scholarly journals Quantitative Models of Phage-Antibiotics Combination Therapy

2019 ◽  
Author(s):  
Rogelio A. Rodriguez-Gonzalez ◽  
Chung-Yin Leung ◽  
Benjamin K. Chan ◽  
Paul E. Turner ◽  
Joshua S. Weitz
Keyword(s):  
Combination Therapy ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
System Level ◽  
Global Public Health ◽  
Bacteriophage Therapy ◽  
Therapeutic Success ◽  
Health Crisis ◽  
Bacterial Mutants

AbstractThe spread of multi-drug resistant (MDR) bacteria is a global public health crisis. Bacteriophage therapy (or “phage therapy”) constitutes a potential alternative approach to treat MDR infections. However, the effective use of phage therapy may be limited when phage-resistant bacterial mutants evolve and proliferate during treatment. Here, we develop a nonlinear population dynamics model of combination therapy that accounts for the system-level interactions between bacteria, phage and antibiotics for in-vivo application given an immune response against bacteria. We simulate the combination therapy model for two strains of Pseudomonas aeruginosa, one which is phage-sensitive (and antibiotic resistant) and one which is antibiotic-sensitive (and phage-resistant). We find that combination therapy outperforms either phage or antibiotic alone, and that therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at sub-inhibitory concentrations of antibiotics, e.g., ciprofloxacin. These in-silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of innate immunity in shaping therapeutic outcomes.

scholarly journals Quantitative Models of Phage-Antibiotic Combination Therapy

mSystems ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Rogelio A. Rodriguez-Gonzalez ◽  
Chung Yin Leung ◽  
Benjamin K. Chan ◽  
Paul E. Turner ◽  
Joshua S. Weitz
Keyword(s):  
Combination Therapy ◽  
Immune Responses ◽  
Bacterial Infections ◽  
System Level ◽  
Innate Immune Responses ◽  
Therapeutic Success ◽  
Content Type ◽  
Therapeutic Outcomes

ABSTRACT The spread of multidrug-resistant (MDR) bacteria is a global public health crisis. Bacteriophage therapy (or “phage therapy”) constitutes a potential alternative approach to treat MDR infections. However, the effective use of phage therapy may be limited when phage-resistant bacterial mutants evolve and proliferate during treatment. Here, we develop a nonlinear population dynamics model of combination therapy that accounts for the system-level interactions between bacteria, phage, and antibiotics for in vivo application given an immune response against bacteria. We simulate the combination therapy model for two strains of Pseudomonas aeruginosa, one which is phage sensitive (and antibiotic resistant) and one which is antibiotic sensitive (and phage resistant). We find that combination therapy outperforms either phage or antibiotic alone and that therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at subinhibitory concentrations of antibiotics, e.g., ciprofloxacin. These in silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of innate immunity in shaping therapeutic outcomes. IMPORTANCE This work develops and analyzes a novel model of phage-antibiotic combination therapy, specifically adapted to an in vivo context. The objective is to explore the underlying basis for clinical application of combination therapy utilizing bacteriophage that target antibiotic efflux pumps in Pseudomonas aeruginosa. In doing so, the paper addresses three key questions. How robust is combination therapy to variation in the resistance profiles of pathogens? What is the role of immune responses in shaping therapeutic outcomes? What levels of phage and antibiotics are necessary for curative success? As we show, combination therapy outperforms either phage or antibiotic alone, and therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at subinhibitory concentrations of antibiotic. These in silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of system-level feedbacks in shaping therapeutic outcomes.

scholarly journals Promises and pitfalls of in vivo evolution to improve phage therapy

2019 ◽  
Author(s):  
James J Bull ◽  
Bruce R. Levin ◽  
Ian J. Molineux
Keyword(s):  
Bacterial Infections ◽  
Computational Models ◽  
Phage Therapy ◽  
Informed Choice ◽  
Resistant Bacteria ◽  
Prior History ◽  
Therapeutic Success ◽  
History Of ◽  
History Of Use

Abstract(Background) Phage therapy is the use of bacterial viruses (phages) to treat bacterial infections. Phages lack the broad host ranges of antibiotics, so individual phages are often used with no prior history of use in treatment. Therapeutic phages are thus often chosen based on limited criteria, sometimes merely an ability to plate on the pathogenic bacterium. It is possible that better treatment outcomes might be obtained from an informed choice of phages. Here we consider whether phages used to treat the bacterial infection in a patient might specifically evolve to improve treatment. Phages recovered from the patient could then serve as a source of improved phages or cocktails for use on subsequent patients. (Methods) With the aid of mathematical and computational models, we explore this possibility for four phage properties expected to promote therapeutic success: in vivo growth, phage decay rate, overcoming resistant bacteria, and enzyme activity to degrade protective bacterial layers. (Results) Phage evolution only sometimes works in favor of treatment, and even in those cases, intrinsic phage dynamics in the patient are usually not ideal. An informed use of phages is invariably superior to reliance on within-host evolution and dynamics, although the extent of this benefit varies with the application.

