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Review

A Century of Clinical Use of Phages: A Literature Review

by
Kevin Diallo
1,* and
Alain Dublanchet
2
1
Department of Infective and Tropical Diseases and Internal Medicine, University Hospital of la Reunion, 97448 Saint-Pierre, France
2
Independent Researcher, 2465 Rue Céline Robert, 94300 Vincennes, France
*
Author to whom correspondence should be addressed.
Antibiotics 2023, 12(4), 751; https://doi.org/10.3390/antibiotics12040751
Submission received: 25 February 2023 / Revised: 9 April 2023 / Accepted: 10 April 2023 / Published: 13 April 2023
(This article belongs to the Special Issue Antibiotics vs. Phage Therapy, 2nd Edition)
Browse Figure
Review Reports Versions Notes

Abstract

:
Growing antibiotic resistance and the broken antibiotic market have renewed interest in the use of phages, a century-old therapy that fell into oblivion in the West after two decades of promising results. This literature review with a particular focus on French literature aims to complement current scientific databases with medical and non-medical publications on the clinical use of phages. While several cases of successful treatment with phages have been reported, prospective randomized clinical trials are needed to confirm the efficacy of this therapy.

1. Introduction

Growing antibiotic resistance and the broken antibiotic market currently pose a major threat to global health. In this context, new therapeutic strategies are needed to avoid returning to the pre-antibiotic era. One potential solution is the use of phages, a century-old therapy that fell into oblivion in the West after two decades of promising results. Phages (or bacteriophages) are bacteria-specific viruses that inject their genome into bacterial cells and use the bacterial metabolism to replicate. The life cycle of phages is either lytic or lysogenic. During the lytic cycle, the injected phage genome replicates and destroys the bacterial cell, thus inhibiting bacterial growth. During the lysogenic cycle, the injected genome remains in the host’s genome, where it enters a dormant state [1,2]. Lytic phages will be the focus of this literature review, as only they have the capacity to destroy infected bacteria.
Phages are well absorbed enterally and transmucosally [3]. They have short half-lives in vivo as they are rapidly destroyed by the immune system, in particular the reticulo-endothelial system. When they infect their target bacteria, however, they can multiply exponentially [4]. Phages have been classified by the International Committee for Taxonomy of Viruses into 12 families, with Straboviridae, Autographiviridae, and Drexlerviridae accounting for over 95% of identified phages [5]. Phages present several advantages: they self-replicate; they have greater specificity than antibiotics; they can be used in patients with allergy to antibiotics; they have a low rate of side effects; their production cost is low; they can be administered through different routes; they can present synergistic effects when combined with antibiotics; they are effective against biofilm; and in the case of bacterial resistance to a specific phage, other phages can be used against the resistant bacterium [1,6]. However, phages also have disadvantages: phage treatment can be initiated only after the causative agent has been identified; multi-bacterial infections require cocktails containing several phages; phage preparations must be sterilized; phage preparations have to be very clean and endotoxin free; phage treatment can induce an immune response in humans; pharmacokinetic data on the action of phages in the human body are lacking; and phages have yet to be properly classified by regulatory agencies [1,6,7].
Many cases of successful treatment with phages have been reported over the last century. Yet, several of these reports are missing from current scientific databases: some fell into oblivion before the advent of databases, others were published in non-medical outlets, and others were written in languages other than English [8]. While many case reports of treatment with phages have an insufficient level of proof, a century of experimentation cannot be ignored.
This literature review with a particular focus on French literature aims to complement current scientific databases with medical and non-medical publications on the clinical use of phages in humans.

2. Context

2.1. History of Phage Therapy

Phages were first described as ultra-microscopic viruses by Frederick Twort in 1915 and characterized as bacteriophages by Félix d’Hérelle two years later [9,10]. They were introduced in the former Eastern Bloc by a student of d’Hérelle, George Eliava, who founded a research institute specifically dedicated to phage therapy in Tbilissi, Georgia, in 1923.
In the 1920s and 1930s, phages were used worldwide for several indications in humans. Several large pharmaceutical companies produced commercial phage preparations at the time: Eli Lilly (Indianapolis, IN, USA) in the early 1930s, Abbott Labs (Chicago, IL, USA) in the early 1930s, and Bristol-Myers Squibb (New York, NY, USA) from the early 1930s to the 1940s [11]. However, phage therapy failed to impose itself in the West due to inconsistent treatment results, a poor understanding of phages’ mechanism of action, and the advent of broad-spectrum antibiotics [1]. The therapy was discredited in two reports published in 1934 and 1941 by Eaton and Krueger [12,13,14,15,16]. While some Western companies continued to produce phages afterwards (in particular for the food processing industry), the use of phages in humans was largely abandoned.
In the former Eastern Bloc, the institute founded by Eliava in Georgia continued to carry out major research on phage therapy and supplied phage products to the USSR throughout the 20th century. Renamed the G. Eliava Institute of Bacteriophages, Microbiology, and Virology in 1988, it pursued its research activities after the fall of the Iron Curtain. In Russia, phages are now produced commercially by the company Microgen.
In 2005, a Phage Therapy Unit was created at the Hirszfeld Institute of Immunology and Experimental Therapy in Wrocław, Poland. This unit is now the second largest center for phage research in Europe after the G. Eliava Institute.
Since the mid-2000s, growing antibiotic resistance has prompted institutes and pharmaceutical laboratories all over the world to create their own phage banks on the model of the G. Eliava Institute [17]. These include: Adaptive Phage Therapeutics in the United States, Biobank, First Affiliated Hospital of Xi’an Jiaotong University, Institute for Protein Science and Phage Research in China, the Bacteriophage Bank of Korea [18], the Israeli Phage Bank at the Hebrew University of Jerusalem in Israel [19], the National Collection of Type Cultures, the Bacteriophage Collection in the United Kingdom, Fagenbank in the Netherlands, DMZ in Germany, Queen Astrid Military Hospital in Belgium, and Pherecydes Pharma in France.
Despite this renewed interest in phage therapy, the efficacy of phages has yet to be demonstrated.

