RESUMEN
The rapid increase in antibiotic resistance presents a dire situation necessitating the need for alternative therapeutic agents. Among the current alternative therapies, phage therapy (PT) is promising. This review extensively summarizes preclinical PT approaches in various in-vivo models. PT has been evaluated in several recent clinical trials. However, there are still several unanswered concerns due to a lack of appropriate regulation and pharmacokinetic data regarding the application of phages in human therapeutic procedures. In this review, we also presented the current state of PT and considered how animal models can be used to adapt these therapies for humans. The development of realistic solutions to circumvent these constraints is critical for advancing this technology.
Asunto(s)
Infecciones Bacterianas , Bacteriófagos , Terapia de Fagos , Animales , Humanos , Terapia de Fagos/métodos , Infecciones Bacterianas/tratamiento farmacológico , Bacteriófagos/fisiología , Farmacorresistencia Bacteriana Múltiple , Modelos Animales , Antibacterianos/uso terapéuticoRESUMEN
Pseudomonas aeruginosa is an important Gram-negative pathogen with intrinsic resistance to many clinically used antibiotics. It is particularly troublesome in nosocomial infections, immunocompromised patients, and individuals with cystic fibrosis. Antimicrobial resistance (AMR) is a huge threat to global health, with a predicted 10 million people dying from resistant infections by 2050. A promising therapy for combatting AMR infections is phage therapy. However, more research is required to investigate mechanisms that may influence the efficacy of phage therapy. An important overlooked aspect is the impact of membrane lipid remodelling on phage binding ability. P. aeruginosa undergoes changes in membrane lipids when it encounters phosphorus stress, an environmental perturbation that is likely to occur during infection. Lipid changes include the substitution of glycerophospholipids with surrogate glycolipids and the over-production of ornithine-containing aminolipids. Given that membrane lipids are known to influence the structure and function of membrane proteins, we propose that changes in the composition of membrane lipids during infection may alter phage binding and subsequent phage infection dynamics. Consideration of such effects needs to be urgently prioritised in order to develop the most effective phage therapy strategies for P. aeruginosa infections.
Asunto(s)
Bacteriófagos , Terapia de Fagos , Infecciones por Pseudomonas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacteriófagos/genética , Glicerofosfolípidos , Glucolípidos , Humanos , Lípidos de la Membrana , Proteínas de la Membrana , Ornitina , Terapia de Fagos/métodos , Fósforo , Infecciones por Pseudomonas/terapia , Pseudomonas aeruginosaRESUMEN
Although several studies have shown promising clinical outcomes of phage therapy in patients with orthopedic device-related infections, questions remain regarding the optimal application protocol, systemic effects, and the impact of the immune response. This study provides a proof-of-concept of phage therapy in a clinically relevant rabbit model of fracture-related infection (FRI) caused by Staphylococcus aureus. In a prevention setting, phage in saline (without any biomaterial-based carrier) was highly effective in the prevention of FRI, compared to systemic antibiotic prophylaxis alone. In the subsequent study involving treatment of established infection, daily administration of phage in saline through a subcutaneous access tube was compared to a single intraoperative application of a phage-loaded hydrogel and a control group receiving antibiotics only. In this setting, although a possible trend of bacterial load reduction on the implant was observed with the phage-loaded hydrogel, no superior effect of phage therapy was found compared to antibiotic treatment alone. The application of phage in saline through a subcutaneous access tube was, however, complicated by superinfection and the development of neutralizing antibodies. The latter was not found in the animals that received the phage-loaded hydrogel, which may indicate that encapsulation of phages into a carrier such as a hydrogel limits their exposure to the adaptive immune system. These studies show phage therapy can be useful in targeting orthopedic device-related infection, however, further research and improvements of these application methods are required for this complex clinical setting. IMPORTANCE Because of the growing spread of antimicrobial resistance, the use of alternative prevention and treatment strategies is gaining interest. Although the therapeutic potential of bacteriophages has been demonstrated in a number of case reports and series over the past decade, many unanswered questions remain regarding the optimal application protocol. Furthermore, a major concern during phage therapy is the induction of phage neutralizing antibodies. This study aimed at providing a proof-of-concept of phage therapy in a clinically relevant rabbit model of fracture-related infection caused by Staphylococcus aureus. Phage therapy was applied as prophylaxis in a first phase, and as treatment of an established infection in a second phase. The development of phage neutralizing antibodies was evaluated in the treatment study. This study demonstrates that phage therapy can be useful in targeting orthopedic device-related infection, especially as prophylaxis; however, further research and improvements of these application methods are required.
