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Abstract

  1. Top of page
  2. Abstract
  3. Outcomes
  4. Patients and methods
  5. Results
  6. Physician-reported VAS scores
  7. Discussion
  8. References
  9. Supporting Information

Objectives:  To evaluate the efficacy and safety of a therapeutic bacteriophage preparation (Biophage-PA) targeting antibiotic-resistant Pseudomonas aeruginosa in chronic otitis.

Design:  Randomised, double-blind, placebo-controlled Phase I/II clinical trial approved by UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Central Office for Research Ethics Committees (COREC) ethical review process.

Setting:  A single specialist university hospital.

Participants:  24 patients with chronic otitis with a duration of several years (2–58). Each patient had, at the time of entry to the trial, an ear infection because of an antibiotic-resistant P. aeruginosa strain sensitive to one or more of the six phages present in Biophage-PA. Participants were randomised in two groups of 12 treated with either a single dose of Biophage-PA or placebo and followed up at 7, 21 and 42 days after treatment by the same otologist. Ears were thoroughly cleaned on each occasion and clinical and microbiological indicators measured.

Main outcome measures:  Physician assessed erythema/inflammation, ulceration/granulation/polyps, discharge quantity, discharge type and odour using a Visual Analogue Scale (VAS). Patients reported discomfort, itchiness, wetness and smell also using a VAS. Bacterial levels of P. aeruginosa and phage counts from swabs were measured initially and at follow-up. At each visit patients were asked about side effects using a structured form. Digital otoscopic images were obtained on days 0 and 42 for illustrative purposes only.

Results:  Relative to day 0, pooled patient- and physician-reported clinical indicators improved for the phage treated group relative to the placebo group. Variation from baseline levels was statistically significant for combined data from all clinic days only for the phage treated group. Variation from baseline levels was statistically significant for the majority of the patient assessed clinical indicators only for the phage treated group. P. aeruginosa counts were significantly lower only in the phage treated group. No treatment related adverse event was reported.

Conclusion:  The first controlled clinical trial of a therapeutic bacteriophage preparation showed efficacy and safety in chronic otitis because of chemo-resistant P. aeruginosa.

Chronic otitis is a common and difficult-to-treat condition. The major pathogens responsible are Pseudomonas aeruginosa and Staphylococcus aureus.1,2 In particular P. aeruginosa infections has proven very hard to eradicate as the bacterium organises itself in a ‘biofilm’ where it can be protected both from antibiotics and immune cells.3,4 Almost all strains have become refractory to treatment with antibiotics.5–8 The use of aminoglycoside antibiotics has to be curtailed because of ototoxic effects in the presence of a perforation of the tympanic membrane.

Bacteriophages-‘eaters of bacteria’– have been known since early 20th century because of the pioneering work of Twort and D’Herelle.9,10 Bacteriophages are viruses which specifically and uniquely seek out and destroy bacteria. They do not attack mammalian cells and exist as partners in microbiological eco-systems in the human body and in the environment. Although many reports on phage therapy are available they are uncontrolled or anecdotal and do not meet the criteria of modern evidence based medicine.11,12 Their brief popularity in the 1930s was superseded by the use of chemical antibiotics and phages ceased to be used therapeutically, at least in Western medicine. However uncritical use of antibiotics have led to the development of multi-resistant strains of bacteria such as S. aureus and P. aeruginosa causing serious illness and occasionally death.

Phages have been investigated for the control of P. aeruginosa infections in mice13 and in guinea pigs.14 More recently, reports of treatment of single cases of a human burn and a dog ear infection15 have indicated that bacteriophages multiplication in such settings is associated with clinical improvement. A small veterinary trial targeting P. aeruginosa ear infection in pet dogs produced positive results.16 This used the same bacteriophages as used in the present report, and provided evidence for their efficacy against mature, antibiotic-refractory ear infections.

No placebo-controlled, double-blind human clinical trial of a bacteriophage therapeutic against its target bacterial infection has yet been reported. This report presents data from the first such trial, targeting chronic otitis.

Outcomes

  1. Top of page
  2. Abstract
  3. Outcomes
  4. Patients and methods
  5. Results
  6. Physician-reported VAS scores
  7. Discussion
  8. References
  9. Supporting Information

The UK Medicines and Healthcare products Regulatory Authority who gave permissions for the trial of this new therapeutic agent, stated that a clinical outcome measure should be the primary indicator. This has been confirmed by the European Medicines Agency and the American Food and Drugs Administration agency which insist on this primary measure for future Phase III trials. Bacterial counts were deemed to be secondary outcomes by the three regulating authorities.

