Antibiotics and antibiotic resistance: from antiquity to the present day. Features of the use of antibacterial drugs in obstetric practice

IN last years hospital-acquired infections are increasingly caused by gram-negative organisms. Microorganisms belonging to the Enterobacteriaceae and Pseudomonas families have acquired the greatest clinical significance. From the family of enterobacteria, microorganisms of the genera Escherichia, Klebsiella, Proteus, Citrobacter, Enterobacter, Serratia - have often been mentioned in the literature as causative agents of postoperative complications, sepsis, meningitis. Most enterobacteria are opportunistic microorganisms, since normally these bacteria (with the exception of the genus Serratia) are obligate or transient representatives of the intestinal microflora, causing infectious processes under certain conditions in debilitated patients.

Intestinal gram-negative bacilli with resistance to third-generation cephalosporins were first identified in the mid-1980s in Western Europe. Most of these strains (Klebsiella pneumoniae, other Klebsiella species and Escherichia coli) were resistant to all beta-lactam antibiotics, with the exception of cephamycins and carbapenems. The genes that encode information about extended spectrum beta-lactamases are localized in plasmids, which facilitates the possibility of dissemination of extended spectrum beta-lactamases among gram-negative bacteria.

Studies of epidemics of nosocomial infections caused by extended-spectrum beta-lactamase-producing enterobacteria indicated that these strains arose in response to heavy use of third-generation cephalosporins.

The prevalence of extended-spectrum beta-lactamases in gram-negative bacilli varies between countries and among institutions within the same country, with frequent dependence on the range of antibiotics used. In a large US study, 1.3 to 8.6% of clinical E. coli and K. pneumoniae strains were resistant to ceftazidime. Some of the isolates in this study have been studied more closely, and it was found that in almost 50% of the strains, resistance was due to the production of extended spectrum beta-lactamase. Over 20 extended-spectrum beta-lactamases have been identified so far.

Clinical trials of antimicrobial therapy for infections caused by extended-spectrum beta-lactamase-producing bacteria are virtually non-existent, and the control databank for these pathogens consists of only anecdotal case reports and limited retrospective information from epidemiological studies. Data on the treatment of nosocomial epidemics caused by gram-negative bacteria that produce these enzymes indicate that some infections (eg, urinary tract infections) can be treated with fourth-generation cephalosporins and carbapenems, but severe infections are not always amenable to such treatment.

There is a sharp increase in the role of enterobacter as a pathogen. Enterobacter spp. notorious due to the ability to acquire resistance to beta-lactam antibiotics during therapy, and it is due to inactivating enzymes (beta-lactamases). The emergence of multidrug-resistant strains occurs through two mechanisms. In the first case, the microorganism is exposed to an enzyme inducer (such as a beta-lactam antibiotic) and increased levels of resistance occur as long as the inducer (antibiotic) is present. In the second case, a spontaneous mutation develops in the microbial cell to a stably derepressed state. Clinically, almost all manifestations of treatment failures are explained by this. Induced beta-lactamases cause the development of multiresistance during antibiotic therapy, including the second (cefamandol, cefoxitin) and third (ceftriaxone, ceftazidime) generations of cephalosporins, as well as antipseudomonal penicillins (ticarcillin and piperacillin).

A report of an outbreak of nosocomial infections in the neonatal intensive care unit shows how the routine use of broad-spectrum cephalosporins can lead to the emergence of resistant organisms. In this department, where for 11 years ampicillin and gentamicin were the standard empirical drugs for suspected sepsis, serious infections caused by gentamicin-resistant strains of K. pneumoniae began to appear. Gentamicin was replaced by cefotaxime and the outbreak was eradicated. But the second outbreak of severe infections caused by cefotaxime-resistant E.cloacae occurred 10 weeks later.

Heusser et al. warn of the dangers of empiric use of cephalosporins in infections of the central nervous system caused by gram-negative microorganisms, which may have inducible beta-lactamases. In this regard, alternative drugs are proposed that are not sensitive to beta-lactamases (trimethoprim / sulfamethoxazole, chloramphenicol, imipenem). Combination therapy with the addition of aminoglycosides or other antibiotics may be an acceptable alternative to cephalosporin monotherapy in the treatment of diseases caused by Enterobacter.

In the mid-1980s, Klebsiella infections became a therapeutic problem in France and Germany, as strains of K.pneumoniae appeared resistant to cefotaxime, ceftriaxone and ceftazidime, which were considered absolutely stable to the hydrolytic action of beta-lactamases. New varieties of beta-lactamases have been discovered in these bacteria. Highly resistant Klebsiella can cause nosocomial epidemics of wound infections and sepsis.

Pseudomonas is no exception in terms of the development of antibiotic resistance. All strains of P.aeruginosa have the cephalosporinase gene in their genetic code. To protect against antipseudomonas penicillins, plasmids carrying TEM-1-beta-lactamase can be imported into them. Also, genes for enzymes that hydrolyze antipseudomonas penicillins and cephalosporins are transmitted through plasmids. Aminoglycosidin-activating enzymes are also not uncommon. Even amikacin, the most stable of all aminoglycosides, is powerless. P. aeruginosa strains resistant to all aminoglycosides are becoming more and more, and for the doctor in the treatment of cystic fibrosis and burn patients, this often proves to be an insoluble problem. P.aeruginosa is increasingly resistant to imipenem as well.

Haemophilus influenzae - how long will cephalosporins work?

In the 1960s and 1970s, physicians followed recommendations about the advisability of using ampicillin against H. influenzae. 1974 marked the end of this tradition. A plasmid-borne beta-lactamase called TEM was then discovered. The frequency of isolation of beta-lactamase-resistant strains of H. influenzae varies between 5 and 55%. In Barcelona (Spain), up to 50% of H.influenzae strains are resistant to 5 or more antibiotics, including chloramphenicol and co-trimoxazole. The first report of resistance of this microorganism to cephalosporins, namely to cefuroxime, when an increased MIC of cefuroxime was found, already appeared in England in early 1992.

Fight against antibiotic resistance in bacteria

There are several ways to overcome the resistance of bacteria associated with the production of beta-lactamase, among them:

Synthesis of antibiotics of new chemical structures that are not affected by beta-lactamases (for example, quinolones), or chemical transformation of known natural structures;

Search for new beta-lactam antibiotics resistant to the hydrolytic action of beta-lactamases (new cephalosporins, monobactams, carbapenems, thienamycin);

Synthesis of beta-lactamase inhibitors.

The use of beta-lactamase inhibitors preserves the benefits of known antibiotics. Although the idea that beta-lactam structures could inhibit beta-lactamase originated as early as 1956, the clinical use of inhibitors did not begin until 1976 after the discovery clavulanic acid. Clavulanic acid acts as a "suicidal" enzyme inhibitor, causing irreversible suppression of beta-lactamases. This inhibition of beta-lactamase occurs by an acylation reaction, similar to the reaction in which a beta-lactam antibiotic binds to penicillin-binding proteins. Structurally, clavulanic acid is a beta-lactam compound. Lacking antimicrobial properties, it irreversibly binds beta-lactamases and disables them.

After the isolation of clavulanic acid, other beta-lactamase inhibitors (sulbactam and tazobactam) were subsequently obtained. In combination with beta-lactam antibiotics (ampicillin, amoxicillin, piperacillin, etc.), they exhibit a wide spectrum of activity against beta-lactamase-producing microorganisms.

Another way to combat antibiotic resistance in microorganisms is to organize monitoring of the prevalence of resistant strains through the creation of an international alert network. Identification of pathogens and determination of their properties, including sensitivity or resistance to antibiotics, must be carried out in all cases, especially when registering a nosocomial infection. The results of such studies must be summarized for each maternity hospital, hospital, microdistrict, city, region, etc. The obtained data on the epidemiological state should be periodically brought to the attention of the attending physicians. This will allow you to choose the right drug in the treatment of the child, to which the majority of strains are sensitive, and not to prescribe the one to which in the given area or medical institution the majority of strains are resistant.

Limiting the development of resistance of microorganisms to antibacterial drugs can be achieved by following certain rules, among which:

Conducting rationally based antibiotic therapy, including indications, targeted selection based on sensitivity and resistance level, dosage (low dosage is dangerous!), Duration (in accordance with the picture of the disease and individual condition) - all this involves advanced training of doctors;

It is reasonable to approach combination therapy, using it strictly according to indications;

The introduction of restrictions on the use medicines("barrier policy"), which implies an agreement between clinicians and microbiologists on the use of the drug only in the absence of the effectiveness of already used drugs (creation of a group of reserve antibiotics).

The development of resistance is an inevitable consequence of the widespread clinical use of antimicrobials. The variety of mechanisms by which bacteria acquire resistance to antibiotics is striking. All this requires efforts to find more effective ways to use available drugs, aimed at minimizing the development of resistance and determining the most effective methods treatment of infections caused by multidrug-resistant microorganisms.

ANTIBIOTICS AND CHEMOTHERAPY, 1998-N4, pp. 43-49.

LITERATURE

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4. Cohen M.L. Science 1992; 257:1050-1055.

