WO2017149381A1 - Système, procédé et utilisations pour le traitement ou la prévention « in situ » d'infections résistant aux agents antimicrobiens ou d'infections difficiles à traiter - Google Patents

Système, procédé et utilisations pour le traitement ou la prévention « in situ » d'infections résistant aux agents antimicrobiens ou d'infections difficiles à traiter Download PDF

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Publication number
WO2017149381A1
WO2017149381A1 PCT/IB2017/000193 IB2017000193W WO2017149381A1 WO 2017149381 A1 WO2017149381 A1 WO 2017149381A1 IB 2017000193 W IB2017000193 W IB 2017000193W WO 2017149381 A1 WO2017149381 A1 WO 2017149381A1
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WO
WIPO (PCT)
Prior art keywords
electric current
infections
local area
period
treatment
Prior art date
Application number
PCT/IB2017/000193
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English (en)
Inventor
Joan GAVALDA SANTAPAU
Victor Franco Puntes
Eduard Torrents Serra
Original Assignee
Fundacio Hospital Universitari Vall D'hebron - Institut De Recerca
Fundacio Institut De Bioenginyeria De Catalunya
Institucio Catalana De Recerca I Estudis Advancats
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Fundacio Hospital Universitari Vall D'hebron - Institut De Recerca, Fundacio Institut De Bioenginyeria De Catalunya, Institucio Catalana De Recerca I Estudis Advancats filed Critical Fundacio Hospital Universitari Vall D'hebron - Institut De Recerca
Publication of WO2017149381A1 publication Critical patent/WO2017149381A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/44—Applying ionised fluids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B1/00—Electrolytic production of inorganic compounds or non-metals
    • C25B1/01—Products
    • C25B1/24—Halogens or compounds thereof
    • C25B1/26—Chlorine; Compounds thereof

