Phage-antibiotic combination is a superior treatment against Acinetobacter baumannii in a preclinical study.

BACKGROUND: Clinical phage therapy is often delivered alongside antibiotics. However, the phenomenon of phage-antibiotic synergy has been mostly studied in vitro. Here, we assessed the in vivo bactericidal effect of a phage-antibiotic combination on Acinetobacter baumannii AB900 using phage øFG02, which binds to capsular polysaccharides and leads to antimicrobial resensitisation in vitro. METHODS: We performed a two-stage preclinical study using a murine model of severe A. baumannii AB900 bacteraemia. In the first stage, with an endpoint of 11 h, mice (n = 4 per group) were treated with either PBS, ceftazidime, phage øFG02, or the combination of phage and ceftazidime. The second stage involved only the latter two groups (n = 5 per group), with a prolonged endpoint of 16 h. The primary outcome was the average bacterial burden from four body sites (blood, liver, kidney, and spleen). Bacterial colonies from phage-treated mice were retrieved and screened for phage-resistance. FINDINGS: In the first stage, the bacterial burden (CFU/g of tissue) of the combination group (median: 4.55 × 105; interquartile range [IQR]: 2.79 × 105-2.81 × 106) was significantly lower than the PBS (median: 2.42 × 109; IQR: 1.97 × 109-3.48 × 109) and ceftazidime groups (median: 3.86 × 108; IQR: 2.15 × 108-6.35 × 108), but not the phage-only group (median: 1.28 × 107; IQR: 4.71 × 106-7.13 × 107). In the second stage, the combination treatment (median: 1.72 × 106; IQR: 5.11 × 105-4.00 × 106) outperformed the phage-only treatment (median: 7.46 × 107; IQR: 1.43 × 107-1.57 × 108). Phage-resistance emerged in 96% of animals receiving phages, and all the tested isolates (n = 11) had loss-of-function mutations in genes involved in capsule biosynthesis and increased sensitivity to ceftazidime. INTERPRETATION: øFG02 reliably drives the in vivo evolution of A. baumannii AB900 towards a capsule-deficient, phage-resistant phenotype that is resensitised to ceftazidime. This mechanism highlights the clinical potential of using phage therapy to target A. baumannii and restore antibiotic activity. FUNDING: National Health and Medical Research Council (Australia).

Colistin-phage combinations decrease antibiotic resistance in Acinetobacter baumannii via changes in envelope architecture.

Multidrug-resistant bacterial infections are becoming increasingly common, with only few last-resort antibiotics such as colistin available for clinical therapy. An alternative therapeutic strategy gaining momentum is phage therapy, which has the advantage of not being affected by bacterial resistance to antibiotics. However, a major challenge in phage therapy is the rapid emergence of phage-resistant bacteria. In this work, our main aim was to understand the mechanisms of phage-resistance used by the top priority pathogen Acinetobacter baumannii. We isolated the novel phage Phab24, capable of infecting colistin-sensitive and -resistant strains of A. baumannii. After co-incubating Phab24 with its hosts, we obtained phage-resistant mutants which were characterized on both genotypic and phenotypic levels. Using whole genome sequencing, we identified phage-resistant strains that displayed mutations in genes that alter the architecture of the bacterial envelope at two levels: the capsule and the outer membrane. Using an adsorption assay, we confirmed that phage Phab24 uses the bacterial capsule as its primary receptor, with the outer membrane possibly serving as the secondary receptor. Interestingly, the phage-resistant isolates were less virulent compared to the parental strains in a Galleria mellonella infection model. Most importantly, we observed that phage-resistant bacteria that evolved in the absence of antibiotics exhibited an increased sensitivity to colistin, even though the antibiotic resistance mechanism per se remained unaltered. This increase in antibiotic sensitivity is a direct consequence of the phage-resistance mechanism, and could potentially be exploited in the clinical setting.

Bacteriophage-resistant Acinetobacter baumannii are resensitized to antimicrobials.

We characterized two bacteriophages, ΦFG02 and ΦCO01, against clinical isolates of Acinetobacter baumannii and established that the bacterial capsule is the receptor for these phages. Phage-resistant mutants harboured loss-of-function mutations in genes responsible for capsule biosynthesis, resulting in capsule loss and disruption of phage adsorption. The phage-resistant strains were resensitized to human complement, beta-lactam antibiotics and alternative phages and exhibited diminished fitness in vivo. Using a mouse model of A. baumannii infection, we showed that phage therapy was effective.