Statistical basis for sample size

The sample size calculations were based on an earlier veterinary field trial in dogs with otitis externa where changes in clinical scores and pseudomonas counts were measured following a single dose of Biophage-PA.

Assuming a 30% success rate in the untreated group (placebo effect), a two group continuity corrected chi-square test with a 0.050 two-sided significance level will have 85% power to detect the difference between group 1(active treatment) proportion, π1, of 0.800 and a group 2 (placebo) proportion, π2, of 0.300 (odds ratio of 0.107) when the sample size in each group is 20.

Patients and methods

  1. Top of page
  2. Abstract
  3. Outcomes
  4. Patients and methods
  5. Results
  6. Physician-reported VAS scores
  7. Discussion
  8. References
  9. Supporting Information

Twenty-four adult patients (of an original target of forty for power criteria based on earlier dog trials) were enrolled through the Royal National Throat, Nose and Ear Hospital, London, UK, and through referrals from other sites in London and surrounding areas. Inclusion criteria included a longstanding, antibiotic resistant, aural discharge. This arose from a variety of conditions including previous mastoid surgery, chronic perforations and longstanding otitis externa. In most patients the problem was unilateral. In those with bilateral problems, the ear with more severe clinical symptoms was chosen for the trial. Principal clinical exclusion criteria before consideration for entry to the trial were: recent history of local surgery, current antibiotic use, HIV positivity and women of child bearing potential. In accordance with trial protocols, all the remaining patients had long-term, antibiotic refractory ear infections with diagnosed P. aeruginosa.

Following entry, 44 patients were assessed and ear swabs taken for microbiological analysis, to confirm infection exclusively or predominantly with P. aeruginosa susceptible to at least one of the six trial bacteriophages. A pre-weighed, numbered swab, provided by CentraLabs, Cambridge was used to collect the sero- or muco purulent discharge from the ear under study. The swab was sent by courier to CentraLabs for analysis the same day. The weight of the swab contents was then measured to allow calculation of the concentration of bacteria and, following treatment, of bacteriophages. Bacteria in samples were identified by culture on blood agar in 5% CO2, blood agar plus metronidazole, MacConkey agar, Chocolate agar plates in 5% CO2, Pseudomonas-selective agar plates, and Sabouraud plates, all at 37 ± 2°C. P. aeruginosa was identified using API 20 NE test strips.

Sensitivity to individual bacteriophages in the therapeutic mixture was determined by plaque assay on isolates from swabs.

Insensitivity to any of the phages to be used in the trial (4) or unusual ear flora, including haemolytic streptococci of groups A, B, C or G, (13) or a positive HIV status (2) were exclusion factors. One patient decided not to enter the trail despite having Pseudomonas growth with phage sensitivity.

Following this assessment, 24 patients went forward to the trial. Mean age was 56.7 years (test group 55.7 years; placebo group 57.6 years). 17 patients were male and seven female (test group eight male, four female; placebo group nine male, three female).

Procedures

Patients meeting both clinical and microbiological entry criteria were treated with bacteriophage or given placebo within 2 weeks of the assessment visit. Only one ear was treated for each patient as for most patients the chronic otitis was unilateral and was related to previous middle ear disease or to mastoid disease and subsequent surgery.

After completion of appropriate documentation, oral and aural temperatures were taken and patients completed a Visual Analogue Scale (VAS) for each of four parameters: discomfort, itchiness, wetness, and smell, rating each from ‘none at all’ to ‘worst ever’ on a 100 mm bar. The attending physician then completed five VASs for: erythema/inflammation, ulceration/granulation/polyps, discharge type (clear/mucoid/mucopurulent), discharge quantity, and odour, rating each from ‘none at all’ to ‘worst ever’ on a 100 mm bar. The ear was swabbed and microbiological analysis for P. aeruginosa was performed using Pseudomonas-selective agar at 37 ± 2°C.

Presence of bacteriophages in the ear was determined using six assay strains of P. aeruginosa, selected so as to permit the growth of only one of the six test bacteriophages (assay at day 0 was to detect the presence of pre-existing bacteriophages. It should be noted that pre-existing bacteriophages could only be detected if one at least of the six assay strains of Pseudomonas was sensitive to the phage).