2.2. Legal Framework for the Use of Phage Therapy in Humans

Phages are classified as drugs in the US and as medicinal products in the EU [20]. Like other drugs, they are subject to marketing and manufacturing authorization from the Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) in the EU.
To obtain marketing authorization, phage therapies must first be validated in preclinical in vitro and in vivo studies. Once these are completed, phase I to IV clinical trials are required to confirm their safety and efficacy in humans. To date, no phage therapy has reached phase IV of clinical trials.
To receive manufacturing authorization, phage products must comply with good manufacturing practice (GMP) standards, which involve a high level of purification and sterilization. However, given the lack of fit between these standards and the viral nature of phages, no phage product has so far been approved for use in humans by the EMA or the FDA. Phage production is authorized only for compassionate use and clinical research under Article 37 of the Declaration of Helsinki.
Marketing regulations and GMP standards are barriers limiting pharmaceutical investment in phage therapy [20].

2.3. Safety of Phage Therapy in Humans

The human body is routinely exposed to large numbers of endogenous phages. Since phages are composed only of proteins and DNA and do not release toxins when they die, their toxicity is low in humans. Phages must nevertheless be purified to reduce their virulence and ensure their safe administration [3].
Bacteria destroyed by phages can release bacterial toxins, and excessive bacterial lysis often causes immune system reactions. These phenomena, however, occur mainly when phages are administered intravenously. Other routes of administration can be used safely.
In 2009, Merabishvili et al. proposed a quality control for the safe use of purified phage cocktails against Staphylococcus aureus and Pseudomonas aeruginosa [21]. In 2014, an international panel composed of 29 experts from ten countries developed quality, safety, and efficacy requirements for sustainable phage therapy products [22]. Such requirements could replace current GMP standards, which would facilitate the use of phage therapy in humans.

2.4. Use of Phages in Food Processing and Plant Disease Control

Several studies have shown the efficacy and safety of using phage products in food processing and plant disease control [23,24,25,26].
Intralytix (Columbia, MA, USA) markets three phage products for food processing: ListShield™ against Listeria monocytogenes, EcoShield™ against Escherichia coli, and SalmoFresh™ against Salmonella spp. Omnilytics (Sandy, UT, USA) sells several phage products, including Agriphage™, for use in agriculture. Elanco (Greenfield, IN, USA) markets Finalyse™, an anti-bacterial spray targeting E. coli O157. In Europe, Micreos (Wageningen, The Netherlands) produces Listex™ and Salmonelex™, both of which were approved by the FDA. APS Biocontrol (Dundee, SC, UK) produces Biolyse®, a phage product sprayed on potatoes during processing. All these products have been approved by the FDA and/or the EMA [6].

3. Literature Review of a Century of Clinical Use of Phages

A search of the MEDLINE database was performed without language restrictions to identify articles on phage therapy published between 1922 and 2022. The following keywords were used: (phage OR phage therapy OR bacteriophage) AND (treatment OR use OR therapy) AND (clinical OR human). The titles and abstracts of identified articles were screened for inclusion. Prospective randomized clinical trials, literature reviews, prospective non-randomized clinical trials, and isolated case reports evaluating the clinical use of phages were included in the review. We excluded articles that did not deal with the use of phages in humans and those referring to articles already cited that did not bring new cases to our analysis.
The reference lists of selected articles were perused to identify other relevant publications on phage therapy. These publications consisted of books, theses, and medical and non-medical articles published between 1915 and 2022. Publications in languages other than English were considered, with a particular focus on French literature. All identified publications describing cases of phage therapy were included in the review.
The main prospective randomized clinical trials, literature reviews, and prospective non-randomized clinical trials are presented in Table 1.
Isolated case reports published after 1945 are shown in Table 2, while those published prior to 1945 appear in Table 3. We took 1945 as a cut-off year as this corresponds to the period when broad-spectrum antibiotic therapy was introduced and phage therapy lost credibility in the West. Moreover, phages were mostly used in isolation before 1945 and were generally combined with antibiotics after that date.
Studies were considered to have demonstrated the efficacy of phage treatment if 50% of evaluated patients had a favorable outcome. Studies that did not specify the number of improvements or cures were classified as unspecified. Figure 1 shows the distribution of articles on phage therapy for the main clinical foci of infection.