Unlocking the next generation of phage therapy: the key is in the receptors.

Phage therapy, the clinical use of viruses that kill bacteria, is a promising strategy in the fight against antimicrobial resistance. Before administration, phages undergo a careful examination of their safety and interactions with target bacteria. This characterization seldom includes identifying the receptor on the bacterial surface involved in phage adsorption. In this perspective article, we propose that understanding the function and location of these phage receptors can open the door to improved and innovative ways to use phage therapy. With knowledge of phage receptors, we can design intelligent phage cocktails, discover new phage-derived antimicrobials, and steer the evolution of phage-resistance towards clinically exploitable phenotypes. In an effort to jump-start this initiative, we recommend priority groups of hosts and phages. Finally, we review modern approaches for the identification of phage receptors, including molecular platforms for high-throughput mutagenesis, synthetic biology, and machine learning.

Which Factors may reduce the Health-Related Quality of Life of Ecuadorian Patients with Diabetes?

OBJECTIVE: To quantify the health-related quality of life (HRQoL) of patients with type 2 diabetes mellitus (DM) in Ecuador and to determine its association, or lack thereof, with demographic and clinical variables, particularly with the comorbidities and complications of DM. METHODS: This was an analytical cross-sectional study with 325 patients attending regular care at a primary health care center in Quito, Ecuador. HRQoL was measured using the EuroQol 5-dimension 3-level (EQ-5D-3L) questionnaire. The patients were screened for diabetic nephropathy, retinopathy, and peripheral artery disease (PAD). Clinical files were reviewed to obtain data regarding gender, age, time since diagnosis, type of treatment, glycemic control, and history (if any) of hypertension and/or dyslipidemia. Associations were verified using the Mann-Whitney U or Kruskal-Wallis test, and the confounding effects of the variables "age" and "gender" were controlled for using logistic regression analysis. RESULTS: The mean HRQoL for the population was 0.844 (±0.215) on the EQ-5D-3L index (EQ-Index) and 80.6 (±18.8) on the EQ visual analogue scale (EQ-VAS). The prevalence of DM complications was 1.8% for nephropathy, 14.8% for retinopathy, and 14.5% for PAD. Of the participating patients, 66.8% presented hypertension and 91.4%, dyslipidemia. Significant associations were found between lower scores on the EQ-Index and age (≥65 years) (0.84 vs. 0.87; p = 0.016), time since diagnosis (≥10 years) (0.81 vs. 0.87; p = 0.005), presence of hypertension (0.83 vs. 0.88; p = 0.017), and, after controlling for age and gender, presence of nephropathy. For the EQ-VAS, only time since diagnosis (≥10 years) was associated with a lower score (77.99 vs. 82.97; p = 0.043). CONCLUSION: Older age, longer disease duration, hypertension, and nephropathy are associated with having a lower HRQoL, in patients with type 2 DM in Quito, Ecuador.

Phage Therapy in the Postantibiotic Era.

Antibiotic resistance is arguably the biggest current threat to global health. An increasing number of infections are becoming harder or almost impossible to treat, carrying high morbidity, mortality, and financial cost. The therapeutic use of bacteriophages, viruses that infect and kill bacteria, is well suited to be part of the multidimensional strategies to combat antibiotic resistance. Although phage therapy was first implemented almost a century ago, it was brought to a standstill after the successful introduction of antibiotics. Now, with the rise of antibiotic resistance, phage therapy is experiencing a well-deserved rebirth. Among the admittedly vast literature recently published on this topic, this review aims to provide a forward-looking perspective on phage therapy and its role in modern society. We cover the key points of the antibiotic resistance crisis and then explain the biological and evolutionary principles that support the use of phages, their interaction with the immune system, and a comparison with antibiotic therapy. By going through up-to-date reports and, whenever possible, human clinical trials, we examine the versatility of phage therapy. We discuss conventional approaches as well as novel strategies, including the use of phage-antibiotic combinations, phage-derived enzymes, exploitation of phage resistance mechanisms, and phage bioengineering. Finally, we discuss the benefits of phage therapy beyond the clinical perspective, including opportunities for scientific outreach and effective education, interdisciplinary collaboration, cultural and economic growth, and even innovative use of social media, making the case that phage therapy is more than just an alternative to antibiotics.

