacy of dual\n                        \u03b2-lactams against\n                      <jats:italic toggle=\"yes\">Mycobacterium abscessus<\/jats:italic>\n                      has been\n                        receiving attention, the efficacy of dual \u03b2-lactams against MAC\n                        remains unclear. Here, we used MAC type strains and clinical isolates to\n                        determine whether dual \u03b2-lactams were effective against MAC and which\n                        combinations synergistically inhibited bacterial growth using a broth\n                        microdilution checkerboard assay with 6 oral and 22 intravenous antibiotics.\n                        The combination effect and antibacterial activity differed between\n                      <jats:italic toggle=\"yes\">M. avium<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">M. intracellulare<\/jats:italic>\n                      . Five\n                        combinations of oral \u03b2-lactams and 78 combinations of intravenous\n                        \u03b2-lactams showed a synergistic effect against the\n                      <jats:italic toggle=\"yes\">M.\n                            avium<\/jats:italic>\n                      type strain. Among the\n                      <jats:italic toggle=\"yes\">M. avium<\/jats:italic>\n                      clinical\n                        isolates, faropenem combined with cefuroxime showed the highest synergistic\n                        effect, and amoxicillin combined with tebipenem showed the lowest minimum\n                        inhibitory concentration. There was no significant difference in the\n                        combination effects between the CLR-susceptible and CLR-resistant\n                      <jats:italic toggle=\"yes\">M.\n                            avium<\/jats:italic>\n                      clinical isolates in these pairs. In conclusion,\n                        regardless of CLR susceptibility, the oral \u03b2-lactam combinations were\n                        effective against\n                      <jats:italic toggle=\"yes\">M. avium<\/jats:italic>\n                      . Thus, when treating MAC\n                        pulmonary disease, it is crucial to determine whether\n                      <jats:italic toggle=\"yes\">M.\n                            avium<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">M. intracellulare<\/jats:italic>\n                      is the cause.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Mycobacterium avium<\/jats:italic>\n                        complex causes chronic respiratory\n                            infections, but treatment is often limited by drug resistance,\n                            intolerance, or interactions. As new therapeutic strategies are urgently\n                            needed, we focused on \u03b2-lactam antibiotics, which are widely used\n                            and well tolerated. Although dual \u03b2-lactams are effective against\n                        <jats:italic toggle=\"yes\">Mycobacterium abscessus<\/jats:italic>\n                        , their utility against\n                        <jats:italic toggle=\"yes\">Mycobacterium avium<\/jats:italic>\n                        complex has remained largely\n                            unexplored. Our\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        study revealed that several\n                            \u03b2-lactam combinations are effective against\n                        <jats:italic toggle=\"yes\">Mycobacterium\n                                avium<\/jats:italic>\n                        , regardless of drug resistance, indicating potential\n                            for clinical use. In contrast,\n                        <jats:italic toggle=\"yes\">Mycobacterium\n                                intracellulare<\/jats:italic>\n                        showed lower susceptibility to\n                            \u03b2-lactams. Given this difference in drug susceptibility, we\n                            emphasize the clinical need to distinguish\n                        <jats:italic toggle=\"yes\">Mycobacterium\n                                avium<\/jats:italic>\n                        and\n                        <jats:italic toggle=\"yes\">Mycobacterium intracellulare<\/jats:italic>\n                        to\n                            optimize treatment of\n                        <jats:italic toggle=\"yes\">Mycobacterium avium<\/jats:italic>\n                        complex\n                            pulmonary disease.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  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