5 Gibbons A. Ibid 1036-1038.

6 Hoppe J.E. Monatsschr Kinderheilk 1995; 143:108-113.

7. Leggiadro R.J. Curr Probl Pediatr 1993; 23:315-321.

9. Doern G.V., Brueggemann A., Holley H.P.Jr., Rauch A.M. Antimicrob Agents Chemother 1996; 40:1208-1213.

10. Klugman K.R. Clin Microbiol Rev 1990; 3:171-196.

11. Munford R.S., Murphy T.V. J Invest Med 1994; 42:613-621.

12. Kanra G.Y., Ozen H., Secmeer G. et al. Pediatr Infect Dis J 1995; 14:490-494.

13. Friedland I.R., Istre G.R. Ibid 1992; 11:433-435. 14. Jacobs M.R. Clin Infect Dis 1992; 15:119-127.

15. Schreiber J.R., Jacobs M.R. Pediatr Clinics North Am 1995; 42:519-537.

16. Bradley J.S., Connor J.D. Pediatr Infect Dis J 1991; 10:871-873.

17. Catalan M. J., Fernandez M., Vasquez A. et al. Clin Infect Dis 1994; 18:766-770.

18. Sloas M.M., Barret F.F., Chesney P.J. et al. Pediatr Infect Dis J 1992; 11:662-666.

19. Webby P.L., Keller D.S., Cromien J.L. et al. Ibid 1994; 13:281-286.

20. Mason E.O., Kaplan S.L., Lamberht L.B. et al. Antimicrob Agents Chemother 1992; 36: 1703-1707.

21. Rice L.B., Shlaes D.M. Pediatric Clin Nothing Am 1995; 42:601-618.

22. Christie C., Hammond J., Reising S. et al. J Pediatr 1994; 125:392-400.

23. Shay D.K., Goldmann D.A., Jarvis W.R. Pediatric Clin North Am 1995; 42:703-716.

24. Gaines R., Edwards J. Infect Control Hosp Epid 1996; 17: Suppl: 18.

25. Spera R.V., Faber B.F. JAMA 1992; 268:2563-2564.

26. Shay D.K., Maloney S.A., Montecalvo M. et al. J Infect Dis 1995; 172:993-1000.

27. Landman D., Mobarakai N.V., Quale J.M. Antimicrob Agents Chemother 1993; 37: 1904-1906.

28. Shlaes D.M., Etter L., Guttman L. Ibid 1991; 35:770-776.

29. Centers for Dis Contr and Prevention 1994; 59: 25758-25770.

30 Hospital Infect Contr Pract Advisory Comm. Infect Control Hosp Epid 1995; 16:105-113.

31. Jones R.N., Kehrberg E.N., Erwin M.E., Anderson S.C. Diagn Microbiol Infect Dis 1994; 19:203-215.

32. Veasy G.L., Tani L.Y., Hill H.R. J Pediatr 1994; 124:9-13.

33. Gerber M.A. Pediatric Clin North Am 1995; 42:539-551.

34. Miyamoto Y., Takizawa K., Matsushima A. et al. Antimicrob Agents Chemother 1978; 13:399-404.

35. Gerber M.A. Pediatrics 1996; 97: Suppl: Part 2: 971-975.

36. Voss A., Milatovic D., Wallrauch-Schwarz C. et al. Eur J Clin Microbiol Infect Dis 1994; 13:50-55.

37. Moreira B.M., Daum R.S. Pediatric Clin North Am 1995; 42:619-648. 38. Meyer R. Pädiatr Prax 1994; 46:739-750.

39. Naquib M.H., Naquib M.T., Flournoy D.J. Chemotherapy 1993; 39:400-404.

40. Walsh T.J., Standiford H.C., Reboli A.C. et al. Antimicrob Agents Chemother 1993; 37:1334-1342.

41. Hill R.L.R., Duckworth G.J., Casewell M.W. J Antimicrob Chemother 1988; 22:377-384.

42. Toltzis P., Blumer J.L. Pediatric Clin North Am 1995; 42:687-702.

43. Philippon A., Labia R., Jacoby G. Antimicrob Agents Chemother 1989; 33:1131-1136.

44 Sirot D., De Champs C., Chanal C. et al. Ibid 1991; 35: 1576-1581.

45. Meyer K.S., Urban C., Eagan J.A. et al. Ann Intern Med 1993; 119:353-358.

46. ​​Bush K., Jacoby G.A., Medeiros A.A. Antimicrob Agents Chemother 1995; 39:1211-1233.

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48. Bryan C.S., John J.F., Pai M.S. et al. Am J Dis Child 1985; 139:1086-1089.

49. Heusser M.F., Patterson J.E., Kuritza A.P. et al. Pediatr Infect Dis J 1990; 9:509-512.

50. Coovadia Y.M., Johnson A.P., Bhana R.H. et al. J Hosp Infect 1992; 22:197-205.

51. Reish O., Ashkenazi S., Naor N. et al. Ibid 1993; 25:287-294.

52. Moellering R.S. J Antimicrob Chemother 1993; 31: Suppl A: 1-8.

53. Goldfarb J. Pediatr Clin North Am 1995; 42:717-735.

54. Schaad U.B. Monatsschr Kinderheilk 1995; 143:1135-1144.

Solving the problem of antibiotic resistance in the hospital requires the development of a strategy for its prevention and containment, which would include several directions. The key ones are: measures aimed at limiting the use of antibiotics, conducting targeted epidemiological surveillance, observing the principles of isolation in case of infections, educating medical personnel and implementing administrative control programs.

Known Facts:

• The resistance of microorganisms to antimicrobial drugs is a global problem.
• Implementation of effective control over the rational use of antibiotics requires the solution of numerous problems.
• Policies that tightly control the use of antibiotics in the hospital can help reduce the incidence of antibiotic misuse and limit the emergence and spread of resistant strains of microorganisms.
• Isolation of sources of infection and the elimination of potential reservoirs of pathogens in the hospital are the most important measures. These sources include pathogen-colonized or infected patients, as well as colonized/infected medical personnel and contaminated medical equipment and supplies. Patients staying in a hospital for a long time are a constant source of infection, especially if they suffer from chronic diseases that occur with various pathological secretions, or have indwelling catheters installed.
• The basis of epidemiological surveillance is continuous monitoring to identify, confirm and register infections, their characteristics, trends in the frequency of development and determine the sensitivity to antimicrobial agents of their pathogens. Of particular importance for addressing the problem of antibiotic resistance is targeted surveillance aimed at monitoring and collecting information on the prescription of antibiotics in the hospital. ICUs are one of the most important sites for such targeted surveillance. The information obtained as a result of its implementation can serve as a basis for the development of a policy for the use of antibiotics in a hospital with the support of the administration.
• Conducting microbiological diagnosis of infection and prompt provision of its results (isolated pathogen and its sensitivity to antibiotics) are the main factors determining the rational choice and prescription of adequate antimicrobial therapy.

Contentious issues:

• Many believe that microbial resistance is solely the result of the misuse of antibiotics. However, resistance to antimicrobials will develop even if they are used correctly. Due to the fact that in modern medicine Antibiotics are an indispensable class of drugs and their use is necessary, the emergence of resistant microorganisms will be an inevitable adverse event in their use. Currently, there is an urgent need to revise many regimens of antibiotic therapy, which, probably, have a direct impact on the emergence of multidrug-resistant strains of microorganisms in a hospital setting.
• It is known that in most cases severe infections (bacteremia, pneumonia) caused by antibiotic-resistant strains of bacteria are accompanied by a higher rate of deaths than the same infections caused by susceptible strains of microorganisms. Despite this, the question of what results in a higher mortality rate requires further study.
• Currently, in many countries, especially in developing countries, there is a lack of adequate microbiological diagnosis of infections and two-way communication between microbiologists and clinicians. This greatly hinders the rational choice of antimicrobials and the implementation of infection control measures in the hospital.
• The use of antibiotics and the development of resistance to them in microorganisms are interrelated phenomena. Many people think that national recommendations and various strategies aimed at limiting the use of this group of drugs have not paid off. Despite this, there is now an unavoidable need to evaluate, review and implement recommendations for the rational choice and use of antibiotics, which should be adapted depending on existing practice and conditions in each particular hospital.

• Develop and implement administrative control measures:
  • antibiotic policy and hospital formularies;
  • protocols that will allow rapid identification, isolation and treatment of patients colonized or infected with antibiotic-resistant strains of bacteria, which in turn will help prevent the spread of infections in the hospital.
• Develop a system that allows monitoring the use of antibiotics (selection of a drug, dose, route of administration, frequency, number of courses), evaluate its results and, based on them, create appropriate recommendations, as well as concentrate resources for these purposes.
• Develop educational programs and conduct training aimed at increasing the knowledge of relevant medical personnel regarding: the consequences of the inappropriate use of antibiotics, the importance of strict implementation of infection control measures in cases of infections caused by multidrug-resistant strains of bacteria and compliance general principles infection control.
• Use a multidisciplinary approach to address antibiotic resistance strategically.

According to the Guidelines for infection control in the hospital. Per. from English / Ed. R. Wenzel, T. Brewer, J.-P. Butzler - Smolensk: IACMAC, 2003 - 272 p.

1

In recent years, the importance of studying microorganisms that can cause pathological changes in the human body. The relevance of the topic is determined by the increasing attention to the problem of microorganism resistance to antibiotics, which is becoming one of the factors leading to the containment of the widespread use of antibiotics in medical practice. This article is devoted to the study of the overall picture of the isolated pathogens and antibiotic resistance of the most common. In the course of the work, data were studied bacteriological research biological material from patients of the clinical hospital and antibiograms for 2013-2015. According to received general information The number of isolated microorganisms and antibiograms is steadily increasing. According to the results obtained in the course of studying the resistance of isolated microorganisms to antibiotics of various groups, it is worth noting its variability first of all. To prescribe adequate therapy and prevent adverse outcomes, it is necessary to obtain timely data on the spectrum and level of antibiotic resistance of the pathogen in each case.

Microorganisms

antibiotic resistance

treatment of infections

1. Egorov N.S. Fundamentals of the doctrine of antibiotics - M .: Nauka, 2004. - 528 p.

2. Kozlov R.S. Modern tendencies antibiotic resistance of pathogens of nosocomial infections in the ICU of Russia: what lies ahead for us? // Intensive therapy. No. 4-2007.

3. Guidelines MUK 4.2.1890-04. Determination of the sensitivity of microorganisms to antibacterial drugs - Moscow, 2004.

4. Sidorenko S.V. Research on the spread of antibiotic resistance: practical implications for medicine//Infections and Antimicrobial Therapy.-2002, 4(2): P.38-41.

5. Sidorenko S.V. Clinical significance of antibiotic resistance of gram-positive microorganisms // Infections and antimicrobial therapy. 2003, 5(2): pp.3–15.

In recent years, the importance of studying microorganisms that can cause pathological changes in the human body has been growing significantly. New species, their properties, influence on the integrity of the body, biochemical processes occurring in it are being discovered and studied. And along with this, there is increasing attention to the problem of microorganism resistance to antibiotics, which is becoming one of the factors leading to the containment of the widespread use of antibiotics in medical practice. Various approaches to the practical use of these drugs are being developed to reduce the occurrence of resistant forms.

The aim of our work was to study the overall picture of the isolated pathogens and antibiotic resistance of the most common.

In the course of the work, the data of bacteriological studies of biological material from patients of the clinical hospital and antibiograms for 2013-2015 were studied.

According to the general information obtained, the number of isolated microorganisms and antibiograms is steadily increasing (Table 1).

