Bacteriophage Rescue Therapy of a Vancomycin-Resistant Enterococcus faecium Infection in a One-Year-Old Child following a Third Liver Transplantation

Abstract

Phage therapy is an experimental therapeutic approach used to target multidrug-resistant bacterial infections. A lack of reliable data with regard to its efficacy and regulatory hurdles hinders a broad application. Here we report, for the first time, a case of vancomycin-resistant Enterococcus faecium abdominal infection in a one-year-old, critically ill, and three times liver transplanted girl, which was successfully treated with intravenous injections (twice per day for 20 days) of a magistral preparation containing two Enterococcus phages. This correlated with a reduction in baseline C-reactive protein (CRP), successful weaning from mechanical ventilation and without associated clinical adverse events. Prior to clinical use, phage genome was sequenced to confirm the absence of genetic determinants conferring lysogeny, virulence or antibiotic resistance, and thus their safety. Using a phage neutralization assay, no neutralizing anti-phage antibodies in the patient’s serum could be detected. Vancomycin-susceptible E. faecium isolates were identified in close relation to phage therapy and, by using whole-genome sequencing, it was demonstrated that vancomycin-susceptible E. faecium emerged from vancomycin-resistant progenitors. Covering a one year follow up, we provide further evidence for the feasibility of bacteriophage therapy that can serve as a basis for urgently needed controlled clinical trials.

Practical Assessment of an Interdisciplinary Bacteriophage Delivery Pipeline for Personalized Therapy of Gram-Negative Bacterial Infections

“…In this study, we aimed to assess phage delivery for personalized therapy in a wellstructured interdisciplinary pipeline to assess and increase the pipeline's efficiency and provide guidelines for each single step for non-phage experts. To date, 'sur-mesure' phage preparations have mostly been used in phage therapy, due to the limited availability of 'prêt-à-porter' phage products, high number of required phages, and need for rapid adaptation to emerging phage resistance during treatment [5][6][7]13,14,23]. The Belgian monograph on the use of magistral phages is a frequently encouraged step towards the implementation of a new regulatory framework for 'sur-mesure' phages [1,14,24,25].…”

“…Phage banks for personalized use of phages incorporate high-quality phage preparations, or phages meeting GMP-standards, but these banks have far from sufficient numbers of therapeutically needed phages for patients [12,16]. For de novo isolated 'sur-mesure' phages, the therapeutic window (the period of time during which a particular treatment can be reasonably applied to a patient) must be open for at least several weeks [5,7,13]. However, critically ill patients, such as ICU patients suffering from respiratory MRGN superinfections, require safe and rapid therapeutic offers.…”

“…(3) Based on previous experiences, the phage treatment plan can take up to several months, which must be planned in advance, from a logistical aspect [13,36,37]. The application of phages, e.g., daily, is adjusted to the needs of the patient.…”

“…This underscores the importance of monitoring the match between phages and bacteria and having several suitable phages in stock as a reserve [16,39,62]. Additionally, phage titre of the formulated phage solution is closely monitored by phage experts to avoid treatment with too low concentrations, as titre drops are common with some phages [13,58]. To monitor phage absorption and distribution in the body, as well as phage clearance by the body, pharmacokinetic studies may accompany the treatment [32,64].…”

“…Several highly relevant clinical trials are underway, and approved phage composites with market authorization may provide access to phage therapy for important applications in the future. However, these static composites can only successfully target a few individual infections, due to the large number of highly specific phages and their potential genetic volatility [1,6,[11][12][13][14][15]. For personalized phage therapy, international phage banks, in line with high quality standards, such as good manufacturing practice (GMP), should be substantially expanded, despite high costs, as phage banks currently have far from sufficient numbers of therapeutically needed phages for patients [12,16].…”