Гипертермия как потенциальный фактор усиления действия антибиотиков



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Аннотация

Сообщается, что регулирование температуры пораженных инфекцией участков тела пациентов может быть важным для преодоления устойчивости бактерий к антибиотикам. Однако в медицинском стандарте не указано целевое значение температуры для лечения инфекционных заболеваний антибиотиками. В то же время, ранее было показано, что повышение температуры с +37 до +42°C улучшает реологические свойства коллоидных жидкостей, расплавляет липиды и/или снижает вязкость липидных и белково-липидных комплексов клеточных мембран человека и микроорганизмов, в соответствии с законом Аррениуса увеличивает скорость химического, биохимические реакции и интенсивность всего клеточного метаболизма.  Дело в том, что такие температурно-зависимые изменения в структуре и функционировании клеток облегчают и ускоряют участие антибиотиков в их метаболизме и усиливают бактериостатический эффект антимикробных препаратов. Также было обнаружено, что гипертермия ускоряет биологические часы микроорганизмов, сокращает их продолжительность жизни и ускоряет изменение популяции. В то же время гипертермия восстанавливала бактериостатический эффект антибиотиков, который отсутствовал, и/или усиливала бактериостатический эффект, который существовал в условиях нормальной температуры тела. Результаты первых экспериментов in vitro и первых клинических наблюдений за острыми местными гнойно-воспалительными процессами и хроническими ранами продемонстрировали безопасность местной гипертермии и ее способность усиливать антимикробный эффект антисептиков и местных антибиотиков. Результаты показали, что гипертермия может повышать бактериостатическую активность антибиотиков за счет улучшения реологических свойств биологических жидкостей, снижения плотности микробных мембран и ускорения бактериального метаболизма при включении антибиотиков. Эти данные указывают на потенциал терапевтической гипертермии для поддержания эффективности антибиотиков и других противомикробных средств при лечении инфекций за счет снижения резистентности микроорганизмов.

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Review article

Hyperthermia as a potential factor in enhancing the effect of antibiotics

 

 

  1. 1. INTRODUCTION

 

The regulation of patients' body temperature is a widely used therapeutic intervention in medical practice [1]. Body temperature monitoring is a mandatory procedure for all infectious diseases, including COVID-19 [2]. Thermal imaging cameras have been increasingly used in recent years to monitor local and overall temperatures [3]. The fact is that these medical devices provide high accuracy of non-contact temperature measurements of exposed body parts in the infrared spectrum of tissue radiation at a distance from the patient [4, 5]. In the field of medicine, local and general hypothermia, but not hyperthermia, is currently most used for therapeutic purposes [6-9]. Since many diseases are inflammatory or accompanied by inflammation, patients often experience an increase in local and/or general temperature and even a pronounced fever [10]. In this regard, it is considered correct to lower the body temperature of patients for a long time. For this, doctors often use non-steroidal anti-inflammatory drugs (NSAIDs) as antipyretic medications in the treatment of many diseases [11-14].

However, new evidence suggests that not only lowering the temperature, but also increasing body temperature can help treat patients with infection [7, 15]. To justify the need for lowering body temperature in patients, the possibility of reducing the body's metabolic demands and increasing patient comfort were commonly cited [16-20]. But in recent years, there have been reports that such a rationale is not convincing enough. In particular, it is pointed out that there is still no standard for regulating body temperature in many diseases [21]. Specific target temperatures are defined only for patients who are unconscious after cardiac arrest and in critical condition. [22-24].

In recent years, there have been reports that in most patients with infection, fever is part of the body's normal adaptive response to an emerging infectious disease [25]. However, there is still no consensus among researchers as to whether fever prevents the body from fighting infection or helps it [26]. In addition, it is unclear whether it is beneficial or harmful for patients with fever and infection to be prescribed antipyretics or physical cooling measures [25, 27, 28]. At the same time, it is known from the history of medicine that in the era before the advent of antibiotics, therapeutic hyperthermia or pyrotherapy was widely used to treat infections [7, 29-31]. Then the advent of antibiotics and their initial high effectiveness led to a loss of interest among researchers and doctors in treating patients with infection by natural methods [32]. However, the pathogens of infectious diseases acquired multiple resistance to chemotherapeutic drugs [33]. This reduces the anti-infective activity of antibiotics and the effectiveness of treatment of infectious diseases using them [34]. Today, this is forcing researchers to look for methods to enhance the anti-infective activity of antibiotics and/or alternative methods of treating infections with them [35]. In our opinion, local hyperthermia can potentiate the anti-infective effect of antibiotics and other chemotherapeutic agents, especially with local use of drugs and hyperthermia in the field of local infectious processes [36].

 

  1. MATERIALS AND METHODS

Methods and terminology

An unstructured literature review was conducted in the Scopus, Web of Science, MedLine, The Cochrane Library, EMBASE, Global Health, CyberLeninka, E-library, Yandex, РИНЦ and PubMed databases using the search terms "infection", "infectious disease", "pathogen", "bacteria", "pathogenic bacteria", "staphylococcus aureus", "microorganisms", "virulence", "temperature", "hyperthermia", "local hyperthermia", "therapeutic hyperthermia", "fever", "targeted temperature management", "hyperpyrexia", "fever management", "heating", "warming", "warm", "warm medicine", "warm antiseptic", “pyolytics”, “hydrogen peroxide”, "warm antibiotic", "antibiotic resistance", "antimicrobial", "chemotherapy", "chemotherapeutic effect", and various combinations of the above-mentioned terms. No time limits were chosen for the research, all types of articles, dissertations, and descriptions of inventions in English and Russian were included. In addition, the information in the “References” section of the selected scientific articles was studied.

