Rational antibiotic therapy: means and tactics

Infections are one of the main problems of the intensive care unit (they can be the main reason for hospitalization of patients in the intensive care unit or a complication of other diseases), the most important criterion for the prognosis of patients. Community-acquired infections requiring hospitalization in the intensive care unit and hospital infections are independent factors of mortality. They lead to an extension of inpatient treatment. Based on the above, the development of an antibacterial therapy strategy is fundamentally important for improving the prognosis of patients.

The complexity of treating bacterial infections in the ICU is due to many factors, but the most important are:

• high level of resistance of pathogens to traditional antibiotics and rapid development of resistance during treatment,
• usually polymicrobial nature of the disease,
• severity of the patients' condition,
• frequent isolation of so-called problem microorganisms,
• frequent relapses or superinfection during and after completion of antibacterial therapy

In addition, the unjustified, unsystematic use of antibiotics leads to the rapid selection and spread of resistant strains of microorganisms.

Factors contributing to the development of infection in patients in the intensive care unit:

• Underlying disease.
• The severity of the patient's condition according to the APACHE II scale for assessing acute and chronic functional changes is >15.
• Age over 60 years.
• Diagnostic and therapeutic invasive procedures:
  • intubation,
  • IVL,
  • bladder catheterization,
  • central venous catheterization.
• Use of antacids and H2 receptor blockers.
• Length of stay in the intensive care unit.

Indiscriminate or widespread prophylactic use of antibiotics. The source of infection may be endogenous (oropharyngeal colonization or aspiration) or exogenous (respiratory equipment, catheters, medical personnel, other patients).

Due to the severity of the patients' condition and the danger of infectious complications for them, antibacterial therapy should be started immediately at the first signs of the disease (without waiting for the results of bacteriological testing), since delay can lead to dangerous consequences. In their daily practice in hospitals, doctors encounter two groups of infectious diseases:

• extra-hospital - arising outside of a hospital and causing hospitalization,
• hospital (nosocomial) - developed in a patient in a hospital.

The main differences between the groups are the types of pathogens and their antibiotic resistance. Community-acquired infections are characterized by a limited and fairly stable composition of the most likely pathogens, depending on the localization of the process. The spectrum of pathogens of hospital infections is usually less predictable. Pathogens of hospital infections are more resistant to antibiotics than pathogens of community-acquired infections. These differences are important for choosing rational empirical therapy.

In hospitals, and especially in intensive care units, favorable conditions are created for the exchange of microorganisms - close contact between patients and staff. At the same time, against the background of intensive treatment, their selection occurs. As a result, a microecological situation arises with the dominance of certain strains (mostly resistant to antibiotics). They are called hospital strains. There are no clear criteria for recognizing a particular strain as hospital strains (antibiotic resistance is important, but not mandatory).

When admitted to a hospital, the patient inevitably comes into contact with hospital strains of bacteria. As the length of stay in a medical institution increases, the probability of replacing the patient's own microflora with hospital microflora increases - the risk of developing infections caused by it increases. It is quite difficult to accurately determine the period required for the patient's body to be colonized by hospital microflora, since it depends on many factors (age, stay in intensive care units, severity of concomitant pathology, antibiotic therapy or prophylaxis). It is also difficult to determine the time interval when the infection should be considered hospital-acquired. In most cases, an infection is considered hospital-acquired when its symptoms appear more than 48 hours after hospitalization.

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Epidemiology and causes of infections

It is difficult to estimate the frequency of hospital infections in our country due to the lack of official registration of such diseases. In intensive care units, the risk of developing infectious complications in patients is 5-10 times higher than in general departments. A quarter of the total number of hospital infections occurs in intensive care units. According to international multicenter studies, the average prevalence of hospital infections in medical institutions is 5-10%, and in intensive care units it reaches 25-49%. Scientific works devoted to the study of their etiology reflect the situation in the hospitals surveyed, so their results are extrapolated to other institutions with a large degree of conventionality. Even multicenter studies are not considered exhaustive, although they are the most representative.

The structure and etiology of infections in the intensive care units (ICU) have been studied most thoroughly. According to the EPIC multicenter study, conducted in one day in 1417 departments in 17 European countries (covering more than 10 thousand patients), 44.8% were diagnosed with infections, with the frequency of ICU-associated infections being 20.6%. The most common infections in the ICU were pneumonia (46.9%), lower respiratory tract infections (17.8%) and urinary tract infections (17.6%), and angiogenic infections (12%). The etiological structure was dominated by gram-negative bacteria of the Enterobacteriaceae family (34.4%), Staphylococcus aureus (30.1%), Pseudomonas aeruginosa (28.7%), coagulase-negative staphylococci (19.1%), and fungi (17.1%). Many etiologically significant microorganisms were found to be resistant to traditional antibiotics; in particular, the prevalence of methicillin-resistant staphylococci was 60%, and 46% of P aeruginosa were resistant to gentamicin.

Similar results on the etiologic structure of infections were obtained in another study. Its results also confirmed that most patients in the ICU (72.9%) were prescribed antibiotics for therapeutic or prophylactic purposes. Moreover, the most common were aminoglycosides (37.2%), carbapenems (31.4%), glycopeptides (23.3%), and cephalosporins (18.0%). The list of drugs indirectly confirms the high level of antibiotic resistance of pathogens in the ICU. Analysis of the results of the US hospital infection control system for 1992-1997 showed the prevalence of urinary tract infections (31%), pneumonia (27%), and primary angiogenic infections (19%) in the ICU. Moreover, 87% of primary angiogenic infections were associated with central venous catheters, 86% of pneumonias - with mechanical ventilation, and 95% of urinary infections - with urinary catheters. The leading causative agents of mechanical ventilation-associated pneumonia (MVAP) were Enterobacteriaceae (64%), P. aeruginosa (21%), S. aureus (20%), among the causative agents of angiogenic infections - coagulase-negative staphylococci (36%), enterococci (16%), S. aureus (13%), fungi (12%). Fungi and Enterobacteriaceae dominated in urinary infections.

