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1.
J Clin Microbiol ; 61(12): e0061423, 2023 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-37962552

RESUMEN

Standardized approaches to phage susceptibility testing (PST) are essential to inform selection of phages for study in patients with bacterial infections. There is no reference standard for assessing bacterial susceptibility to phage. We compared agreement between PST performed at three centers: two centers using a liquid assay standardized between the sites with the third, a plaque assay. Four Pseudomonas aeruginosa phages: PaWRA01ø11 (EPa11), PaWRA01ø39 (EPa39), PaWRA02ø83 (EPa83), PaWRA02ø87 (EPa87), and a cocktail of all four phages were tested against 145 P. aeruginosa isolates. Comparisons were made within measurements at the two sites performing the liquid assay and between these two sites. Agreement was assessed based on coverage probability (CP8), total deviation index, concordance correlation coefficient (CCC), measurement accuracy, and precision. For the liquid assay, there was satisfactory agreement among triplicate measurements made on different days at site 1, and high agreement based on accuracy and precision between duplicate measurements made on the same run at site 2. There was fair accuracy between measurements of the two sites performing the liquid assay, with CCCs below 0.6 for all phages tested. When compared to the plaque assay (performed once at site 3), there was less agreement between results of the liquid and plaque assays than between the two sites performing the liquid assay. Similar findings to the larger group were noted in the subset of 46 P. aeruginosa isolates from cystic fibrosis. Results of this study suggest that reproducibility of PST methods needs further development.


Asunto(s)
Bacteriófagos , Fibrosis Quística , Infecciones por Pseudomonas , Humanos , Pseudomonas aeruginosa , Reproducibilidad de los Resultados , Infecciones por Pseudomonas/tratamiento farmacológico , Fibrosis Quística/microbiología , Antibacterianos/uso terapéutico
2.
Am J Transplant ; 19(9): 2631-2639, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31207123

RESUMEN

Bacteriophage therapy (BT) uses bacteriophages to treat pathogenic bacteria and is an emerging strategy against multidrug-resistant (MDR) infections. Experience in solid organ transplant is limited. We describe BT in 3 lung transplant recipients (LTR) with life-threatening MDR infections caused by Pseudomonas aeruginosa (n = 2) and Burkholderia dolosa (n = 1). For each patient, lytic bacteriophages were selected against their bacterial isolates. BT was administered for variable durations under emergency Investigational New Drug applications and with patient informed consent. Safety was assessed using clinical/laboratory parameters and observed clinical improvements described, as appropriate. All patients received concurrent antibiotics. Two ventilator-dependent LTR with large airway complications and refractory MDR P. aeruginosa pneumonia received BT. Both responded clinically and were discharged from the hospital off ventilator support. A third patient had recurrent B. dolosa infection following transplant. Following BT initiation, consolidative opacities improved and ventilator weaning was begun. However, infection relapsed on BT and the patient died. No BT-related adverse events were identified in the 3 cases. BT was well tolerated and associated with clinical improvement in LTRs with MDR bacterial infection not responsive to antibiotics alone. BT may be a viable adjunct to antibiotics for patients with MDR infections.


Asunto(s)
Infecciones Bacterianas/prevención & control , Infecciones Bacterianas/terapia , Farmacorresistencia Bacteriana Múltiple , Enfermedades Pulmonares/cirugía , Trasplante de Pulmón , Terapia de Fagos/métodos , Adulto , Anciano , Antibacterianos/uso terapéutico , Burkholderia , Femenino , Humanos , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/microbiología , Trasplante de Pulmón/efectos adversos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Pseudomonas aeruginosa , Infecciones del Sistema Respiratorio/microbiología , Receptores de Trasplantes
3.
Front Microbiol ; 15: 1386245, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39171268