Table 1. General information.

Basically, the following pathogens were isolated: about a third - Enterobacteria, a third - Staphylococcus, the rest (Streptococci, non-fermenting bacteria, Candida fungi) are slightly less. At the same time, from the top respiratory tract, ENT organs, wounds - gram-positive coccal flora was more often isolated; gram-negative rods - more often from sputum, wounds, urine.

The pattern of antibiotic resistance of S. aureus over the years under study does not allow us to identify unambiguous patterns, which is quite expected. So, for example, resistance to penicillin tends to decrease (however, it is at a fairly high level), and to macrolides it increases (table 2).

Table 2. Resistance of S.aureus.

Penicillins
Methicillin
Vancomycin
Linezolid
Fluoroquinolones
Macrolides
Azithromycin
Aminoglycosides
Synercid
Nitrofurantoin
Trimethaprim/sulfamethoxazole
Tigecycline
Rifampicin

In accordance with the result obtained in the treatment of this pathogen, effective drugs (resistance to which is falling) are: Cephalosporins of I-II generations, "Protected" Penicillins, Vancomycin, Linezolid, Aminoglycosides, Fluoroquinolones, Furan; undesirable - Penicillins, Macrolides.

As for the studied streptococci, group A pyogenic streptococcus retains high sensitivity to traditional antibiotics, that is, their treatment is quite effective. Variations occur among isolated group B or C streptococci, where resistance gradually increases (Table 3). For treatment, Penicillins, Cephalosporins, Fluoroquinolones should be used, and Macrolides, Aminoglycosides, Sulfonamides should not be used.

Table 3. Streptococcus resistance.

Enterococci are more resistant by nature, so the range of choice of drugs is very narrow initially: "Protected" Penicillins, Vancomycin, Linezolid, Furan. The growth of resistance, according to the results of the study, is not observed. "Simple" Penicillins, Fluoroquinolones remain undesirable for use. It is important to consider that Enterococci have species resistance to Macrolides, Cephalosporins, Aminoglycosides.

A third of the isolated clinically significant microorganisms are Enterobacteria. Isolated from patients of the departments of Hematology, Urology, Nephrology, they are often low-resistant, in contrast to those sown in patients of intensive care units (Table 4), which is also confirmed in all-Russian studies. When prescribing antimicrobial drugs, a choice should be made in favor of the following effective groups: "Protected" Amino- and Ureido-Penicillins, "Protected" Cephalosporins, Carbapenems, Furan. It is undesirable to use Penicillins, Cephalosporins, Fluoroquinolones, Aminoglycosides, resistance to which has increased in the last year.

Table 4. Resistance of Enterobacteria.

Penicillins
Amoxicillin/clavulonate
Piperacillin/tazobactam
III (=IV) generation cephalosporins
Cefoperazone/sulbactam
Carbapenems
Meropenem
Fluoroquinolones
Aminoglycoside
Amikacin
Nitrofurantoin
Trimethaprim/sulfamethoxazole
Tigecycline

According to the results obtained in the course of studying the resistance of isolated microorganisms to antibiotics of various groups, it is worth noting its variability first of all. Accordingly, a very important point is the periodic monitoring of the dynamics and the application of the data obtained in medical practice. To prescribe adequate therapy and prevent adverse outcomes, it is necessary to obtain timely data on the spectrum and level of antibiotic resistance of the pathogen in each specific case. The irrational prescription and use of antibiotics can lead to the emergence of new, more resistant strains.

Bibliographic link

Styazhkina S.N., Kuzyaev M.V., Kuzyaeva E.M., Egorova E.E., Akimov A.A. THE PROBLEM OF ANTIBIOTIC RESISTANCE OF MICROORGANISMS IN A CLINICAL HOSPITAL // International Student Scientific Bulletin. - 2017. - No. 1.;
URL: http://eduherald.ru/ru/article/view?id=16807 (date of access: 01/30/2020). We bring to your attention the journals published by the publishing house "Academy of Natural History"

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Modern views on the problem of antibiotic resistance and its overcoming in clinical pediatrics

We know that antibiotic resistance has always existed. Until now, there has not been (and probably hardly ever will be) an antibiotic effective against all pathogenic bacteria.

Resistance of microorganisms to antibiotics can be true and acquired. True (natural) resistance is characterized by the absence of an antibiotic target in microorganisms or the inaccessibility of the target due to initially low permeability or enzymatic inactivation. When bacteria are naturally resistant, antibiotics are clinically ineffective.

Acquired resistance is understood as the property of individual strains of bacteria to remain viable at those concentrations of antibiotics that suppress the bulk of the microbial population. The emergence of acquired resistance in bacteria is not necessarily accompanied by a decrease in the clinical effectiveness of the antibiotic. The formation of resistance in all cases is genetically determined - the acquisition of new genetic information or a change in the level of expression of one's own genes.

The following biochemical mechanisms of bacterial resistance to antibiotics are known: modification of the target of action, inactivation of the antibiotic, active removal of the antibiotic from the microbial cell (efflux), impaired permeability of the external structures of the microbial cell, formation of a metabolic shunt.

The reasons for the development of resistance of microorganisms to antibiotics are diverse, among them a significant place is occupied by the irrationality, and sometimes the fallacy of the use of drugs.

1. Unreasonable appointment antibacterial agents.

An indication for the appointment of an antibacterial drug is a documented or suspected bacterial infection. The most common mistake in outpatient practice, observed in 30-70% of cases, is the appointment antibacterial drugs with viral infections.

2. Mistakes in choosing an antibacterial drug.

The antibiotic should be selected taking into account the following main criteria: the spectrum of antimicrobial activity of the drug in vitro, the regional level of resistance of pathogens to the antibiotic, proven efficacy in controlled clinical trials.

3. Errors in choosing the dosage regimen of the antibacterial drug.

Errors in choosing the optimal dose of an antibacterial agent can be both in insufficient and excessive doses of the prescribed drug, as well as in the wrong choice of intervals between injections. If the antibiotic dose is insufficient and does not create concentrations in the blood and tissues of the respiratory tract that exceed the minimum inhibitory concentrations of the main infectious agents, which is a condition for the eradication of the corresponding pathogen, then this becomes not only one of the reasons for the ineffectiveness of therapy, but also creates real prerequisites for the formation of resistance of microorganisms.

The wrong choice of intervals between the administration of antibacterial drugs is usually due not so much to the difficulties of parenteral administration of drugs on an outpatient basis or the negative mood of patients, but to the ignorance of practitioners about some pharmacodynamic and pharmacokinetic features of drugs that should determine their dosing regimen.

4. Mistakes in the combined prescription of antibiotics.

One of the mistakes of antibiotic therapy in community respiratory infections is the unreasonable prescription of a combination of antibiotics. In the current situation, with a wide arsenal of highly effective broad-spectrum antibacterial drugs, the indications for combined antibiotic therapy are significantly narrowed, and the priority in the treatment of many infections remains with monotherapy.

5. Errors associated with the duration of antibiotic therapy.

In particular, at present, in some cases, unreasonably long antibiotic therapy is carried out in children. Such an erroneous tactic is primarily due to a lack of understanding of the purpose of the antibiotic therapy itself, which comes down primarily to the eradication of the pathogen or its suppression. further growth, i.e. aimed at suppressing microbial aggression.

In addition to these errors in prescribing antibacterial drugs, the development of antibiotic resistance is facilitated by the social problem of inadequate access to drugs, which leads to the appearance on the market of low-quality but cheap drugs, the rapid development of resistance to them and, as a result, the prolongation of the disease.

In general, the development of antibiotic resistance of microorganisms is associated with biochemical mechanisms developed in the course of evolution. There are the following ways of realization of antibiotic resistance in bacteria: modification of the target of antibiotic action, inactivation of the antibiotic itself, decrease in the permeability of the external structures of bacterial cells, formation of new metabolic pathways, and active removal of the antibiotic from the bacterial cell. Different bacteria have their own resistance development mechanisms.

Bacterial resistance to beta-lactam antibiotics develops when normal penicillin-binding proteins (PBPs) change; gaining the ability to produce additional PVR with low affinity for beta-lactams; excessive production of normal PBPs (PBP-4 and -5) with a lower affinity for beta-lactam antibiotics than PBP-1, -2, -3. In gram-positive microorganisms, the cytoplasmic membrane is relatively porous and directly adjacent to the peptidoglycan matrix, and therefore cephalosporins quite easily reach RVR. In contrast, the outer membrane of gram-negative microorganisms has a much more complex structure: it consists of lipids, polysaccharides and proteins, which is an obstacle to the penetration of cephalosporins into the periplasmic space of a microbial cell.

A decrease in the affinity of PVR for beta-lactam antibiotics is considered as the leading mechanism for the formation of resistance. Neisseria gonorrhea and S treptococcus pneumoniae to penicillin. Methicillin-resistant strains Staphylococcus aureus(MRSA) produce PBP-2 (PBP-2a), which are characterized by a significant decrease in affinity for penicillin-resistant penicillins and cephalosporins. The ability of these "new" PBP-2a to replace essential PBPs (with higher affinity for beta-lactams) eventually results in MRSA resistance to all cephalosporins.

Undoubtedly, objectively, the most clinically significant mechanism for the development of resistance of gram-negative bacteria to cephalosporins is beta-lactamase production.

Beta-lactamases are widely distributed among gram-negative microorganisms, and are also produced by a number of gram-positive bacteria (staphylococci). To date, more than 200 types of enzymes are known. Recently, up to 90% of resistant strains of bacteria isolated in the clinic are capable of producing beta-lactamases, which determines their resistance.

Not so long ago, the so-called extended-spectrum beta-lactamases encoded by plasmids (extended-spectrum beta-lactamases - ESBL) were also discovered. ESBLs are derived from TEM-1, TEM-2, or SHV-1 due to a point mutation in the active site of enzymes and are predominantly produced Klebsiella pneumoniae. ESBL products are associated with high level resistance to aztreonam and third-generation cephalosporins - ceftazidime, etc.

Production of beta-lactamases is under the control of chromosomal or plasmid genes, and their production can be induced by antibiotics or mediated by constitutional factors in the growth and distribution of bacterial resistance with which plasmids carry genetic material. The genes encoding antibiotic resistance either arise as a result of mutations or get inside the microbes from the outside. For example, when resistant and susceptible bacteria are conjugated, resistance genes can be transferred using plasmids. Plasmids are small genetic elements in the form of DNA strands enclosed in a ring, capable of transferring from one to several resistance genes not only among bacteria of the same species, but also among microbes of different species.