3.1. Prospective Randomized Clinical Trials

Our search of the MEDLINE database identified nine prospective randomized trials evaluating phage therapy.
In 2021, Leitner et al. performed a randomized placebo-controlled clinical trial at the Alexander Tsulukidze National Centre of Urology in Tbilisi, Georgia, to assess the efficacy of Pyophage in 97 men with urinary tract infection [30]. Between 2017 and 2018, 28 men received Pyophage, 32 a placebo, and 37 an antibiotic treatment. No difference in treatment success rates was observed between the three groups.
In 2019, Febvre et al. and Gingin et al. presented the results of the Bacteriophage for Gastrointestinal Health (PHAGE) study, which aimed to determine the safety and tolerability of phages in healthy adults with mild to moderate gastrointestinal distress [39,40]. The PHAGE study was a randomized, double-blind, placebo-controlled crossover intervention, in which 32 patients received a treatment containing four strains of phages (LH01-Myoviridae, LL5-Siphoviridae, T4D-Myoviridae and LL12-Myoviridae) and a placebo, each for a period of 28 days. Febvre et al. reported that phage consumption caused minimal disruption to the gut microbiota. Gindin et al. found no effect of treatment sequence on comprehensive metabolic panel outcomes.
In 2019, Ooi et al. published the results of a phase I clinical trial assessing the safety, tolerability, and preliminary efficacy of intranasal doses of experimental phage cocktail AB-SA01 in patients with recalcitrant chronic rhinosinusitis who had positive S. aureus cultures sensitive to AB-SA01 [46]. Three cohorts of three patients each received successive intranasal doses of AB-SA01 twice daily at a concentration of 3 × 10⁸ PFU for seven days (cohort 1), 3 × 108 PFU for 14 days (cohort 2), and 3 × 109 PFU for 14 days (cohort 3). Treatment was well tolerated overall, and no serious adverse events or deaths were reported. Preliminary efficacy results showed favorable outcomes, with clinical and microbiological evidence of infection eradication in two of the nine evaluated patients.
The results of the “PhagoBurn” phase I/II randomized clinical trial were published in 2018 by Jault et al. [52]. The aim of this trial was to compare the efficacy and tolerability of a cocktail of anti-P. aeruginosa phages to standard of care (silver sulfadiazine) in the treatment of burn wound infections. Twenty-seven patients were randomly allocated to receive a topical application of either treatment daily for 7 days, with 14 days of follow-up. Safety was evaluated in all patients who received at least one phage dressing (treatment group) or one silver sulfadiazine dressing (control group). However, in this study, the applied phage titer was extremely low, which contributed to clinical failure. The trial was stopped before termination due to insufficient efficacy of their phage cocktail.
The 2016 trial by Sarker et al., supported by a grant from Nestlé Nutrition and Nestlé Health Science, assessed the safety and efficacy of a T4-like phage cocktail compared to the Microgen ColiProteus phage cocktail and a placebo in Bangladeshi children hospitalized with acute bacterial infection or diarrhea [52]. No adverse event attributable to the oral application of phages was reported. Treated children had higher fecal phage prevalence and titers than those who received a placebo. However, the oral phages failed to achieve intestinal replication and to improve diarrhea outcome, possibly because phage coverage was insufficient and E. coli pathogen titers were too low.
In 2009, Rhoads et al. conducted a phase I trial to evaluate the safety of a phage cocktail for the treatment of venous leg ulcers in humans [59]. Forty-two patients with chronic venous leg ulcers were included, 39 of whom completed the trial. The ulcers were treated with either a saline control or a phage preparation targeting P. aeruginosa, S. aureus, and E. coli for a period of 12 weeks. Follow-up continued through week 24. No adverse events attributable to the phage cocktail were observed. No significant difference was found between the test and control groups in terms of frequency of adverse events, rate of cure or frequency of cure.
In 2009, Wright et al. published the results of a phase I/II trial assessing the safety and efficacy of the phage preparation Biophage-PA in patients with chronic otitis caused by an antibiotic-resistant strain of P. aeruginosa [60]. A total of 24 patients randomized into two groups of 12 were treated with a single dose of Biophage-PA or a placebo and were followed up 7, 21, and 42 days after local application by the same otologist. The main outcomes were the symptoms observed by physicians (erythema, inflammation, ulceration, granulation, polyps, amount of discharge, type of discharge, and odor) and those reported by patients (discomfort, itchiness, wetness, and smell). No adverse events were observed. In the phage-treated group, pooled clinical indicators significantly improved, and P. aeruginosa counts significantly decreased from baseline, demonstrating the efficacy of the phage preparation.
In 2005, Bruttin et al. evaluated the safety of E. coli phage T4 in 15 healthy adult volunteers [62]. All patients included in this crossover study received a low dose of phage T4 (103 plaque-forming units (PFU)/mL), a high dose of phage (10⁵ PFU/mL), and a placebo in their drinking water. No adverse event related to the application of phage T4 was reported. Phage T4 was detected in a dose-dependent manner in the feces of patients orally exposed to phages. However, oral phage application did not result in a decrease in total fecal E. coli counts. Moreover, no substantial replication of phage T4 was observed in the commensal population of E. coli.
Three of the four trials evaluating the clinical efficacy of phages showed negative results. As the other trials were designed to evaluate the safety, tolerability and/or preliminary efficacy of phage therapy, one cannot conclude on the clinical efficacy of phages based on their results.