Asunto(s)
Antibacterianos/uso terapéutico , Fracturas Óseas/microbiología , Terapia de Fagos/métodos , Infecciones Relacionadas con Prótesis/terapia , Infecciones Estafilocócicas/terapia , Fagos de Staphylococcus/crecimiento & desarrollo , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana/genética , Femenino , Fracturas Óseas/patología , Hidrogeles/uso terapéutico , Prueba de Estudio Conceptual , Infecciones Relacionadas con Prótesis/microbiología , Conejos , Infecciones Estafilocócicas/prevención & control , Fagos de Staphylococcus/inmunología , Staphylococcus aureus/virologíaRESUMEN
We rationally designed a bacteriophage cocktail to treat a 56-year-old male liver transplant patient with complex, recurrent prostate and urinary tract infections caused by an extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) (UCS1). We screened our library for phages that killed UCS1, with four promising candidates chosen for their virulence, mucolytic properties, and ability to reduce bacterial resistance. The patient received 2 weeks of intravenous phage cocktail with concomitant ertapenem for 6 weeks. Weekly serum and urine samples were collected to track the patient's response. The patient tolerated the phage therapy without any adverse events with symptom resolution. The neutralization of the phage activity occurred with sera collected 1 to 4 weeks after the first phage treatment. This was consistent with immunoassays that detected the upregulation of immune stimulatory analytes. The patient developed asymptomatic recurrent bacteriuria 6 and 11 weeks following the end of phage therapy-a condition that did not require antibiotic treatment. The bacteriuria was caused by a sister strain of E. coli (UCS1.1) that remained susceptible to the original phage cocktail and possessed putative mutations in the proteins involved in adhesion and invasion compared to UCS1. This study highlights the utility of rationally designed phage cocktails with antibiotics at controlling E. coli infection and suggests that microbial succession, without complete eradication, may produce desirable clinical outcomes.
Asunto(s)
Infecciones por Escherichia coli/tratamiento farmacológico , Terapia de Fagos/métodos , Infecciones Urinarias/terapia , Antibacterianos/uso terapéutico , Bacteriófagos , Escherichia coli/patogenicidad , Escherichia coli/virología , Humanos , Trasplante de Hígado , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Medicina de Precisión/métodos , Receptores de Trasplantes , VirulenciaRESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Enterococcus faecium/efectos de los fármacos , Infecciones por Bacterias Grampositivas/terapia , Trasplante de Hígado/efectos adversos , Terapia de Fagos/métodos , Vancomicina/farmacología , Infección Hospitalaria , Farmacorresistencia Bacteriana Múltiple , Enterococcus faecium/genética , Femenino , Genoma Bacteriano , Infecciones por Bacterias Grampositivas/etiología , Humanos , Lactante , Pruebas de Sensibilidad Microbiana , Resultado del Tratamiento , Enterococos Resistentes a la Vancomicina , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: Urinary tract infections (UTIs) are among the most prevalent microbial diseases and their financial burden on society is substantial. In the context of increasing antibiotic resistance, finding alternative treatments for UTIs is a top priority. We aimed to determine whether intravesical bacteriophage therapy with a commercial bacteriophage cocktail is effective in treating UTI. METHODS: We did a randomised, placebo-controlled, clinical trial, at the Alexander Tsulukidze National Centre of Urology, Tbilisi, Georgia. Men older than 18 years of age, who were scheduled for transurethral resection of the prostate (TURP), with complicated UTI or recurrent uncomplicated UTI but no signs of systemic infection, were allocated by block randomisation in a 1:1:1 ratio to receive intravesical Pyo bacteriophage (Pyophage; 20 mL) or intravesical placebo solution (20 mL) in a double-blind manner twice daily for 7 days, or systemically applied antibiotics (according to sensitivities) as an open-label standard-of-care comparator. Urine culture was taken via urinary catheter at the end of treatment (ie, day 7) or at withdrawal from the trial. The primary outcome was microbiological treatment response after 7 days of treatment, measured by urine culture; secondary outcomes included clinical and safety parameters during the treatment period. Analyses were done in a modified intention-to-treat population of patients having received at least one dose of the allocated treatment regimen. This trial is registered with ClinicalTrials.gov, NCT03140085. FINDINGS: Between June 2, 2017, and Dec 14, 2018, 474 patients were screened for eligibility and 113 (24%) patients were randomly assigned to treatment (37 to Pyophage, 38 to placebo, and 38 to antibiotic treatment). 