Mental health determines the quality of life in patients with cancer-related neuropathic pain in Quito, Ecuador, / La salud mental determina la calidad de vida de los pacientes con dolor neuropático oncológico en Quito, Ecuador

Abstract Objective: To identify the main factors determining the health related quality of life (HRQL) in patients with cancer-related neuropathic pain in a tertiary care hospital. Methods: A cross-sectional analytical study was performed on a sample of 237 patients meeting criteria for cancer-related neuropathic pain. Clinical and demographic variables were recorded including, cancer type, stage, time since diagnosis, pain intensity, physical functionality with the palliative performance scale (PPS), and anxiety and depression with the hospital anxiety and depression scale (HADS). Their respective correlation coefficients (r) with HRQL assessed with the SF-36v2 Questionnaire were then calculated. Linear regression equations were then constructed with the variables that showed an r > 0.5 with the HRQL. Results: The HRQL scores of the sample were 39.3 ± 9.1 (Physical Component) and 45.5 ± 13.8 (Mental Component). Anxiety and depression strongly correlated with the mental component (r = -0.641 and r = -0.741, respectively) while PPS score correlated with the physical component (r = 0.617). The linear regression model that better explained the variance of the mental component was designed combining the Anxiety and Depression variables (r = 77.3%; p < 0.001). Conclusions: The strong influence of psychiatric comorbidity on the HRQL of patients with cancer-related neuropathic pain makes an integral management plan essential for these patients to include interventions for its timely diagnosis and treatment.

Resumen Objetivo: Identificar los principales determinantes de la calidad de vida relacionada con la salud (CVRS) de pacientes con dolor neuropático oncológico en un hospital de tercer nivel de atención. Métodos: Estudio transversal analítico. En una muestra de 237 pacientes con criterios de dolor neuropático de origen oncológico, se midieron variables clínico-demográficas: tipo de cáncer, estadio, tiempo de diagnóstico, intensidad del dolor, funcionalidad física con la escala PPS, y ansiedad y depresión con la escala HADS. Se calcularon sus respectivos coeficientes de correlación (r) con la CVRS medida con el cuestionario SF-36v2TM. Con las variables que mostraron r > 0,5 con la CVRS, se construyeron ecuaciones de regresión lineal. Resultados: La población mostró puntuaciones de CVRS de 39,3 ±9,1 (componente físico) y 45,5 ±13,8 (componente mental). Ansiedad y depresión tuvieron correlación fuerte con el componente mental (r = -0,641 y r = -0,741 respectivamente), mientras que la PPS la tuvo con el componente físico (r = 0,617). El modelo de regresión lineal que mejor explicó la varianza del componente mental fue diseñado con las variables ansiedad y depresión combinadas (R= 77,3%; p< 0,001). Conclusiones: La fuerte influencia de la comorbilidad psiquiátrica en la CVRS de los pacientes con dolor neuropático oncológico hace necesario que el plan de atención integral de estos pacientes incluya intervenciones para su oportuno diagnóstico y tratamiento.

[Mental Health Determines the Quality of Life in Patients With Cancer-Related Neuropathic Pain in Quito, Ecuador]. / La salud mental determina la calidad de vida de los pacientes con dolor neuropático oncológico en Quito, Ecuador.

OBJECTIVE: To identify the main factors determining the health related quality of life (HRQL) in patients with cancer-related neuropathic pain in a tertiary care hospital. METHODS: A cross-sectional analytical study was performed on a sample of 237 patients meeting criteria for cancer-related neuropathic pain. Clinical and demographic variables were recorded including, cancer type, stage, time since diagnosis, pain intensity, physical functionality with the Palliative Performance Scale (PPS), and anxiety and depression with the Hospital Anxiety and Depression Scale (HADS). Their respective correlation coefficients (r) with HRQL assessed with the SF-36v2 Questionnaire were then calculated. Linear regression equations were then constructed with the variables that showed an r≥.5 with the HRQL. RESULTS: The HRQL scores of the sample were 39.3±9.1 (Physical Component) and 45.5±13.8 (Mental Component). Anxiety and depression strongly correlated with the mental component (r=-.641 and r=-.741, respectively) while PPS score correlated with the physical component (r=.617). The linear regression model that better explained the variance of the mental component was designed combining the Anxiety and Depression variables (R=77.3%; P<.001). CONCLUSIONS: The strong influence of psychiatric comorbidity on the HRQL of patients with cancer-related neuropathic pain makes an integral management plan essential for these patients to include interventions for its timely diagnosis and treatment.