Bacteriophage-antibiotic combination therapy against extensively drug-resistant Pseudomonas aeruginosa infection to allow liver transplantation in a toddler

Abstract

Post-operative bacterial infections are a leading cause of mortality and morbidity after ongoing liver transplantation. Bacteria causing these infections in the hospital setting can exhibit high degrees of resistance to multiple types of antibiotics, which leads to major therapeutic hurdles. Alternate ways of treating these antibiotic-resistant infections are thus urgently needed. Phage therapy is one of them and consists in using selected bacteriophage viruses – viruses who specifically prey on bacteria, naturally found in various environmental samples – as bactericidal agents in replacement or in combination with antibiotics. The use of phage therapy raises various research questions to further characterize what determines therapeutic success or failure. In this work, we report the story of a toddler who suffered from extensively drug-resistant Pseudomonas aeruginosa sepsis after liver transplantation. He was treated by a bacteriophage-antibiotic intravenous combination therapy for 86 days. This salvage therapy was well tolerated, without antibody-mediated phage neutralization. It was associated with objective clinical and microbiological improvement, eventually allowing for liver retransplantation and complete resolution of all infections. Clear in vitro phage-antibiotic synergies were observed. The occurrence of bacterial phage resistance did not result in therapeutic failure, possibly due to phage-induced virulence tradeoffs, which we investigated in different experimental models.

Selective bacteriophages reduce the emergence of resistant bacteria in the bacteriophage-antibiotic combination therapy

“…The combination of phages and antibiotics has been widely used to enhance the eradication of drug-resistant bacteria and mitigate the spread of antibiotic resistance worldwide (8, 46, 47). Several studies have examined the mechanisms underlying phage-antibiotic synergy.…”

“…Several studies have examined the mechanisms underlying phage-antibiotic synergy. Owing to the selection pressure on bacteria caused by phage infection, some toxicity, drug sensitivity, and growth factors are lost, and phage-resistant strains are often less toxic, more sensitive to antibiotics, and grow at a slower rate than wild-type strains (46, 47). Combining phages with antibiotics can reduce resistant clones, as our study showed, but the type of phage utilized will affect the outcome (Fig.…”

Engineered superinfective Pf phage prevents dissemination ofPseudomonas aeruginosain a mouse burn model

“…In the same vein, a combinatorial treatment of phages and antibiotics is likely even more effective (39). For example, bacteriophage cocktailantibiotic combination therapy against extensively drug-resistant P. aeruginosa infection allowed liver transplantation in a toddler with recalcitrant infection (40). The rationale is that the target for this phage may be selected against, and therefore multiple venues of attack make evolutionary escape less likely.…”

Gut dysbiosis in nonalcoholic fatty liver disease: pathogenesis, diagnosis, and therapeutic implications

“…Unlike the major therapeutic hurdles of antibiotics and other chemotherapies caused by high degrees of bacteria resistance in clinic, phage therapy provides a new therapeutic approach for precisely editing the intestinal microbiota, completely resolving bacteria resistance and treating liver diseases. Although great advances have presented in various bacterial infection ( Mitropoulou et al., 2022 ; Van Nieuwenhuyse et al., 2022 ), due to the diversity and complexity of gut microbiome, more clinical trials with larger cohorts are required to validate the relevance of the findings in NAFLD patients.…”