Phage Therapy Administration Route, Regimen, and Need for Supplementary Antibiotics in Patients with Chronic Suppurative Lung Disease

Abstract

Antimicrobial resistance is leading to increased mortality, posing risk to those with chronic suppurative lung disease (CSLD). One therapeutic option may be to target treatment-resistant bacteria using viruses (bacteriophages [phages]). Currently, patients receiving phage therapy on compassionate grounds may not be receiving optimal treatment as there is no defined approach for phage use. This review aims to explore administration route, regimen, and need for supplementary antibiotics in phage therapy to treat bacterial infection in CSLD. Twelve articles totaling 18 participants included details of numerous phage administration routes with varying regimens. All articles reported an initial reduction of bacterial load or an improvement in patient symptoms, highlighting the potential of phage therapy in CSLD. Fifteen out of 18 used supplementary antibiotics. Standardized protocols informed by high-quality research are necessary to ensure safe and effective phage therapy. In the interim, systematic recording of information within case reports may be useful.

Introduction

Throughout history, bacterial infection has been a major cause of morbidity and mortality. Modern medicine relies heavily on antimicrobials, particularly antibiotics, to cure and prevent infectious diseases. Misuse and overuse of antimicrobials have caused some pathogens to evolve and become resistant to almost all antimicrobials, earning the colloquial name of “superbugs.”¹ There were ∼1.27 million deaths attributable to superbugs globally in 2019, and this is estimated to increase to 10 million deaths annually by 2050.²

Antimicrobial resistance (AMR) is a serious threat to global health and development, and the World Health Organization (WHO) has identified AMR as one of the top 10 global public health threats facing humanity.¹ AMR is causing increased deaths, disability, and economic burden as patients become increasingly difficult to treat, needing longer hospital stays and more expensive treatment regimens.³ There are few antibiotics currently in drug development¹ with a diminishing number of pharmaceutical companies investing in antibiotic research.⁴ Consequently, alternatives or adjuncts to antibiotics are important on both individual and global levels.

One potential option may be to harness naturally occurring viruses that infect bacteria, termed bacteriophages (phages), and use them to target treatment-resistant bacteria. Phages are recognized as the most ubiquitous entity on earth, they exist in every ecosystem and are highly specialized, targeting a single bacterial species or even a subset of a single bacterial species.⁵ This level of specialization means phages do not directly damage human cells or the surrounding microbiota,^6,7 and may be a safe alternative to antibiotics.

Phages evolve with their target bacterium, reducing the likelihood of bacteria developing permanent resistance. In previous reports where resistance has occurred, bacteria have been unable maintain resistance to both phage and antibiotics.⁸ There can be an evolutionary trade-off between mechanisms of phage resistance and antibiotic resistance,^8,9 termed “phage steering”⁸; however, this is often unpredictable and the ideal mutations do not always occur.⁹ Where it does arise, phage steering has the potential to prevent and reverse AMR of the target bacterium.⁸ This could support phage therapy as an adjunct to prolong the utility of existing antibiotics and increase their effectiveness in patients with resistant infections.

Current research describes the use of phage therapy in a broad range of human disease, including respiratory, gastrointestinal, urinary tract, joint, and skin bacterial infections.¹⁰ Phage application may be a single phage, or multiple phages, termed “phage cocktail.” Phages can be administered through various routes, those relevant to respiratory conditions include intravenous (IV), oral, inhaled/nebulized, intranasal, bronchoscopic, or a combination of these.⁶ The treatment course length varies significantly in reports for respiratory infection, from 2 h¹¹ to indefinite treatment courses.¹² Dosage of phage administration is not standardized, so dose also varies significantly among the literature for use in respiratory disease.^11–22

One cohort of individuals frequently faced with the complications of AMR are children and adults with chronic suppurative lung disease (CSLD). CSLD describes a group of diseases that feature a vicious cycle of mucus hypersecretion, chronic infection, and localized inflammation, leading to a reduced quality of life and life expectancy for patients.^23–26 Bronchiectasis, a severe subtype of CSLD with clear structural damage, is diagnosed if irreversible airway dilatation is seen on cross-sectional radiological imaging.²⁷ CSLD includes conditions such as chronic obstructive pulmonary disease with chronic bronchitis, asthma with mucus hypersecretion, protracted bacterial bronchitis, and genetic conditions such as cystic fibrosis and primary ciliary dyskinesia.