97 patients (28 Pyophage, 32 placebo, 37 antibiotics) received at least one dose of their allocated treatment and were included in the primary analysis. Treatment success rates did not differ between groups. Normalisation of urine culture was achieved in five (18%) of 28 patients in the Pyophage group compared with nine (28%) of 32 patients in the placebo group (odds ratio [OR] 1·60 [95% CI 0·45-5·71]; p=0·47) and 13 (35%) of 37 patients in the antibiotic group (2·66 [0·79-8·82]; p=0·11). Adverse events occurred in six (21%) of 28 patients in the Pyophage group compared with 13 (41%) of 32 patients in the placebo group (OR 0·36 [95% CI 0·11-1·17]; p=0·089) and 11 (30%) of 37 patients in the antibiotic group (0·66 [0·21-2·07]; p=0·47). INTERPRETATION: Intravesical bacteriophage therapy was non-inferior to standard-of-care antibiotic treatment, but was not superior to placebo bladder irrigation, in terms of efficacy or safety in treating UTIs in patients undergoing TURP. Moreover, the bacteriophage safety profile seems to be favourable. Although bacteriophages are not yet a recognised or approved treatment option for UTIs, this trial provides new insight to optimise the design of further large-scale clinical studies to define the role of bacteriophages in UTI treatment. FUNDING: Swiss Continence Foundation, the Swiss National Science Foundation, and the Swiss Agency for Development and Cooperation. TRANSLATIONS: For the Georgian and German translations of the abstract see Supplementary Materials section.
Asunto(s)
Bacteriófagos/crecimiento & desarrollo , Terapia de Fagos/métodos , Resección Transuretral de la Próstata/efectos adversos , Infecciones Urinarias/terapia , Anciano , Antibacterianos/uso terapéutico , Método Doble Ciego , Georgia , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/etiologíaRESUMEN
Escherichia coli is the most common cause of Gram-negative prosthetic joint infections (PJIs) and ciprofloxacin is the first-line antibiofilm antibiotic. Due to the emergence of fluoroquinolone resistance, management of E. coli PJIs has become challenging and is associated with high treatment failure rates. We evaluated the efficacy of a newly isolated bacteriophage ɸWL-3 as a therapeutic agent in combination with ciprofloxacin, fosfomycin, gentamicin, meropenem or ceftriaxone against biofilm of a ciprofloxacin/ceftriaxone-resistant E. coli strain and the ATCC 25922 reference strain. ɸWL-3 was first characterised in terms of virion morphology, absorption rate, burst size and killing kinetics against both E. coli strains. The tested antibiotics presented high inhibitory concentrations (ranging from 16 to >1024 µg/mL) when tested alone against biofilms. Co-administration of ɸWL-3 with antibiotics improved the antibiotic efficacy against biofilm, especially after staggered exposure, reducing the minimum biofilm bactericidal concentration (MBBC) up to 512 times. The in vivo antimicrobial activity of ɸWL-3/fosfomycin combination against both E. coli strains was assessed in a Galleria mellonella invertebrate infection model. Treatment of infected larvae after lethal doses of E. coli resulted in enhanced survival rates when combinatorial therapy with ɸWL-3/fosfomycin was applied on E. coli ATCC 25922-infected larvae compared with monotherapy, but not for EC1-infected larvae, which we speculated could be due to higher release of endotoxins in a shorter period in EC1-infected larvae exposed to ɸWL-3. Our study provides new insights into the use of bacteriophages and antibiotics in the treatment of biofilm-associated infections caused by antibiotic-resistant bacteria.