In addition to plasmids, resistance genes can enter bacteria with the help of bacteriophages or be captured by microbes from environment. In the latter case, free DNA of dead bacteria are carriers of resistance genes. However, the introduction of resistance genes by bacteriophages or the capture of free DNA containing such genes does not mean that their new host has become resistant to antibiotics. For the acquisition of resistance, it is necessary that the genes encoding it be incorporated into plasmids or into bacterial chromosomes.

Inactivation of beta-lactam antibiotics by beta-lactamase at the molecular level is presented as follows. Beta-lactamases contain stable combinations of amino acids. These groups of amino acids form a cavity into which the beta-lactam enters such that the serine at the center cuts the beta-lactam bond. As a result of the free reaction hydroxyl group the amino acid serine, which is part of the active center of the enzyme, with the beta-lactam ring, an unstable acyl ester complex is formed, which is rapidly hydrolyzed. As a result of hydrolysis, the active enzyme molecule and the destroyed antibiotic molecule are released.

From a practical point of view, when characterizing beta-lactamases, several parameters must be taken into account: substrate specificity (the ability to hydrolyze individual beta-lactam antibiotics), sensitivity to inhibitors, and gene localization.

The generally accepted classification of Richmond and Sykes divides beta-lactamases into 5 classes depending on the effect on antibiotics (according to Yu.B. Belousov, 6 types are distinguished). Class I includes enzymes that break down cephalosporins, class II includes penicillins, and class III and IV include various broad-spectrum antibiotics. Class V includes enzymes that break down isoxazolylpenicillins. Chromosome-associated beta-lactamases (I, II, V) cleave penicillins, cephalosporins, and plasmid-associated (III and IV) cleave broad-spectrum penicillins. In table. 1 shows the classification of beta-lactamase according to K. Bush.

Individual members of the family Enterobacteriaceae(Enterobacter spp., Citrobacter freundii, Morganella morganii, Serratia marcescens, Providencia spp.), as well as Pseudomonasaeruginosa demonstrate the ability to produce inducible chromosomal cephalosporinases, characterized by a high affinity for cephamycins and third-generation cephalosporins. Induction or stable "derepression" of these chromosomal beta-lactamases during the period of "pressure" (use) of cephamycins or third-generation cephalosporins will eventually lead to the formation of resistance to all available cephalosporins. The spread of this form of resistance increases in cases of treatment of infections, primarily caused by Enterobacter cloaceae And Pseudomonas aeruginosa, broad-spectrum cephalosporins.

Chromosomal beta-lactamases produced by gram-negative bacteria are divided into 4 groups. The 1st group includes chromosomal cephalosporinases (I class of enzymes according to Richmond - Sykes), the 2nd group of enzymes cleaves cephalosporins, in particular cefuroxime (cefuroximases), the 3rd group includes beta-lactamases with a wide spectrum of activity, the 4th group includes enzymes produced by anaerobes.

Chromosomal cephalosporinases are divided into two subtypes. The first group includes beta-lactamases produced by E.coli, Shigella, P. mirabilis; in the presence of beta-lactam antibiotics, they do not increase the production of beta-lactamase. In the same time P.aeruginosae, P. rettgeri, Morganella morganii, E.cloaceae, E.aerogenes, Citrobacter, Serratia spp. can produce large amounts of enzymes in the presence of beta-lactam antibiotics (second subtype).

For infection caused P.aeruginosae, the production of beta-lactamase is not the main mechanism of resistance, i.e. only 4-5% of resistant forms are due to the production of plasmids and chromosome-associated beta-lactamases. Basically, resistance is associated with a violation of the permeability of the bacterial wall and an abnormal structure of the PSP.

Chromosomal cefuroximases are low molecular weight compounds that are active in vitro against cefuroxime and are partially inactivated by clavulanic acid. Cefuroximases are produced P. vulgaris, P. cepali, P. pseudomallei. Labile first-generation cephalosporins stimulate the production of this type of beta-lactamase. Possible induction of cefuroximases and stable cephalosporins. Klebsiella synthesize chromosomally determined class IV beta-lactamases, which destroy penicillin, ampicillin, first-generation cephalosporins (broad-spectrum beta-lactamases), and other cephalosporins.

Chromosomal beta-lactamases of Gram-negative bacteria ( Morganella, Enterobacter, Pseudomonas) are more intensively produced in the presence of ampicillin and cefoxitin. However, their production and activity are inhibited by clavulanic acid and especially sulbactam.

Plasmid-associated beta-lactamases produced by gram-negative bacteria, primarily E. coli and P.aeruginosae, determine the overwhelming number of nosocomial strains resistant to modern antibiotics. Numerous beta-lactamase enzymes inactivate not only penicillins, but also oral cephalosporins and first-generation drugs, as well as cefomandol, cefazolin, and cefoperazone. Enzymes such as PSE-2, OXA-3 hydrolyze and determine the low activity of ceftriaxone and ceftazidime. The stability of cefoxitin, cefotetan, and lactamocef to enzymes such as SHV-2 and CTX-1 has been described.

Since beta-lactamases play an important role in the ecology of a number of microorganisms, they are widely distributed in nature. So, in the chromosomes of many species of gram-negative microorganisms, beta-lactamase genes are found in natural conditions. It is obvious that the introduction of antibiotics into medical practice has radically changed the biology of microorganisms. Although the details of this process are unknown, it can be assumed that some of the chromosomal beta-lactamases were mobilized into mobile genetic elements (plasmids and transposons). The selective advantages conferred on microorganisms by the possession of these enzymes have led to the rapid spread of the latter among clinically relevant pathogens.

The most common enzymes with chromosomal localization of genes are class C beta-lactamases (group 1 according to Bush). The genes for these enzymes are found on the chromosomes of almost all Gram-negative bacteria. Class C beta-lactamases with chromosomal localization of genes are characterized by certain features of expression. Some microorganisms (for example, E.coli) chromosomal beta-lactamases are constantly expressed, but at a very low level, insufficient even for the hydrolysis of ampicillin.

For microorganisms of the group Enterobacter, Serratia, Morganella and others, an inducible type of expression is characteristic. In the absence of antibiotics in the environment, the enzyme is practically not produced, but after contact with some beta-lactams, the rate of synthesis increases sharply. In violation of regulatory mechanisms, constant overproduction of the enzyme is possible.

Despite the fact that more than 20 class C beta-lactamases localized on plasmids have already been described, these enzymes have not yet become widespread, but in the near future they may become a real clinical problem.

Chromosomal beta-lactamases K.pneumoniae, K.oxytoca, C. diversus And P. vulgaris belong to class A, they are also characterized by differences in expression. However, even in the case of hyperproduction of these enzymes, microorganisms remain sensitive to some third-generation cephalosporins. The chromosomal beta-lactamases of Klebsiella belong to the 2be group according to Bush, and the beta-lactamases C. diversus And P. vulgaris- to group 2e.

For reasons that are not entirely clear, the mobilization of class A beta-lactamases to mobile genetic elements is more efficient than class C enzymes. Thus, there is every reason to assume that SHV1 plasmid beta-lactamases, which are widespread among gram-negative microorganisms, and their derivatives originated from chromosomal beta-lactamases K.pneumoniae.

Historically, the first beta-lactamases to cause serious clinical problems were staphylococcal beta-lactamases (Bush group 2a). These enzymes effectively hydrolyze natural and semi-synthetic penicillins, partial hydrolysis of first generation cephalosporins is also possible, they are sensitive to the action of inhibitors (clavulanate, sulbactam and tazobactam).

Enzyme genes are localized on plasmids, which ensures their rapid intra- and interspecies distribution among Gram-positive microorganisms. Already by the mid-1950s, in a number of regions, more than 50% of staphylococcal strains produced beta-lactamase, which led to a sharp decrease in the effectiveness of penicillin. By the end of the 1990s, the frequency of beta-lactamase production among staphylococci exceeded 70-80% almost everywhere.

In gram-negative bacteria, the first class A plasmid beta-lactamase (TEM-1) was described in the early 1960s, shortly after the introduction of aminopenicillins into medical practice. Due to the plasmid localization of the genes, TEM-1 and two other class A beta-lactamases (TEM-2, SHV-1) spread within a short time among members of the family Enterobacteriaceae and other gram-negative microorganisms almost everywhere.

These enzymes are called broad-spectrum beta-lactamases. Broad-spectrum beta-lactamases are group 2b according to the Bush classification. Practically important properties broad spectrum beta-lactamase are as follows:

- III-IV generation cephalosporins and carbapenems are resistant to them;

- the ability to hydrolyze natural and semi-synthetic penicillins, cephalosporins of the first generation, partially cefoperazone and cefamandol;

The period from the late 60s to the mid-80s was marked by the intensive development of beta-lactam antibiotics; carboxy- and ureidopenicillins, as well as three generations of cephalosporins, were introduced into practice. In terms of the level and spectrum of antimicrobial activity, as well as pharmacokinetic characteristics, these drugs were significantly superior to aminopenicillins. Most cephalosporins II and III generation, in addition, were resistant to broad-spectrum beta-lactamases.

For some time after the introduction of II-III generation cephalosporins into practice, there was practically no acquired resistance to them among enterobacteria. However, already in the early 1980s, the first reports of strains with plasmid localization of resistance determinants to these antibiotics appeared. Rather quickly it was established that this resistance is associated with the production by microorganisms of enzymes genetically related to broad-spectrum beta-lactamases (TEM-1 and SHV-1), the new enzymes were called extended-spectrum beta-lactamases (ESBLs).

The first extended spectrum enzyme identified was TEM-3 beta-lactamase. To date, about 100 derivatives of the TEM-1 enzyme are known. TEM-type beta-lactamases are most often found among E.coli And K.pneumoniae, however, their detection is possible among almost all representatives Enterobacteriaceae and a number of other Gram-negative microorganisms.

