Abstract Pandoraea species are rare, multidrug-resistant, non-fermenting Gram-negative bacilli primarily described in cystic fibrosis (CF) but increasingly identified in non-CF hosts with structural lung disease. Their recognition remains difficult due to frequent misidentification and limited susceptibility data. We describe an unusual case where Pandoraea pulmonary isolation emerged after modification of long-term Mycobacterium avium-intracellulare (MAC) therapy, initially raising concern for recurrent MAC infection. A 90-year-old woman with COPD, chronic bronchiectasis, and recurrent MAC pulmonary infection was followed for progressive respiratory symptoms. She had previously completed a multidrug regimen of azithromycin, rifampin, and ethambutol, achieving sputum culture conversion and radiographic stability. During follow-up, she developed increased sputum production and fatigue, with cultures again positive for MAC. The regimen was reinitiated for twelve months. Toward the latter half of therapy, medication intolerance prompted discontinuation of rifampin and ethambutol, while azithromycin was continued to complete the treatment window. Upon completion, she was transitioned to erythromycin every other day for prophylaxis of recurrent infection and COPD exacerbations. Several months later, she developed worsening dyspnea and sputum discoloration. CT of the chest demonstrated progression of bilateral ground-glass opacities, mucus impaction, and worsening bronchiectasis. Bronchoscopy with bronchoalveolar lavage revealed benign bronchial mucosa without granulomatous inflammation or malignancy. Acid-fast bacilli and fungal stains were negative; however, cultures grew moderate Pandoraea species. This unexpected finding initially raised concern for recurrence of MAC infection but instead revealed colonization by an uncommon multidrug-resistant organism. Therapy targeting recurrent MAC infection was continued. The patient was maintained on erythromycin and started on inhaled liposomal amikacin, yielding clinical stabilization. This case highlights the diagnostic and therapeutic complexity of Pandoraea in non-CF lung disease, where chronic airway remodeling and prolonged antibiotic exposure create conditions for rare, multidrug-resistant pathogens to emerge. Although primarily reported in CF, Pandoraea is increasingly identified in non-CF hosts, emphasizing diagnostic vigilance and stewardship when adjusting long-term macrolide therapy. Accurate identification is difficult, as standard microbiologic systems often misclassify Pandoraea, delaying targeted management. There are no standardized treatment guidelines, and antimicrobial susceptibility varies across species and isolates. Macrolide resistance is common, while trimethoprim-sulfamethoxazole, tetracyclines, and select carbapenems may retain activity. Although its clinical significance here was uncertain, isolation in a symptomatic host with progressive imaging warranted consideration of pathogenicity. This case adds to the growing literature on rare, emerging airway pathogens and reinforces the need for diagnostic precision in the era of chronic antimicrobial use. This abstract is funded by: None
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