Asunto(s)
Antibacterianos/uso terapéutico , Infecciones por Escherichia coli/tratamiento farmacológico , Escherichia coli/efectos de los fármacos , Mariposas Nocturnas/microbiología , Terapia de Fagos/métodos , Animales , Bacteriófagos/metabolismo , Biopelículas/efectos de los fármacos , Ceftriaxona/uso terapéutico , Ciprofloxacina/uso terapéutico , Terapia Combinada/métodos , Modelos Animales de Enfermedad , Farmacorresistencia Bacteriana Múltiple/genética , Escherichia coli/genética , Escherichia coli/virología , Fluoroquinolonas/farmacología , Fosfomicina/uso terapéutico , Gentamicinas/uso terapéutico , Meropenem/uso terapéutico , Pruebas de Sensibilidad Microbiana , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Infecciones Relacionadas con Prótesis/microbiologíaAsunto(s)
Microbioma Gastrointestinal/fisiología , Hepatopatías/microbiología , Hepatopatías/terapia , Terapia de Fagos , Animales , Bacteriófagos/fisiología , Etanol/metabolismo , Hígado Graso Alcohólico/genética , Hígado Graso Alcohólico/microbiología , Hígado Graso Alcohólico/patología , Hígado Graso Alcohólico/terapia , Trasplante de Microbiota Fecal/métodos , Predisposición Genética a la Enfermedad , Humanos , Klebsiella pneumoniae/metabolismo , Klebsiella pneumoniae/virología , Hepatopatías/genética , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/microbiología , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/terapia , Trastornos Nutricionales/complicaciones , Trastornos Nutricionales/genética , Trastornos Nutricionales/microbiología , Trastornos Nutricionales/prevención & control , Terapia de Fagos/métodos , Saccharomyces/metabolismoRESUMEN
The use of bacteriophages (phages) for antibacterial therapy is under increasing consideration to treat antimicrobial-resistant infections. Phages have evolved multiple mechanisms to target their bacterial hosts, such as high-affinity, environmentally hardy receptor-binding proteins. However, traditional phage therapy suffers from multiple challenges stemming from the use of an exponentially replicating, evolving entity whose biology is not fully characterized (e.g., potential gene transduction). To address this problem, we conjugate the phages to gold nanorods, creating a reagent that can be destroyed upon use (termed "phanorods"). Chimeric phages were engineered to attach specifically to several Gram-negative organisms, including the human pathogens Escherichia coli, Pseudomonas aeruginosa, and Vibrio cholerae, and the plant pathogen Xanthomonas campestris The bioconjugated phanorods could selectively target and kill specific bacterial cells using photothermal ablation. Following excitation by near-infrared light, gold nanorods release energy through nonradiative decay pathways, locally generating heat that efficiently kills targeted bacterial cells. Specificity was highlighted in the context of a P. aeruginosa biofilm, in which phanorod irradiation killed bacterial cells while causing minimal damage to epithelial cells. Local temperature and viscosity measurements revealed highly localized and selective ablation of the bacteria. Irradiation of the phanorods also destroyed the phages, preventing replication and reducing potential risks of traditional phage therapy while enabling control over dosing. The phanorod strategy integrates the highly evolved targeting strategies of phages with the photothermal properties of gold nanorods, creating a well-controlled platform for systematic killing of bacterial cells.
Asunto(s)
Antibacterianos/administración & dosificación , Bacteriófagos/fisiología , Oro/química , Hipertermia Inducida , Nanotubos/química , Terapia de Fagos/métodos , Infecciones por Pseudomonas/terapia , Animales , Perros , Farmacorresistencia Bacteriana Múltiple , Humanos , Rayos Infrarrojos , Células de Riñón Canino Madin Darby , Nanopartículas del Metal/química , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/fisiologíaRESUMEN
We report a case of a 58-year-old renal transplant patient who developed a recurrent urinary tract infection with an extended-spectrum ß-lactamase (ESBL)-positive Klebsiella pneumoniae strain in the first month posttransplant. Even though it tested susceptible to carbapenems and despite repeated meropenem treatment, his infection recurred. The infection eventually evolved into epididymitis that was successfully treated with meropenem and bacteriophages. This case demonstrates the difficulty of treating relapsing ESBL-positive Gram-negative infections in renal transplant patients.