The information contained in the description of inventions was searched using the following databases: Google Patents, EAPATIS, RUPTO, USPTO, Espacenet, PATENTSCOPE, PatSearch, DWPI and FIIP (RF). In addition, analogues and prototypes indicated in the selected inventions were studied.

The search for clinical studies was carried out by NU, LL and AS, experimental studies were studied by DN, AO, MR and VOO, while AU, VA, FE, ABA and YO searched for laboratory, microbiological, biochemical and biophysical studies. Due to the wide coverage of the review, which included data from tests conducted before the formation of temperature pharmacology and the advent of thermal imagers and in the modern era, when monitoring the dynamics of local temperature using infrared thermography began to be widely implemented in laboratory research and clinical trials, a structured approach proved impractical.

The article uses various terms to describe the temperature regimes of human body tissues, such as fever, hyperthermia, therapeutic hyperthermia, heating, fever, as well as normothermia and hypothermia. In doing so, we proceeded from the most widely accepted understandings. In particular, we assumed that "fever" is the condition of a patient with an infectious disease with a body temperature of ≥37.7°C. We have used the term "hyperthermia" to describe any increase in the general body temperature or the local temperature of any part of the body above normal temperature. At the same time, we assumed that the body temperature of all parts of the body is different and it changes cyclically, since there is a circadian rhythm and the dependence of local temperature on local metabolism and blood circulation.  We used the term "therapeutic hyperthermia" to refer to an artificially elevated body temperature or part of it to the maximum permissible safe level of +42 °C. We used the term "normothermy" to refer to the active maintenance of body temperature in the range of daily fluctuations associated with the circadian rhythm. In addition, the text presents some data on the local heating of malignant tumors using a combination of chemotherapy and various heating modalities, such as heating by radio frequencies, ultrasound, microwaves, and magnetic nanoparticles. We assumed that the chemotherapy of infectious diseases with antibiotics could be upgraded in the future due to the achievements of local hyperthermic chemotherapy of malignant tumors, since there are many similarities between them.

 

Warnings and side effects of therapeutic hyperthermia

Although the review article highlights the benefits of hyperthermic chemotherapy for infections, there is very little direct clinical evidence on this. (Drewry A, Mohr NM, 2022; Drewry AM, Mohr NM, Ablordeppey EA, et al.б 2022; Markota A, Kalamar Ž, Fluher J, et al., 2023). Laboratory and experimental studies that describe the potential mechanisms of action of local hyperthermia have been conducted under various conditions. Few microbiological and virological studies of the effect of hyperthermia on the vital activity and reproduction of microorganisms in the presence of antibiotics and antiseptics have been conducted in vitro. A significant number of studies on the effects of hyperthermia on the pharmacokinetics and pharmacodynamics of local medicinal products have been aimed at determining the potential chemical, biochemical, and physico-chemical effects of local hyperthermia on the condition of various colloidal tissues, including thick sputum, mucus, blood, and purulent masses.  These studies were performed in vitro and in vivo (in rabbits). Due to the lack of clinical data, it is necessary to take into account possible adverse events, the occurrence of which is most likely when using general hyperthermia rather than local hyperthermia. The fact is that people's body temperature values are not constant throughout the hours and days due to the presence of a circadian rhythm. Therefore, it is necessary to monitor the dynamics of body temperature throughout each day and night. It should be borne in mind that in the evening, the patient's body temperature may exceed 40.5 ° C and heat stroke may develop. The basis of therapy for such a critical condition is direct physical cooling (Drewry A, Mohr NM, 2022). Local hyperthermia of selected body areas is practically safe for all patients. When combining local antibiotics with it, it should be assumed that the local effect of drugs (in this case, medicinal solutions) is largely determined not by the dose, but by the magnitude of their concentration, osmotic and acidic activity, and the duration of direct interaction (Urakov AL, 2015).

 

  1. RESULTS

Bacterial infections remain very common diseases that can develop at any time and in any part of the human body. The causative agents of most infectious diseases are pathogenic bacteria that are constantly present around people in the environment in cold conditions. Bacteria are prokaryotic microorganisms that reproduce by binary division, since their cells do not contain a nucleus. The genetic information is contained in a bacterial cell in the form of a double-stranded circular DNA molecule [37]. The structural features of the bacterium are shown in Figure 1.

 

 

 

Figure 1.  Structure of a bacterium. Reproduced from Bannister BA, Begg NT, and Gillespie SH (eds.) (1996) Structure and classification of pathogens. In: Infectious Disease, 2nd edn., ch. 2, pp. 23–34. Oxford, UK: Blackwell Science Ltd., with permission from Blackwell Publishing.

 

In conditions of normal human body temperature, pathogenic bacteria can quickly divide and multiply. Therefore, it takes only a small number of microorganisms to become infected, and it takes several hours for the infectious disease to progress. It is important to note that in the process of evolution, the adaptive human response to infection in the form of fever has been consolidated. Despite this, by now fever remains an indication for the appointment of antipyretic medications [11]. However, the target temperature for the treatment of infections has not been definitively determined [2, 3]. In addition to antipyretic drugs, antibiotics are used [32]. However, the chemotherapeutic effect of antibiotics under different temperature conditions has not been studied. It is reported that in recent decades, bacteria have adapted to many chemotherapeutic agents and acquired antibiotic resistance. This is a concern in the world, as antibiotic resistance reduces the effectiveness of infection treatment and increases economic costs [28-35]. At the same time, there are reports that hyperthermia may enhance the effects of antimicrobial drugs, in particular the antiseptic hydrogen peroxide [36].