The ear was then meticulously cleaned under the microscope with suction and digital otoscopic photography (for illustrative purposes only) and audiometry were performed. One 200 μL dose of therapeutic or placebo was then administered.

Randomisation

The ‘dosage’ was randomised into groups of four, two test and two placebo, and coded to ensure blinding. The test preparation and the placebo were both colourless liquids provided in identical plastic vials and the contents could not be distinguished by the clinician (AW). The randomization was performed by Parexel, the clinical trial agent employed to perform both this and the data verification. The code was kept in a sealed envelope by the trial nurse at the Royal National Throat Nose and Ear Hospital. Consecutive patients who qualified for the trial were assigned the next available numbered vial.

Materials

Test material contained 100 000 plaque-forming units (PFU; standardised at the date of manufacture) of each of six bacteriophages (BC-BP-01 to BC-BP-06,15 NCIMB deposit numbers 41174–41179) containing 2.4 ng protein and 0.06 ng DNA suspended in 10% glycerol in phosphate-buffered saline. Placebo material consisted only of glycerol-PBS diluent. The liquid was drawn up into a 1 mL syringe and then a 27 gauge spinal needle was attached and used to apply 0.2 mL of the clear liquid into the ear. Patients were observed for 6 h, after which oral and aural temperatures were again taken. Patients kept daily diary cards throughout the study and attended for clinic visits at 7, 21 and 42 days after treatment. No further test or placebo material was administered.

During visits at 7, 21 and 42 days, patients were questioned about adverse events and study compliance, and patient, physician, microbiological assessments and aural cleaning using micro suction were carried out as at day 0. The audiogram and digital otoscopic photography were performed only at day 0 and 42, and the 6-h observation period only at day 0. No other treatment was used, specifically no antibiotics, systemic or topical were used, no other non-antibiotic drops were used and no aural toilet was performed other than at days 7, 21 and 42. Microbiological assays were performed by CentraLabs Clinical Research, and trial monitoring was carried out by Parexel International.

Statistical analysis

Statistical planning and analysis was carried out by Farmovs-Parexel. All variables were tabulated for each patient with descriptive statistics (number, arithmetic mean, arithmetic SD, median, minimum, maximum and P-value). Microbiological counts were recorded and total VAS scores calculated for patient- and physician-reported variables. To enter the trial the patients all had a long history of at least 2 years of continuous ear problems. Whilst there were small fluctuations, for better or worse, in their symptoms from month to month they had all reached a stable state and it was accepted by the statistical advisors at Farmovs-Parexel that a ‘change from baseline’ was an acceptable method of analysis.

The change from baseline to individual days (day 7, 21 and 42) of the variables mentioned below in the test and placebo groups were calculated using the Wilcoxon-signed rank test. Comparisons between test and placebo groups were carried out using analysis of covariance (ancova) with the baseline value as covariate using PROC MIXED of version 8.2 or higher of the SAS System for Windows (SAS), and chi-square tests (with responder defined as 30% improvement), utilising PROC FREQ of sas (SAS Institute, Cary, North Carolina, USA). ‘Stopping rules’ where when a blind interim analysis showed results relating to the patient and clinician assessments VAS scores with a power of 80%.

Registration and role of the funding source

This trial is registered with the European Clinical Trials Database as EUDRACT number 2004-001691-39 and with the Royal Free Hospital and Medical School Research Ethics Committee under project reference 04/Q0501/72. The sponsors met all costs of clinical, microbiological, and regulatory work involved in this study. Randomisation of trial materials, oversight and analysis was provided by Parexel International. The Consort flow chart is shown in Fig. 1.

image

Figure 1.  Randomised prospective double blind trial of bacteriophage preparation in the treatment of Pseudomonas chronic otitis.

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Results

  1. Top of page
  2. Abstract
  3. Outcomes
  4. Patients and methods
  5. Results
  6. Physician-reported VAS scores
  7. Discussion
  8. References
  9. Supporting Information

Entry

Of 44 patients screened, 29 met microbiological entry criteria. Of these, four were excluded because of lack of sensitivity of swab-sampled P. aeruginosa to the test bacteriophages, indicating that 86.2% of isolates were sensitive. This is in agreement with prior in vitro studies which, based on assay of 57 isolates from human ear infections, indicated that 86% should be susceptible to at least one of the six test bacteriophages. The other patient was excluded because of a delayed admission of HIV positivity. About 24 patients were entered into the trial, and all completed the full monitoring period without withdrawing. The analysis was by ‘intention to treat’ which in this study coincided with ‘as treated’.

