Table 3.

Some of the problems with early therapeutic phage research and the ways they have been addressed in more recent studies or can be addressed in the future

ProblemCommentsSolution and/or required approach
Narrow host range of phagesBecause of the high specificity of phages, many negative results may have been obtained because of the failure to select phages lytic for the targeted bacterial species (19).Determine the phage susceptibility of the etiologic agent before using phages therapeutically (40, 77); use polyvalent phage cocktails which lyse the majority of strains of the etiologic agent (15, 45, 58, 59).
Insufficient purity of phage preparationsEarly therapeutic phages were in crude lysates of host bacteria, and they contained numerous contaminants (including endotoxins) that may have counteracted the effect of phages.Ion-exchange chromatography, high-speed centrifugation, and other modern purification techniques should be used to obtain phage preparations of high purity (11).
Poor stability and/or viability of phage preparationsSome commercial phage preparations were supplemented with mercurials or oxidizing agents or were heat treated to ensure bacterial sterility (14). Many of these treatments also may have inactivated the phages, resulting in ineffective phage preparations.Advanced purification techniques can be used to purify phages and to ensure that they are bacterium free. The viability and titer of phages should be determined before using them therapeutically.
Lack of understanding of the heterogeneity and mode of action of phages (i.e., lytic vs lysogenic phages)Failure to differentiate between lytic and lysogenic phages may have resulted in some investigators using lysogenic phages, which are much less effective than lytic phages.Carefully select for lytic phages. This is also critical for avoiding the possible horizontal transfer of bacterial toxin, antibiotic resistance, etc., genes by lysogenic phages (3) (Fig.2).
Exaggerated claims of effectiveness of commercial phage preparationsOne example of this would be the preparation calledEnterophagos, which was marketed as being effective against herpes infections, urticaria, and eczema (8)—conditions against which phages could not possibly be effective.Phage preparations should be accompanied by specific, scientifically supported information about their efficacy against specific bacterial pathogens, their possible side-effects, etc.
Failure to establish scientific proof of efficacy of phage treatmentMost clinical studies using therapeutic phages were conducted without placebo controls; also, when placebo controls were used, data were evaluated in a subjective manner questioned by many peers (20, 26).Carefully controlled, double-blinded placebo studies with highly purified, lytic phages should be conducted, and results must be evaluated based on both clinical observations and scrupulous laboratory analysis.