 

3.1. Targeted temperature management in tissues affected by an infectious process as an unsolved problem in the treatment of infectious diseases

 

It is surprising, but in medicine and pharmacology until their time the question of targeted temperature management (TTM) in full health and infectious diseases has not been finally solved not only individual organs and tissues affected by infection, but the whole organism as a whole  [38].  Moreover, even for intensive care unit (ICU) patients, there are no temperature standards set for them [39]. It has not yet been definitively established what is better for human health in infectious diseases and why: normothermia, hypothermia or hyperthermia [7, 25, 29, 40]. At the same time, there is no doubt that temperature is an important factor in chemistry, physics, biochemistry and life activity of the micro- and macro-world as a whole. The optimal temperatures for each of them have long been determined [41-44]. However, there are no generally accepted recommendations regarding the "correct" temperature of human organs and tissues for optimal chemotherapeutic effects of antibiotics on them before and during an infectious disease [45, 46]. 

Nevertheless, it is no secret that the temperature of the human body changes every day, both normally and in any disease, including infectious diseases [47-49] (Figure 2).

 

Figure 2. Diurnal variation in body temperature, ranging from about 37.5 °C (99.5 °F) from 10 a.m. to 6 p.m., and falling to about 36.4 °C (97.5 °F) from 2 a.m. to 6 a.m. (Based on figure in entry for 'Animal Heat' in 11th edition of the Encyclopædia Britannica, 1910).

 

The normal range of daily body temperature fluctuations in healthy individuals is usually about 1.1 °C. It has been shown that the lowest and highest body temperatures are usually observed in the early morning (between 4 and 6 o'clock) and early evening (between 16 and 18 o'clock) respectively [50]. At the same time, with diseases and medical interventions, this range can be increased by 10 or more times. It has been reported that the most significant changes in the temperature of organs and tissues occur with direct physical exposure to heat carriers (for example, with open surgical procedures on the organs of the abdominal and thoracic cavities) and with infectious diseases. During abdominal and thoracic surgery, patients' body temperature is mostly decreased, leading to hypothermia. In patients with infectious diseases, body temperature increases, which is manifested by fever. The greatest range of safe changes in body temperature in patients is possible with a targeted temperature change towards hypothermia. A smaller range of safe body temperature changes in patients is possible with a targeted temperature change towards hyperthermia [51].

Such difference in the range of decrease and increase of human body temperature is explained by the existence of maximum permissible values of cell temperatures of organs and tissues of human body at its change towards increase and decrease from the normal temperature level of +36.7 °С. The fact is that a decrease in temperature from the level of +36.7 °C is permissible up to 0 °C, and a temperature increase from the specified level is permissible only up to +42 °C.  This is due to the fact that cooling human body tissues below 0 °C can lead to frostbite due to the freezing of water and its transformation into ice crystals. In turn, the temperature increase above +42 °С can cause cell death due to temperature damage of protein molecules of irreversible nature. These maximum permissible levels of cooling and heating of human body parts relative to the temperature level of +36.7 °C are the basis of such medical concepts as hypothermia, normothermia and hyperthermia [52]. 

In addition, experts in the field of chemistry, biology and medicine have long been aware of the dependence of the rates of chemical and biochemical reactions on temperature. This dependence is known as the Arrhenius law [53]. In its most general form, the Arrhenius law states that an increase in temperature by 10 °C increases the rate of a chemical reaction by 2 times. It follows that hyperthermia similarly increases the intensity of metabolic processes in living biological objects, that is, it stimulates metabolism [52].  That is why warm-blooded animals have a more intense metabolism than cold-blooded animals [54]. It is this temperature dependence that is used in sports to achieve a higher athletic result by increasing the temperature of the athlete's skeletal muscles [55].

At the same time, fever, which accompanies many infectious diseases, is manifested by an increase in the body temperature of patients to almost the maximum possible value (Figure 3).

 

Figure 3. Febrile cycle seen in tertian malaria caused by Plasmodium vivax infection. Reproduced from El-Radhi AS. Fever in Common Infectious Diseases. Clinical Manual of Fever in Children. 2019 Jan 2:85–140.

 

Thus, fever is a natural hyperthermia. However, the Arrhenius law is not properly used to achieve a scientifically proven higher anti-infective effect of antibiotics and other chemotherapeutic drugs in the treatment of infectious diseases [56].

At the same time, recently there has been a report that fever, as a natural hyperthermia, can play a protective role in infections rather than a negative one. Therefore, the expediency of using antipyretic drugs has been questioned [7]. However, discussions about the usefulness and harmfulness of fever and hyperthermia continue [57]. Moreover, the dominant opinion is about the harm of fever to health [58, 59]. Therefore, antipyretic drugs continue to be used in the treatment of fever [60].

 

3.2. Temperature as the most important factor of drug interaction in their local application

 

Generally accepted ideas about the use of drugs are devoid of recommendations for purposeful temperature changes as a factor of drug interaction when applied topically in order to purposefully change the mechanism of action of drugs in the "right" place (parts of the human and/or animal body) [61]. However, in recent years, reports have begun to appear that changes in the temperature of organs and tissues can alter the effect of drugs on them [62-64]. To date, it has been proven that temperature is the most important factor in the interaction of many drugs when applied topically. Temperature changes have been shown to alter the chemical, mechanical, physical-chemical, biochemical, and biophysical properties of drugs and biological tissues [52, 61-65]. It is shown that in 1988 the foundations of temperature pharmacology were laid in Russia [66, 67].