RESUMEN

Phage therapy is a promising antibacterial strategy, especially given that drug-resistant bacterial infections are escalating worldwide. Because phages are not active against all strains of a given species, phages being considered for therapeutic use would ideally be tested against bacterial isolates from individual patients prior to administration. Standardized, clinically validated phage susceptibility testing (PST) methods are needed for assessing in vitro phage activity. This study compared two high-throughput liquid-based PST assays. The first, using the Biolog Omnilog™, assessed changes in microbial respiration leading to color changes based on a tetrazolium dye. The second, Agilent BioTek Cytation 7, assessed changes in optical density. Both used 96-well microtiter plate formats. A total of 55 diverse phages with activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, or Enterococcus faecalis were studied against their respective susceptible bacterial hosts and non-susceptible controls, with susceptibility defined based on plaque assay. PST was performed by both assays in replicates, with results compared in terms of hold times (time through which bacterial growth is inhibited by phage compared to controls). Coefficients of variance and interclass correlation coefficients were used to assess inter- and intra-assay reproducibility. Based on a ≤50% coefficient of variance cutpoint, 87% of Biolog and 84% of Agilent assays were considered valid for susceptible bacteria, with 100% considered valid for non-susceptible bacteria by both systems. Using a 8 h hold time cutpoint, 100% of the results matched between the two assays. The interclass correlation coefficient showed 26% excellent agreement, 35% good agreement, and 17% moderate agreement between the two assays for susceptible isolates and 100% excellent agreement for non-susceptible isolates. Overall, the assays compared provided good/fair statistical reproducibility for the assessment of phage susceptibility.

4.
Med ; 4(9): 600-611.e4, 2023 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-37562400

RESUMEN

BACKGROUND: A growing number of compassionate phage therapy cases were reported in the last decade, with a limited number of clinical trials conducted and few unsuccessful clinical trials reported. There is only a little evidence on the role of phages in refractory infections. Our objective here was to present the largest compassionate-use single-organism/phage case series in 16 patients with non-resolving Pseudomonas aeruginosa infections. METHODS: We summarized clinical phage microbiology susceptibility data, administration protocol, clinical data, and outcomes of all cases treated with PASA16 phage. In all intravenous phage administrations, PASA16 phage was manufactured and provided pro bono by Adaptive Phage Therapeutics. PASA16 was administered intravenously, locally to infection site, or by topical use to 16 patients, with data available for 15 patients, mainly with osteoarticular and foreign-device-associated infections. FINDINGS: A few minor side effects were noted, including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 patients (86.6%). Two clinical failures were reported. The minimum therapy duration was 8 days with a once- to twice-daily regimen. CONCLUSIONS: PASA16 with antibiotics was found to be relatively successful in patients for whom traditional treatment approaches have failed previously. Such pre-phase-1 cohorts can outline potential clinical protocols and facilitate the design of future trials. FUNDING: The study was funded in part by The Israeli Science Foundation IPMP (ISF_1349/20), Rosetrees Trust (A2232), United States-Israel Binational Science Foundation (2017123), and the Milgrom Family Support Program.


Asunto(s)
Bacteriófagos , Infecciones por Pseudomonas , Fagos Pseudomonas , Humanos , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Ensayos de Uso Compasivo , Antibacterianos/uso terapéutico
5.
Viruses ; 14(7)2022 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-35891419

RESUMEN

A small subset of acidic hot springs sampled in Yellowstone National Park yielded rod-shaped viruses which lysed liquid host cultures and formed clear plaques on lawns of host cells. Three isolates chosen for detailed analysis were found to be genetically related to previously described isolates of the Sulfolobus islandicus rod-shaped virus (SIRV), but distinct from them and from each other. Functional stability of the new isolates was assessed in a series of inactivation experiments. UV-C radiation inactivated one of the isolates somewhat faster than bacteriophage λ, suggesting that encapsidation in the SIRV-like virion did not confer unusual protection of the DNA from UV damage. With respect to high temperature, the new isolates were extremely, but not equally, stable. Several chemical treatments were found to inactivate the virions and, in some cases, to reveal apparent differences in virion stability among the isolates. Screening a larger set of isolates identified greater variation of these stability properties but found few correlations among the resulting profiles. The majority of host cells infected by the new isolates were killed, but survivors exhibited heritable resistance, which could not be attributed to CRISPR spacer acquisition or the loss of the pilus-related genes identified by earlier studies. Virus-resistant host variants arose at high frequency and most were resistant to multiple viral strains; conversely, resistant host clones generated virus-sensitive variants, also at high frequency. Virus-resistant cells lacked the ability of virus-sensitive cells to bind virions in liquid suspensions. Rapid interconversion of sensitive and resistant forms of a host strain suggests the operation of a yet-unidentified mechanism that acts to allow both the lytic virus and its host to propagate in highly localized natural populations, whereas variation of virion-stability phenotypes among the new viral isolates suggests that multiple molecular features contribute to the biological durability of these viruses.


Asunto(s)
Virus de Archaea , Manantiales de Aguas Termales , Sulfolobus , Virus , Virus de Archaea/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , América del Norte , Virus/genética
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