Definitions

  • the present invention generally relates to the technical field of treatment or prevention of infections. More particularly, the present invention is in the technical field of low-amperage electrical current by means of electrolysis under conditions of physiologic saline and generation of hypochlorous acid 'in situ' to treat and prevent antimicrobial resistant infections and biofilm infections.
  • AMR Antimicrobial Resistance
  • 'ESKAPE' pathogens are E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter spp.
  • the most prominent threat of AMR is the rapidly rising tide of resistance among AMR, 'ESKAPE' bacteria that cause hospital-based infections in the last years.
  • AMR E. coli remains the main cause of mortality in hospitalized patients.
  • MDR/XDR ⁇ .aeruginosa incidence 25-50%) only a few therapeutic options are available, among these are polymyxins.
  • MDR/XDR P. aeruginosa presence of resistance to polymyxins or aminoglycosides is an important warning that options for the treatment of infected patients are becoming even more limited.
  • few antibiotics are effective enough for therapy.
  • the antibiotics that still do work, frequently have major side effects, are less efficacious, or are very expensive (tigecycicline).
  • AMR is not only costly in terms of human suffering but also in monetary terms.
  • AMR currently claim at least 50,000 lives each year across Europe and the US alone and about 700,000 lives worlwide; at the estimated cost of more than 1.5 billion EUR or 35$ billion annually.
  • AMR bacteria could dramatically set back modern medicine to the dark age of the pre- antibiotic era; achievements in modern medicine, such as decrease in the safety of childbirth, caesarean sections, treatment of preterm babies, major or even dirty minor surgery, treatment of pneumonia, sexual transmitted diseases, organ transplantation and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections with antibiotics.
  • stents such as stents, shunts, prostheses, implants, endotracheal tubes, pacemakers, and various types of catheters, to name a few, have all been shown to support colonization and biofilm formation by different bacterial species or Candida spp. These bacterial species or Candida biofilms are 30 to 2,000 times more resistant than planktonic cells to antimicrobial agents.
  • EP 2190442B1 discloses an apparatus for treatment and prevention of infectious disease and a method for the treatment of bacterial diseases based on the antibacterial characteristic of the electrically released of silver ions.
  • the method includes the implantation of a small electrode including silver in an infected bone, embedding another small electrode including another metallic element subcutaneously, and initiating the release of silver ions by applying a small current between the two electrodes. The initiation current is applied for a very short time and then discontinued. After this a continuous release of the silver ions will take place for a long time while spreading the silver ions to the surrounding tissue as well. This process assures a long-term antibacterial effect, which after accomplishing the infection healing will also provide preventive care.
  • the apparatus comprises all of the components necessary to carry out the method.
  • EP 2403588B1 discloses methods for the treatment of bone, cartilage and other types of hard tissue.
  • the treatments which are suitable for extended treatment, include the treatment and prevention of pathologies through the controllable use of silver, iron, zinc, or magnesium ions. These pathologies may include a pathology which is at least partially induced or aggravated by an infectious disease, for example a bacterial disease.
  • the electrically released ions are silver ions, which are known to have antibacterial properties.
  • WO 2011078511 refers to a sterilization method and apparatus for medical instruments that proposes preparing a solution containing chlorine and having a temperature of about 60° C.
  • the electrode disposing at least one electrode in a container containing the solution and immersing at least one medical instrument in the solution such that the medical instrument is disposed over the electrode; and electrolyzing the solution by applying a current to the electrode to generate sterilizing components of free chlorine comprising hypochlorous acid, hydrogen peroxide (H202), OH radical, and ozone (03) and thus sterilize the medical instrument by the sterilizing components which move up in the opposite direction of gravity from the electrode.
  • free chlorine comprising hypochlorous acid, hydrogen peroxide (H202), OH radical, and ozone (03)
  • New methods and systems for 'in situ' treating or preventing antimicrobial resistant infections, and also infections difficult to treat, are therefore needed, to preserve antibiotic effectiveness.
  • embodiments of the present invention provide according to a first aspect a system for 'in situ' treatment or prevention of antimicrobial resistant infections or infections difficult to be treated or at risk to be infected.
  • the proposed system comprises a delivering unit configured to deliver during a treatment period an amount of a saline solution (0.9% NaCl) to a local area of a patient infected by antimicrobial resistant microorganisms or microorganisms growing in biofilms or at risk to be infected, a device configured to be placed to the local area of the patient, an electrical power source and a control unit operatively connected to the device and/or to the electrical power source.
  • a delivering unit configured to deliver during a treatment period an amount of a saline solution (0.9% NaCl) to a local area of a patient infected by antimicrobial resistant microorganisms or microorganisms growing in biofilms or at risk to be infected
  • a device configured to be placed to the local area of the patient,