Temperature pharmacology is a new scientific and practical field in which the local interaction of drugs is considered, taking into account the local temperature of selected areas of the human body (or animals) when drugs are applied topically [61-67]. In particular, it has been shown that an increase in the local temperature of bleeding wounds and vasoconstrictor drugs when applied topically from +37 to +42 °C accelerates hemostasis in parenchymal bleeding by stimulating blood clotting and enhancing the vasoconstrictive effect of drugs in the wound. Then, at the beginning of the 21st century, it was shown that a similar local hyperthermia enhances the effect of local bleachers of blood and bruises, as well as enhances the effect of bleaching cleaners of dental surfaces and dentures from plaque and surfaces of household ceramic products from food stains [46, 68-71]. In recent years, it has been shown that topical application of pyolytics heated to +42 °C potentiates their therapeutic effect in the treatment of chronic wounds, purulent bronchitis, tonsillitis, bronchial asthma, blood asphyxia and COVID-19 [36, 72-76]. In addition, the group of pyolytics received an alternative name - warm alkaline hydrogen peroxide solutions (WAHPSs). This name of the new group of drugs speaks for itself that they are all warm, meaning their temperature is higher than human body temperature.

Specific formulations of drugs proposed in combination with local hyperthermia to enhance pharmacological activity when applied topically are described in the inventions listed in Table 1.

Table 1. List of patents for inventions that use hyperthermia to enhance the action of drugs in local interactions

Number in order

Authors, title, invention patent number, date of publication

 

Local hyperthermia is used to enhance antiseptic, hemostatic and vasoconstrictive action of drugs in wound and mucosal surfaces

 

1

Strelkov NS, Urakov АL, Korovyakov AP, et al. Method of treatment of long non-healing wounds. RU2187287C1, 20.08.2002.

2

Krukov NI, Urakova NA, Kravchuk AP, et al. Method of stop nose bleeds.

RU2204336C2, 20.05.2003. 

3

Krukov NI, Kravchuk AP, Urakov AL, et al. Method of treatment of chronic rhinitis.   RU2205618C2, 10.06.2003

4

Urakova NA, Urakov AL, Sokolova NV, et al. Method for interrupting uterine hemorrhage. RU 2288656C1, 10.12.2006

5

Strelkov NS, Urakov AL. Urakova NA, et al. Method for treating pleural empyema cases.  RU2308894C2, 27.10.2007

6

Michailova NA, Urakova NA, Urakov AL, et al. Uterine lavage technique.  RU2327471C1, 27.06.2008

7

Strelkov NS, Urakov AL, Urakova NA, et al. Method of postoperative adhesions prevention. RU2330648C1, 10.08.2008

8

Urakov AL, Urakova NA, Otvagin IV, et al. Method and means for removal of sulphur plug. RU2468776C2, 10.12.2012

9

Urakov AL, Urakova NA, Kasatkin AA, et al. Method for skin discoloration in bruising area. RU2586278C1, 10.06.2016

10

Urakov AL, Urakova NA, Nikitjuk DB, et al. Method for skin discoloration in bruising area. RU2582215C1, 20.04.2016

11

Urakov AL, Urakova NA, Urakova NV. Anti-adhesion means. RU2645074C1, 15.02.2018

12

Urakova NA, Urakov AL, Urakova ТV, et al.   Bleaching opener of dried blood for wrapping bandages adhered to a wound. RU2653465C1, 08.05.2018

13

Urakov AL. Method for whitening of sore under nail. RU2631592C1, 25.09.2017

14

Urakova NA, Urakov AL, Gadelshina AA, et al. Method for blue nail treatment.  RU2641386C1, 17.01.2018

15

Urakov AL. Decolorant of blood. RU2647371C1, 15.03.2018

16

Urakov AL, Urakova NA, Urakoa TV, et al. Method for whitening of bruise under eye. RU2639283C1, 20.12.2017

17

Urakova NA, Urakov AL, Urakova TV, et al. Means for intravital skin whitening near blue eyes.  RU2639485C1, 21.12.2017

18

Urakov AP, Reshetnikov AP, Gadelshina AA. Bleaching cleanser of dentures. RU 2659952C1,  04.07.2018

19

Urakova NA, Urakov AL. Method of emergency bleaching of skin hematoma under eye. RU2679334, 07.02.2019

20

Urakov AL, Ales MY, Shabanov PD. Method of using plaque removal solution with irrigation agent. RU2723138C1, 09.06.2020

21

Urakov AL, Urakova NA, Urakova TV, et al. Cream-milk for zoster treatment.   RU2634264C1, 24.10.2017

 

Topical hyperthermia is used to enhance the discoloring, hemolytic, anti-inflammatory, and keratolytic action of drugs on the skin, within the skin, under the skin, and under the nail

 

22

Reshetnikov AP, Urakov AL, Urakova NA, et al. Method of express cleaning of blood stains off clothes. RU 2371532C1, 27.10.2009

23

Urakov AL, Stolyarenko AP. Gel for children's skin. RU2713943C1, 11.02.2020

24

Urakov AL, Ales MY, Samilina IA, et al. Peeling agent for foot hyperkeratosis. RU2730451C1, 24.08.2020

 

Local hyperthermia is used to enhance the mucolytic, pyolytic, hemolytic action of drugs within the intra-airways

 

25

Urakov AL, Reshetnikov AP, Martyusheva VI, et al. Method of treatment of compensated form of chronic tonsillitis. RU2806490C1, 01.11.2023

26

Samilina IA, Ales MY, Urakov AL, et al. Aerosol for inhalations in obstructive bronchitis. RU2735502C1, 03.11.2020

27

 Urakov AL, Urakova NA. Aerosol for invasive mechanical ventilation in COVID-19.  RU2742505C1, 08.02.2021

28

Urakov AL, Urakova NA, Shabanov PD, et al. Warm alkaline solution of hydrogen peroxide for intrapulmonary injection. RU2807851C1, 21.11.2023.