These conditions may later develop into bronchiectasis (particularly in cases of uncontrolled airway infection), but bronchiectasis may be present without a previous diagnosis of a CSLD condition.^27,28 Owing to the nature of the disease process, antibiotics are frequently required for both regular prophylaxis and rescue therapy.²⁶ Pathogens seen in CSLD, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus,^26,29 feature in the high or critical category of the WHO priority pathogens list (Supplementary Appendix Table S1), signifying their extremely high level of AMR.³⁰

To supplement this, these pathogens were identified as a substantial cause of death in the global burden of disease study (2019).³¹ Other infecting pathogens such as Achromobacter species and Mycobacterium abscessus are also frequently treatment resistant.^32,33 Patients often become colonized with these pathogens, causing chronic infection and recurrent exacerbations, which often require hospital admission and IV antibiotics.²⁹ Therefore, phages could be an important option for patients with CSLD, and recent reports feature compassionate use for patients who have exhausted available treatment options.

Rationale and Aim

In the United Kingdom, phage therapy is considered on a named-patient basis, but there are currently no regulations or defined approach for this compassionate use.^34,35 This review aims to explore current literature for evidence on the need for supplementary antibiotics, administration route, and treatment regimen in the use of phages for treatment-resistant bacterial infection in CSLD.

Methods

Literature was searched between January 1, 2000 and June 1, 2022 using PubMed and Google Scholar. Searches included various combinations of the following phrases: “bacteriophage”; “phage”; “phage therapy”; “nebulis*”; “intravenous”; “oral”; “respiratory”; “chronic suppurative lung disease”; “CSLD”; “Bronchiectasis”; “Cystic Fibrosis.” Boolean operators were used to obtain articles of highest relevance (e.g., “intravenous” AND “phage”).

Inclusion criteria involved English-language full-text articles involving phage therapy administered to humans for treatment of respiratory disease, which detailed outcomes for the patient. The success of treatment was measured through reduction of bacterial load in samples; reduced inflammatory markers and/or clinical improvements such as reduced cough; fever, dyspnea, and improved lung function testing. Only articles available through University of Exeter subscriptions were accessed due to lack of funding.

During this search, duplicates were removed, abstracts and subsequently full articles were screened and selected in accordance with inclusion criteria, as described in Supplementary Appendix Figure S1.

The University of Exeter does not expect ethical review to be necessary for projects involving literary or artistic criticism, that does not engage directly with the individuals or groups researched. The project was reviewed by the Sponsor Representative of the University of Exeter to confirm the project did not require ethical review.

Results

The literature search yielded 9 case reports and 3 case series, including 18 participants in total (9 male, 8 female, 1 not stated), summarized in Supplementary Appendix Table S2. The infecting pathogens included P. aeruginosa (n = 7); A. baumannii (n = 5); Achromobacter xylosoxidans (n = 3); M. abscessus (n = 2); S. aureus (n = 2); Burkholderia dolosa (n = 1). Twelve patients received predefined phage cocktails, three patients received personalized phage treatments, and three patients received both predefined cocktails and personalized phage treatments. Fifteen patients received supplementary antibiotics. Most of the patients received nebulized phage therapy, either alone (n = 7), combined with oral (n = 2), or combined with bronchoscopic application (n = 1).

Other participants received IV phage therapy, either alone (n = 4), or in combination with nebulized phage (n = 2). Finally, one participant received oral phage only.¹² Treatment regimens varied from 1 h to indefinite courses, with administration from once every 2 h up to once every 4–6 weeks.^11–22 Clinical improvements were seen in 14 patients after administration of phage,^{11,13–17,19,20,22} but one of these patients relapsed.¹⁷ The patients who did not see clinical improvements did see a reduction in bacterial load^11,18,21 except in one patient who died before the sample was taken.¹¹ Negative cultures were seen in eight patients,^{11,14,15,18–20,22} and this was maintained at follow-up appointments between 2 and 27 months for six patients,^{14,15,18–20,22} and the remaining two patients did not have follow-up cultures.¹¹

Discussion

Supplementary antibiotics

Of the 18 patients included, 15 of them continued on and/or were given new antibiotics alongside their phage therapy.^{11,12,15–22} Of the remaining three, one patient received IV antibiotics between phage therapy cycles over 1 year, one patient had a single course of oral antibiotics over 2 years of phage therapy. The final patient received no antibiotics for the duration of their indefinite phage therapy. Successful eradication of the target bacteria was reported in this patient, but evidence for this was a single negative sputum sample after 4 years of daily phage therapy.¹² Therefore, more evidence is needed to determine if phages are capable of eradicating bacterial infection in respiratory conditions without supplementary antibiotics.