3.2. Literature Reviews

Twenty-one literature reviews evaluating the efficacy of phage therapy were identified. The following nine reviews covered the largest number of patients.
The 2021 literature review by Genevière et al. included 20 case reports of 51 patients treated with phages for bone and joint infections [28]. The overall success rate was 71%.
In 2020, Clarke et al. published a literature review of 17 case reports assessing the safety and efficacy of phage therapy in 277 patients with bone and joint infections [33]. Clinical resolution was observed in 93.1% of cases.
The efficacy of phage therapy was evaluated in two meta-analyses: one by Abedon et al. (2011) and the other by Kutter et al. (2014) [53,57]. Both meta-analyses included studies carried out in the former Eastern Bloc. The disparity in methods used and the wide variety of treated infections make it difficult to conclude on the efficacy of evaluated treatments.
In their 2012 literature review, Miecdzybrodzki et al. retrospectively evaluated 153 patients treated with phages at the Hirszfeld Institute of Immunology and Experimental Therapy in Poland between January 2008 and December 2010 [56]. They found phages to be well tolerated and to have overall efficacy.
In 2009, Chanishvili et al. reported several cases of patients treated with phages at the G. Eliava Institute in Georgia [58]. One cannot not conclude on the efficacy of phages due to the disparity in methods used and the range of treated infections.
In their 2000 literature review, Weber-Dabrowska et al. from the Hirszfeld Institute of Immunology and Experimental Therapy in Poland reported 1307 cases of treatment with phages in patients with suppurative bacterial infections caused by different species of multidrug-resistant bacteria [64]. Their conclusions indicated a very high efficacy of phage therapy: complete cure was observed in 85.9% of cases, partial cure in 10.9% of cases, and failure in 3.8% of cases.
Two theses were identified that reviewed cases of patients treated with phages. The thesis by Domrault, published in 1998, reported 557 cases of treatment with phages in patients infected with resistant P. aeruginosa. Treatment was successful in the majority of cases [65]. In his 1931 thesis, the oldest to evaluate phage therapy, Pesce reviewed 622 cases of phage treatment and described his own use of phages in 14 patients with cutaneous infections. Here again, results were mainly positive [67].
The majority of reviews showed positive results. Seven reviews were not referenced in the MEDLINE database. Of these, two were found in articles (one in French and one in English), three in theses (all in French), and two in books (both in English). Thus, our literature review adds more than 1000 patients to the existing data.

3.3. Prospective Non-Randomized Clinical Trials

Three prospective non-randomized clinical trials were identified.
The 2021 prospective study by Patel et al. evaluated the efficacy of phage therapy in 48 patients presenting with a wound that had failed to heal after 6 weeks of conventional therapy [32]. The patients received either a phage for single bacterial infection or a cocktail of phages specific to two or more infecting bacteria. Phage treatment was applied on the wound surface five to seven times over a period of 9 months, and patients were followed for 3 months. A cure rate of 81.2% was obtained.
In 2019, Gupta et al. conducted a prospective study in 20 Indian patients treated with phages for chronic nonhealing wounds infected with E. coli, S. aureus, and P. aeruginosa [41]. A cocktail of customized phages was applied over the wounds in three to five doses. A significant improvement in wound healing was observed, with seven patients cured at Day 21.
In their 1987 prospective study, Cislo et al. evaluated the effectiveness of phage therapy in 31 patients with chronic suppurative skin infections caused by Pseudomonas spp., Staphylococcus spp., Klebsiella spp., Proteus spp., and Escherichia spp. [66]. The outcome was favorable in 23 patients.

3.4. Isolated Case Reports

Our search of the literature identified 95 case reports published since 1945. These reports concerned more than 2500 patients, and the majority showed positive results (87/95). Phage therapy was associated with antibiotic therapy in 71 of the reports. A total of 12 case reports were not referenced in the MEDLINE database. Of these, eight were found in articles (four in French and four in English), and four in theses (all in French). These case reports add 200 patients to the existing data (Table 2). The main indications and the success rate associated were osteoarticular (94%, 16/17), pulmonary (86%, 12/14), skin (91%, 10/11), and digestive (77%, 7/9) infections.
A total of 119 case reports published before 1945 were identified. The majority showed positive results (101/118). These reports concerned nearly 4000 patients. A total of 102 case reports were not referenced in the MEDLINE database. Of the identified case reports, 78 were found in articles (45 in French and 33 in English), and 23 in theses (all in French). More than 2600 patients are thus added to the existing data (Table 3). The main indications and the success rate associated were bacteremia (79%, 15/19), skin (92%, 24/26), and digestive (86%, 12/14) infections.