29

Urakov AL, Urakova NA, Fisher EL. Oxygenated warm alkaline solution of hydrogen peroxide for intrapulmonary injection. RU2831821C1, 16.12.2024.

 

Finally, in 2023, it was shown that local hyperthermia, which can develop at injection sites of medicinal solutions, plays an important role in the development of local post-injection complications [4]. There were also early reports that temperature changes may be a factor in the antimicrobial and anti-infective activity of not only antiseptics and pyolytics, but also antibiotics [7, 77-80]. However, there is currently insufficient data to accurately explain the role of therapeutic hyperthermia when combined with antibiotics and other chemotherapeutic drugs in the treatment of local infectious processes. At the same time, the results of the conducted studies indicate the tolerance of patients to local hyperthermia, which indicates its safety.

 Therefore, there is a hyperthermic method for optimizing the chemical, physical, physical-chemical, mechanical, biochemical, biophysical properties and mechanism of action of coagulants, antiseptics, pyolytics, bleaching, cleansing, vasoconstrictor and hemostatic drugs when applied topically. This method is based on artificially increasing the local temperature in a selected part of the patient's body from +37 to +42 °C with the local interaction of drugs. It is assumed that, in accordance with the Arrhenius law, an increase in temperature of 5 °C accelerates  by 1.5 times the rate of chemical and physical-chemical processes underlying the local action of these drugs. In addition, hyperthermia improves the elasticity of protein, lipid, and protein-lipid complexes and tissues, reduces the specific gravity of tissues and drugs, and optimizes the rheological properties of both at the same time [62, 63, 67, 71, 76, 81-84]. This accelerates the diffusion of drugs into biological tissues and increases the penetrating activity of drugs.

 

3.3. Temperature at +37 °C as a factor of virulence of pathogenic bacteria, their reproduction and lifespan

 

Before entering the human body, pathogenic bacteria (and other infectious agents) are present in the air, water, food, and/or in the organisms of biological objects that carry infections, in particular insects (mosquitoes, ticks, etc.). Since microorganisms and insects are cold-blooded, their temperature depends on the ambient temperature, which is usually lower than the human body temperature [85]. In other words, pathogenic microorganisms are in cold conditions until they enter the human body [86] (Figure 4).

 

 Figure 4. Habitat of pathogenic microorganisms. Reproduced with permission from Engelkirk PG and Burton GR (eds.) (2006) Epidemiology and public health. In: Burton’s Microbiology for the Health Sciences, 8th edn., ch. 11. Baltimore: Lippincott Williams and Wilkins.

 

It has been established that pathogenic microorganisms have low virulence and reproduction rate in cold conditions, but this activity increases with increasing temperature from +22 to +42 °C [87-90]. The authors have shown that an increase in temperature from +22 °C to +37 °C is of great importance for pathogenic microorganisms. The fact is when the temperature of microorganisms increases from the level of cold atmospheric air to the level of human body temperature, temperature activation of virulence genes occurs in microorganisms. In addition, it has been shown that the virulence of pathogenic microorganisms can increase with an increase in temperature above +37 °C up to +42 °C. However, the temperature regulation of the virulence of pathogenic microorganisms, which controls their adaptation to cold outside the human body and to heat inside the human body, remains insufficiently studied.

Other authors have shown that temperature changes greatly alter the metabolic rate and vital activity of pathogenic microorganisms [91-93]. It has been shown that an increase in the temperature of the habitat of such microorganisms from +30 to +37 °C increases the intensity of their metabolism and vital activity. Moreover, it has been found that a temperature change in the specified temperature range, even by 1 or 2 degrees Celsius, significantly alters the metabolism and vital activity of bacteria and viruses adapted to exist at normal human body temperature. In addition, it was found that in the temperature range between +35 and +37 °C, the conformational properties of gene proteins change, which may be responsible for the antigenic properties of pathogenic microorganisms and vaccines [85, 94-97]. It has also been reported that temperature affects not only the vital activity of pathogenic microorganisms, but also their life expectancy and the intensity of their population change. When the temperature rises to +37 °C, the lifespan of microorganisms is shortened and the change of their populations is accelerated [98-100]. It has also been reported that a sudden decrease in the temperature of bacteria from +37 to +20 °C has an effect on them that can be characterized as a low-temperature shock. The obtained results allowed the authors to assume that a change in temperature changes not only the intensity of metabolism, vital activity of microorganisms and population change, but also the conformational properties of genes. Therefore, temperature can affect the quality of vaccination and use of gamma-globulins in patients.

 

3.4. Temperature in the range +37 - +42 °C as a factor of effectiveness of antibacterial therapy

 

In recent years, there has been a growing interest in research aimed at combating the resistance of microorganisms to chemotherapeutic agents. In this regard, a number of researchers have begun to pay great attention to screening and evaluating the antimicrobial activity of antibiotics, antiseptics, and other antimicrobial agents under various in vitro model conditions. [101-103]. Earlier it was reported that the peculiarity of studies of the mechanism of action of drugs in vitro is that it is not so much the chemical formula of the main active substance and its dose that is of great importance, as the quality of the finished drug (powder, tablet, solution, ointment, cream, aerosol, etc.) [63, 81, 82, 104, 105]. The authors have shown that the local type of drug action depends not only on controlled indicators of drug quality, but also on uncontrolled physical-chemical properties of drugs and factors of local interaction. Moreover, the most important factor of local interaction is the local temperature [61, 62, 63, 75, 81, 105].

