Introduction
Bacterial infection has always been an important threat to human beings. For solid organ transplant recipients, there is a threat of donor-derived infection, intraoperative infection and postoperative infection. For patients waiting for organ transplantation, if there is a bacterial infection at the site to be transplanted, the transplant center often refuses to offer the transplant to such patients for fear that the transplanted organ will be infected. The use of antibiotics has been effective in most cases, but as bacterial resistance has increased, cases of“Superbug” infections, which can cause graft failure and even threaten the life of the recipient, occur frequently. Phage therapy, a natural treatment that isn’t constrained by antibiotic resistance, is back in the minds of transplant doctors. At present, there are ongoing clinical trials of phage therapy in China, the United States, Europe, Israel, Georgia and other countries, nearly 20 cases of phage therapy for transplant-related infections have been reported in published papers, a clinical trial of phage therapy in Shanghai has also treated 12 patients with organ transplant-related infections (11 of which have not yet been published) . Read on to find out.
1、Phage therapy
Bacteriophages are a class of microorganisms that specifically“Eat” bacteria. They are widely distributed and abundant in our body and the surrounding environment, and play an important role in maintaining bacterial balance. Lytic bacteriophages multiply and lyse bacteria after infecting bacteria, and have natural precision bactericidal ability. Since the French Canadian microbiologist d’hérelle pioneered phage therapy in 1919, phage therapy has gone through a century of history.In the early days of liberation, China also developed and produced bacteriophages and achieved good results in preventing dysentery. In 1958, Professor Yu Yi from the Shanghai Institute of Immunology successfully treated burn patients with Pseudomonas aeruginosa infection using bacteriophages, creating a great story in the field of microbiology in China. However, since the industrial production and use of antibiotics in the 1950s, phage therapy with specific bactericidal properties has gradually been replaced by broad-spectrum antibiotics. Until the beginning of this century, with the increasingly severe problem of bacterial resistance, phage therapy was once again valued and regarded as a highly promising new generation of antibacterial therapy.
2、Bacterial resistance
The brilliant history of antibiotic application is accompanied by the history of bacterial resistance, and the problem of bacterial resistance is becoming more and more serious. In 2009, the Infectious Diseases Society of America (Ida) lists Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli (ESKAPE) as the six“Superbugs” that pose the greatest clinical threat. In 2017, the who identified 12“Superbugs” in urgent need of new antimicrobial therapies, in addition to the six described above. These bacteria have strong drug resistance and lack of effective antibiotics, and are the main pathogenic bacteria for phage therapy.
3、Solid organ transplantation and bacterial infection
With the development of clinical medicine, hygienics and immunosuppressive drug, organ transplantation and postoperative anti-rejection management are becoming more and more mature. However, organ transplant recipients still face a severe test of drug-resistant bacterial infections. Pre-operative infection, perioperative nosocomial infection and post-operative Opportunistic infection due to immunosuppression are important risk factors for graft failure and even life-threatening complications. The prevalence of multidrug-resistant bacteria in kidney, liver, heart and lung transplant recipients is as high as 14% , 15% , 25% and 37%-51% , respectively. In addition, refractory P. aeruginosa and M. abscessus infections often occur in patients with chronic lung disease awaiting lung transplantation.
For solid organ transplantation, there is a high risk of infection with drug-resistant bacteria during organ harvesting, preservation, transportation, organ implantation, and wound healing, however, due to the lack of environmental bactericidal intensity, frequency and bactericide effect, as well as the delay of bacterial identification and inadequate isolation, the spread of superbugs among hospitalized patients can not be ignored. In addition, because transplant recipients need to take immunosuppressants to suppress organ rejection, Opportunistic infection also increases the risk of infection, which is often more severe
4、Transplant infection and phage therapy
To date, there have been many published reports of organ transplantation after phage therapy for transplanted infection and phage therapy for control of bacterial infection, involving a total of 19 patients (Table 1) . The basic situation is as follows:
Patient type: lung transplant, kidney transplant, liver transplant, heart transplant, and waiting for lung transplant, with children as young as 1 year of age (after liver transplant) ; Target bacteria: Pseudomonas aeruginosa, klebsiella pneumoniae, Escherichia coli, Enterococcus faecium, mycobacterium abscessus, Achromobacter and Burkholderia cepacia; Administration: intravenous, nebulized/bronchoscopic lavage (lung) , local irrigation, gel/wet compress (skin) , nasogastric tube, and rectal suppository; Combined antibiotics: most cases were treated with phage combined antibiotics (not affecting the antibiotic regimen) for a minimum of 5 days and a maximum of 31/2 years Treatment effect: 13 cases of bacterial infection and clinical symptoms were improved, 3 cases of target bacterial infection were controlled and met the conditions of organ transplantation, 2 cases of target bacteria were cleared but clinical symptoms did not improve, the target bacteria and clinical symptoms did not improve in 1 patient; adverse reactions: only 1 patient with pulmonary infection developed fever after phage therapy (possibly related to RNA phage) .