Asunto(s)
Trasplante de Riñón/efectos adversos , Infecciones por Klebsiella/terapia , Klebsiella pneumoniae , Terapia de Fagos , Infecciones Urinarias/terapia , Antibacterianos/administración & dosificación , Enfermedad Crónica , Farmacorresistencia Bacteriana Múltiple , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/etiología , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimología , Masculino , Meropenem/administración & dosificación , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Países Bajos , Terapia de Fagos/métodos , Recurrencia , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/etiología , beta-Lactamasas/metabolismoRESUMEN
Bacteriophage therapy has recently attracted increased interest, particularly in difficult-to-treat infections. Although it is not a novel concept, standardized treatment guidelines are currently lacking. We present the first steps towards the establishment of a "multidisciplinary phage task force" (MPTF) and a standardized treatment pathway, based on our experience of four patients with severe musculoskeletal infections. After review of their medical history and current clinical status, a multidisciplinary team found four patients with musculoskeletal infections eligible for bacteriophage therapy within the scope of Article 37 of the Declaration of Helsinki. Treatment protocols were set up in collaboration with phage scientists and specialists. Based on the isolated pathogens, phage cocktails were selected and applied intraoperatively. A draining system allowed postoperative administration for a maximum of 10 days, 3 times per day. All patients received concomitant antibiotics and their clinical status was followed daily during phage therapy. No severe side-effects related to the phage application protocol were noted. After a single course of phage therapy with concomitant antibiotics, no recurrence of infection with the causative strains occurred, with follow-up periods ranging from 8 to 16 months. This study presents the successful outcome of bacteriophage therapy using a standardized treatment pathway for patients with severe musculoskeletal infection. A multidisciplinary team approach in the form of an MPTF is paramount in this process.
Asunto(s)
Bacteriófagos , Enfermedades Musculoesqueléticas/terapia , Grupo de Atención al Paciente/normas , Terapia de Fagos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacterias/clasificación , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Bacterias/virología , Bacteriólisis , Protocolos Clínicos/normas , Terapia Combinada , Farmacorresistencia Bacteriana Múltiple , Humanos , Pruebas de Sensibilidad Microbiana , Enfermedades Musculoesqueléticas/microbiología , Osteomielitis/microbiología , Osteomielitis/terapia , Periodo Perioperatorio , Terapia de Fagos/métodos , Terapia de Fagos/normas , Resultado del TratamientoRESUMEN
Endophthalmitis due to infection with Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Given that the frequency of this condition caused by vancomycin-resistant Enterococcus faecalis has been increasing, the development of novel therapeutics is urgently required. We have demonstrated the therapeutic potential of bacteriophage ΦEF24C-P2 in a mouse model of endophthalmitis caused by vancomycin-sensitive (EF24) or vancomycin-resistant (VRE2) strains of E. faecalis Phage ΦEF24C-P2 induced rapid and pronounced bacterial lysis in turbidity reduction assays with EF24, VRE2, and clinical isolates derived from patients with E. faecalis-related postoperative endophthalmitis. Endophthalmitis was induced in mice by injection of EF24 or VRE2 (1 × 104 cells) into the vitreous. The number of viable bacteria in the eye increased to >1 × 107 CFU, and neutrophil infiltration into the eye was detected as an increase in myeloperoxidase activity at 24 h after infection. A clinical score based on loss of visibility of the fundus as well as the number of viable bacteria and the level of myeloperoxidase activity in the eye were all significantly decreased by intravitreous injection of ΦEF24C-P2 6 h after injection of EF24 or VRE2. Whereas histopathologic analysis revealed massive infiltration of inflammatory cells and retinal detachment in vehicle-treated eyes, the number of these cells was greatly reduced and retinal structural integrity was preserved in phage-treated eyes. Our results thus suggest that intravitreous phage therapy is a potential treatment for endophthalmitis caused by vancomycin-sensitive or -resistant strains of E. faecalis.
Asunto(s)
Bacteriófagos/genética , Endoftalmitis/terapia , Endoftalmitis/virología , Enterococcus faecalis/virología , Infecciones Bacterianas del Ojo/terapia , Resistencia a la Vancomicina/genética , Vancomicina/farmacología , Animales , Antibacterianos/farmacología , Modelos Animales de Enfermedad , Endoftalmitis/microbiología , Femenino , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Infecciones por Bacterias Grampositivas/virología , Inyecciones , Ratones , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana/métodos , Terapia de Fagos/métodosRESUMEN
This special issue of Viruses asks experts in the field about "Hurdles to phage therapy (PT) to become a reality" [...].
Asunto(s)
Infecciones Bacterianas/terapia , Investigación Biomédica/tendencias , Terapia de Fagos/métodos , Terapia de Fagos/tendencias , Animales , Aprobación de Drogas , Evaluación Preclínica de Medicamentos/métodos , HumanosRESUMEN
As more antibiotics are rendered ineffective by drug-resistant bacteria, focus must be shifted towards alternative therapies for treating infections. Although several alternatives already exist in nature, the challenge is to implement them in clinical use. Advancements within biotechnology, genetic engineering, and synthetic chemistry have opened up new avenues towards the search for therapies that can substitute for antibiotics. This review provides an introduction to the various promising approaches that have been adopted in this regard. Whilst the use of bacteriophages and antibodies has been partly implemented, other promising strategies, such as probiotics, lysins, and antimicrobial peptides, are in various stages of development. Propitious concepts such as genetically modified phages, antibacterial oligonucleotides, and CRISPR-Cas9 are also discussed.