scholarly journals Promises and Pitfalls of In Vivo Evolution to Improve Phage Therapy

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1083 ◽  
Author(s):  
James J. Bull ◽  
Bruce R. Levin ◽  
Ian J. Molineux
Keyword(s):  
Decay Rate ◽  
Bacterial Infections ◽  
Computational Models ◽  
Phage Therapy ◽  
Treatment Success ◽  
Medical Intervention ◽  
Resistant Bacteria ◽  
Therapeutic Success ◽  
Phage Growth

Phage therapy is the use of bacterial viruses (phages) to treat bacterial infections, a medical intervention long abandoned in the West but now experiencing a revival. Currently, therapeutic phages are often chosen based on limited criteria, sometimes merely an ability to plate on the pathogenic bacterium. Better treatment might result from an informed choice of phages. Here we consider whether phages used to treat the bacterial infection in a patient may specifically evolve to improve treatment on that patient or benefit subsequent patients. With mathematical and computational models, we explore in vivo evolution for four phage properties expected to influence therapeutic success: generalized phage growth, phage decay rate, excreted enzymes to degrade protective bacterial layers, and growth on resistant bacteria. Within-host phage evolution is strongly aligned with treatment success for phage decay rate but only partially aligned for phage growth rate and growth on resistant bacteria. Excreted enzymes are mostly not selected for treatment success. Even when evolution and treatment success are aligned, evolution may not be rapid enough to keep pace with bacterial evolution for maximum benefit. An informed use of phages is invariably superior to naive reliance on within-host evolution.

scholarly journals Assessment of the microbiome during bacteriophage therapy in combination with systemic antibiotics to treat a case of staphylococcal device infection

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Andre Mu ◽  
Daniel McDonald ◽  
Alan K. Jarmusch ◽  
Cameron Martino ◽  
Caitriona Brennan ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Phage Therapy ◽  
Ecological Impacts ◽  
Skin Microbiome ◽  
Bacteriophage Therapy ◽  
Bacterial Diseases ◽  
Device Infection ◽  
Global Health Issue ◽  
Serious Bacterial Infections ◽  
Systemic Antibiotics

Abstract Background Infectious bacterial diseases exhibiting increasing resistance to antibiotics are a serious global health issue. Bacteriophage therapy is an anti-microbial alternative to treat patients with serious bacterial infections. However, the impacts to the host microbiome in response to clinical use of phage therapy are not well understood. Results Our paper demonstrates a largely unchanged microbiota profile during 4 weeks of phage therapy when added to systemic antibiotics in a single patient with Staphylococcus aureus device infection. Metabolomic analyses suggest potential indirect cascading ecological impacts to the host (skin) microbiome. We did not detect genomes of the three phages used to treat the patient in metagenomic samples taken from saliva, stool, and skin; however, phages were detected using endpoint-PCR in patient serum. Conclusion Results from our proof-of-principal study supports the use of bacteriophages as a microbiome-sparing approach to treat bacterial infections.

scholarly journals A Review of the Combination Therapy of Low Frequency Ultrasound with Antibiotics

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Yun Cai ◽  
Jin Wang ◽  
Xu Liu ◽  
Rui Wang ◽  
Lei Xia
Keyword(s):  
Combination Therapy ◽  
Bacterial Infections ◽  
Bacterial Resistance ◽  
Low Frequency ◽  
Bactericidal Effect ◽  
Low Frequency Ultrasound ◽  
Biofilm Bacteria ◽  
Frequency Ultrasound

Single antimicrobial therapy has been unable to resist the global spread of bacterial resistance. Literatures of availablein vitroandin vivostudies were reviewed and the results showed that low frequency ultrasound (LFU) has a promising synergistic bactericidal effect with antibiotics against both planktonic and biofilm bacteria. It also can facilitate the release of antibiotics from medical implants. As a noninvasive and targeted therapy, LFU has great potential in treating bacterial infections. However, more in-depth and detailed studies are still needed before LFU is officially applied as a combination therapy in the field of anti-infective treatment.

scholarly journals Bacteriophage Therapy To Reduce Campylobacter jejuni Colonization of Broiler Chickens