According to the Bush classification, TEM- and SHV-type beta-lactamases belong to the 2be group. Practically important properties of BLRS are the following:

- the ability to hydrolyze cephalosporins I-III and, to a lesser extent, IV generation;

— carbapenems are resistant to hydrolysis;

- cefamycins (cefoxitin, cefotetan and cefmetazole) are resistant to hydrolysis;

- sensitivity to the action of inhibitors;

— plasmid localization of genes.

Among the TEM- and SHV-type beta-lactamases, enzymes with a peculiar phenotype have been described. They are not sensitive to the action of inhibitors (clavulanate and sulbactam, but not tazobactam), but their hydrolytic activity against most beta-lactams is lower than that of precursor enzymes. The enzymes, called "inhibitor-resistant TEM" (IRT), are included in group 2br according to the Bush classification. In practice, microorganisms possessing these enzymes show high resistance to protected beta-lactams, but are only moderately resistant to I-II generation cephalosporins and sensitive to III-IV generation cephalosporins. However, it should be noted that some beta-lactamases combine resistance to inhibitors and an extended spectrum of hydrolytic activity.

Enzymes whose number of representatives has increased quite rapidly in recent years include CTX-type beta-lactamases (cefotaximases), which represent a clearly defined group that differs from other class A enzymes. The preferred substrate for these enzymes, in contrast to TEM and SHV derivatives, is not ceftazidime or cefpodoxime, but cefotaxime. Cefotaximases are found in various representatives Enterobacteriaceae(mainly for E.coli And Salmonella enterica) in geographically remote regions of the world. At the same time, the distribution of clone-related strains has been described in Eastern Europe. Salmonella typhimurium producing the CTX-M4 enzyme. According to the Bush classification, CTX-type beta-lactamases belong to the 2be group. The origin of CTX-type enzymes is unclear. A significant degree of homology is found with chromosomal beta-lactamases K.oxytoca, C. diversus, P. vulgaris, S.fonticola. A high degree of homology with chromosomal beta-lactamase has recently been established. Kluyvera ascorbata.

A number of rare class A enzymes are also known to have a phenotype characteristic of ESBL (the ability to hydrolyze third-generation cephalosporins and sensitivity to inhibitors). These enzymes (BES-1, FEC-1, GES-1, CME-1, PER-1, PER-2, SFO-1, TLA-1 and VEB-1) were isolated from a limited number of strains. various kinds microorganisms in various regions of the world from South America to Japan. The listed enzymes differ in their preferred substrates (certain representatives of III generation cephalosporins). Most of these enzymes were described after the publication of Bush et al., and therefore their position in the classification has not been determined.

ESBL also includes class D enzymes. Their precursors, broad-spectrum beta-lactamases, which hydrolyze predominantly penicillin and oxacillin, are weakly sensitive to inhibitors, are distributed mainly in Turkey and France among P.aeruginosa. The genes for these enzymes are usually localized on plasmids. Most of the enzymes showing the extended spectrum phenotype (preferential hydrolysis of cefotaxime and ceftriaxone - OXA-11, -13, -14, -15, -16, -17, -8, -19, -28) are derived from the beta-lactamase OXA-10. According to the Bush classification, OXA-type beta-lactamases belong to group 2d.

Bush identifies several more groups of enzymes that differ significantly in properties (including the spectrum of action), but are usually not considered as extended-spectrum beta-lactamases. For enzymes from group 2, the predominant substrates are penicillins and carbenicillin, they are found among P.aeruginosa, Aeromonas hydrophilia, Vibrio cholerae, Acinetobacter calcoaceticus and some other gram-negative and gram-positive microorganisms, genes are more often localized on chromosomes.

For group 2e enzymes, cephalosporins are the predominant substrate, chromosomal inducible cephalosporinases are considered as a typical example. P. vulgaris. Beta-lactamases of this group are also described in Bacteroides fragilis and, less commonly, other microorganisms.

Group 2f includes rare class A enzymes capable of hydrolyzing most beta-lactams, including carbapenems. Livermore classifies these enzymes as extended-spectrum beta-lactamases, other authors do not.

In addition to the listed beta-lactamases, it is necessary to mention the last two groups of enzymes included in the Bush classification. Group 3 enzymes include rare but potentially extremely important class B metallo-beta-lactamases, regularly found among Stenotrophomonas maltophilia and rarely found in other microorganisms ( B. fragilis, A. hydrophila, P.aeruginosa and etc.). A distinctive feature of these enzymes is the ability to hydrolyze carbapenems. Group 4 includes poorly studied penicillinases P.aeruginosa suppressed by clavulanic acid.

The incidence of ESBL varies greatly in certain geographic regions. Thus, according to the multicenter study MYSTIC, in Europe, the highest incidence of ESBL is consistently noted in Russia and Poland (more than 30% of all studied strains of enterobacteria). In some medical institutions of the Russian Federation, the frequency of ESBL production among Klebsiella spp. exceeds 90%. Depending on the specifics of the medical institution, the most common in it can be various mechanisms resistance (methicillin resistance, resistance to fluoroquinolones, hyperproduction of chromosomal beta-lactamases, etc.).

ESBLs, as already mentioned, have a wide spectrum of activity; to one degree or another, they hydrolyze almost all beta-lactam antibiotics, with the exception of cephamycins and carbapenems.

However, the presence in a microorganism of a determinant of resistance to any antibiotic does not always mean a clinical failure in the treatment with this drug. So, there are reports of high efficiency III generation cephalosporins in the treatment of infections caused by ESBL-producing strains.

Worldwide, in order to improve the effectiveness and safety of antibacterial and antiviral agents and preventing the development of antibiotic resistance, societies and associations are being created, declarations are being adopted, and educational programs on rational antibiotic therapy are being developed. The most important of them include:

- “Public health action plan to combat antibiotic resistance”, proposed by the American Society for Microbiology and several US agencies, 2000;

— WHO Global Strategy to Contain Antibiotic Resistance, 2001.

In addition, Canada (2002) adopted the World Declaration on Combating Antimicrobial Resistance, which states that antibiotic resistance correlates with their clinical failure, it is man-made, and only man can solve this problem, and unreasonable use of antibiotics by the population, misconceptions and underestimation of the problem of resistance by doctors and pharmacists who prescribe antibiotics can lead to the spread of resistance.

In our country, in 2002, in accordance with the order of the Ministry of Health of Ukraine No. 489/111 of December 24, 2002, a commission was established to control the rational use of antibacterial and antiviral agents.

The main tasks in the study of antibiotic sensitivity and antibiotic resistance are as follows:

— development of local and regional standards for the prevention and treatment of hospital and community-acquired infections;

- substantiation of measures to limit the spread of antibiotic resistance in hospitals;

— identifying the initial signs of the formation of new sustainability mechanisms;

— identification of patterns of global spread of individual resistance determinants and development of measures to limit it.

— implementation of a long-term forecast of the spread of individual resistance mechanisms and substantiation of directions for the development of new antibacterial drugs.

Antibiotic resistance and antibiotic sensitivity are studied both by "point" methods (within the same institution, district, state), and through dynamic observations of the spread of resistance.

It is difficult to compare data obtained using commercial antibiotic susceptibility testing systems from different manufacturers. Further complicating the situation are the existence of different national sensitivity criteria. Thus, only among European countries, national sensitivity criteria exist in France, Great Britain, Germany and a number of others. In individual institutions and laboratories, the methods for collecting material and assessing the clinical significance of isolates often differ significantly.

However, it should be noted that the use of an antibiotic does not always lead to antibiotic resistance (evidence of this is the sensitivity Enterococcus faecalis to ampicillin, which has not changed for decades) and, moreover, does not depend on the duration of use (resistance may develop during the first two years of its use or even at the stage of clinical trials).

There are several ways to overcome bacterial resistance to antibiotics. One of them is the protection of known antibiotics from being destroyed by bacterial enzymes or from being removed from the cell by means of membrane pumps. This is how "protected" penicillins appeared - combinations of semi-synthetic penicillins with bacterial beta-lactamase inhibitors. There are a number of compounds that inhibit the production of beta-lactamase, some of them have found their application in clinical practice:

- clavulanic acid;

- penicillanic acids;

- sulbactam (penicillanic acid sulfone);

- 6-chloropenicillanic acid;

- 6-iodopenicillanic acid;

- 6-bromopenicillanic acid;

- 6-acetylpenicillanic acid.

There are two types of beta-lactamase inhibitors. The first group includes antibiotics that are resistant to enzymes. Such antibiotics, in addition to antibacterial activity, have beta-lactamase inhibitory properties, which appear at high concentrations of antibiotics. These include methicillin and isoxazolylpenicillins, monocyclic beta-lactams such as carbapenem (thienamycin).

The second group consists of beta-lactamase inhibitors, which exhibit inhibitory activity at low concentrations and antibacterial properties at high concentrations. Examples include clavulanic acid, halogenated penicillanic acids, penicillanic acid sulfone (sulbactam). Clavulanic acid and sulbactam block the hydrolysis of penicillin by staphylococci.

The most widely used beta-lactamase inhibitors are clavulanic acid and sulbactam, which have hydrolytic activity. Sulbactam blocks beta-lactamase II, III, IV and V classes, as well as chromosome-mediated class I cephalosporinases. Clavulanic acid has similar properties. The difference between the drugs is that at much lower concentrations, sulbactam blocks the formation of chromosome-mediated beta-lactamases, and clavulanic acid blocks the formation of plasmid-associated enzymes. Moreover, sulbactam has an irreversible inhibitory effect on a number of lactamases. Inclusion of the beta-lactamase inhibitor clavulanic acid in the medium increases the sensitivity of penicillin-resistant staphylococci from 4 to 0.12 μg/ml.

Combinations of antibiotics also appear to be promising approaches to overcome bacterial resistance to antibiotics; conducting targeted and narrowly targeted antibiotic therapy; synthesis of new compounds belonging to known classes of antibiotics; search for fundamentally new classes of antibacterial drugs.

In order to prevent the development of resistance of microorganisms to drugs, the following principles should be followed:

1. Carry out therapy with the use of antibacterial drugs in maximum doses until the disease is completely overcome (especially in severe cases); the preferred route of drug administration is parenteral (taking into account the localization of the process).