  • the device includes two or more conductive electrodes configured to be placed in contact with the amount of saline solution to produce hypochlorous acid during the treatment period; one or more sensors configured to provide information about temperature and pH in the local area during the treatment period; and a support structure to hold the conductive electrodes and the sensors.
  • the electrical power source is configured to generate and apply via the two or more conductive electrodes an electric current to the local area during a given period of time of the treatment period depending on the type and severity of the infection to be treated, thus producing the hypochlorous acid at the local area via the saline solution
  • the control unit is configured to control the extent of said given period of time in which the electric current is applied and the value of the electric current.
  • the electric current is kept at a value between 1 mA and 20 mA, that is, being a low-amperage electrical current.
  • a continuous direct current provided by a DC source For instance, a continuous direct current provided by a DC source.
  • the value of the applied electric current is controlled by the control unit based on the temperature and pH information provided by the one or more sensors.
  • the given period of time in which the electric current is applied can be comprised between 1 and 30 minutes.
  • the temperature during the treatment period is kept to not exceed 40-42 °C and the pH is kept between 6.5 and 8.5.
  • the control unit can be an independent unit to the electrical power source or can be integrated therein.
  • Embodiments of the present invention also provides according to a second aspect, a method for treatment and prevention "in situ" of antimicrobial resistant infections or difficult to treat infections by electric current, in particular low-amperage electrical current, to generate electrolysis under conditions of physiologic saline and generation of hypochlorous acid.
  • the method comprises placing a device to a local area of a patient infected by antimicrobial resistant microorganisms or microorganisms growing in biofilms or at risk to be infected, said device preferably including two or more conductive electrodes to be in contact with the local area of the patient during a treatment period; one or more sensors at least providing information about temperature and pH in said local area during the treatment period; and a support structure to hold the conductive electrodes and the sensor(s).
  • the method further comprises delivering, by a delivering unit, an amount of a saline solution, such as 0.9% NaCl, to the local area to be in contact with the conductive electrodes; connecting the two or more conductive electrodes to an electrical power source which generates the electric current to be applied to the local area during a given period of time of the treatment period, depending on the type and severity or difficulty of the infection to be treated, producing the hypochlorous acid via the saline solution at said local area.
  • a control unit is configured to control the extent of the given period of time in which the electrical current is applied and its value, preferably based on the temperature and pH information.
  • the temperature during the treatment period is kept to not exceed 40-42 °C and the pH is kept between 6.5 and 8.5.
  • an antimicrobial treatment is further provided to the patient.
  • the proposed method is capable of creating "in situ" hypochlorous acid, a potent oxidant with antimicrobial capacity in order to kill microorganisms avoiding volatility losses occurring in case the hypochlorous acid being conveyed from a remote point, i.e. not produced at the local area of infection.
  • hypochlorous acid HOC1
  • ROS reactive oxygen species
  • the electric current can be applied in a single period of time, i.e. a shot, or in various periods of time, different shots, depending on the severity of the infection to be treated.
  • the infection to be treated can be kept under control by means of common diagnostic techniques of infection (for example imaging or microbiology), or alternatively, by means of acquisition and control of said temperature and pH information.
  • the delivering of the saline solution (0.9% NaCl) is performed under a controlled release over said local area.
  • the disclosed method/technology can be used, provided as a third aspect of the present invention, as adjuvant therapy of antimicrobial/surgical therapy of difficult to treat infections as abscesses (cerebral, subdural empyema, epidural, pulmonary, pleural, hepatic, splenic, nephritic or perinephric, gynecological, intraperitoneal, muscular, subcutaneous), mediastinitis, acute and chronic osteomyelitis, diabetic foot infections, prosthetic infection (e.g.
  • orthopedic implant-associated Infections vascular graft infection, tracheal stent infection
  • lock therapy of long-term catheter-related bloodstream infections chronic prostatitis, decolonization or disinfection of infected or colonized endotracheal tube or urinary catheters, Cerebrospinal Fluid Shunt and Drain Infections, Cellulitis, and Subcutaneous Tissue Infections.
  • the disclosed method can be used as adjunctive therapy of difficult to treat Candida spp. biofilm infections
  • the method can also be used to treat or prevent gram negative rod (GNR) bacterial infections caused by MDR/XDR Pseudomonas aeruginosa, MDR/XDR Klebsiella pneumoniae, MDR/XDR Acinetobacter baumanii, Escherichia coli and others GNR resistant to more than two classes of antimicrobials. Moreover, it would be effective against MDR gram positive cocci bacterial infections caused by methicillin-resistant Staphylococcus aureus.
  • GNR gram negative rod
  • the method may be used to treat infections due to Candida spp or bacteria or growing in biofilms, especially coagulase-negative staphylococci, Staphylococcus aureus and Pseudomonas aeruginosa.