2005 ◽  
Vol 71 (11) ◽  
pp. 6554-6563 ◽  
Author(s):  
C. Loc Carrillo ◽  
R. J. Atterbury ◽  
A. El-Shibiny ◽  
P. L. Connerton ◽  
E. Dillon ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Broiler Chickens ◽  
Phage Therapy ◽  
Experimental Models ◽  
Human Infection ◽  
Lytic Bacteriophage ◽  
Bacteriophage Therapy ◽  
Bacteriophage Infection ◽  
Low Passage

ABSTRACT Colonization of broiler chickens by the enteric pathogen Campylobacter jejuni is widespread and difficult to prevent. Bacteriophage therapy is one possible means by which this colonization could be controlled, thus limiting the entry of campylobacters into the human food chain. Prior to evaluating the efficacy of phage therapy, experimental models of Campylobacter colonization of broiler chickens were established by using low-passage C. jejuni isolates HPC5 and GIIC8 from United Kingdom broiler flocks. The screening of 53 lytic bacteriophage isolates against a panel of 50 Campylobacter isolates from broiler chickens and 80 strains isolated after human infection identified two phage candidates with broad host lysis. These phages, CP8 and CP34, were orally administered in antacid suspension, at different dosages, to 25-day-old broiler chickens experimentally colonized with the C. jejuni broiler isolates. Phage treatment of C. jejuni-colonized birds resulted in Campylobacter counts falling between 0.5 and 5 log10 CFU/g of cecal contents compared to untreated controls over a 5-day period postadministration. These reductions were dependent on the phage-Campylobacter combination, the dose of phage applied, and the time elapsed after administration. Campylobacters resistant to bacteriophage infection were recovered from phage-treated chickens at a frequency of <4%. These resistant types were compromised in their ability to colonize experimental chickens and rapidly reverted to a phage-sensitive phenotype in vivo. The selection of appropriate phage and their dose optimization are key elements for the success of phage therapy to reduce campylobacters in broiler chickens.

scholarly journals Bacteriophage therapy: experience from the Eliava Institute, Georgia

2008 ◽  
Vol 29 (2) ◽  
pp. 96 ◽  
Author(s):  
Nina Chanishvili ◽  
Richard Sharp
Keyword(s):  
Soviet Union ◽  
Former Soviet Union ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Effective Means ◽  
Resistant Bacteria ◽  
Bacteriophage Therapy ◽  
Antibiotic Resistant ◽  
Bacterial Diseases ◽  
Wide Range

The lysis of bacteria by bacteriophage was independently discovered by Frederick Twort and Felix d?Herelle but it was d?Herelle who proposed that bacteriophage might be applied to the control of bacterial diseases. Within the former Soviet Union (FSU), bacteriophage therapy was researched and applied extensively for the treatment of a wide range of bacterial infections. In the West, however, it was not explored with the same enthusiasm and was eventually discarded with the arrival of antibiotics. However, the increase in the incidence of multi-antibiotic-resistant bacteria and the absence of effective means for their control has led to increasing international interest in phage therapy and in the long experience of the Eliava Institute. The Eliava Institute of Bacteriophage, Microbiology and Virology (IBMV), which celebrates its 85th anniversary in 2008, was founded in Tbilisi in 1923 through the joint efforts of d?Herelle and the Georgian microbiologist, George Eliava.

scholarly journals Plant essential oils against bacteria isolated from fish: an in vitro screening and in vivo efficacy of Lippia origanoides

2019 ◽  
Vol 49 (6) ◽  
Author(s):  
Guerino Bandeira Junior ◽  
Carine de Freitas Souza ◽  
Matheus Dellaméa Baldissera ◽  
Sharine Nunes Descovi ◽  
Bibiana Petri da Silveira ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Essential Oils ◽  
Bacterial Infections ◽  
Cupressus Sempervirens ◽  
Therapeutic Success ◽  
Plant Essential Oils ◽  
In Vitro Antibacterial Activity ◽  
Fish Bacteria

ABSTRACT: The use of natural products, such as essential oils (EOs), is a potential novel approach to treat fish bacterial infections with a lower risk of developing resistance. There has been a number of studies reporting the activity of EOs as those obtained from the species Achyrocline satureioides, Aniba parviflora, Aniba rosaeodora, Anthemis nobilis, Conobea scoparioides, Cupressus sempervirens, Illicium verum, Lippia origanoides, and Melaleuca alternifolia against bacteria. However, there are few studies investigating the effect of these EOs against fish bacteria. Therefore, the aim of this study was to evaluate the in vitro antibacterial activity of EOs against the following fish bacteria, Aeromonas hydrophila, Citrobacter freundii, and Raoultella ornithinolytica. Additionally, the in vivo antibacterial activity of the EO L. origanoides was evaluated against experimentally induced A. hydrophila infection of silver catfish (Rhamdia quelen). The EO of L. origanoides was chosen as it showed the highest in vitro antibacterial activity, with minimum inhibitory concentrations ranging from 0.2 to 0.8 mg mL-1. This EO also presented a therapeutic success of 58.33%, on a 30 day A. hydrophila infection. Therefore, we suggested that the EO of L. origanoides may be a viable alternative as a treatment for A. hydrophila infection.