Under these conditions, some researchers began to take into account the dependence of the local antimicrobial effect of drugs not only on their dose and concentration, but also on the acid activity of drug solutions [106-108]. A very small part of the researchers took into account the local temperature. Nevertheless, thermosensitivity of the growth process of colonies of Staphylococcus aureus and E. Coli was shown [109]. It turned out that abactal, ciprobai, cefazolin, cefamizine, thienam and metrogil in concentrations of 0.025 mg/l delayed the growth of colonies of daily culture of Staphylococcus aureus and E. coli at 42 °C more effectively than at 37, 20 and 10 °C. Moreover, solutions of all chemotherapeutic agents of equal concentration had different antimicrobial activity under all temperature conditions. It was reported that cefamezin had the most pronounced antimicrobial activity, and metrogil had the weakest. In addition, such chemotherapy drugs as tienam and metrogil were deprived of antibacterial activity in hypothermia. These results led to the conclusion that an increase in the incubation temperature from +37 to +42 °C stimulates the growth of colonies of E. coli and Staphylococcus aureus and at the same time increases the antimicrobial activity of chemotherapeutic drugs.

Consequently, there is little evidence that hyperthermia can enhance bacteriostatic activity and optimize antibiotic-assisted chemotherapy in the treatment of patients with infection. Therefore, there is currently insufficient data to make a definitive conclusion about the usefulness of therapeutic hyperthermia in combination with antibiotic therapy [7]. Nevertheless, in recent years, a lot of data has appeared that clearly indicate a large influence of ambient temperature on the condition of laboratory animals in experiments, since temperature affects all animal functions, including immunity, the development of inflammation and the course of infections [110-116]. Similar data have also appeared on the effect of temperature on inflammation and immunity in humans [117].

In addition, in recent years, there have been reports of the effect of temperature regimes of +20 and +40 ° C on the vital activity and viability of the coronavirus associated with severe acute respiratory syndrome-2 (SARS-CoV-2). The results showed that when the virus was incubated at a temperature of +20 °C, the half-life of SARS-CoV-2 was from 1.7 to 2.7 days, and when SARS-CoV-2 was incubated at a temperature of +40 ° C, the half-life of the virus was reduced to several hours [118]. The authors reported that with an initial viral load, generally equivalent to the highest titers released by infected patients, SARS-CoV-2 survived on the surfaces of glass, stainless steel, paper or polymer banknotes for up to 28 days at a temperature of 20 °C, and died earlier than 24 hours at a temperature of +40 °C. Other authors have obtained similar data on the effect of temperature on the lifespan of viruses [119, 120]. The authors reported that an increase in temperature and relative humidity accelerated the inactivation of SARS-CoV-2 with antiseptic solutions on surfaces.

  1. DISCUSSION

Antibiotics are the mainstay of treatment for most infectious diseases. The antimicrobial effect of antibiotics is explained by the fact that they are included in the metabolism of microorganisms, thereby disrupting it and the functioning of bacteria, which impairs their reproduction [121, 122]. However, over many decades of antibiotic use, bacteria have acquired resistance to the due to various chemical, physics-chemical, and biochemical adaptation mechanisms, many of which depend on temperature [123, 124]. Antibiotic resistance reduces the effectiveness of antibiotic treatment of infectious diseases, increases economic costs and mortality [125-128].

To prevent antibiotic resistance, doctors everywhere are trying to improve rational antibacterial therapy using new chemotherapeutic antimicrobials [129-131]. However, experience in the treatment of chronic infectious diseases in elderly patients has shown that the exacerbation of infection in them is increasingly caused by microorganisms with cross-resistance [132, 133]. Therefore, even new antibiotics have not provided an urgent recovery for patients in recent years [134-136].

In these conditions, in recent years, there has been a proposal to consider hyperthermia as a possible natural ways to optimize infection treatment [7, 15, 137, 138]. But the rapid recognition of controlled hyperthermia as a method of treating infectious diseases is hampered by the opinion about the correctness of using antipyretic drugs for fever, which often accompanies many infectious diseases [11-14, 60]. Nevertheless, in recent years, reports have appeared, the authors of which remind that hyperthermia (fever) in an infectious disease may not always harm the patient's health, since initially (in the process of evolution) it was formed as a normal adaptive reaction of most healthy people to an infectious disease [7, 25]. However, the opposite view of fever still dominates among experts, namely, the idea of the harm of fever to health. In addition, until recently it was unknown how hyperthermia changes the resistance of microorganisms to antibiotics and antiseptics [35]. That is why the issue of the target temperature for antibiotic therapy of infectious diseases has not yet been resolved [38,45,46.57,58].

At the same time, our review showed that the maximum safe level of hyperthermia for human body cells is limited to a temperature of +42 °C [52]. This means that the maximum range of temperature rise (hyperthermia) for people with normothermia (+36.7 °C) is about 5 °C. An increase in temperature by 5 °C increases the rate of chemical reactions by 1.5 times (in accordance with the Arrhenius law) [42]. Consequently, a 5 °C increase in temperature provides a very significant increase in the intensity of microbial metabolism. Despite this, hyperthermic stimulation of the intensity of microbial metabolism is not adequately used to increase the antimicrobial activity of antibiotics and reduce the resistance of pathogenic microorganisms to them [56]. Nevertheless, hyperthermia can play just such a role, since there are reports that an increase in the temperature of organs and tissues from +37 to +42 ° C changes the chemical, mechanical, physico-chemical, biochemical and biophysical properties of biological tissues and some finished medicines (tablets, injection solutions, etc.) [52, 61-67, 139]. In particular, it has been shown that the topical use of hydrogen peroxide solutions heated to +42 °C enhances their anti-infective effect in the treatment of chronic wounds, purulent bronchitis, tonsillitis, bronchial asthma, blood asphyxia and COVID-19 [36, 72-76]. It has also been reported that the combination of hydrogen peroxide with local hyperthermia provides enhanced anti-infective effects. At the same time, a whole group of new anti-infective drugs was developed, called WAHPSs [75, 76, 140, 141]. In addition, the results of the development made it possible to convert hydrogen peroxide from antiseptics to pyolytics [82].