3.5. Research Prospects

In 2017, Leitner et al. proposed a methodology for randomized controlled trials evaluating the use of phages in the treatment of urinary tract infections [282].
A 2020 literature review by Melo et al. reported the results of preclinical studies on phage treatments conducted in Western countries over the previous ten years [283]. Some of these results are encouraging and suggest the need to conduct randomized clinical trials to confirm the efficacy of phage treatments.

4. Conclusions

This literature review identified multiple cases of successful treatment with phages in patients infected with different types of microorganisms. A total of 120 publications dealing with approximately 4000 patients were added to the existing data. However, the significant publication bias and the non-standardization of methods for the assessment of phage therapy do not allow us to conclude on the efficacy of phages. Relevant pharmacological data, including treatment dosage and duration, should be collected to help standardize evaluation methods. As we have shown previously, the literature also seems to show good results from the combination of phages and antibiotics, by a synergistic effect [284]. Prospective randomized clinical trials could then be conducted to confirm or disprove the clinical efficacy of different phage treatments. Lastly, literature reviews should be performed in different countries to identify non-referenced and/or non-translated publications on phage therapy.

Author Contributions

Conceptualization, K.D. and A.D.; methodology, K.D. and A.D.; writing—review and editing, K.D. and A.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors would like to thank Arianne Dorval for her editorial assistance.

Conflicts of Interest

The authors declare no conflict of interest.

