4. Discussion
infection, PJI, bacterial toxemia
ACUTE PHASE RESPONSE, ADVERSE DRUG REACTION, LYSIS, ACUTE PHASE REACTION, INFECTION
In our original protocol of PJI treatment, one of the main requirements for achieving a good clinical and microbiological result is maintenance of an effective therapeutic bacteriophage titer, which is achieved by injection of bacteriophage solutions into the periprosthetic area and measurement of the bacteriophage titer in wound fluid from periprosthetic drains by the Appelman method [The aim of this study was to compare the outcomes of two PJI treatment variants: combination phage/antibiotics therapy versus etiotropic systemic and local antibiotic therapy. Given our results, the efficacy of the antibiotic–bacteriophage combination therapy was one third higher in terms of the PJI relapse-free rate than a typical antibiotic regimen in these patients (difference = 31.9%; 95% CI for difference = 0.0443–0.5503), which resulted in an eight-fold decrease in the rate of PJI relapses in the SG compared to that in the CG (Fisher’s two-sided exact test We can compare our results on the 95.5% response rate to treatment (95% CI = 0.7511–0.9976) using phage-antibiotic combination therapy in the SG only with systematic reviews published in 2020–2021, by Clarke et al. [Importantly, the use of phage therapy does not guarantee complete infection eradication [An analysis of the phage titer in accordance with our proposed method [In this study, we assessed the inhibition of infection based on changes in the acute phase reaction markers, ESR and CRP, as additional criteria for PJI [Only two patients had an increase in temperature after the administration of phages, and the temperature returned to normal without additional treatment. This adverse drug reaction (ADR) can be explained by bacterial toxemia due to massive bacterial lysis during phage therapy. Otherwise, all other patients would also have had such an ADR after phage administration if the phage preparation had been insufficiently purified.The hypothesis about the association between an increase in CRP level and the lytic activity of phages in the SG is also supported by a normalization of the CRP values on day 12 ± 2, and the absence of extremely high CRP values (outliers) in the SG on days 7 ± 1 and 12 ± 2, whereas such CRP values were recorded in several patients in the CG. The obtained data also indicated substantial differences in the CRP levels on day 3 ± 1 and a two-fold difference trend in CRP levels on day 7 ± 1 for the SG and CG, respectively. The faster, and continuous, decrease in the median and especially the third quartile values of CRP in the SG compared to the CG indicate a more effective elimination of PJI pathogens in the SG. Otherwise, the median CRP values in the patient groups on days 3 ± 1 and 7 ± 1 after surgery would be the same, and would reflect the usual acute phase response of the patient’s body to surgery. Such results can be explained by the possible phage-antibiotic synergy, which previously was described as a promising therapeutic effect in several in vitro experiments, in vivo animal model studies, and in a few clinical studies [It is worth noting that in some cases, phage-antibiotic interactions can be antagonistic, depending on the class of antibiotic and the characteristics of the phage life cycle. So, the type of phage-antibiotic interaction should be checked before the use of phages with antibiotics, taking into account the antibiogram data and phage peculiarities. Additionally, the most effective combination of antibiotic and bacteriophage can be tested in such experiments.Another important factor is that the antibiotics used at the inpatient stage of treatment in the SG are not biofilm-penetrating. Although we did not analyze microbial strains for their ability to form biofilm, the possibility of biofilm formation cannot be completely ruled out, especially given the duration of infection in the studied patients before revision surgery. In this case, microorganisms present in various biofilm layers can be affected only by bacteriophages possessing special enzymes to penetrate the biofilm, destroy its lipopolysaccharide structure [Notably, our study had two limitations related to the study design: no randomization and no placebo control. Such drawbacks often become the subject of discussion in relation to surgical methods of treatment [