Anna Kirpichnikova

Bio: Anna Kirpichnikova is an academic researcher from University of Stirling. The author has contributed to research in topics: Boundary (topology) & Diffraction. The author has an hindex of 5, co-authored 26 publications receiving 260 citations. Previous affiliations of Anna Kirpichnikova include Russian Academy of Sciences & Steklov Mathematical Institute.

Formulation, stabilisation and encapsulation of bacteriophage for phage therapy

Abstract: Against a backdrop of global antibiotic resistance and increasing awareness of the importance of the human microbiota, there has been resurgent interest in the potential use of bacteriophages for therapeutic purposes, known as phage therapy. A number of phage therapy phase I and II clinical trials have concluded, and shown phages don't present significant adverse safety concerns. These clinical trials used simple phage suspensions without any formulation and phage stability was of secondary concern. Phages have a limited stability in solution, and undergo a significant drop in phage titre during processing and storage which is unacceptable if phages are to become regulated pharmaceuticals, where stable dosage and well defined pharmacokinetics and pharmacodynamics are de rigueur. Animal studies have shown that the efficacy of phage therapy outcomes depend on the phage concentration (i.e. the dose) delivered at the site of infection, and their ability to target and kill bacteria, arresting bacterial growth and clearing the infection. In addition, in vitro and animal studies have shown the importance of using phage cocktails rather than single phage preparations to achieve better therapy outcomes. The in vivo reduction of phage concentration due to interactions with host antibodies or other clearance mechanisms may necessitate repeated dosing of phages, or sustained release approaches. Modelling of phage-bacterium population dynamics reinforces these points. Surprisingly little attention has been devoted to the effect of formulation on phage therapy outcomes, given the need for phage cocktails, where each phage within a cocktail may require significantly different formulation to retain a high enough infective dose. This review firstly looks at the clinical needs and challenges (informed through a review of key animal studies evaluating phage therapy) associated with treatment of acute and chronic infections and the drivers for phage encapsulation. An important driver for formulation and encapsulation is shelf life and storage of phage to ensure reproducible dosages. Other drivers include formulation of phage for encapsulation in micro- and nanoparticles for effective delivery, encapsulation in stimuli responsive systems for triggered controlled or sustained release at the targeted site of infection. Encapsulation of phage (e.g. in liposomes) may also be used to increase the circulation time of phage for treating systemic infections, for prophylactic treatment or to treat intracellular infections. We then proceed to document approaches used in the published literature on the formulation and stabilisation of phage for storage and encapsulation of bacteriophage in micro- and nanostructured materials using freeze drying (lyophilization), spray drying, in emulsions e.g. ointments, polymeric microparticles, nanoparticles and liposomes. As phage therapy moves forward towards Phase III clinical trials, the review concludes by looking at promising new approaches for micro- and nanoencapsulation of phages and how these may address gaps in the field.

Focusing Waves in Unknown Media by Modified Time Reversal Iteration

Abstract: We study the wave equation on a bounded domain $M$ in $\mathbb{R}^m$ or on a compact Riemannian manifold with boundary. Assume that we do not know the coefficients of the wave equation but are given only the hyperbolic Robin-to-Dirichlet map that corresponds to physical measurements on a part of the boundary. In this paper we show that at a fixed time $t_0$ a wave can be cut off outside a suitable set. That is, if $N\subset M$ is a union of balls in the travel time metric having centers at the boundary, then we can modify a given Robin boundary value of a wave such that at time $t_0$ the modified wave is arbitrarily close to the original wave inside $N$ and arbitrarily small outside $N$. Also, at time $t_0$ the time derivative of the modified wave is arbitrarily small in all of $M$. We apply this result to construct a sequence of Robin boundary values so that at a time $t_0$ the corresponding waves converge to a delta distribution $\delta_{\widehat{x}}$ while the time derivative of the waves converge to zero. Such boundary values are generated by an iterative sequence of measurements. In each iteration step we apply time reversal and other simple operators to measured data and compute boundary values for the next iteration step. A key feature of this result is that it does not require knowledge of the coefficients in the wave equation, that is, of the material parameters inside the media. However, we assume that the point $\widehat{x}$ where the wave focuses is known in travel time coordinates, and $\widehat{x}$ satisfies a certain geometrical condition.

A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability

Abstract: There is an inherent tension in Quantitative Systems Pharmacology (QSP) between the need to incorporate mathematical descriptions of complex physiology and drug targets with the necessity of developing robust, predictive and well-constrained models. In addition to this, there is no "gold standard" for model development and assessment in QSP. Moreover, there can be confusion over terminology such as model and parameter identifiability; complex and simple models; virtual populations; and other concepts, which leads to potential miscommunication and misapplication of methodologies within modeling communities, both the QSP community and related disciplines. This perspective article highlights the pros and cons of using simple (often identifiable) vs. complex (more physiologically detailed but often non-identifiable) models, as well as aspects of parameter identifiability, sensitivity and inference methodologies for model development and analysis. The paper distills the central themes of the issue of identifiability and optimal model size and discusses open challenges.

A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability

Abstract: There is an inherent tension in Quantitative Systems Pharmacology (QSP) between the need to incorporate mathematical descriptions of complex physiology and drug targets with the necessity of developing robust, predictive and well-constrained models. In addition to this, there is no "gold standard" for model development and assessment in QSP. Moreover, there can be confusion over terminology such as model and parameter identifiability; complex and simple models; virtual populations; and other concepts, which leads to potential miscommunication and misapplication of methodologies within modeling communities, both the QSP community and related disciplines. This perspective article highlights the pros and cons of using simple (often identifiable) vs. complex (more physiologically detailed but often non-identifiable) models, as well as aspects of parameter identifiability, sensitivity and inference methodologies for model development and analysis. The paper distills the central themes of the issue of identifiability and optimal model size and discusses open challenges.