In addition, a review of patents for inventions showed that in 29 inventions, local hyperthermia was used to enhance the mechanism of action of drugs from several pharmacological groups when applied topically.

In our opinion, the positive role of hyperthermia can be explained by the fact that an increase in temperature to +42 ° C improves the elasticity of protein, lipid and protein-lipid complexes and tissues, reduces the specific gravity of tissues and drugs, optimizes the rheological properties of both of them and stimulates the metabolism of macroorganism cells and microorganisms [62, 63, 67, 71, 76, 81-84]. In this regard, hyperthermia accelerates the diffusion of drugs into biological tissues, increases the penetrating activity of antibiotics into the depths of human tissues and into the cells of microorganisms. That is why hyperthermia can be considered as a factor facilitating the process of including antibiotics in the biochemical processes of pathogenic bacteria.

In order to form ideas about therapeutic hyperthermia as a physical factor in stimulating the intensity of metabolism and vital activity of microorganisms, it is proposed to recall that pathogenic microorganisms are located outside the human body in cold conditions [91-93, 142]. In the human body, the temperature of infectious agents rises to +37 °C, which stimulates their metabolism, activates virulence genes, shortens the life of microorganisms and accelerates the change of their populations [91-93, 98-100]. However, a very small number of researchers consider hyperthermia as a factor of bacterial resistance to antibiotics. Only one dissertation was devoted to this problem [109]. It has been reported that abactal, ciprobai, cefazolin, cefamizine, thienam and metrogil in concentrations of 0.025 mg/l delay the growth of colonies of daily culture of Staphylococcus aureus and E. coli at +42 ° C more effectively than at +37, +20 and +10 ° C. At the same time, it was reported that an increase in the incubation temperature from +37 to +42 ° C stimulates the growth of colonies of E. coli and Staphylococcus aureus and at the same time increases the antimicrobial activity of chemotherapeutic drugs. Similar data on the acceleration of metabolism, shortening the life span of microorganisms, and enhancing the anti-infective effect of solutions of local antiseptics on them were obtained in experiments with pathogenic viruses when their temperature rose to +40 °C in vitro [118-120].

Nevertheless, these data obtained on Staphylococcus aureus and first published in 2005 were confirmed in studies by other authors only 15 years later [143-147]. The authors reported that the optimal growth temperature of these bacteria ranges from +33 to +41 °C. An increase in temperature above +41 °C can inhibit the growth and mobility of bacteria, which, in turn, can cause autolysis and damage to their cell wall. In this regard, the authors suggested that the use of hyperthermia in combination with antimicrobial drugs may lead to synergistic effects and reduce problems with antibiotic resistance. Therefore, the authors believe that the combination of antimicrobial drugs with therapeutic hyperthermia may increase the effectiveness of treatment of infectious diseases in the future.

In the last two decades, metal-organic frameworks (MOFs) with high structural restructuring ability and porosity have been used to achieve local therapeutic hyperthermia. They have become nanocarriers of medicines in the biomedical field. In particular, nanoscale MOFs (nanoMOFs) have been extensively researched due to their potential biocompatibility, high drug concentration, and gradual release. To achieve this goal, MOFs have been combined with magnetic nanoparticles (MNPs) to form magnetic nanocomposites (MNP@MOF) with additional functionalities. It has been reported that due to the magnetic properties of the MNPs, their presence in the nanosystems enables potential combinatorial magnetic targeted temperature management and diagnosis [148-152].

It has been reported that local hyperthermia and local chemotherapy have a high prospect in the treatment of malignant tumors in the future [153, 154]. In clinical conditions, it has been shown that an increase in local temperature to +39 - +45 °C induces sensitization of tumor cells to radiation and chemotherapy. Therefore, local hyperthermia enhances the chemotherapeutic activity of antitumor drugs. It was also reported that a breakthrough in targeted drug delivery "to the right place" is expected in the future. This, according to the authors, may further enhance the popularity of the combination of hyperthermia with tumor chemotherapy. In addition, it is reported about the possibility of using magnetic viral transduction in combination with local hyperthermia, which provides for the use of magnetic viral vectors in cancer therapy, regenerative medicine, tissue engineering, cell sorting and virus isolation [155-157].

Thus, there is every reason to assume that the study of the possibilities of treating infectious diseases using a combination of local hyperthermia with antibiotics is a promising direction in medical chemistry, medical physics and pharmacology. A review of the relevant literature and inventions shows that in recent years, the world has seen progress in research conducted in the field of targeted local hyperthermic and chemotherapeutic engineering. The first results indicate that the combination of local hyperthermia and chemotherapeutic drugs can enhance the inhibition of the proliferation of malignant cells and pathogenic bacteria. However, we still have a lot of research to do so that the developments made in the field of hyperthermic tumor chemotherapy can be successfully implemented not only in oncology, but also in hyperthermic chemotherapy of infectious diseases with antibiotics. To do this, it is necessary to conduct comprehensive large-scale studies of the temperature dependence of microbial resistance to antibiotics.