Interim analysis

Following observation of some rapid improvements in the patient group, an interim analysis was requested by the Chief Investigator (AW). This was carried out by Farmovs-Parexel. No un-blinding was carried out by the investigators or the sponsors of the trial.

The interim analysis indicated that there was evidence suggesting efficacy, and consultations with independent statisticians and regulatory advisors indicated that the available data was sufficient to support and to inform the design of a larger, pivotal (phase III) clinical trial. On this basis it was decided to stop the trial after completion of the then active group, ending the trial at patient 24.

Outcomes of the trial

Significant clinical improvements from baseline were observed in the phage treated group but not in the placebo group. P. aeruginosa counts were significantly reduced in the phage treated group whereas they were unchanged in the placebo group. This was independent of the cause of the discharge, in other words, mastoid cavities, perforations and chronic otitis externas were equally distributed between the treatment and control arms of the trial. Bacteriophage replication was demonstrated in human subjects under trial conditions. There were no reportable side effects, and no evidence of local or systemic toxicity.

Patient-reported VAS scores

Mean indicators for combined patient-reported VAS scores relative to baseline are shown in Fig. 2a.

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Figure 2.  Patient- and physician-reported VAS scores by clinic day, means for phage and placebo groups.

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In the phage treated group significant reductions were: discomfort on day 7 (= 0.001), day 21 (= 0.007), day 42(= 0.020); itchiness on day 7 (= 0.025), on day 21 (= 0.001), day 42 (= 0.001); wetness on day 7 (= 0.001), day 21(= 0.001), day 42 (= 0.006); smell on day 7 (= 0.026). In the placebo treated group, significant reductions were: smell on day 7 (= 0.008), day 21 (= 0.008).

Combined scores for all clinic days

For the phage treated group significant (< 0.05) reduction from baseline in median patient assessment VAS scores were observed for combined data from all clinic days for three of four assessed variables (discomfort, = 0.003; itchiness, = 0.001; wetness, = 0.001), and for pooled patient-reported VAS scores (= 0.001). No significant reduction was observed for placebo group variables, either individually or pooled.

Physician-reported VAS scores

  1. Top of page
  2. Abstract
  3. Outcomes
  4. Patients and methods
  5. Results
  6. Physician-reported VAS scores
  7. Discussion
  8. References
  9. Supporting Information

Means and medians

Physician-reported scores relative to day 0 are shown in Fig. 2b. Again, while variability was high, phage treated grouped means were lower than those of the placebo group for all clinic days.

In the phage treated group significant reductions were: erythema/inflammation on day 7 (= 0.021), day 21 (= 0.014); ulceration/granulation/polyps on day 7 (P = 0.017), day 42 (= 0.025); odour on day 7 (= 0.002), day 21 (= 0.034). In the placebo treated group significant reductions were: discharge type on day 7 (= 0.029); odour on day 7 (= 0.002).

Combined scores for all clinic days

For the test group, statistically significant (< 0.05) reductions from baseline in median physician assessment VAS scores were observed for combined data from all clinic days for four of five assessed variables (erythema/inflammation, = 0.027; ulceration/granulation/polyps, = 0.040; discharge type, = 0.043; odour, = 0.026) and for pooled physician-reported VAS scores (= 0.012). No significant reduction was observed for the placebo group variables, either individually or pooled. (Fig. 2c).

Total VAS scores

Mean indicators for total (patient- and physician-reported) VAS scores relative to day 0 are shown in Fig. 3. It is seen that in the phage treated group all but one patient improved. Three patients had an almost complete recovery, with more than 80% reduction. Mean reduction was 50%. In the placebo group, nine were improved and three deteriorated. No placebo patients showed an improvement above 80%. Mean reduction was 20%.

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Figure 3.  Clinical VAS scores, mean of all clinic days for phage (test) and placebo groups as percentage of day 0 score.

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Pseudomonas counts

The effects of phage treatment on P. aeruginosa counts are shown in Fig. 4. The individual patient data for each visit is given in Table 1. The change from baseline in median P. aeruginosa counts was statistically significant on day 21(= 0.009) and day 42(= 0.016). Overall significance for accumulated results from all three follow-up days was high (< 0.0001).