  • the method may be used to treat MDR or extreme resistant Mycobacterium tuberculosis or other atypical mycobacteria difficult to treat.
  • the method is also suitable to be used to treat fungal infections including, among others, Candida spp., Aspergillus spp and Zygomycetes.
  • Figs. 1A and IB illustrate two different embodiments of the proposed system.
  • Fig. 2 illustrates, according to an embodiment, the effect of the present invention with different electric current applied in TSB/BFfl or NSS by a) Pa3 b) Kp3 c) Abll d) CA176 e) CP54 and f) Af4751 g) R0868 strains on planktonic growth.
  • Fig. 3 illustrates the effect of the present invention applied in TSB or NSS at different time-point by Kp3 strain.
  • Fig. 4 illustrates the effect of the present invention in preventing both microorgani sm adhesion and biofilm formation by P. aeruginosa and S. epidermidis on silicone discs.
  • Fig. 5 illustrates the effect of the present invention by PAOl strain on silicone discs.
  • Fig. 6 illustrates the effect of the present invention applied in TSB/BHI or NSS by a) PAOl b) MRSA 15 c) MRSA 16 d) SE 14 e) SE 94 and f) CA176 strains on silicone discs.
  • Fig. 7 illustrates the effect of the present invention by PAOl, MRSA 15, MRSA 16 and CA176 strains on silicone discs visualized using the LIVE/DEAD® staining viability kit.
  • Fig. 8 illustrates the effect of the present invention by a) PAOl and b) MRSA 15 strains on titanium discs.
  • Fig. 1A illustrates a first embodiment of the proposed system.
  • the system of this first embodiment comprises a device which is configured to be placed to a local area 1 of a patient infected by antimicrobial resistant microorganisms or microorganisms growing in biofilms or at risk to be infected.
  • the device includes a delivering unit 11 which is configured to deliver an amount of a saline solution to the local area 1.
  • the device also has two conductive electrodes 12, 13, such as platinum electrodes, among others, configured to be in contact with the amount of saline solution to produce hypochlorous acid.
  • the device also includes two sensors 14, 15 configured to provide information about temperature and pH in the local area during the treatment period. All the elements of the device are held on a support structure 16 which is kept on the local area 1 during the treatment.
  • the system of Fig. 1 further includes an electrical power source 20 configured to generate the electric current via the two conductive electrodes 12, 13 during a given or determined period of time, and a control unit (not shown).
  • the control unit is integrated in the electrical power source 20, however, in alternative embodiments of the invention, not illustrated, the control unit may be an independent unit connected to the device and/or to the electrical power source.
  • the control unit is configured to control the extent of said period of time in which the electric current is applied and the value of the electric current, preferably, based on the temperature and pH information provided by the sensors 14, 15.
  • said period of time in which the electric current is applied "in situ” is comprised between 1 and 30 minutes, and said electric current is kept between 1 mA and 20 mA (i.e. low-amperage current).
  • the temperature is kept during the treatment to not exceed 40-42 °C, and the pH is kept between 6.5 and 8.5.
  • the delivering system 11 alternatively to the embodiment of Fig. 1, not illustrated, could be a reservoir or cavity included in the support 16 itself.
  • Fig. IB illustrates a second embodiment of the proposed system.
  • the device contrary to the first embodiment, the device only comprises the two conductive electrodes 12, 13, the two sensors 14, 15 and the support 16, being the delivering unit 21 independent of the device.
  • the delivering unit 21 is a syringe.
  • the performance of the electrical power source 20 and of the control unit is in this case the same as in the first embodiment.
  • the device could include only one sensor configured to provide the temperature and the pH.
  • the device could only include the two conductive electrodes 12, 13 hold on the support 16, being the sensors 14, 15 (or the single sensor) independents of the device.
  • the support 16 in any of the embodiments of the invention and depending on the local area or the patient to be applied may have different shapes and may be of different materials. Following a detailed explanation of embodiments of the proposed method will be made. i) Parameters
  • strains were stored in skim milk at -80°C in cryovial storage containers. Prior to each experiment, strains were subcultured in Trypticase Soy Agar (TSA) for 24h at 37°C.
  • TSA Trypticase Soy Agar
  • aS susceptible; R, resistant; AMP, ampicillin; CAZ, ceftazidime; FEP, cefepime; IMP, imipenem; MEM, meropenem; CIP, ciprofloxacin; GEN, gentamicin; AK, amikacin; T/S, trimethoprim/sulfamethoxazole; FOS, fosfomycin; CST, colistin.
  • the aim of the experiment was to evaluate the ability to generate hypochlorous acid with electrolysis of the new system.
  • the two electrodes were used without separating the anodic and cathodic compartments.
  • using the electrodes has quantified the concentration of electrochemically generated hypochlorous acid in NSS 0.9% NaCl.
  • 4 ml NSS at 37 ° C was used.
  • the electrodes introduced and applied the current required during the time required for electrolysis.
  • Quantification of hypochlorous acid has been performed using the spectrophotometric method ASTM 4500-CI. All measurements for each value of current / time applied were performed in triplicate and also, it has been calculated the coefficient of variation.
  • Electric current of 2mA 5 min applied in Pa3 and Kp3 need two shots (2 applications of electric current) to achieved significantly lower (P>0.001) compared to Control NSS.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Apparatus For Disinfection Or Sterilisation (AREA)

