Phage therapy, a century-long treatment targeting bacterial infection, was widely abandoned after the clinical availability of antibiotics in the mid-20th century. However, the crisis of antimicrobial resistance today led to its revival in many countries. While many articles dive into its clinical application now, little research is presenting phage therapy from a regulatory perspective. Here, we focus on the regulations of phage therapy by dividing sections into Eastern Europe where it was never abandoned and Western Europe, Australia, the United States, India, and China where it only re-attracted researchers’ attention in recent decades. New insights about its regulations in China are provided as little English literature has specifically discussed this previously. Ultimately, by introducing the regulations in phage therapy for human health across representative countries, we hope to provide ideas of how countries may borrow each other’s adapting legislation in phage therapy to best overcome the current regulatory hurdles.

Phage therapy is recognized as a promising alternative to antibiotics in treating pulmonary bacterial infections, however, its use has not been reported for treating secondary bacterial infections during virus pandemics such as coronavirus disease 2019 (COVID-19). We enrolled 4 patients hospitalized with critical COVID-19 and pulmonary carbapenem-resistant Acinetobacter baumannii (CRAB) infections to compassionate phage therapy (at 2 successive doses of 10⁹ plaque-forming unit phages). All patients in our COVID-19-specific intensive care unit (ICU) with CRAB positive in bronchoalveolar lavage fluid or sputum samples were eligible for study inclusion if antibiotic treatment failed to eradicate their CRAB infections. While phage susceptibility testing revealed an identical profile of CRAB strains from these patients, treatment with a pre-optimized 2-phage cocktail was associated with reduced CRAB burdens. Our results suggest the potential of phages on rapid responses to secondary CRAB outbreak in COVID-19 patients.

CreTA, CRISPR-regulated toxin-antitoxin (TA), safeguards CRISPR-Cas immune systems by inducing cell dormancy/death upon their inactivation. Here, we characterize a bacterial CreTA associating with the I-F CRISPR-Cas in Acinetobacter. CreT is a distinct bactericidal small RNA likely targeting several essential RNA molecules that are required to initiate protein synthesis. CreA guides the CRISPR effector to transcriptionally repress CreT. We further demonstrate a proof-of-concept antimicrobial strategy named ATTACK, which AssociaTes TA and CRISPR-Cas to Kill multidrug resistant (MDR) pathogens. In this design, CRISPR-Cas is programed to target antibiotic resistance gene(s) to selectively kill MDR pathogens or cure their resistance, and when CRISPR-Cas is inactivated or suppressed by unwanted genetic or non-genetic events/factors, CreTA triggers cell death as the last resort. Our data highlight the diversity of RNA toxins coevolving with CRISPR-Cas, and illuminate a combined strategy of CRISPR and TA antimicrobials to ‘ATTACK’ MDR pathogens.

A double‐stranded RNA (dsRNA) phage phiYY is able to kill a pyomelanin‐producing Pseudomonas aeruginosa strain, which was isolated from a 40‐year‐old man with interstitial lung disease (ILD) and chronic lung infection. Phage therapy was used as a last resort for this patient. The three‐course nebulized phiYY treatment was used to reduce the bacterial burden and clinical symptoms of the patient. Recurrences of P. aeruginosa infections were observed 1–3 days post phage therapy. The recurrent isolates exhibited distinct antibiotic‐susceptibility profiles compared with the original strain yet were still susceptible to phiYY. This assay represents the application of dsRNA phage in the treatment of chronic lung infection, albeit the safety and efficacy of the dsRNA phage require further assessment.