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Antibiotics 12 00751 g001 550
Figure 1. Distribution of articles on phage therapy for the main clinical foci of infection.
Figure 1. Distribution of articles on phage therapy for the main clinical foci of infection.
Antibiotics 12 00751 g001
Table
Table 1. Main prospective randomized clinical trials, literature reviews, and prospective non-randomized clinical trials.
Table 1. Main prospective randomized clinical trials, literature reviews, and prospective non-randomized clinical trials.
YearNumber of Publications and/or Patients Clinical FocusMicroorganismMain ResultsReference
202241 reports/63 patientsVariedVariedClinical success in 55 patients[27]
202120 reports/51 patientsOsteoarticular VariedClinical success[28]
20219 reports/23 patientsOsteoarticularVariedClinical success[29]
202028 patientsUrinaryP. aeruginosaClinical failure[30]
202114 clinical trials/35 case reportsVariedVariedUnspecified[31]
202148 patientsCutaneousVariedClinical success[32]
2020277 patientsOsteoarticularVariedClinical success[33]
202013 studiesDiabetic foot infectionVariedClinical success in 11 studies
Non-significant results
in 2 studies		[34]
202013 patientsSevere infectionsS. aureusSafety demonstrated[35]
202022 patientsDigestiveE. coliClinical success[36]
202027 reportsCutaneousVariedClinical success[37]
201910 studiesVariedVariedClinical success in 5 studies;
efficacy not determined
in 5 studies		[38]
201936 patientsDigestiveE. coliSafety demonstrated[39]
201936 patientsDigestiveVariedSafety demonstrated[40]
201920 patientsCutaneousE. coli
P. aeruginosa
S. aureus		Clinical failure[41]
201927 patientsCutaneousP. aeruginosaClinical failure[42]
201912 studiesVariedVariedClinical success[43]
20198 studiesVariedVariedClinical success[44]
201929 case reports/1971 patientsVariedVariedClinical success[45]
20199 patientsENTS. aureusSafety demonstrated[46]
20196 studiesVariedVariedSafety demonstrated[47]
201830 studiesVariedE. coli
S. aureus
Klebsiella pneumoniae
Acinetobacter baumannii
P. aeruginosa		Clinical success[48]
201810 patientsENTS. aureusSafety demonstrated[49]
2018234 patientsCutaneousUnspecifiedClinical success[50]
2016No publications or patients addedVariedVariedClinical success[51]
201679 patientsDigestiveE. coliClinical failure[52]
2014No publications or patients addedVariedVariedDescription of other studies[53]
2013No publications or patients addedVariedP. aeruginosaClinical success[54]
2012No publications or patients addedWoundsVariedDescription of other studies[55]
2012157 patientsVariedVariedClinical success in 44% of patients[56]
2011No publications or patients addedVariedVariedDescription of other studies[57]
2009No publications or patients addedVariedVariedDescription of other studies[58]
200939 patientsCutaneousP. aeruginosa
S. aureus
E. coli		Clinical failure[59]
200924 patientsENTP. aeruginosaClinical success[60]
2008No publications or patients addedVariedVariedDescription of other studies[61]
200515 patientsDigestiveE. coliClinical failure[62]
2001No publications or patients addedVariedVariedDescription of other studies[63]
20001307 patientsSuppurative infectionsVariedClinical success[64]
1998557 patientsVariedP. aeruginosaClinical success[65]
198731 patientsCutaneousStaphylococcus spp.
Pseudomonas spp.		Clinical success[66]
1931636 patientsCutaneousS. aureusClinical success[67]
Table
Table 2. Case reports published since 1945.
Table 2. Case reports published since 1945.
YearNumber of PatientsClinical FocusMicroorganismAntibiotic Association Y/NMain ResultsReference
20221CutaneousMycobacterium chelonaeYClinical success[68]
20211OsteoarticularStaphylococcus epidermidisYClinical success[69]
20211OsteoarticularP. aeruginosaYClinical success[70]
20211UrinaryVariedYClinical success[71]
20211OsteoarticularP. aeruginosaYClinical success[72]
20211PulmonaryAchromobacter
xylosoxidans		YClinical success[73]
20211DigestiveEnterococcus faeciumYClinical success[74]
20211OsteoarticularS. aureusYClinical success[75]
20211PulmonaryA. baumanniiYClinical success[76]
20214PulmonaryA. baumanniiYClinical success in 2 patients;
death in 2 patients		[77]
202010VariedMainly, P. aeruginosa
S. aureus
Mycobacterium abscessus		YClinical success[78]
20201UrinaryK. pneumoniaeYClinical success[79]
20201OsteoarticularK. pneumoniaeYClinical success[80]
20201OsteoarticularS. aureusYClinical success[81]
20201CardiacS. aureus and
Cutibacterium acnes		YClinical success[82]
20203OsteoarticularS. aureusYClinical success[83]
20201PulmonaryAchromobacter spp.YClinical success[84]
20201CardiacS. aureusYClinical success[85]
20201UrinaryK. pneumoniaeYClinical success[86]
20208Cardiothoracic surgeryS. aureus
E. faecium
P. aeruginosa
K. pneumoniae
E. coli		YClinical success[87]
20191CardiacS. aureusYClinical success[88]
20193PulmonaryP. aeruginosa
Burkholderia dolosa		YClinical success[89]
20191Uro-digestive colonizationK. pneumoniaeYClinical success[90]
20191PulmonaryM. abcessusYClinical success[91]
201913VariedVariedYClinical success[92]
201915UnspecifiedVariedYUnspecified[93]
20191CardiacS. aureusYClinical success[94]
20191UrinaryK. pneumoniaeYClinical success[95]
20191PulmonaryP. aeruginosaYClinical success[96]
20191PulmonaryP. aeruginosaYClinical success[97]
20191OsteoarticularA. baumanii and K. pneumoniaeYClinical success[98]