Abstract

Le système comprend : une unité de distribution (11, 21) pour la distribution de solution saline en direction d'une zone localisée (1) infectée ou risquant d'être infectée par des microorganismes résistant aux agents antimicrobiens ou par des microorganismes se développant dans des biofilms ; un dispositif à placer au niveau de ladite zone localisée (1), le dispositif comprenant deux électrodes conductrices (12, 13) destinées à être mises en contact avec ledit volume de solution saline pour produire de l'acide hypochloreux, des capteurs (14, 15) pour fournir des informations concernant la température et le pH dans la zone localisée et un support (16) ; une source d'alimentation électrique (20) pour générer et appliquer, par l'intermédiaire des électrodes conductrices (12, 13), un courant électrique au niveau de la zone localisée (1) pendant un laps de temps déterminé qui est fonction du type et de la gravité de l'infection ; et une unité de commande pour déterminer la durée dudit laps de temps et la valeur du courant électrique sur la base des informations de température et de pH.
PCT/IB2017/000193 2016-03-02 2017-03-02 Système, procédé et utilisations pour le traitement ou la prévention « in situ » d'infections résistant aux agents antimicrobiens ou d'infections difficiles à traiter WO2017149381A1 (fr)

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US201662302316P 2016-03-02 2016-03-02
US62/302,316 2016-03-02

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6007686A (en) * 1994-08-26 1999-12-28 Medical Discoveries, Inc. System for elctrolyzing fluids for use as antimicrobial agents
WO2011078511A2 (fr) 2009-12-23 2011-06-30 한국돌기 주식회사 Méthodes de stérilisation et de désinfection d'instruments médicaux pouvant être mises en oeuvre rapidement tout en se conformant à des critères de stérilisation de haut niveau, et dispositif associé
EP2190442B1 (fr) 2007-08-30 2012-10-10 Ortho-Ion Ltd. Dispositif pour traiter et prevenir une maladie infectieuse
US20130209964A1 (en) * 2007-09-05 2013-08-15 Biolectrics Llc Concurrent Treatment of Oral and Systemic Maladies Using Direct Current Electricity
WO2015073877A1 (fr) * 2013-11-14 2015-05-21 Paul Mikus Procédés, systèmes et appareils d'administration de produits d'électrolyse
EP2403588B1 (fr) 2009-03-02 2016-06-08 Ortho-Ion Ltd. Système permettant d'implanter, d'activer, et de faire fonctionner une pile implantable

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6007686A (en) * 1994-08-26 1999-12-28 Medical Discoveries, Inc. System for elctrolyzing fluids for use as antimicrobial agents
EP2190442B1 (fr) 2007-08-30 2012-10-10 Ortho-Ion Ltd. Dispositif pour traiter et prevenir une maladie infectieuse
US20130209964A1 (en) * 2007-09-05 2013-08-15 Biolectrics Llc Concurrent Treatment of Oral and Systemic Maladies Using Direct Current Electricity
EP2403588B1 (fr) 2009-03-02 2016-06-08 Ortho-Ion Ltd. Système permettant d'implanter, d'activer, et de faire fonctionner une pile implantable
WO2011078511A2 (fr) 2009-12-23 2011-06-30 한국돌기 주식회사 Méthodes de stérilisation et de désinfection d'instruments médicaux pouvant être mises en oeuvre rapidement tout en se conformant à des critères de stérilisation de haut niveau, et dispositif associé
WO2015073877A1 (fr) * 2013-11-14 2015-05-21 Paul Mikus Procédés, systèmes et appareils d'administration de produits d'électrolyse

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