Last October Dutch people were “informed” about the potential of bacteriophages. In short, “bacteriophages work where antibiotics fail because of resistance in critically ill patients, something that is already known for 100 years, and that is neglected by modern medicine”. Some questions were raised, see here and here, but curretly Dutch physicians receive many/daily requests from patients on phage therapy and the most desperate patients pay thousands of euros to seek help abroad, without reimbursement from health insurance. Last week, we had invited the most experienced clinical experts and scientists acting at the cutting edge of preclinical bacteriophage research. Here is my impression of the clinical part.
As a first note, all presenters provided a balanced overview of experiences. From the clinical perspective we had speakers from the Eliava Institute in Tblisi, Georgia, and the Queen Astrid Military Hospital in Brussels, whom I think have most experience with using bacteriophages.
The Eliava Institute has the longest experience, about 80 years, and has several (about 5) different phage cocktails for a wide range of infections. These cocktails are used as oral treatment, nebulization or in impregnated wound dressings, but there is no data coming from a randomized, or placebo-controlled experiment. The data presented coming closest to a trial were from 1947:
“I brigade applied phages to 2,500 soldiers, among them gangrene symptoms were revealed in 35 (1.4%) cases. In the control group of 7,918 soldiers gangrene was registered in 342 (4.3%) cases.”
“II brigade applied phage treatment for 941 soldiers, only 14 (1.5%) got sick. In the control group 6.8% were infected.”
“III brigade applied phage treatment for 2,584 soldiers, gangrene was developed in 18 (0.7%) cases, while in the control group incidence of infection was 2.3%.”
And 2 references from the 1970s:
- Buryakovsky, 1974, Ukraine
Experiment involved 49,523 children from kindergarten; Experimental group – 30,023, control group – 19,500; Incidence of disease decreased for 2.6 times in the experimental group
- Ferdinand et al., 1978, Russia
Experiments were held in 93 towns; Experimental towns – 50, control 43; Food and dairy production personnel and kindergarten teachers were involved into the study; n=3000, kindergarten n=20,000; In different towns frequency of infection decreased for 30-60%
And what about treatment of critically ill patients? “A staphylococcal bacteriophage was successfully used in the 1970-80s for treatment of generalized and local infections, such as chronic and acute sepsis, pulmonary infections, septic staphylodermia, osteomyelitis, septicaemia, purulent arthritis, lung abscesses, surgery-related infetions of bones and skull (M. Kutateladze et al., Medecine et Maladies Infectieuses, 2008, v.38, issue 8).” Yet, as intravenous phage treatment is currently not approved in Georgia, no patients have been treated as such in recent years. Treatments are provided in out-patient clinics only, with little uptake in the clinical setting.
In Belgium, the interest in phage therapy also stems from the military. The partnered in the EU-funded trial Phagoburn in burn wound patients. The trial has been finalized, with results still being under embargo. In that trial, phages for either Pseudomonas aeruginosa or E. coli were used for wound treatment, compared to a reference antibiotic treatment (silver sulfadiazine). Manufacturing of investigational products took 20 months and most of the budget. Patient enrolment was slow as physicians were reluctant to use the “1-species cocktail” for patients that were mostly infected with multiple bacterial species.
The Belgium team has also used bacteriophages in 14 patients under Article 37 of the declaration of Helsinki: “in the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physicians’ judgement it offers hope of saving life, re-establishing health or alleviating suffering.” The patients treated had wounds (n=6), osteomyelitis (n=2), pneumonia (n=1), respiratory tract infections (n=3), chronic sinusitis (n=1) and sepsis (n=1). Only the last one received IV treatment, see.
One trial is under way: double-blind placebo-controlled in men with bacteria in urine before undergoing transurethral resection of prostate, comparing “do nothing” to antibiotics to a phage cocktail (tested for activity to the bacteria in the individual patient), see. The trial was planned as multicenter in Switzerland and Tblisi, but did not yet get IRB-approval in Switzerland. 38 of the planned 81 patients (3×27) have been enrolled in Tblisi.
Quantifying the effect of effects if phages in humans is complex. Phages are everywhere, in most of the things we eat and no objection against fecal transplantation. We accept that patients buy phages abroad and be treated with it in our own hospitals. Yet, if we want to learn if it works, we’re entering the area of human research with a medicine, where nebulization of a natural product is similar to intrathecal vincristine. In Belgium it is now allowed to produce phages under a law that pragmatically centers on the magistral preparation of tailor-made phage medicines, see. I sincerely hope, that our Dutch government will also allow this approach. If not, we will not be able to extent the scientific evidence base on the effectiveness of phage therapy for difficult to treat infections. All presenters acknowledged the medical need for such studies.
In the meantime all persons that stimulate and/or assist desperate patients to seek non-reimbursed medical help abroad should be aware of the above-listed evidence for clinical effectiveness (and should inform their patients!).
PS: for the above I used texts from slides presented and my recollection of answers given in the discussions.