Asunto(s)
Antibacterianos/uso terapéutico , Infecciones Bacterianas/terapia , Terapia Biológica/métodos , Farmacorresistencia Bacteriana , Animales , Anticuerpos Monoclonales/uso terapéutico , Péptidos Catiónicos Antimicrobianos/uso terapéutico , Bacteriocinas/uso terapéutico , Bacteriófagos , Biotecnología , Sistemas CRISPR-Cas , Modelos Animales de Enfermedad , Farmacorresistencia Bacteriana/efectos de los fármacos , Trasplante de Microbiota Fecal , Ingeniería Genética , Humanos , Microbiota , Oligonucleótidos/uso terapéutico , Terapia de Fagos/métodos , Probióticos/uso terapéuticoRESUMEN
Carbapenem-resistant Acinetobacter baumannii (CRAB) is a perilous nosocomial pathogen causing substantial morbidity and mortality. Current treatment options for CRAB are limited and suffer from pharmacokinetic limitations, such as high toxicity and low plasma levels. As a result, CRAB is declared as the top priority pathogen by the World Health Organization for the investment in new drugs. This urgent need for new therapies, in combination with faster FDA approval process, accelerated new drug development and placed several drug candidates in the pipeline. This article reviews available information about the new drugs and other therapeutic options focusing on agents in clinical or late-stage preclinical studies for the treatment of CRAB, and it evaluates their expected benefits and potential shortcomings.
Asunto(s)
Infecciones por Acinetobacter/tratamiento farmacológico , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Anticuerpos Monoclonales/uso terapéutico , Farmacorresistencia Bacteriana Múltiple/fisiología , Terapia de Fagos/métodos , Carbapenémicos/uso terapéutico , Descubrimiento de Drogas , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
Cholera remains a major risk in developing countries, particularly after natural or man-made disasters. Vibrio cholerae El Tor is the most important cause of these outbreaks, and is becoming increasingly resistant to antibiotics, so alternative therapies are urgently needed. In this study, a single bacteriophage, Phi_1, was used to control cholera prophylactically and therapeutically in an infant rabbit model. In both cases, phage-treated animals showed no clinical signs of disease, compared with 69% of untreated control animals. Bacterial counts in the intestines of phage-treated animals were reduced by up to 4 log10 colony-forming units/g. There was evidence of phage multiplication only in animals that received a V. cholerae challenge. No phage-resistant bacterial mutants were isolated from the animals, despite extensive searching. This is the first evidence that a single phage could be effective in the treatment of cholera, without detectable levels of resistance. Clinical trials in human patients should be considered.
Asunto(s)
Cólera/prevención & control , Cólera/terapia , Terapia de Fagos/métodos , Animales , Carga Bacteriana , Bacteriófagos/crecimiento & desarrollo , Modelos Animales de Enfermedad , Intestinos/microbiología , Conejos , Resultado del Tratamiento , Vibrio cholerae/virologíaRESUMEN
Although aquaculture activity has experienced a great development over the past three decades, infectious diseases have become a limiting factor for further intensification. Because the use of antibiotics has led to the widespread emergence of antibiotic resistance, the search for alternative environmentally friendly approaches is urgently needed. This Opinion paper offers an update on the successes and challenges of biological approaches for bacterial disease prevention and control in aquaculture. Although most of these approaches are still in research and development stages, some of them have shown promising results in field trials. Therefore, a better understanding of the mechanisms of action of these approaches will help to maximise their beneficial properties.
