http://www.cell.com/article/S0092867422014611/pdf

Phage therapy: From biological mechanisms to future directions

Antibiotics have transformed modern medicine. They are essential for treating infectious diseases and enable vital therapies and procedures. However, despite this success, their continued use in the 21st century is imperiled by two orthogonal challenges. The first is that the microbes targeted by these drugs evolve resistance to them over time. The second is that antibiotic discovery and development are no longer cost-effective using traditional reimbursement models. Consequently, there are a dwindling number of companies and laboratories dedicated to delivering new antibiotics, resulting in an anemic pipeline that threatens our control of infections. The future of antibiotics requires innovation in a field that has relied on highly traditional methods of discovery and development. This will require substantial changes in policy, quantitative understanding of the societal value of these drugs, and investment in alternatives to traditional antibiotics. These include narrow-spectrum drugs, bacteriophage, monoclonal antibodies, and vaccines, coupled with highly effective diagnostics. Addressing the antibiotic crisis to meet our future needs requires considerable investment in both research and development, along with ensuring a viable marketplace that encourages innovation. This review explores the past, present, and future of antimicrobial therapy. Description Antibiotics are imperiled by antimicrobial resistance, but innovations in antimicrobial discovery hold promise for the future.

The past, present, and future of antibiotics

Antibiotic resistance in bacterial pathogens presents a substantial threat to the control of infectious diseases. Development of new classes of antibiotics has slowed in recent years due to pressur...

Phage Therapy for Antibiotic-Resistant Bacterial Infections.

Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct to conventional antimicrobials. Expanded access and compassionate use cases have risen exponentially but have varied widely in approach, methodology, clinical situations in which phage therapy might be considered, dosing, route of administration, and outcomes. ABSTRACT Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct to conventional antimicrobials. Expanded access and compassionate use cases have risen exponentially but have varied widely in approach, methodology, and clinical situations in which phage therapy might be considered. Large gaps in knowledge contribute to heterogeneity in approach and lack of consensus in many important clinical areas. The Antibacterial Resistance Leadership Group (ARLG) has convened a panel of experts in phage therapy, clinical microbiology, infectious diseases, and pharmacology, who worked with regulatory experts and a funding agency to identify questions based on a clinical framework and divided them into three themes: potential clinical situations in which phage therapy might be considered, laboratory testing, and pharmacokinetic considerations. Suggestions are provided as answers to a series of questions intended to inform clinicians considering experimental phage therapy for patients in their clinical practices.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923208

Considerations for the Use of Phage Therapy in Clinical Practice

Abstract Background Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. Methods Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. Results No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. Conclusions Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease

An 81-year-old immunocompetent patient with bronchiectasis and refractory Mycobacterium abscessus lung disease was treated for 6 months with a three-phage cocktail active against the strain. In this case study of phage to lower infectious burden, intravenous administration was safe and reduced the M. abscessus sputum load tenfold within one month. However, after two months, M. abscessus counts increased as the patient mounted a robust IgM- and IgG-mediated neutralizing antibody response to the phages, which was associated with limited therapeutic efficacy.

Potent antibody-mediated neutralization limits bacteriophage treatment of a pulmonary Mycobacterium abscessus infection.

Low rates of macrolide-resistant Mycobacterium avium complex in cystic fibrosis despite chronic azithromycin therapy.

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Potent antibody-mediated neutralization limits bacteriophage treatment of a pulmonary Mycobacterium abscessus infection.

Low rates of macrolide-resistant Mycobacterium avium complex in cystic fibrosis despite chronic azithromycin therapy.