表1. 已发表论文中实体器官移植感染相关案例汇总（截至2023年2月28日）
5、Application potential of phages in solid organ transplantation
Bacteriophage has been used in the treatment of bacterial infection before and after organ transplantation. Phage therapy has been reported in our country, including Zhongshan Hospital affiliated to Fudan University, Shanghai Public Health Clinical Center, Shanghai Jiahui International Hospital, Shenzhen No. 3 People’s Hospital and Shenzhen People’s Hospital. The Shanghai Phage and drug resistance research institute team has carried out phage therapy in more than 10 cases of transplant infection in Zhongshan Hospital and Public Health Center: including 10 cases of infection after kidney transplantation, one case of infection after liver-kidney transplantation and one case of interstitial pneumonia (lung transplantation after phage therapy) were reported, which were caused by Klebsiella pneumoniae, acinetobacter Bowman and Pseudomonas aeruginosa The administration methods were bladder irrigation (urinary tract infection) , aerosol inhalation (pulmonary infection) , washing via catheter (abdominal infection) and wet dressing (wound infection) The duration of treatment ranged from 1 to 5 rounds (1-3 days per round with 2 daily phage administrations) . Compared with conventional antibiotic therapy, phage personalized screening for drug-resistant bacteria in patients often has better therapeutic effect and lower side effects.
Drug-resistant pathogens may also be present in hospitals, operating rooms, and the home environment, leading to transplant-related infections, conventional chemical (such as chlorine-containing disinfectants) or physical (such as ultraviolet) disinfection is often not suitable for use in the environment where people and valuables/equipment are located because of its harmfulness to people and corrosion to objects. As a natural bactericide that specifically infects bacteria (but not human cells) , bacteriophages can satisfy the environmental killing of drug-resistant bacteria in the above scenario. The team of Shanghai Institute of Bacteriophage and drug resistance has achieved good results in the prevention and control of nosocomial infection by using bacteriophage environmental spray in Taiwan and Shanghai.
In addition, during organ preservation and transport, perfusate may contaminate drug-resistant bacteria and cause donor-derived infections. Although no clinical trials have been reported, there is potential to prevent infection of organs with superbugs during preservation and transport by adding a broad-spectrum phage cocktail against common clinical pathogens to the organ perfusion fluid. Phages can also be used to sterilize donor organs infected with known pathogens to avoid waste of donor organs.
Summary
Organ transplantation is the preferred treatment for end-stage organ failure. Multidrug-resistant bacterial infections seriously affect the success rate of organ transplantation and the health of recipients after transplantation. For a long time, because the mechanism of action and potential risks of phage therapy are still insufficiently understood in the academic community, the development of phage therapy has become a hot topic, in addition, phages are highly specific to the host (narrow bactericidal spectrum) , bacteria are prone to phage-resistant mutations and other factors that restrict the efficacy of phage therapy, phage therapy has not been widely used in clinical practice under the impact of broad-spectrum antibiotics. Phage therapy is still difficult to carry out, and there is a lack of standardized and large-scale clinical controlled trials. There are no approved phage drugs in China, the United States and the European Union, both the cases mentioned above and the ongoing phage therapy are in clinical trials. With the rapid development of molecular biology, synthetic biology and sequencing technology, multi-center phage therapy applications (such as Shanghai Zhongshan Hospital, Public Health Center, Jiahui Hospital, Shenzhen Tertiary Hospital, People’s Hospital, First Affiliated Hospital of Xi’an Jiaotong University) , the rise of companies focused on the development of innovative phage drugs and personalized medicine technologies (such as chemtime, target antibiotics, and SEATO BIO) , bacteriophages will have a broad development space in the prevention, control and treatment of transplant-related drug-resistant bacterial infections.
References：
[1]吴楠楠, 朱同玉. 噬菌体在实体器官移植中的应用. 器官移植, 2019, 10(4): 410-415.
[2]Nicholls and Aslam. Role of bacteriophage therapy for resistant infections in transplant recipients. Curr Opin Organ Transplant. 2022 Dec 1;27(6):546-553.
[3]Uyttebroek et al. Safety and efficacy of phage therapy in difficult-to-treat infections: a systematic review. Lancet Infect Dis. 2022 Aug;22(8):e208-e220.