scholarly journals Comparison of Delivery Methods in Phage Therapy against Flavobacterium columnare Infections in Rainbow Trout

Antibiotics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 914
Author(s):  
Heidi M. T. Kunttu ◽  
Anniina Runtuvuori-Salmela ◽  
Mathias Middelboe ◽  
Jason Clark ◽  
Lotta-Riina Sundberg
Keyword(s):  
Rainbow Trout ◽  
Oral Delivery ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Culture Media ◽  
Total Mortality ◽  
Flavobacterium Columnare ◽  
Delivery Methods ◽  
Flow Through

Viruses of bacteria, bacteriophages, specifically infect their bacterial hosts with minimal effects on the surrounding microbiota. They have the potential to be used in the prevention and treatment of bacterial infections, including in the field of food production. In aquaculture settings, disease-causing bacteria are often transmitted through the water body, providing several applications for phage-based targeting of pathogens, in the rearing environment, and in the fish. We tested delivery of phages by different methods (via baths, in phage-coated material, and via oral delivery in feed) to prevent and treat Flavobacterium columnare infections in rainbow trout fry using three phages (FCOV-S1, FCOV-F2, and FCL-2) and their hosts (FCO-S1, FCO-F2, and B185, respectively). Bath treatments given before bacterial infection and at the onset of the disease symptoms were the most efficient way to prevent F. columnare infections in rainbow trout, possibly due to the external nature of the disease. In a flow-through system, the presence of phage-coated plastic sheets delayed the onset of the disease. The oral administration of phages first increased disease progression, although total mortality was lower at the end of the experiment. When analysed for shelf-life, phage titers remained highest when maintained in bacterial culture media and in sterile lake water. Our results show that successful phage therapy treatment in the aquaculture setting requires optimisation of phage delivery methods in vivo.

scholarly journals Novel Lytic Phages Protect Cells and Mice against Pseudomonas aeruginosa Infection

2021 ◽  
Author(s):  
Feng Chen ◽  
Xingjun Cheng ◽  
Jianbo Li ◽  
Xiefang Yuan ◽  
Xiuhua Huang ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Mouse Models ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Inflammatory Responses ◽  
Multi Drug Resistance ◽  
Bacterial Strains ◽  
Genetic Traits

With the fast emergence of serious antibiotic resistance and the lagged discovery of novel antibacterial drugs, phage therapy for pathogenic bacterial infections has acquired great attention in the clinics. However, development of therapeutic phages also faces tough challenges, such as laborious screening and time to generate effective phage drugs since each phage may only lyse a narrow scope of bacterial strains. Identifying highly effective phages with broad host ranges is crucial for improving phage therapy. Here, we isolated and characterized several lytic phages from various environments specific for Pseudomonas aeruginosa by testing their growth, invasion, host ranges, and potential for killing targeted bacteria. Importantly, we identified several therapeutic phages (HX1, PPY9, and TH15) with broad host ranges to lyse laboratory strains and clinical isolates of P. aeruginosa with multi-drug resistance (MDR) both in vitro and in mouse models. In addition, we analyzed critical genetic traits related to the high-level broad host coverages by genome sequencing and subsequent computational analysis against known phages. Collectively, our findings establish that these novel phages may have potential for further development as therapeutic options for patients who fail to respond to conventional treatments. IMPORTANCE Novel lytic phages isolated from various environmental settings were systematically characterized for their critical genetic traits, morphology structures, host ranges against laboratory strains and clinical multi-drug resistant (MDR) Pseudomonas aeruginosa, and antibacterial capacity both in vitro and in mouse models. First, we characterized the genetic traits and compared with other existing phages. Furthermore, we utilized acute pneumonia induced by laboratorial strain PAO1, and W19, an MDR clinical isolate and chronic pneumonia by agar beads laden with FDR1, a mucoid phenotype strain isolated from the sputum of a cystic fibrosis (CF) patient. Consequently, we found that these phages not only suppress bacteria in vitro but also significantly reduce the infection symptom and disease progression in vivo, including lowered bug burdens, inflammatory responses and lung injury in mice, suggesting that they may be further developed as therapeutic agents against MDR P. aeruginosa.

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