In Vitro Activity of Imipenem/Relebactam Alone and in Combination Against Cystic Fibrosis Isolates of Mycobacterium abscessus

Abstract

Background: Mycobacterium abscessus (MABS) is an opportunistic pathogen that causes chronic, difficult-to-treat pulmonary infections, particularly in people with cystic fibrosis (PwCF), leading to rapid lung function decline and increased morbidity and mortality. Treatment is particularly challenging due to the pathogen's resistance mechanisms and the need for prolonged multidrug therapy, which is characterized by poor clinical outcomes and highlights the urgent need for novel therapeutic strategies. Imipenem/relebactam, a novel β-lactam-β-lactamase inhibitor combination, demonstrates in vitro activity against resistant MABS strains and effective pulmonary penetration. Prior research indicates synergistic activity of imipenem with various antibiotics against M. abscessus.

Objectives: This study aims to evaluate the in vitro activity of imipenem/relebactam, alone and in combination with various antibiotics, against MABS clinical isolates from PwCF (n = 28).

Methods: Susceptibility and synergy were assessed using broth microdilution and checkerboard assays. Extracellular time-kill assays were performed to evaluate the bactericidal activity of synergistic three-drug combinations containing imipenem/relebactam.

Results: Imipenem/relebactam demonstrated potent in vitro activity against clinical MABS isolates, exhibiting substantial synergy with cefuroxime, cefdinir, amoxicillin, and cefoxitin. Rifabutin, azithromycin, moxifloxacin, clofazimine, and minocycline also demonstrated additive effects with imipenem/relebactam. Extracellular time-kill assays identified imipenem/relebactam + cefoxitin + rifabutin and imipenem/relebactam + cefoxitin + moxifloxacin as the most effective combinations.

Conclusions: These findings suggest that imipenem/relebactam may offer a significant advancement in the management of MABS infections in PwCF. The promising efficacy of multidrug regimens combining imipenem/relebactam with agents like cefoxitin, azithromycin, moxifloxacin, clofazimine, and rifabutin highlights potential therapeutic strategies.

Keywords: Mycobacterium abscessus; combination therapy; cystic fibrosis; imipenem/relebactam; synergy.

Figure 1

Percentages of synergistic, additive, and indifferent effects of antibiotics combined with imipenem/relebactam in M. abscessus CF clinical isolates. CXM = cefuroxime, CFD = cefdinir, AMX = amoxicillin, CFX = cefoxitin, RFB = rifabutin, AZM = azithromycin, MFX = moxifloxacin, CFZ = clofazimine, MNC = minocycline.

Figure 2

Mean bacterial loads (log₁₀ CFU/mL) of M. abscessus ATCC 1997 over 72 h with (A) single-agent therapies and (B) three-drug combination therapies with imipenem/relebactam (IMI/REL). Data are presented as the mean with standard errors of the mean. Asterisks denote significant differences compared to the untreated control. The horizontal dashed line marks a 3-log reduction in CFU/mL relative to the initial count of the untreated control, denoting bactericidal activity. (* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, post hoc Tukey’s HSD test.) AZM = azithromycin, CFX = cefoxitin, MFX = moxifloxacin, RFB = rifabutin, CFZ = clofazimine.

Figure 3

(A) Bacterial load (log₁₀ CFU/mL) of M. abscessus ATCC 19977 over 72 h with single-agent therapies and three-drug combination therapies with imipenem/relebactam (IMI/REL) at 1× MIC. (B) M. abscessus CF isolate 13 bacterial load over 72 h with IMI/REL, cefoxitin, rifabutin, and their combination at 1× MIC. (C) M. abscessus CF isolate 258 bacterial load over 72 h with the same treatments as in B. Data are presented as the mean with standard errors of the mean. The horizontal dashed line marks the lower limit of detection. (* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, post hoc Tukey’s HSD test.) AZM = azithromycin, MFX = moxifloxacin, CFX = cefoxitin, CFZ = clofazimine, RFB = rifabutin.