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Figure 4. Pseudomonas aeruginosa counts (colony forming units per gram) by clinic day, mean (a) and median (b) for phage (test) and placebo (control) groups as a percentage of day 0 count.

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Table 1.   Colony forming units per gram (CFU/g) of material in placebo and test groups at the four sampling intervals
Pseudomonas aeruginosa, CFU/g
Patient numberDay 0Day 7Day 21Day 42
Placebo
 35.70E + 094.80E+091.10E+101.80E+09
 41.00E+101.40E + 095.30E + 092.00E + 09
 64.30E + 095.00E + 092.10E + 094.00E + 10
 81.50E + 084.20E + 091.80E + 095.60E + 09
 91.30E + 076.80E + 079.30E + 09Not detected
 113.70E + 095.20E + 091.50E + 092.40E + 09
 135.60E + 081.10E + 081.40E + 091.90E + 09
 143.30E + 093.90E + 108.70E + 095.60E + 09
 191.40E + 103.80E + 101.90E + 101.30E + 10
 201.20E + 104.00E + 094.10E + 08Not detected
 221.60E + 096.00E + 09Not detectedNot detected
 232.30E + 103.10E + 099.60E + 081.30E + 10
Mean6.5E + 099.2E + 095.1E + 097.1E + 09
SD7.0E + 091.4E + 105.8E + 091.2E + 10
Day 0 (%) 141.6%78.5%108.9%
Test
 14.30E + 081.40E + 084.80E + 083.00E + 08
 22.20E + 091.00E + 083.20E + 084.70E + 09
 58.60E + 093.40E + 10Not detected8.50E + 09
 71.40E + 104.80E + 08Not detectedNot detected
 108.00E + 092.60E + 093.90E + 097.40E + 09
 121.20E + 09Not detectedNot detectedNot detected
 151.30E + 102.80E + 091.30E + 094.10E + 09
 162.30E + 063.00E + 085.20E + 088.00E + 07
 174.50E + 102.30E + 101.10E + 101.50E + 09
 181.50E + 10Not detectedNot detectedNot detected
 212.50E + 08Not detected1.80E + 091.90E + 07
 243.80E + 097.20E + 064.30E + 071.80E + 07
Mean9.3E + 095.3E + 091.6E + 092.2E + 09
SD1.3E + 101.3E + 103.7E + 093.3E + 09
Day 0 (%) 56.9%17.4%23.9%

There was no significant change from base line in median P. aeruginosa counts at any follow-up visit in the placebo group. Cumulated results from all three follow-up days were not significant (= 0.835). In the phage treated group, among the twelve patients and three clinic days there were a total of 10 days when no P. aeruginosas could be detected, against four in the placebo group. In two of the test patients but none of the placebo patients no P. aeruginosa was detected at any time after treatment.

Bacteriophage counts

Replication of all six bacteriophages was seen in patients from the phage treated group. Of the six test bacteriophages, the maximum number of bacteriophages observed to replicate in an individual patient was five. Replication of some therapeutic bacteriophages may have been masked by pre-existing bacteriophages which grew on the assay strains. These were seen in 10 patients, five from each of the placebo and test groups. The presence of pre-existing bacteriophages did not seem to be associated with clinical improvement.

The mean recovery of bacteriophage from swabs taken from the ears of the phage group over all three post-treatment clinic visits was 1.27 × 108 from individual swabs. This compares with an input dose of 6 × 105, suggesting an average amplification in the treated ear in excess of 200 times the input dose, allowing only for bacteriophage collected on the swab. Mean recovery of material from the ear was 17.8 mg in the test group (against 20.8 mg in the placebo group), so it is likely that much higher levels were present in the whole ear. It should however be noted that even 109 bacteriophages would equate to sub-microgram quantities of bacteriophages.17

Duration of the therapeutic effect

The mean duration of bacteriophage replication in the test group was 23.1 days (median 21 days), and clearance of bacteriophages was observed after resolution of infection in all cases where this occurred. Following the single dose treatment, clinical scores rose in some cases by day 42 from a low on day 21(Fig. 2b). However, neither mean nor median values for any individual or pooled indicator were higher than the day 0 values for the phage treated group. In the placebo group, multiple scores on day 42 exceeded day 0 values. These were itchiness (107%), erythema (102%), odour (109%), and P. aeruginosa count (119%) for mean scores; and erythema (120%) and odour (105%) for median scores.

Audiometry

There were no significant adverse changes in the audiometric findings in any patient and no deterioration in the bone conduction thresholds.