20194OsteoarticularP. aeruginosa, S. epidermidis, S. aureus, Enterococcus faecalisYClinical success[99]
20191OsteoarticularP. aeruginosaYClinical success[100]
20188Bacteraemia, endocarditis and pulmonaryS. aureus and P. aeruginosaYClinical success[101]
20181PulmonaryP. aeruginosaYClinical success[102]
20181Vascular prosthesisP. aeruginosaYClinical success[103]
20183OsteoarticularS. aureusYClinical success[104]
20181OsteoarticularP. aeruginosaYLocal success but patient death[105]
20186Diabetic footS. aureusYClinical success[106]
20181Diabetic footS. aureusYClinical success[107]
20181PulmonaryA. xylosoxidansYClinical success[108]
20181NeurosurgicalA. baumaniiNLocal success but patient death[109]
201815VariedMainly, S. aureusYClinical success in 12 patients[110]
20189UrinaryVariedNClinical success[111]
20171BacteraemiaP. aeruginosaYClinical success[112]
20171UrinaryP. aeruginosaYClinical success[113]
201787CutaneousS. aureusNClinical success[114]
20171DigestiveA. baumaniiYClinical success[115]
20173CutaneousS. aureusNClinical success[116]
20171CutaneousS. aureusNClinical success[117]
20166Diabetic footS. aureusYClinical success[118]
20169UrinaryVariedNClinical success[119]
20151OcularS. aureusUnknownClinical success[120]
20149CutaneousS. aureus and P. aeruginosaNClinical failure[121]
20111UrinaryP. aeruginosaYClinical success[122]
20111PulmonaryS. aureusYClinical success[123]
20102OsteoarticularS. aureusYClinical success[124]
200928OcularStaphylococcus spp.NClinical success[125]
20093UrinaryE. faecalisNClinical success[126]
200937OsteoarticularMainly, S. aureusYSignificant
improvement		[127]
20071ENTS. aureusYClinical success[128]
20071PulmonaryP. aeruginosaYClinical success[129]
20061Digestive
colonization		S. aureusNClinical success[130]
20061CutaneousP. aeruginosaYClinical success[131]
20061ENTStaphylococcus hominisNClinical success[132]
20052CutaneousS. aureusYClinical success[133]
200394SepsisVariedYClinical success[134]
200296CutaneousVariedNClinical success[135]
200120VariedVariedUnknownClinical success[136]
199030CutaneousP. aeruginosaNClinical success[137]
1987550Suppurative infectionsUnspecifiedYClinical success[138]
1985273VariedMainly Staphylococcus spp.YClinical success[139]
1985114VariedVariedYClinical success[140]
1985370VariedVariedYClinical success[141]
1984150VariedVariedYClinical success[142]
1983138VariedVariedYClinical success[143]
19818CutaneousS. aureusNClinical success[144]
19797OsteoarticularVariedYClinical success[145]
19781VascularSerratia marcescensYClinical failure[146]
197125DigestiveVibrio choleraeNClinical failure[147]
19651DigestiveSalmonella panamaNClinical success[148]
196245DigestiveE. coliNProphylaxis; 1 clinical failure[149]
196010VariedP. aeruginosaYClinical success[150]
195934VariedVariedYClinical success[151]
19591NeurologicalP. aeruginosaYClinical success[152]
19581NeurologicalE. coliYClinical success[153]
19532OsteoarticularS. aureus and Streptococcus spp.NClinical success[154]
194977VariedStaphylococcus spp.NClinical success[155]
194914DigestiveUnspecifiedNClinical success[156]
19481OsteoarticularUnspecifiedNClinical success[157]
19471EndocarditisStaphylococcus spp.YClinical success[158]
194656DigestiveS. typhiNUnspecified[159]
19469VariedStaphylococcus spp.YClinical success[160]
19451EndocarditisS. aureusYClinical success[161]
19457CutaneousMainly, S. aureusNClinical success[162]
ENT: ear-nose-throat; N: no; Y: yes.
Table
Table 3. Case reports published before 1945.
Table 3. Case reports published before 1945.
YearNumber of
Patients		Clinical FocusMicroorganismMain ResultsReference
194345ThrombophlebitisS. aureusUnspecified[163]
194310NeurologicalStaphylococcus spp.Clinical success[164]
1942385BacteraemiaS. aureusUnspecified[165]
19412NeurologicalS. aureusNo significant improvement[166]
19415VariedStaphylococcus spp.Clinical success[167]
19411BacteraemiaS. aureusClinical success[168]
19419SurgicalVariedClinical success[169]
194036BacteraemiaS. aureusClinical success[170]
194012Osteoarticular and bacteraemiaS. aureusClinical success[171]
19388Breast abscessMainly Staphylococcus spp.Clinical success[172]
193719UrinaryE. coliClinical success[173]
193788GynaecologicalNeisseria gonorrhoeaeClinical success[174]
19375Varied surgicalS. aureusClinical success[175]
19373OsteoarticularS. aureusClinical success[176]
1937106Osteoarticular and bacteraemiaS. aureusUnspecified[177]
19371OsteoarticularS. aureusClinical success[178]
19372BacteraemiaS. aureusClinical success[179]
193710CutaneousUnspecifiedClinical success[180]
19361BacteraemiaS. aureusClinical success[181]
193627VariedS. aureusClinical success[182]
19364NeurologicalS. aureusClinical success[183]
193615BacteraemiaS. aureusClinical success[184]
1936100BacteraemiaS. aureusUnspecified[185]
1936Around 10CutaneousUnspecifiedClinical success[186]
19361PulmonaryE. coliClinical success[187]
19361PulmonaryPolymicrobialClinical success[188]
19351BacteraemiaS. aureusClinical success[189]
19351NeurologicalS. aureusClinical success[190]
19352EndocarditisS. aureus and Streptococcus viridansClinical success[191]
1935>100CutaneousUnspecifiedClinical success[192]
19351Cutaneous and osteoarticularUnspecifiedClinical success[193]
19351Osteoarticular and bacteraemiaStaphylococcus albus, Staphylococcus haemolyticus, Streptococcus spp.Clinical success[194]
1935UnspecifiedCutaneousUnspecifiedUnspecified[195]
19351BacteraemiaS. aureusClinical success[196]