2. Periodically replace widely used drugs with newly created or rarely prescribed (reserve) ones.

3. Theoretically, the combined use of a number of drugs is justified.

4. Drugs to which microorganisms develop resistance of the streptomycin type should not be prescribed as monotherapy.

5. Do not replace one antibacterial drug with another, to which there is cross-resistance.

6. To antibacterial drugs prescribed prophylactically or externally (especially in aerosol form), resistance develops faster than when they are administered parenterally or orally. Topical use of antibiotics should be kept to a minimum. In this case, as a rule, agents are used that are not used for systemic treatment and with a low risk of rapid development of resistance to them.

7. Evaluate the type of antibacterial drug (about once a year), which is most often used for therapeutic purposes, and analyze the results of treatment. It is necessary to distinguish between antibacterial drugs used most often and in severe cases, reserve and deep reserve.

8. Systematize diseases depending on the location of the focus of inflammation and the severity of the patient's condition; select antibacterial drugs for use in the relevant area (organ or tissue) and for use in exceptionally severe cases, and their use must be authorized by competent persons who are specifically involved in antibacterial therapy.

9. Evaluate periodically the type of pathogen and the resistance of strains of microorganisms circulating in the hospital environment, outline control measures to prevent nosocomial infection.

10. With the uncontrolled use of antibacterial agents, the virulence of infectious agents increases and drug-resistant forms appear.

11. Limit the use in the food industry and veterinary medicine of those drugs that are used to treat people.

12. As a way to reduce the resistance of microorganisms, the use of drugs with a narrow spectrum of action is recommended.

DECLARATION

on the fight against antimicrobial resistance, adopted at world day resistance (September 16, 2000, Toronto, Ontario, Canada)

We have found the enemy, and the enemy is us.

Recognized:

1. Antimicrobials (APs) are non-renewable resources.

2. Resistance correlates with clinical failure.

3. Resistance is created by man, and only man can solve this problem.

4. Antibiotics are social drugs.

5. Excessive use of AP by the population, misconceptions and underestimation of the problem of resistance by doctors and pharmacists who prescribe AP, lead to the spread of resistance.

6. The use of AP in agriculture and veterinary medicine contributes to the accumulation of resistance in the environment.

Actions:

1. Resistance monitoring and epidemiological surveillance should become routine both in the clinic and in the hospital.

2. Worldwide, the use of antibiotics as growth promoters in livestock must be stopped.

3. Rational use of AP is the main measure to reduce resistance.

4. Creation of educational programs for doctors and pharmacists who prescribe AP.

5. Development of new AP.

Offers:

1. It is necessary to create specialized institutions for the introduction of new AP and control over the development of resistance.

2. Committees for the control of AP should be established both in all medical institutions in which AP is prescribed, and in countries and regions to develop and implement policies for their use.

3. The duration of treatment and dosing regimens of AP should be reviewed in accordance with the structure of resistance.

4. It is advisable to conduct studies to determine the most active drug in the groups of antibiotics to control the development of resistance.

5. It is necessary to reconsider approaches to the use of AP for preventive and therapeutic purposes in veterinary medicine.

7. Development of antibiotics that specifically act on pathogens or are tropic to various organs and systems of the human body.

9. Pay more attention to educational work among the population.

WHO global strategy to contain antimicrobial resistance

On September 11, 2001, the World Health Organization released the Global Strategy to Contain Antimicrobial Resistance. This program aims to ensure the effectiveness of life-saving drugs such as antibiotics, not only for the current generation of people, but also in the future. Without concerted action by all countries, many of the great discoveries made by medical scientists over the past 50 years may lose their significance due to the spread of antibiotic resistance.

Antibiotics are one of the most significant discoveries of the 20th century. Thanks to them, it became possible to treat and cure those diseases that were previously fatal (tuberculosis, meningitis, scarlet fever, pneumonia). If mankind fails to protect this greatest achievement of medical science, it will enter the post-antibiotic era.

Over the past 5 years, more than $17 million has been spent by the pharmaceutical industry on research and development of drugs used to treat infectious diseases. If drug resistance develops rapidly in microorganisms, most of these investments may be lost.

The WHO strategy to contain antimicrobial resistance concerns everyone involved in one way or another in the use or prescribing of antibiotics, from patients to physicians, from hospital administrators to health ministers. This strategy is the result of 3 years of work by experts from WHO and collaborating organizations. It aims to promote the prudent use of antibiotics to minimize resistance and enable future generations to use effective antimicrobials.

Informed patients will be able not to put pressure on doctors to prescribe antibiotics. Educated physicians will prescribe only those drugs that are actually required to treat the patient. Hospital administrators will be able to conduct detailed monitoring of the effectiveness of medicines in the field. Ministers of health will be able to ensure that most drugs that are really needed are available for use, while ineffective drugs are not used.

The use of antibiotics in the food industry also contributes to the growth of antibiotic resistance. To date, 50% of all antibiotics produced are used in agriculture not only to treat sick animals, but also as growth stimulants for cattle and birds. Resistant microorganisms can be transmitted from animals to humans. To prevent this, WHO recommends a series of actions, including mandatory prescription of all antibiotics used in animals and phase-out of antibiotics used as growth promoters.

Antibiotic resistance is a natural biological process. We now live in a world where antibiotic resistance is spreading rapidly and a growing number of life-saving drugs are becoming ineffective. Microbial resistance has now been documented against antibiotics used to treat meningitis, sexually transmitted diseases, hospital infections, and even a new class of antiretroviral drugs used to treat HIV infection. In many countries, Mycobacterium tuberculosis is resistant to at least two of the most effective drugs used to treat tuberculosis.

This problem applies equally to both highly developed and industrialized and developing countries. The overuse of antibiotics in many developed countries, the short duration of treatment in the poor - ultimately creates the same threat to humanity as a whole.

Antibiotic resistance - global problem. There is no country that can afford to ignore it, and no country that can afford not to respond to it. Only simultaneous action to curb the growth of antibiotic resistance in each individual country will be able to positive results worldwide.

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Antibiotics are one of the greatest achievements of medical science, saving the lives of tens and hundreds of thousands of people every year. However, as folk wisdom says, there is a hole in the old woman. What used to kill pathogens no longer works the way it used to. So what is the reason: antimicrobials have become worse or antibiotic resistance is to blame?

Definition of antibiotic resistance

Antimicrobial drugs (ANTs), commonly referred to as antibiotics, were originally developed to fight bacterial infection. And due to the fact that various diseases can be caused not by one, but by several varieties of bacteria combined into groups, the development of drugs that are effective against a certain group of infectious pathogens was initially carried out.

But bacteria, although the simplest, but actively developing organisms, over time, acquiring more and more new properties. The instinct of self-preservation and the ability to adapt to various living conditions make pathogenic microorganisms stronger. In response to a threat to life, they begin to develop the ability to resist it, releasing a secret that weakens or completely neutralizes the effect of the active substance of antimicrobials.

It turns out that once effective antibiotics simply cease to fulfill their function. In this case, we talk about the development of antibiotic resistance to the drug. And the point here is not at all the effectiveness of the active substance AMP, but the mechanisms of improvement of pathogens, due to which bacteria become insensitive to antibiotics designed to fight them.

So, antibiotic resistance is nothing more than a decrease in the susceptibility of bacteria to antimicrobials that were created to destroy them. It is for this reason that treatment with seemingly correctly selected drugs does not give the expected results.

The problem of antibiotic resistance

The lack of effect of antibiotic therapy associated with antibiotic resistance leads to the fact that the disease continues to progress and becomes more severe, the treatment of which becomes even more difficult. Of particular danger are cases when a bacterial infection affects vital organs: the heart, lungs, brain, kidneys, etc., because in this case, delay in death is similar.

The second danger is that some diseases with insufficient antibiotic therapy can become chronic. A person becomes a carrier of improved microorganisms that are resistant to antibiotics of a certain group. It is now a source of infection, which is becoming pointless to fight with the old methods.

All this pushes the pharmaceutical science to the invention of new, more effective means with other active ingredients. But the process again goes in a circle with the development of antibiotic resistance to new drugs from the category of antimicrobial agents.

If it seems to someone that the problem of antibiotic resistance has arisen quite recently, he is very mistaken. This problem is as old as the world. Well, maybe not so much, and yet she already has 70-75 years. According to the generally accepted theory, it appeared along with the introduction of the first antibiotics into medical practice somewhere in the 40s of the twentieth century.

Although there is a concept of an earlier emergence of the problem of microbial resistance. Before the advent of antibiotics, this problem was not particularly dealt with. After all, it is so natural that bacteria, like other living beings, tried to adapt to adverse environmental conditions, did it in their own way.

The problem of resistance of pathogenic bacteria reminded of itself when the first antibiotics appeared. True, then the question was not yet so urgent. At that time, various groups of antibacterial agents were being actively developed, which in some way was due to the unfavorable political situation in the world, military operations, when soldiers died from wounds and sepsis only because they could not be given effective help due to the lack of necessary drugs. They just didn't exist yet.

The largest number of developments was carried out in the 50-60s of the twentieth century, and over the next 2 decades they were improved. Progress did not end there, but since the 80s, developments in relation to antibacterial agents have become noticeably less. Whether this is due to the high cost of this enterprise (the development and production of a new drug in our time already reaches the border of $ 800 million) or the banal lack of new ideas regarding "belligerent" active substances for innovative drugs, but in this regard, the problem of antibiotic resistance is reaching a new frightening level.

By developing promising AMPs and creating new groups of such drugs, scientists hoped to win multiple views bacterial infection. But everything turned out to be not so simple "thanks" to antibiotic resistance, which is developing quite quickly in individual strains of bacteria. Enthusiasm gradually dries up, but the problem remains unresolved for a long time.

It remains unclear how microorganisms can develop resistance to drugs that were supposed to kill them? Here you need to understand that the "killing" of bacteria occurs only when the drug is used for its intended purpose. But what do we really have?

Causes of antibiotic resistance

Here we come to the main question, who is to blame for the fact that bacteria, when exposed to antibacterial agents, do not die, but are downright reborn, acquiring new properties that are far from helping humanity? What provokes such changes that occur with microorganisms that are the cause of many diseases that humanity has been fighting for decades?

It is clear that the true reason for the development of antibiotic resistance is the ability of living organisms to survive in various conditions, adapting to them in different ways. But after all, bacteria do not have the ability to dodge a deadly projectile in the face of an antibiotic, which, in theory, should bring death to them. So how is it that they not only survive, but also improve in parallel with the improvement of pharmaceutical technologies?