Safety

No serious adverse events were reported. Eleven (11) (46%) patients reported a total of 26 treatment-emergent adverse events (Table S1). Thirteen (13) treatment-emergent adverse events were reported by six (50%) patients in the test group and 13 treatment-emergent events were reported by five (42%) patients in the placebo group. All treatment-emergent adverse events were mild to moderate, and none were considered to be related to the investigational product administration by the trial clinician. All but two had resolved by day 42.

Recovery

All of these patients were ‘difficult’ cases with long histories (2–50 + years) of ear problems that had not responded to multiple treatments including topical and systemic antibiotics, and even surgery. To get them symptom free using a single dose of bacteriophage was challenging.

By the final day of the trial, three of the twelve phage treated patients had shown reduction to <10% of day 0 values for total VAS scores (range for all phage treated patients, 1–101% of day 0 values). In all three patients, P. aeruginosa (and all therapeutic bacteriophage) levels were below the limit of detectability on day 42. Digital photography of one such patient (A0012) is shown in Fig. 5. None of the placebo group showed such reduction in VAS scores (range for all placebo patients, 26% to 294% of day 0 values).

image

Figure 5.  Digital photography before (a) and after (b) in patient A0012. Patient A0012 had a longstanding resistant otitis externa. There was swelling of the deep canal skin and ulceration in the roof of the canal adjacent to the tympanic membrane. By day 42 this had resolved and the patient was essentially symptom free.

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Discussion

  1. Top of page
  2. Abstract
  3. Outcomes
  4. Patients and methods
  5. Results
  6. Physician-reported VAS scores
  7. Discussion
  8. References
  9. Supporting Information

Evidence was obtained for the replication of bacteriophages in treated patients, and for the clearance of bacteriophages after elimination of the target bacterial infection. It should be emphasised that in contrast to antibiotics which requires gram amounts of drug given at regular intervals over several weeks, phage therapy uses a minuscule dose, in this case only 2.4 ng of protein given once. Even so it has an effect lasting several weeks and in three previously untreatable cases appeared to effect a complete cure. The clinical investigator (AW) asked for a blind interim assessment of the trial results because after twenty patients it was clear to him that there was a marked effect in approximately half the patients. The blinded trial continued whilst the analysis was undertaken. With the results available to Parexel (but not AW), it was agreed to stop the trial after patient 24. The phages are self-replicating as long as the target bacteria are present. When the target bacteria is reduced or eliminated the phage replication ceases.

Replication of the bacteriophages lasted for a mean of 23 days after a single dose and when the P. aeruginosa were not completely cleared there was an increase in the clinical scores in some patients. This suggests a role for repeated treatment after three to four weeks, which will be evaluated in future trials.

During infections P. aeruginosa is organised in a biofilm which renders it resistant both to antibiotics and immune cells. 18–20 It should be noted that phages have evolved strategies to break down biofilm through specific enzymes21 and are therefore able to reach and kill their target. Naturally this facet of phage action could also render the Pseudomonas more susceptible to conventional antibiotics and innate immune defences. This suggests possible combined therapies of alternating bacteriophage treatment with staged antibiotic treatment to maximise effectiveness and, hopefully minimise antibiotic resistance.

The present controlled trial of bacteriophages indicates that this form of biological therapy has considerable promise. Its further development should be according to modern scientific principles and regulatory scrutiny in a multi centre Phase III trial. This would involve selection of phages, formulation, and stability testing as well as potential replacement in line with any development of resistance. New combinations of bacteriophages may need to be developed in due course to meet the changing nature of Pseudomonas colonisation. The clinical evaluation must be in the form of randomised, double blind trials as infections sometimes resolve spontaneously. Biophage-PA will now be further developed in larger trials including chronic otitis as well as other infections – such as infected burn sites or the lung infections in children with cystic fibrosis- where P. aeruginosa is the causative bacterial infection.

References

  1. Top of page
  2. Abstract
  3. Outcomes
  4. Patients and methods
  5. Results
  6. Physician-reported VAS scores
  7. Discussion
  8. References
  9. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Outcomes
  4. Patients and methods
  5. Results
  6. Physician-reported VAS scores
  7. Discussion
  8. References
  9. Supporting Information

Table  S1.  Overall incidence of treatment-emergent adverse events.

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FilenameFormatSizeDescription
COA_1973_sm_Table S1.doc104KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.