 

CONCLUSION

As described in the studies presented in this article, hyperthermia is increasingly being studied as a promising factor in enhancing the chemotherapeutic effect of antimicrobial and antitumor drugs on pathogenic bacteria and malignant tumor cells, as well as as a promising factor in disinfection of various surfaces using antiseptics. It has been shown that the safe range of hyperthermia for human body cells is 5 °C and is between +36.7 and +42 °C. It has been established that a local increase in temperature to +42 ° C softens the lipid and protein-lipid complexes of such biological tissues of the human body as blood, mucus, sputum, serous fluid and thick pus together with microorganisms. The consequence of this is an improvement in their rheological properties, which increases the penetrating ability of antibiotics when applied locally. This improves the local pharmacokinetics of antibiotics and facilitates their interaction with bacterial cells in their population. At the same time, hyperthermia accelerates the chemical, biochemical reactions, metabolism, vital activity of bacteria and their biological clock. It is reported that in the absence of antimicrobial drugs, hyperthermia shortens the lifespan of bacteria, increases the intensity of their reproduction and population change.  However, in the presence of antiseptics and antibiotics, hyperthermia promotes the death of microorganisms, reducing their resistance to antibiotics and antiseptics. At the same time, local hyperthermia remains safe for the patient's body. In other words, hyperthermia alters the chemical, biochemical, and physico-chemical properties of human biological tissues and pathogens of infectious diseases in such a way that it increases the antimicrobial activity of local antibiotics and antiseptics.

To date, the effect of hyperthermia on the resistance of Staphylococcus aureus and E. coli bacteria to antibiotics such as abactal, ciprobai, cefazolin, cefamizine, thienam and metrogil at concentrations of 0.025 mg/l has been studied. It was shown that these antibiotics delayed the growth of colonies of daily cultures of Staphylococcus aureus and E. coli at a temperature of +42 ° C more effectively than at temperatures of +37, +20 and +10 ° C. The results indicate that an increase in the incubation temperature from +37 to +42 °C reduces the resistance of Staphylococcus aureus and E. coli to antibiotics.

In vitro studies show that hyperthermia is an important factor in reducing bacterial resistance to antibiotics. In general, despite the few laboratory studies, it can be assumed that the combination of antibiotics with therapeutic hyperthermia can optimize the use of antibiotics in the treatment of infectious diseases caused by pathogenic bacteria. The promise of this direction is confirmed by the successes achieved in the chemotherapy of malignant tumors using a combination of local hyperthermia and cytostatic drugs. There is reason to hope that hyperthermia can optimize the chemotherapy of infectious processes with antibiotics in a similar way to the chemotherapy of malignant tumors. The fact is that a limited purulent-inflammatory focus caused by infection with pathogenic bacteria and a malignant tumor have similarities. This similarity lies in the fact that they are an accumulation of a mass of intensively multiplying cells, the metabolism, vital activity and reproduction of which are equally amenable to temperature regulation by changing the local temperature and chemotherapeutic drugs.  It is hoped that the use of metal-organic frameworks (MOFs) with a high ability to rearrange the structure and porosity can become nanocarriers of antibiotics in the future.

In turn, the properties of MOFs with antibiotics may soon be significantly improved due to combined with magnetic nanoparticles (MNPs) to form magnetic nanocomposites (MNP@MOF). Therefore, we can hope that these medical technologies will be upgraded in the near future. It is likely that effective technologies of hyperthermic chemotherapy of malignant tumors will appear, which can also be used in hyperthermic therapy of infectious diseases. It is hoped that hyperthermic antibiotic therapy will reduce the resistance of pathogenic microorganisms to "old" and "new" antibiotics in the future.

 

AUTHOR CONTRIBUTIONS

AU, NU and DN provided the conceptualization, the methodology was adopted by AO, MR, LL and AS, software was developed by VOO, validation was performed by AS, VA and FE, formal analysis was conducted by AU, NU, AS and MR, LL and AS investigated the study, the resources were provided by FE and ABA, data were curated by AU, writing—original draft preparation was done by AU, MR, VA, FYA and VOO, writing-review and editing was performed by AU, MR and LL, AU and DN supervised the study. All authors contributed to drafting the first manuscript, and read, and approved the final manuscript.

 

LIST OF ABBREVIATIONS

ICU = intensive care unit

MOFs = metal-organic frameworks

MNPs = magnetic nanoparticles

NSAIDs = non-steroidal anti-inflammatory drugs

SARS-CoV-2 = severe acute respiratory syndrome-related coronavirus-2 is an enveloped single-stranded RNA virus from the coronavirus family

TTM = targeted temperature management

WAHPSs  = warm alkaline hydrogen peroxide solutions

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.           

 

×

Об авторах

Александр Ливиевич Ураков

Ижевская государственная медицинская академия Минздрава РФ, Ижевск

Автор, ответственный за переписку.
Email: alurakov@bk.ru
ORCID iD: 0000-0002-9829-9463
SPIN-код: 1613-9660

доктор медицинских наук, профессор, заведующий кафедрой 

Россия, 426034, Россия, Ижевск, ул. Коммунаров, 281.

Петр Дмитриевич Шабанов

Институт экспериментальной медицины

Email: pdshabanov@mail.ru
ORCID iD: 0000-0003-1464-1127
SPIN-код: 8974-7477

д-р мед. наук, профессор

Россия, Санкт-Петербург, Россия, 197022, ул. Академика Павлова, 12

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