Diffraction by a line of curvature jump (a special case)

Abstract: We consider the problem of diffraction of a short-wave field by a cylindrical body with the boundary that consists of a half plane and a convex-cylindrical surface jointed together along a straight line. The main feature of the problem under consideration is the jump of curvature of the boundary on the line. The problems with the Dirichlet, Neumann, and impedance boundary conditions are considered. The main terms of asymptotic expansion of wave fields for the problems are constructed.

Emerging Strategies to Combat ESKAPE Pathogens in the Era of Antimicrobial Resistance: A Review.

Abstract: The acronym ESKAPE includes six nosocomial pathogens that exhibit multidrug resistance and virulence: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. Persistent use of antibiotics has provoked the emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) bacteria, which render even the most effective drugs ineffective. Extended spectrum β-lactamase (ESBL) and carbapenemase producing Gram negative bacteria have emerged as an important therapeutic challenge. Development of novel therapeutics to treat drug resistant infections, especially those caused by ESKAPE pathogens is the need of the hour. Alternative therapies such as use of antibiotics in combination or with adjuvants, bacteriophages, antimicrobial peptides, nanoparticles, and photodynamic light therapy are widely reported. Many reviews published till date describe these therapies with respect to the various agents used, their dosage details and mechanism of action against MDR pathogens but very few have focused specifically on ESKAPE. The objective of this review is to describe the alternative therapies reported to treat ESKAPE infections, their advantages and limitations, potential application in vivo, and status in clinical trials. The review further highlights the importance of a combinatorial approach, wherein two or more therapies are used in combination in order to overcome their individual limitations, additional studies on which are warranted, before translating them into clinical practice. These advances could possibly give an alternate solution or extend the lifetime of current antimicrobials.

Considerations and Caveats in Combating ESKAPE Pathogens against Nosocomial Infections

Abstract: ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are among the most common opportunistic pathogens in nosocomial infections. ESKAPE pathogens distinguish themselves from normal ones by developing a high level of antibiotic resistance that involves multiple mechanisms. Contemporary therapeutic strategies which are potential options in combating ESKAPE bacteria need further investigation. Herein, a broad overview of the antimicrobial research on ESKAPE pathogens over the past five years is provided with prospective clinical applications.

Phage therapy: What factors shape phage pharmacokinetics and bioavailability? Systematic and critical review.

Abstract: Bacteriophages are not forgotten viruses anymore: scientists and practitioners seek to understand phage pharmacokinetics in animals and humans, investigating bacteriophages as therapeutics, nanocarriers or microbiome components. This review provides a comprehensive overview of factors that determine phage circulation, penetration, and clearance, and that in consequence determine phage applicability for medicine. It makes use of experimental data collected by the phage community so far (PubMed 1924-2016, including non-English reports), combining elements of critical and systematic review. This study covers phage ability to enter a system by various routes of administration, how (and if) the phage may access various tissues and organs, and finally what mechanisms determine the courses of phage clearance. The systematic review method was applied to analyze (i) phage survival in the gut (gut transit) and (ii) phage ability to enter the mammalian system by many administration routes. Aspects that have not yet been covered by a sufficient number of reports for mathematical analysis, as well as mechanisms underlying trends, are discussed in the form of a critical review. In spite of the extraordinary diversity of bacteriophages and possible phage applications, the analysis revealed that phage morphology, phage specificity, phage dose, presence of sensitive bacteria or the characteristics of treated individuals (age, taxonomy) may affect phage bioavailability in animals and humans. However, once phages successfully enter the body, they reach most organs, including the central nervous system. Bacteriophages are cleared mainly by the immune system: innate immunity removes phages even when no specific response to bacteriophages has yet developed.

Bacteriophage therapy as an alternative treatment for human infections. A comprehensive review.

Abstract: Bacteriophages, or phages, are viruses that infect bacteria They were discovered around a century ago and have been used ever since for therapeutic purposes, particularly in former Soviet Union countries Their use in Western countries was abandoned after the discovery and broad use of penicillin The rising problem of antimicrobial resistance has revived interest in bacteriophage therapy The aim of this article is to provide a comprehensive review of all aspects of natural phage therapy

Phage therapy for respiratory infections.

Abstract: A respiratory infection caused by antibiotic-resistant bacteria can be life-threatening. In recent years, there has been tremendous effort put towards therapeutic application of bacteriophages (phages) as an alternative or supplementary treatment option over conventional antibiotics. Phages are natural parasitic viruses of bacteria that can kill the bacterial host, including antibiotic-resistant bacteria. Inhaled phage therapy involves the development of stable phage formulations suitable for inhalation delivery followed by preclinical and clinical studies for assessment of efficacy, pharmacokinetics and safety. We presented an overview of recent advances in phage formulation for inhalation delivery and their efficacy in acute and chronic rodent respiratory infection models. We have reviewed and presented on the prospects of inhaled phage therapy as a complementary treatment option with current antibiotics and as a preventative means. Inhaled phage therapy has the potential to transform the prevention and treatment of bacterial respiratory infections, including those caused by antibiotic-resistant bacteria.