You need to understand that if there is a problem (in our case, the development of antibiotic resistance in pathogenic microorganisms), then there are provoking factors that create conditions for it. It is in this issue that we will now try to figure it out.

Factors in the development of antibiotic resistance

When a person comes to the doctor with health complaints, he expects qualified help from a specialist. When it comes to respiratory tract infections or other bacterial infections, the task of the doctor is to prescribe an effective antibiotic that will not allow the disease to progress, and determine the dosage necessary for this purpose.

The doctor's choice of medicines is quite large, but how to determine exactly the drug that will really help to cope with the infection? On the one hand, for a justified prescription of an antimicrobial drug, it is necessary to first find out the type of pathogen, according to the etiotropic concept of choosing a drug, which is considered the most correct. But on the other hand, it can take up to 3 or more days, while the most important condition for a successful cure is timely therapy for early dates illness.

The doctor has no choice but to act almost at random in the first days after making a diagnosis in order to somehow slow down the disease and prevent it from spreading to other organs (empirical approach). When prescribing outpatient treatment, the practitioner assumes that certain types of bacteria can be the causative agent of a particular disease. This is the reason for the initial choice of the drug. The appointment may change depending on the results of the analysis of the pathogen.

And it’s good if the doctor’s prescription is confirmed by the results of the tests. Otherwise, not only time will be lost. The fact is that for successful treatment there is another necessary condition - complete deactivation (in medical terminology there is the concept of "irradiation") of pathogenic microorganisms. If this does not happen, the surviving microbes will simply "get sick", and they will develop a kind of immunity to the active substance of the antimicrobial drug that caused them "disease". This is as natural as the production of antibodies in the human body.

It turns out that if the antibiotic is chosen incorrectly or the dosing and administration of the drug is ineffective, pathogenic microorganisms may not die, but change or acquire capabilities that were not previously characteristic of them. Reproducing, such bacteria form entire populations of strains that are resistant to antibiotics of a particular group, i.e. antibiotic resistant bacteria.

Another factor negatively affecting the susceptibility of pathogenic microorganisms to the effects of antibacterial drugs is the use of AMPs in animal husbandry and veterinary medicine. The use of antibiotics in these areas is not always justified. In addition, the determination of the causative agent of the disease in most cases is not carried out or carried out with a delay, because antibiotics are mainly treated for animals that are in a rather serious condition, when time is everything, and it is not possible to wait for the results of the tests. And in the village, the veterinarian does not always even have such an opportunity, so he acts “blindly”.

But that would be nothing, only there is another big problem - the human mentality, when everyone is his own doctor. Moreover, the development of information technology and the ability to purchase most antibiotics without a doctor's prescription only exacerbate this problem. And if we consider that we have more unqualified self-taught doctors than those who strictly follow the doctor's prescriptions and recommendations, the problem becomes global.

Mechanisms of antibiotic resistance

Recently, antibiotic resistance has become the number one problem in the pharmaceutical industry involved in the development of antimicrobials. The thing is that it is characteristic of almost all known varieties of bacteria, and therefore antibiotic therapy is becoming less and less effective. Common pathogens such as staphylococci, Escherichia coli, Pseudomonas aeruginosa, and Proteus have resistant strains that are more common than their antibiotic-exposed ancestors.

Resistance to different groups of antibiotics, and even to individual drugs, develops in different ways. The good old penicillins and tetracyclines, as well as newer developments in the form of cephalosporins and aminoglycosides, are characterized by the slow development of antibiotic resistance, in parallel with this, their therapeutic effect. What can not be said about such drugs, the active substance of which is streptomycin, erythromycin, rimfampicin and lincomycin. Resistance to these drugs develops rapidly, and therefore the appointment has to be changed even during the course of treatment, without waiting for its completion. The same applies to the drugs oleandomycin and fusidine.

All this suggests that the mechanisms of development of antibiotic resistance to different drugs are significantly different. Let's try to figure out what properties of bacteria (natural or acquired) do not allow antibiotics to produce their irradiation, as originally intended.

To begin with, let's determine that the resistance of a bacterium can be natural (protective functions granted to it initially) and acquired, which we discussed above. So far, we have mainly talked about true antibiotic resistance associated with the characteristics of the microorganism, and not with incorrect choice or prescription of the drug (in this case, we are talking about false antibiotic resistance).

Each living being, including protozoa, has its own unique structure and some properties that allow it to survive. All this is laid down genetically and passed down from generation to generation. Natural resistance to specific active ingredients of antibiotics is also genetically determined. Moreover, in different types of bacteria, resistance is directed to a certain type of drugs, which is the reason for the development of various groups of antibiotics that affect a particular type of bacteria.

Factors that cause natural resistance may be different. For example, the structure of the protein shell of a microorganism may be such that an antibiotic cannot cope with it. But antibiotics can only affect the protein molecule, destroying it and causing the death of the microorganism. Development effective antibiotics implies taking into account the structure of bacterial proteins against which the drug is directed.

For example, the antibiotic resistance of staphylococci to aminoglycosides is due to the fact that the latter cannot penetrate the microbial membrane.

The entire surface of the microbe is covered with receptors, with certain types of which AMPs bind. A small number of suitable receptors or their complete absence leads to the fact that binding does not occur, and hence there is no antibacterial effect.

Among other receptors, there are those that serve as a kind of beacon for the antibiotic, signaling the location of the bacterium. The absence of such receptors allows the microorganism to hide from danger in the form of AMPs, which is a kind of disguise.

Some microorganisms have a natural ability to actively remove AMP from the cell. This ability is called efflux and it characterizes the resistance of Pseudomonas aeruginosa against carbapenems.

Biochemical mechanism of antibiotic resistance

In addition to the above natural mechanisms for the development of antibiotic resistance, there is another one that is associated not with the structure of the bacterial cell, but with its functionality.

The fact is that in the body bacteria can produce enzymes that can have a negative effect on the molecules of the active substance of AMP and reduce its effectiveness. When interacting with such an antibiotic, bacteria also suffer, their action is noticeably weakened, which creates the appearance of a cure for the infection. However, the patient remains a carrier of the bacterial infection for some time after the so-called "recovery".

In this case, we are dealing with a modification of the antibiotic, as a result of which it becomes inactive against this type of bacteria. Enzymes produced different types bacteria may vary. Staphylococci are characterized by the synthesis of beta-lactamase, which provokes the rupture of the lactem ring of antibiotics. penicillin series. The production of acetyltransferase can explain the resistance to chloramphenicol of gram-negative bacteria, etc.

Acquired antibiotic resistance

Bacteria, like other organisms, are no strangers to evolution. In response to "military" actions against them, microorganisms can change their structure or begin to synthesize such an amount of an enzyme substance that can not only reduce the effectiveness of the drug, but also destroy it completely. For example, the active production of alanine transferase makes Cycloserine ineffective against bacteria that produce it in large quantities.

Antibiotic resistance can also develop as a result of a modification in the structure of a protein cell, which is also its receptor, with which AMP must bind. Those. this type of protein may be absent in the bacterial chromosome or change its properties, as a result of which the connection between the bacterium and the antibiotic becomes impossible. For example, loss or alteration of the penicillin-binding protein causes insensitivity to penicillins and cephalosporins.

As a result of the development and activation of protective functions in bacteria that were previously exposed to the destructive action of a certain type of antibiotics, the permeability of the cell membrane changes. This can be done by reducing the channels through which the active substances of AMP can penetrate into the cell. It is these properties that are responsible for the insensitivity of streptococci to beta-lactam antibiotics.

Antibiotics can affect the cellular metabolism of bacteria. In response, some microorganisms have learned to do without chemical reactions that are affected by the antibiotic, which is also a separate mechanism for the development of antibiotic resistance, which requires constant monitoring.

Sometimes bacteria go to a certain trick. By attaching to a dense substance, they are combined into communities called biofilms. As part of the community, they are less sensitive to antibiotics and can safely tolerate dosages that are lethal for a single bacterium that lives outside the "collective".

Another option is to combine microorganisms into groups on the surface of a semi-liquid medium. Even after cell division, part of the bacterial "family" remains within the "group" that is not affected by antibiotics.

Antibiotic resistance genes

There are concepts of genetic and non-genetic drug resistance. We are dealing with the latter when we consider bacteria with an inactive metabolism that are not prone to reproduction under normal conditions. Such bacteria can develop antibiotic resistance to certain types of drugs, however, this ability is not transmitted to their offspring, since it is not genetically incorporated.

This is characteristic of pathogenic microorganisms that cause tuberculosis. A person can become infected and not be aware of the disease for many years, until his immunity fails for some reason. This is the impetus for the reproduction of mycobacteria and the progression of the disease. But for the treatment of tuberculosis, all the same drugs are used, since the bacterial offspring are still sensitive to them.

The same is the case with the loss of protein in the composition of the cell wall of microorganisms. Recall, again, the bacteria that are sensitive to penicillin. Penicillins inhibit the synthesis of a protein that serves to build the cell membrane. Under the influence of AMPs of the penicillin series, microorganisms can lose the cell wall, the building material of which is penicillin-binding protein. Such bacteria become resistant to penicillins and cephalosporins, which now have nothing to bind to. This phenomenon is temporary, not associated with the mutation of genes and the transmission of a modified gene by inheritance. With the advent of the cell wall characteristic of previous populations, antibiotic resistance in such bacteria disappears.

Genetic antibiotic resistance is said to occur when changes in cells and metabolism within them occur at the gene level. Gene mutations can cause changes in the structure of the cell membrane, provoke the production of enzymes that protect bacteria from antibiotics, and also change the number and properties of bacterial cell receptors.

There are 2 ways of development of events: chromosomal and extrachromosomal. If a gene mutation occurs in that part of the chromosome that is responsible for sensitivity to antibiotics, they speak of chromosomal antibiotic resistance. By itself, such a mutation occurs extremely rarely, usually it is caused by the action of drugs, but again not always. It is very difficult to control this process.

Chromosomal mutations can be passed on from generation to generation, gradually forming certain strains (varieties) of bacteria that are resistant to a particular antibiotic.

The culprits of extrachromosomal resistance to antibiotics are genetic elements that exist outside the chromosomes and are called plasmids. It is these elements that contain the genes responsible for the production of enzymes and the permeability of the bacterial wall.