All three patients who did not receive antibiotics clinically improved,^12,13 which brings into question whether it is always necessary to subject patients to the side effects of antibiotics. However, antibiotics may have other roles as it is suggested that antibiotics may reduce risk of bacteria developing lasting phage resistance.^36,37 Phage resistance was seen in patients who did not receive antibiotics between phage cycles¹² and a patient who discontinued antibiotics during their phage treatment.¹⁵ Previous literature has suggested that using cocktails of two or more phages may also reduce resistance^8,38; however, this literature review reveals evidence of resistance developing in patients receiving phage cocktails.¹² To add to this, combined therapy has also seen the reversal of antibiotic resistance in the target bacteria, which gives the patient another treatment option.^10,37

In summary, current literature favors supplementary treatment with antibiotics. However, further evidence is needed to ascertain whether use of supplementary antibiotics may be of benefit for improving the efficacy of phage treatments.

Route

The route of administration to treat bacterial respiratory infection varies across the literature between IV, oral, or nebulized administration, which on one occasion was combined with bronchoscopic administration. All articles reported either reduced bacterial load or clinical improvements; however, one article reported a relapse of bacterial load when using IV administration. This was thought to occur due to high antiphage antibodies, potentially due to the long treatment course of 196 days.²¹

Literature states there is an increased risk of antiphage antibodies occurring in IV and oral administration due to the increased amount of circulating phage compared with nebulized phage.¹⁰ It is not known whether this study was the only one to see a relapse of bacterial load during treatment because not all articles reported sputum culture results after starting phage therapy.^11,13 The lack of consistency in reporting sputum cultures makes it difficult to determine the success of treatment, suggesting a need for a standardized data collection framework.

IV administration of any therapeutic can be associated with increased risk of infection if appropriate infection control procedures are not followed during administration.³⁹ In addition, IV administration is more costly as it requires inpatient stays or frequent community care,⁴⁰ which may be difficult to arrange due to the frequency of some IV phage regimens.^16,17 However, not all patients can tolerate nebulizers¹² and long-term nebulization compliance may be poor due the time commitment and lifestyle restrictions,⁴¹ so IV may be an alternative⁴⁰ in these scenarios.

Among the included articles, Wu et al. reported the most serious side effect, a cytokine storm, when they used nebulized administration.¹¹ The cytokine levels returned to normal within a day and it is unclear whether mechanical ventilation was started due to the cytokine storm. The patient was receiving phage therapy due to secondary bacterial infection after COVID-19, a virus known to cause a cytokine storm.⁴² The authors state the observed cytokine storm did not match the characteristics of previously reported cytokine storms related to COVID-19.¹¹

However, there were no other reports of a cytokine storm using nebulized phages in current literature and considering the patient was acutely unwell, phage therapy may not have been responsible. Dedrick et al. were the only other authors to report side effects, where the patient experienced flushing after administration of IV phage therapy.²⁰ Multiple case reports using phage therapy for other ailments also describe side effects such as flushing, chills, nausea,⁴³ hypotension,⁴⁴ and altered liver function.⁴⁵ Infusion-related reactions may be caused by bacterial toxins that are difficult to purify from phage preparations, such as endotoxins,⁴⁶ although phage manufacturers have methods to remove it.⁴⁷

There are limits to the amount of endotoxins permitted in IV phage products, which may reduce the occurrence of infusion-related reactions; however, no similar limits yet exist for nebulized phage.⁴⁸ In addition, immune responses to phage have been documented and it is thought they may relate to route of administration.⁴⁶ This highlights the need for further research into the safety of phage preparations and standardized documentation of side effects. Owing to increased inconvenience of administration regimens, greater risk of infection and side effects as well as higher costs, IV therapy may be considered less favorable. However, clinical improvements and bacterial eradication have been seen in patients on IV regimens,^16,17,22 so further study for optimizing phage delivery is required.

Lebeaux et al. delivered the first dose of phage through bronchoscopy, and then followed this up with 14 days of nebulized phage. They do not state the reason for bronchoscopic application, but this may have been to deliver a larger more targeted initial dose. Thirty milliliters of phage preparation (phage titer of 5 × 10⁹ pfu/mL) was administered through bronchoscopy, whereas only 5 mL of the same phage titer was administered through nebulization.¹⁴ No other article used a targeted initial dose, but they still saw success in their treatment,^{11,13,15,17,18} so this may not be necessary. As current literature only includes one patient who has received bronchoscopic administration of phages, further research is needed to determine whether it is a beneficial route of application. The associated risks of the bronchoscopy procedure, such as hypoxia, respiratory depression, airway trauma, bleeding, and infection,⁴⁹ need to be taken into account in this scenario.