193518Cutaneous, urinary and ophthalmologicalVariedClinical success[197]
193534UrinaryMainly, E. coliClinical success[198]
19344VariedVariedClinical success[199]
193414UrinaryColon bacillusClinical success[200]
19344BacteraemiaColon bacillusNo significant improvement[201]
193414DigestiveUnspecifiedClinical success[202]
19341OsteoarticularStreptococcus spp. and Staphylococcus spp.Clinical success[203]
19341BacteraemiaS. aureusClinical success[204]
19342DigestiveUnspecifiedClinical success[205]
19347CutaneousStaphylococcus spp.Clinical success[206]
19341Osteo-articularStreptococcus spp.Clinical success[207]
1934110CutaneousStaphylococcus spp.Clinical success[208]
1933100OsteoarticularMainly Staphylococcus spp.Significant improvement[209]
193322Surgical UnspecifiedUnspecified[210]
1933200CutaneousUnspecifiedUnspecified[211]
19338DigestiveSalmonella typhi and S. paratyphiClinical success[212]
19339CutaneousStaphylococcus spp.Clinical success[213]
19331ENTStaphylococcus spp.Clinical success[214]
193349Gynaecological and bacteraemiaVariedSome clinical success[215]
19331OsteoarticularStaphylococcus spp.–S. viridansClinical success[216]
19331OsteoarticularStaphylococcus spp.Clinical success[217]
19332ENTS. aureusClinical success[218]
193330SurgicalVariedClinical success[219]
19331BacteraemiaUnspecifiedClinical success[220]
193210OsteoarticularS. aureusClinical failure[221]
19324UrinaryE. coliClinical success[222]
19328DigestiveDysenteric bacillusClinical success[223]
1932173PlagueYersin’s bacillusClinical success[224]
19321DigestiveDysenteric bacillusClinical success[225]
19327Cutaneous and bacteraemiaStaphylococcus spp. and E. coliClinical success[226]
19327Cutaneous, pulmonary and urinaryVariedClinical success[227]
19321NeurologicalS. aureusClinical success[228]
19327Urinary and gynaecologicalVariedClinical success[229]
1932191UrinaryE. coliClinical failure[230]
1931266DigestiveV. choleraeClinical success[231]
19314SurgicalVariedClinical success[232]
1931UnspecifiedVariedVariedUnspecified[233]
19311PulmonaryUnspecifiedClinical success[234]
193146UrinaryMainly, E. coliClinical success[235]
193114ENTUnspecifiedClinical success[236]
193120CutaneousStaphylococcus spp.Clinical success[237]
19311DigestiveUnspecifiedClinical success[238]
19311OsteoarticularUnspecifiedClinical success[239]
1931115CutaneousStaphylococcus spp.Clinical success[240]
19311OsteoarticularS. aureusClinical success[241]
19311CutaneousUnspecifiedClinical success[242]
19312Cavernous sinus thrombophlebitisS. aureusNo significant improvement[243]
19311OsteoarticularStaphylococcus spp.Clinical success[244]
19306CutaneousDucrey’s bacillusClinical success[245]
193013CutaneousMainly, S. aureusClinical success[246]
19304DigestiveS. typhiClinical success[247]
19305UrinaryE. coliClinical success[248]
19302CutaneousUnspecifiedClinical success[249]
19301Bacteraemia/UrinaryE. coliClinical success
via intravenous route;
clinical failure via intravesical route and subcutaneous		[250]
19291CutaneousS. aureusClinical success[251]
192966DigestiveDysenteric bacillusClinical success[252]
19291BacteraemiaS. aureusClinical success[253]
1929264CutaneousS. aureusClinical success[254]
19291ENTUnspecifiedClinical success[255]
19291ENTUnspecifiedClinical success[256]
19293ENTVariedClinical success[257]
1929>300VariedVariedClinical success[258]
192976VariedS. aureus
E. coli		Clinical success[259]
192812UrinaryE. coli and P. aeruginosaClinical success[260]
192865Urinary, digestive and otherVariedClinical failure[261]
1928Around 200VariedS. aureus
S. albus
E. coli
P. aeruginosa		Clinical success[262]
19273DigestiveD. bacillusClinical success[263]
192658ENTMainly, S. aureusClinical success[264]
1926>100Cutaneous, ENT and urinaryS. aureusClinical success[265]
19264UrinaryE. coliClinical success[266]
192530UrinaryE. coli and S. aureusClinical success[267]
19254Bubonic plagueYersinia pestisClinical success[268]
19257UrinaryE. coliClinical success[269]
192411Urinary and digestiveE. coli
Salmonella spp.		Clinical success[270]
19244CutaneousS. aureusClinical success[271]
192414CutaneousS. aureusClinical success[272]
192311UrinaryE. coliClinical success[273]
19232CutaneousS. aureusClinical success[274]
19231DigestiveSalmonella spp.Clinical success[275]
19237VariedVariedClinical success[276]
19231UrinaryE. coliClinical success[277]
19227CutaneousS. aureusClinical failure[278]
19226CutaneousS. aureusClinical success[279]
19221UrinaryE. coliClinical success[280]
192212DigestiveE. coliNo significant improvement[281]
ENT: ear-nose-throat.
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Diallo, K.; Dublanchet, A. A Century of Clinical Use of Phages: A Literature Review. Antibiotics 2023, 12, 751. https://doi.org/10.3390/antibiotics12040751

AMA Style

Diallo K, Dublanchet A. A Century of Clinical Use of Phages: A Literature Review. Antibiotics. 2023; 12(4):751. https://doi.org/10.3390/antibiotics12040751

Chicago/Turabian Style

Diallo, Kevin, and Alain Dublanchet. 2023. "A Century of Clinical Use of Phages: A Literature Review" Antibiotics 12, no. 4: 751. https://doi.org/10.3390/antibiotics12040751

APA Style

Diallo, K., & Dublanchet, A. (2023). A Century of Clinical Use of Phages: A Literature Review. Antibiotics, 12(4), 751. https://doi.org/10.3390/antibiotics12040751

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