Asunto(s)
Antibacterianos/efectos adversos , Profilaxis Antibiótica/efectos adversos , Profilaxis Antibiótica/veterinaria , Acuicultura/métodos , Infecciones Bacterianas/prevención & control , Farmacorresistencia Microbiana , Animales , Antibacterianos/administración & dosificación , Bacterias , Bacteriófagos , Control de Enfermedades Transmisibles/métodos , Enfermedades de los Peces/prevención & control , Terapia de Fagos/métodos , Extractos Vegetales/uso terapéutico , Prebióticos , Probióticos/uso terapéutico , Percepción de Quorum , Simbióticos , Vacunación/métodos , VacunasRESUMEN
Allergic disorders pose a growing challenge to medicine and our society. Therefore, novel approaches to prevention and therapy are needed. Recent progress in studies on bacterial viruses (phages) has provided new data indicating that they have significant immunomodulating activities. We show how those activities could be translated into beneficial effects in allergic disorders and present initial clinical data that support this hope. Impact statement Allergic disorders pose a growing challenge to medicine and our society, so new approaches to prevention and therapy are urgently needed. Our article summarizes progress that has been recently made and presents a shift in our understanding of the immunobiological significance of bacterial viruses (phages). Currently, phages may be considered not only as mere "bacteria eaters" but also as regulators of immunity. The new understanding of phages as important factors in maintenance of immune homeostasis opens completely new perspectives for their use in controlling aberrant immune responses. It is likely that this new knowledge could be translated into novel means of immunotherapy of allergic disorders.
Asunto(s)
Bacteriófagos/inmunología , Hipersensibilidad/terapia , Factores Inmunológicos/farmacología , Inmunoterapia/métodos , Terapia de Fagos/métodos , Animales , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos , HumanosRESUMEN
BACKGROUND: Urinary tract infections (UTI) are among the most prevalent microbial diseases and their financial burden on society is substantial. The continuing increase of antibiotic resistance worldwide is alarming. Thus, well-tolerated, highly effective therapeutic alternatives are urgently needed. Although there is evidence indicating that bacteriophage therapy may be effective and safe for treating UTIs, the number of investigated patients is low and there is a lack of randomized controlled trials. METHODS AND DESIGN: This study is the first randomized, placebo-controlled, double-blind trial investigating bacteriophages in UTI treatment. Patients planned for transurethral resection of the prostate are screened for UTIs and enrolled if in urine culture eligible microorganisms ≥104 colony forming units/mL are found. Patients are randomized in a double-blind fashion to the 3 study treatment arms in a 1:1:1 ratio to receive either: a) bacteriophage (i.e. commercially available Pyo bacteriophage) solution, b) placebo solution, or c) antibiotic treatment according to the antibiotic sensitivity pattern. All treatments are intended for 7 days. No antibiotic prophylaxes will be given to the double-blinded treatment arms a) and b). As common practice, the Pyo bacteriophage cocktail is subjected to periodic adaptation cycles during the study. Urinalysis, urine culture, bladder and pain diary, and IPSS questionnaire will be completed prior to and at the end of treatment (i.e. after 7 days) or at withdrawal/drop out from the study. Patients with persistent UTIs will undergo antibiotic treatment according to antibiotic sensitivity pattern. DISCUSSION: Based on the high lytic activity and the potential of resistance optimization by direct adaptation of bacteriophages, and considering the continuing increase of antibiotic resistance worldwide, bacteriophage therapy is a very promising treatment option for UTIs. Thus, our randomized controlled trial investigating bacteriophages for treating UTIs will provide essential insights into this potentially revolutionizing treatment option. TRIAL REGISTRATION: This study has been registered at clinicaltrials.gov ( www.clinicaltrials.gov/ct2/show/NCT03140085 ). April 27, 2017.
Asunto(s)
Bacteriófagos , Terapia de Fagos/métodos , Resección Transuretral de la Próstata/efectos adversos , Infecciones Urinarias/terapia , Bacteriófagos/crecimiento & desarrollo , Método Doble Ciego , Humanos , Masculino , Resultado del Tratamiento , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/etiologíaRESUMEN
The three main oral diseases of humans, that is, caries, periodontal diseases, and oral candidiasis, are associated with microbiome shifts initiated by changes in the oral environment and/or decreased effectiveness of mucosal immune surveillance. In this review, we discuss the role that microbial-based therapies may have in the control of these conditions. Most investigations on the use of microorganisms for management of oral disease have been conducted with probiotic strains with some positive but very discrete clinical outcomes. Other strategies such as whole oral microbiome transplantation or modification of community function by enrichment with health-promoting indigenous oral strains may offer more promise, but research in this field is still in its infancy. Any microbial-based therapeutics for oral conditions, however, are likely to be only one component within a holistic preventive strategy that should also aim at modification of the environmental influences responsible for the initiation and perpetuation of microbiome shifts associated with oral dysbiosis.