Oral therapy was used in three patients,^12,13 of whom resistance occurred in two. A decline of their clinical status necessitated new phage isolates.¹² In contrast, new phage isolates were not necessary for patients receiving nebulized phages in this literature review. Additional research is needed to examine the relationship between administration route and the occurrence of resistance necessitating new phage isolates.

One patient received oral phage therapy alone for P. aeruginosa and S. aureus coinfection. Although they improved clinically immediately, they did not obtain a negative sputum sample until 4 years of regular treatment courses.¹² As this was the last sample taken by the researchers, it is not known if the absence of bacteria was maintained. This took much longer than patients receiving nebulized and IV phage, who saw a significant decrease in bacterial concentrations in sputum after their initial dose^11,18 and had negative cultures after 7 days,¹⁵ which lasted up to 27 months in some cases.¹⁴

Some routes were quicker than others in eradicating target bacteria, but there was no route that consistently achieved bacterial eradication. Owing to the nature of these studies, it is difficult to determine whether phage therapy was responsible for bacterial eradication of if there were other explanations, such as a change in antibiotics. Larger scale trials with uniform regimens should aim to reveal the administration route most capable of time efficient reduction of bacterial load. These trials will need to demonstrate that phage therapy is responsible for bacterial load reduction potentially by confirming phage replication within the patient.

To summarize, previous studies have used one or a combination of IV, nebulized, bronchoscopic, or oral route to administer phages. The pros and cons of these found in this review are outlined in Supplementary Appendix Table S3. The variation of administration route reflects the lack of standardized protocols available for phage therapy. Therefore, further research is necessary to evaluate the efficacy of each method, their side effect profile, and the effects they have on human health.

Duration and regimen

Course duration varied from two doses in 1 h¹¹ to twice a day indefinitely,¹² as described in Supplementary Appendix Table S2.

Wu et al. delivered one or two courses of two doses of phage cocktail over 1 h to four patients in an intensive care unit with carbapenem-resistant A. baumanni (CRAB) secondary to COVID-19. They saw a small clinical improvement and reduced CRAB burden after one course in two patients.¹¹ However, these patients were also given other treatments, including up to three antibiotics, mechanical ventilation, and extracorporeal membrane oxygenation during the short period of phage therapy. Considering this, and that the other two patients did not experience improvement of symptoms and died due to respiratory failure,¹¹ it is unclear as to whether the phage therapy aided clinical improvement or reduced bacterial burden. In addition, this was not a chronic presentation of antibiotic-resistant bacterial infection, because these patients were not colonized before COVID-19 infection.

Likewise, Maddocks et al. saw success in a short 7-day course for their patient with 23 days of P. aeruginosa infection after pulmonary surgery.¹⁹ These participants are not direct representatives of those with chronic disease, and if a short course was successful here, it may not be in CSLD.

On the other end of the scale, Zaldastanishvili et al. reported two patients on indefinite phage therapy. For one patient, it took 4 years before eradication of her P. aeruginosa infection was observed. It should be noted that this was the only negative sputum sample as no further samples were obtained, so it cannot be said with certainty that the patient remained free of infection. The other patient never obtained negative sputum samples, but the bacterial load of the infecting P. aeruginosa was significantly reduced.¹² Indefinite courses of phage therapy may be unappealing to patients because they can be disruptive to one's lifestyle.⁴¹

In addition, Zaldastanishvili et al. saw long production times for their personalized phages.¹² Phages are generally manufactured by smaller-scale units as opposed to large pharmaceutical companies, which could mean production is limited by the capacity to manufacture.⁵⁰ Supply issues have previously been noted in other ailments,⁵¹ so shorter treatment plans will reduce the chance of running out of the therapeutic. Several articles have reported success with shorter courses,^13–15,18 so research is needed to establish whether indefinite phage courses are necessary.

Aslam et al. delivered phage therapy to treat B. dolosa without an end date of treatment. Initially the patient saw reduced symptoms and a decreased bacterial burden; however, this success was not maintained and treatment was discontinued at 84 days because there did not seem to be a continued therapeutic effect.¹⁷ This further highlights the need for a limited course length or review date, which would give a cutoff point to avoid unnecessarily treating a patient, which could postpone seeking other options, as well as waste resources and money.