Antibiotic resistance is most often the result of horizontal gene transfer, where bacteria transfer certain genes to others that are not their descendants. But sometimes one can also observe unrelated point mutations in the pathogen genome (size 1 in 108 in one process of copying the DNA of the mother cell, which is observed during chromosome replication).

So in the fall of 2015, scientists from China described the MCR-1 gene found in pork meat and intestines of pigs. A feature of this gene is the possibility of its transfer to other organisms. Some time later, the same gene was found not only in China, but also in other countries (USA, England, Malaysia, European countries).

Antibiotic resistance genes can stimulate the production of enzymes that were not previously produced in the body of bacteria. For example, the enzyme NDM-1 (metal-beta-lactamase 1), discovered in the bacteria Klebsiella pneumoniae in 2008. It was first discovered in bacteria native to India. But in subsequent years, the enzyme providing antibiotic resistance to most AMPs was also found in microorganisms in other countries (Great Britain, Pakistan, USA, Japan, Canada).

Pathogenic microorganisms can show resistance both to certain drugs or groups of antibiotics, and to different groups of drugs. There is such a thing as cross antibiotic resistance, when microorganisms become insensitive to drugs with a similar chemical structure or mechanism of action on bacteria.

Antibiotic resistance of staphylococci

Staphylococcal infection is considered one of the most common among community-acquired infections. However, even in hospital conditions, about 45 different strains of staphylococcus can be found on the surfaces of various objects. This suggests that the fight against this infection is almost a priority for health workers.

The difficulty of this task lies in the fact that most strains of the most pathogenic staphylococci Staphylococcus epidermidis and Staphylococcus aureus are resistant to many types of antibiotics. And the number of such strains is growing every year.

The ability of staphylococci to multiple genetic mutations, depending on habitat conditions, makes them practically invulnerable. Mutations are passed on to offspring and in a short time whole generations of infectious agents resistant to antimicrobial drugs from the genus Staphylococcus appear.

The biggest problem is methicillin-resistant strains, which are resistant not only to beta-lactams (beta-lactam antibiotics: certain subgroups of penicillins, cephalosporins, carbapenems and monobactams), but also to other types of AMPs: tetracyclines, macrolides, lincosamides, aminoglycosides, fluoroquinolones, chloramphenicol.

For a long time, it was possible to destroy the infection only with the help of glycopeptides. Currently, the problem of antibiotic resistance of such strains of staphylococcus is being solved by means of a new type of AMP - oxazolidinones, a prominent representative of which is linezolid.

Methods for determining antibiotic resistance

When creating new antibacterial drugs, it is very important to clearly define its properties: how they act and against which bacteria they are effective. This can only be determined with the help of laboratory tests.

Antibiotic resistance testing can be done using various methods, the most popular of which are:

• Disk method, or AMP diffusion into agar according to Kirby-Bayer
• Serial dilution method
• Genetic identification of mutations causing drug resistance.

The first method is by far the most common due to its low cost and ease of execution. The essence of the disc method is that the strains of bacteria isolated as a result of research are placed in a nutrient medium of sufficient density and covered with paper discs soaked in an AMP solution. The concentration of the antibiotic on the discs is different, so when the drug diffuses into the bacterial environment, a concentration gradient can be observed. By the size of the zone of absence of growth of microorganisms, one can judge the activity of the drug and calculate the effective dosage.

A variant of the disc method is the E-test. In this case, instead of disks, polymer plates are used, on which a certain concentration of antibiotic is applied.

The disadvantages of these methods are the inaccuracy of calculations associated with the dependence of the concentration gradient on various conditions (density of the medium, temperature, acidity, calcium and magnesium content, etc.).

The serial dilution method is based on the creation of several variants of a liquid or solid medium containing various concentrations of the test drug. Each of the options is populated with a certain amount of the studied bacterial material. At the end of the incubation period, bacterial growth or its absence is assessed. This method allows you to determine the minimum effective dose of the drug.

The method can be simplified by taking as a sample only 2 media, the concentration of which will be as close as possible to the minimum required to inactivate bacteria.

The serial dilution method is considered to be the gold standard for determining antibiotic resistance. But because of the high cost and complexity, it is not always applicable in domestic pharmacology.

The mutation identification technique provides information about the presence of modified genes in a particular strain of bacteria that contribute to the development of antibiotic resistance to specific drugs, and in this regard, to systematize emerging situations, taking into account the similarity of phenotypic manifestations.

This method is distinguished by the high cost of test systems for its execution, however, its value for forecasting genetic mutations in bacteria is undeniable.

No matter how effective the above methods for studying antibiotic resistance are, they cannot fully reflect the picture that will unfold in a living organism. And if we also take into account the fact that the body of each person is individual, the processes of distribution and metabolism of drugs can take place in it in different ways, the experimental picture is very far from the real one.

Ways to overcome antibiotic resistance

No matter how good this or that drug is, but with the attitude we have towards treatment, the fact that at some point the sensitivity of pathogenic microorganisms to it may change cannot be ruled out. The creation of new drugs with the same active ingredients also does not solve the problem of antibiotic resistance. And to new generations of drugs, the sensitivity of microorganisms with frequent unjustified or incorrect prescriptions is gradually weakening.

A breakthrough in this regard is the invention combined drugs which are called protected. Their use is justified in relation to bacteria that produce enzymes that are destructive to conventional antibiotics. Protection of popular antibiotics is carried out by including special agents in the composition of a new drug (for example, inhibitors of enzymes that are dangerous for a certain type of AMP), which stop the production of these enzymes by bacteria and prevent the drug from being removed from the cell by means of a membrane pump.

As beta-lactamase inhibitors, it is customary to use clavulanic acid or sulbactam. They are added to beta-lactam antibiotics, thereby increasing the effectiveness of the latter.

Currently, drugs are being developed that can affect not only individual bacteria, but also those that have united in groups. Bacteria within a biofilm can only be combated after it has been destroyed and the organisms previously linked by chemical signals are released. In terms of the possibility of biofilm destruction, scientists are considering such a type of drugs as bacteriophages.

The fight against other bacterial "groups" is carried out by transferring them to a liquid medium, where microorganisms begin to exist separately, and now they can be fought with the usual drugs.

Faced with the phenomenon of resistance during drug treatment, doctors solve the problem of prescribing various drugs that are effective against isolated bacteria, but with a different mechanism of action on pathogenic microflora. For example, drugs with bactericidal and bacteriostatic action are used simultaneously or one drug is replaced by another from a different group.

Prevention of antibiotic resistance

The main objective of antibiotic therapy is the complete destruction of the population of pathogenic bacteria in the body. This problem can be solved only by prescribing effective antimicrobial drugs.

The effectiveness of the drug, respectively, is determined by the spectrum of its activity (whether the identified pathogen is included in this spectrum), the possibilities of overcoming the mechanisms of antibiotic resistance, the optimally selected dosing regimen, in which the death of pathogenic microflora occurs. In addition, when prescribing the drug, the likelihood of developing side effects and the availability of treatment for each individual patient.

With an empirical approach to the treatment of bacterial infections, it is not possible to take into account all these points. It requires high professionalism of the doctor and constant monitoring of information about infections and effective drugs to combat them, so that the appointment is not unjustified and does not lead to the development of antibiotic resistance.

Creation equipped with high-tech equipment medical centers allows you to practice etiotropic treatment, when the pathogen is first detected in a shorter time, and then an effective drug is prescribed.

Prevention of antibiotic resistance can be considered and the control of prescribing drugs. For example, in ARVI, the prescription of antibiotics is not justified in any way, but it contributes to the development of antibiotic resistance of microorganisms that are in a "sleeping" state for the time being. The fact is that antibiotics can provoke a weakening of the immune system, which in turn will cause the multiplication of a bacterial infection that has been buried inside the body or that has entered it from the outside.

It is very important that the prescribed drugs correspond to the goal to be achieved. Even a drug prescribed for prophylactic purposes must have all the properties necessary to destroy pathogenic microflora. The choice of a drug at random can not only not give the expected effect, but also aggravate the situation by the development of resistance to the drug of a certain type of bacteria.

Particular attention should be paid to the dosage. Small doses, ineffective in fighting infection, again lead to the formation of antibiotic resistance in pathogens. But you should not overdo it either, because during antibiotic therapy there is a high probability of developing toxic effects and anaphylactic reactions that are life-threatening for the patient. Especially if the treatment is carried out on an outpatient basis in the absence of control by the medical staff.

Through the media, it is necessary to convey to people the danger of self-treatment with antibiotics, as well as incomplete treatment, when bacteria do not die, but only become less active with a developed mechanism of antibiotic resistance. The same effect is exerted by cheap unlicensed drugs, which are positioned by illegal pharmaceutical companies as budget analogues of already existing drugs.

A highly effective measure for the prevention of antibiotic resistance is considered to be constant monitoring of existing infectious pathogens and the development of antibiotic resistance in them, not only at the level of a district or region, but also throughout the country (and even the whole world). Alas, this is only a dream.

In Ukraine, there is no infection control system as such. Only a few provisions have been adopted, one of which (as early as 2007!), concerning obstetric hospitals, provides for the introduction of various methods for monitoring nosocomial infections. But everything again depends on finances, and such studies are generally not carried out on the ground, not to mention doctors from other branches of medicine.

IN Russian Federation the problem of antibiotic resistance was treated with greater responsibility, and the proof of this is the project "Map of Antimicrobial Resistance in Russia". Such large organizations as the Research Institute of Antimicrobial Chemotherapy, the Interregional Association of Microbiology and Antimicrobial Chemotherapy, and the Scientific and Methodological Center for Monitoring Antibiotic Resistance, established at the initiative of the Federal Agency for Health and Social Development, were engaged in research in this area, collecting information and systematizing it to fill in the antibiotic resistance map.

The information provided within the framework of the project is constantly updated and is available to all users who need information on antibiotic resistance and effective treatment infectious diseases.

Understanding how relevant today the issue of reducing the sensitivity of pathogens and finding a solution to this problem comes gradually. But this is already the first step towards effectively combating the problem called “antibiotic resistance”. And this step is extremely important.

It is important to know!

Natural antibiotics not only do not weaken the body's defenses, but rather strengthen it. Antibiotics of natural origin have long helped to fight against various diseases. With the discovery of antibiotics in the 20th century and the large-scale production of synthetic antibacterial drugs, medicine has learned to deal with severe and incurable diseases.