NEW YORK — Two treatments that don't involve antibiotics have moved from the laboratory into clinical testing for control of nontuberculous mycobacteria (NTM) pulmonary disease, according to separate updates presented at the 6th World Bronchiectasis & NTM Conference (WBC) 2023.
There continue to be many hurdles for the widespread clinical application of either bacteriophage therapy or treatment with inhaled nitric oxide (NO). Nevertheless, both of these novel strategies remain viable after years of study and are being avidly pursued for control of persistent NTM infections, particularly infections with Mycobacterium abscessus, according to investigators directly involved in their development.
Both treatments have now been employed on a compassionate use basis in cases in which antibiotic therapies have failed. Responses have ranged from encouraging to lifesaving improvement.
Bacteriophages are viruses. Their therapeutic potential was recognized not long after they were first identified approximately 100 years ago. Extremely common in the environment, these viruses are specific to the particular bacteria that they infect. After entering bacteria, the viruses reproduce their genome, killing the bacteria. As a therapy in cases involving resistant bacteria, they have promise for having highly targeted bactericidal effects, along with the potential of a very low risk of side effects.
Abandoned and then resurrected as potential therapies over the decades, they have been difficult to deploy in treatment because their ability to invade bacteria is highly specific to the isolate. Each bacteriophage must be matched to its targeted pathogen, explained Jerry A. Nick, MD, director of the Adult Cystic Fibrosis Program, National Jewish Hospital, Denver.
Recently, Nick and other researchers pursuing the promise of phage therapy have focused on its potential for controlling M abscessus, a multidrug-resistant NTM that is a common source of poorly controlled pulmonary disease. Because of the limited number of treatment options, M abscessus infections have become one of the most common type of infection in cases that are now referred for this treatment as a last resort, according to Nick.
There are proof-of-concept success stories. In one case study, a patient with a life-threatening NTM that was related to a treatment-resistant M abscessus infection received two bacteriophages engineered to have a lytic effect on isolates grown from the patient’s sputum. The 26-year-old patient, who had NTM related to cystic fibrosis, received the bacteriophages by intravenous administration.
Within days of administration, phage-induced lysis of the bacterium was detected on molecular and metabolic assays. Airway cultures became predominantly negative 118 days after initiation of treatment, and progressive lung improvement was observed on imaging.
On the basis of evidence that the M abscessus infection was controlled, the patient became eligible for a lung transplant. The transplant was completed successfully 389 days after bacteriophage therapy was initiated. On examination, the patient’s explanted lungs were free of disseminated M abscessus, although the organism's DNA was detected by bronchoscopy and bronchoalveolar lavage in three lobes. The patient regained normal lung function after transplantation.
In a larger case series, for which Nick served as a co-author, phage therapy was again offered on a compassionate use basis. In this case, lytic phages that were identified for 55 isolates were administered intravenously to 20 patients with NTM and M abscessus infections. Eleven of the patients demonstrated some degree of clinical or microbiologic response. There were no serious adverse events.
"Favorable outcomes have now been observed in several patients who lacked an alternative treatment option, and these provide the basis for continuing to pursue phage therapy as an adjunct to other management in resistant Mycobacterium infections," Nick reported.
Inhaled NO has also been employed in case studies. It, too, has faced multiple obstacles in the course of an extended period of development. Much of the focus of this therapy in the setting of NTM is also M abscessus infections.
NO has numerous functions in normal physiology and is produced by numerous cell types. It has attracted attention for use in controlling NTM because it is implicated in signaling that improves host defenses against infection. Inhaled NO is approved as a pulmonary dilator. Experimental evidence of antimicrobial effects provided the basis for a small number of clinical studies, according to Patrick A. Flume, MD, a professor of pulmonary and critical care medicine at the Medical University of South Carolina, Charleston.
Flume, who has been active in the study of inhaled NO as a therapy for M abscessus infection for several years, was the first author of a recently published pilot study of the use of inhaled NO for 10 patients who had been receiving long-term NTM antibiotic therapy. NO was administered for 50 minutes 3 times per day, 5 days per week, for 3 weeks. The results were promising.
"Of the 10 patients, four met the primary outcome measure of negative sputum cultures after 3 weeks of therapy," Flume reported. He further noted that the therapy was well tolerated.
Although patients again had positive cultures within months of therapy discontinuation, the bacterial load appeared to remain suppressed relative to baseline levels. Other published reports, such as one case study in which treatment with a lower bacterial load was associated with improved quality of life, have also supported the potential use of inhaled NO for patients with difficult M abscessus infections.
One problem is that the therapeutic window for inhaled NO is narrow, so risks increase and benefit is lost above certain exposures. These and other challenges are being addressed in ongoing research, and Flume is optimistic that this therapy will emerge as a viable adjunctive tool for treating patients with M abscessus or other challenging NTM infections.
James Chalmers, MD, PhD, professor of medicine, University of Dundee, Scotland, appreciates the underlying concepts of bacteriophage and inhaled NO therapy, but he remains focused on the obstacles that stand in the way of the routine application of these therapies. He noted that both treatments have been the focus of studies over many years and that progress has been slow.
“The data on inhaled NO so far are not all that convincing,” he said, noting that NO is a large molecule that has difficulty penetrating the deep recesses of the lung, where it is probably most needed for difficult infections. He also thinks that the protocols for patient selection and the most effective regimens in the context of the narrow therapeutic window remain poorly defined.
The promise of bacteriophages is supported by the case study that Nick recounted, but Chalmers considers the need to match specific bacteriophages to specific M abscessus isolates is a potential limitation for developing this treatment for routine use in clinical care. He indicated that the obstacles to routine use of these therapies might eventually be surmounted, but there is still work to do.
Nick reports no potential conflicts of interest. Flume reports a financial relationship with Insmed. Chalmers reports financial relationships with AstraZeneca, Boehringer Ingelheim, Chiesi, Gilead, GlaxoSmithKline, Grifols, Insmed, Janssen, Novartis, Pfizer, and Zambon.
6th World Bronchiectasis & NTM Conference (WBC) 2023: Presented July 20, 2023
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