Long courses saw an increased incidence of antiphage antibodies²¹ and phage resistance.^12,17 Evidence suggests using supplementary antibiotics to avoid resistance^36,37 as discussed earlier. However, it is not appropriate to expose a patient to the side effects of antibiotics longer than is necessary, so future research should seek to make courses as short as possible. Long courses may also give rise to risk of an immune response against phage proteins. Dedrick et al. saw a weak cytokine response to phage proteins, which peaked on day 29 of phage therapy. This is contrary to previous literature, which states phage therapy is expected to elicit a negligible immune response⁵² and some reported anti-inflammatory effects.⁵³ The discrepancy may be because the literature does not investigate the inflammatory responses after such an extended period of phage application.^10,52

Hoyle et al. administered phage therapy for 20 days, and repeated the cycle at 1, 3, 6, and 12 months postinitial treatment.¹³ This regimen was associated with alleviation of symptoms, improved lung function, and reduced need for antibiotics while avoiding continuous phage use. Regimens including intervals may be used because once phages have lysed their bacterial host, they are released from the target bacterium, providing an ongoing presence of phages without continuous phage administration.^5,14 Dose intervals provide opportunity to reflect on whether a dosing regimen is optimal. For example, Kvachadze et al. administered one dose at 4- to 6-week intervals and saw a decrease in bacterial load but did not see clinical improvement in the patient. As the phage seemed to be correctly targeting the bacteria, one dose per round may not have been enough to eliminate sufficient amounts of bacteria to allow clinical improvements.¹⁸

All reports that saw clinical improvement in patients with CSLD gave phage therapy for at least 14 days.^12–15 Success seen in treatment lengths shorter than 14 days was not seen in patients with CSLD.^11,19 High-quality trials to determine a course length for patients with CSLD is needed to determine successful treatment while avoiding the numerous disadvantages of overtreating the patient discussed earlier.

Nebulized phage regimens varied in number of daily phage administrations given. Tan et al. delivered phage twice a day and saw the eradication of bacteria at follow-up. Hoyle et al. also delivered phages twice daily but did not report sputum culture results¹³ making it impossible to ascertain their success. Lebeaux et al. saw successful eradication of bacteria with three times a day nebulized phage.¹⁴ Finally, Zaldastanishvili et al. reported once a day nebulized phage over several years but still had positive sputum cultures.¹² This implies that once-a-day nebulization may not be enough to eliminate the bacteria, although this could vary depending on the patient and the infecting bacteria.

As twice-daily administration was successful in bacterial elimination,¹⁵ three times a day may be unnecessarily inconvenient for the patient and reduce compliance.⁵⁴ Well-conducted clinical trials are needed to establish the appropriate daily regimen for CSLD patients. However, this is a lengthy process, and it is already possible to apply for compassionate use of phage therapy on the National Health Service.^35,55 Previous publications guide the regimens for compassionate use, but clinicians are not well informed if articles do not provide the same information, as seen here. This raises a need for a structured data collection framework for case reports.

In conclusion, current regimens vary significantly and the effects this has on the efficacy and safety of patients is uncertain. High-quality clinical trials are urgently needed to determine the appropriate regimen for patients with CSLD. In the interim, a universal systematic approach for collecting data on regimens used in phage therapy could be useful for guiding future NHS approved compassionate use of phage.¹⁰

Limitations

The first limitation of this review is the small amount of literature on phage therapy in CSLD or relevant respiratory conditions, which means no strong conclusions for treatment route, regimen, and need for supplementary antibiotics can be drawn at this time. Second, the level of evidence provided by the included articles was relatively low as they were all either case reports or case series. This is because no clinical trials for phage use in respiratory disease had been published at the time of writing.

Conclusions

This review found a limited number of articles detailing numerous routes of phage administration with a wide variety of regimens. Despite their many differences, they all saw either an initial reduction in bacterial load or an improvement of patient symptoms, highlighting the potential of phage therapy in CSLD. Most articles reported use of supplementary antibiotics, which may reduce the risk of resistance against phage, but further research is needed to determine whether this is necessary. For safer and more effective use of phage therapy on compassionate grounds, robust protocols are needed informed by high-quality clinical trials. In the interim, as compassionate use of phages for treating CSLD in the United Kingdom is expected to increase in near future,⁵⁵ uniform recording of information from case studies may be useful to better inform treatment plans.

Future Research

High-quality research is required to provide evidence for phage therapy protocols in CSLD. From said trials, protocols need to be developed to allow for the safest and most effective application of phage therapy.

Authors' Contributions

Conceptualization, methodology, investigation, writing—original draft preparation, writing—reviewing and editing, and project administration by J.W. Writing—reviewing and editing by J.S. and B.T. Supervision, conceptualization, and writing—reviewing and editing by P.J.M.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

The authors received no funding for the research, writing or publication of this article.

Supplementary Material

Supplementary Appendix Figure S1

Supplementary Appendix Table S1

Supplementary Appendix Table S2

Supplementary Appendix Table S3