Based on the primary localization of the source of infection, one can judge the presumed etiology of the disease, which, of course, serves as a reliable guideline for choosing an empirical regimen of antibacterial therapy.

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Principles of planning antibacterial therapy for infections

Taking into account the above-mentioned difficulties in treating hospital infections (the severity of the patients’ condition, their often polymicrobial nature, the possibility of isolating pathogens with multiple resistance to antibacterial agents in nosocomial infections), it is necessary to highlight the following principles of rational use of antibiotics in intensive care units:

• Antibacterial therapy begins immediately after the infection is detected, without waiting for the results of bacteriological testing.
• The choice of the initial empirical therapy regimen should be programmable, taking into account the probable spectrum of pathogens and their possible resistance (data from local monitoring of antibiotic resistance).
• The initial assessment of the effectiveness of therapy is carried out 48-72 hours after its onset of a decrease in the severity of fever and intoxication. If there is no positive effect within the specified time frame, the therapy regimen is adjusted.
• It is irrational and undesirable to use antibiotics prophylactically in the postoperative period or during mechanical ventilation (in the absence of clinical signs of infection).
• Antibiotics are administered in accordance with official instructions. The main routes of administration are intravenous, intramuscular, and oral. Other routes (intra-arterial, endolymphatic, intra-abdominal, endotracheal, etc.) have no proven advantages over traditional ones.

The choice of an antibacterial drug can be made on the basis of the established etiology of the disease and the specified sensitivity of the pathogen to antibiotics - etiotropic therapy. In situations where the pathogen is unknown, the drug is prescribed based on an empirical approach. In the latter case, the antibiotic is selected based on the known list of microorganisms that cause infection in a certain localization and knowledge of the main trends in antibiotic resistance of the most likely pathogens. It is clear that in clinical practice, most often before specifying the etiology of the disease, the doctor is forced to use an empirical approach.

In severe infections, the principle of maximum initial empirical therapy should be followed - the prescription of drugs that act on the maximum number of potential pathogens of a given localization. It is especially necessary to adhere to this principle when treating NPILV, peritonitis, and severe sepsis. Since it has been established that in the case of inadequate initial therapy, the risk of death increases significantly (for example, for NPILV - by 3 times).

Adequate empirical antibacterial therapy means:

• when the selected mode is selected, all potential pathogens are affected,
• when choosing an antibacterial drug, the risk of multi-resistance of pathogens is taken into account,
• The treatment regimen should not promote selection of resistant strains in the department.

Empirical and targeted etiotropic antibacterial therapy

Conducting rational antibacterial therapy of hospital infections in the intensive care unit is impossible without modern knowledge of the etiological structure of diseases and antibiotic resistance of their pathogens. In practice, this means the need to identify the pathogen using microbiological methods and determine its antibiotic sensitivity. Discussing the choice of the optimal antibacterial drug is possible only after conducting the above studies.

However, in practical medicine the situation is not so simple, and even the most modern microbiological methods are often unable to give the doctor a quick answer or even specify the causative agent of the disease. In such cases, knowledge about the most likely causative agents of specific forms of hospital infections, the spectrum of natural activity of antibiotics and the level of acquired resistance to them in a given region and a specific hospital come to the rescue. The latter condition is most important when planning antibacterial therapy for hospital infections in intensive care units, where the level of acquired resistance is highest. Since the insufficient equipment of microbiological laboratories and the low level of standardization of studies to assess antibiotic susceptibility do not allow us to form a real idea of the epidemiological situation in a medical institution and develop balanced recommendations for treatment.

The etiology of infectious diseases is the main factor determining the strategy and tactics of antibacterial therapy. Due to the impossibility of express diagnostics of bacterial infections and assessment of antibiotic sensitivity of their pathogens, the prescription of antibacterial therapy in intensive care is usually empirical.

Despite the significant diversity of pathogens in intensive care, only a limited number of bacterial species play a leading role in their etiology. Based on the commonality of the spectrum of natural sensitivity to antibacterial drugs and resistance mechanisms, they can be combined into four groups:

1. S. aureus and a taxonomically heterogeneous subgroup of coagulase-negative staphylococci,
2. Enterococcus spp. (mainly E. faecalis),
3. representatives of the family Enterobacteriaceae,
4. Pseudomonas aeruginosa.

The listed pathogens are the sources of more than 80% of urinary and respiratory tract infections, intra-abdominal and surgical site infections, as well as angiogenic infections. Certain etiological features are characteristic of infections of various localizations. For example, angiogenic infections are most often caused by staphylococci, and urinary tract infections by gram-negative microorganisms, while enterococci practically do not affect the respiratory tract. The greatest etiological diversity is characteristic of intra-abdominal and wound infections.

The data presented can serve as a first guideline for choosing empirical antibacterial therapy. A very simple and, in some cases, extremely useful study is microscopy of a smear from the site of infection. Unfortunately, such a simple method is given very little attention in most institutions, despite the fact that information on the prevalence of gram-positive or gram-negative flora is extremely important for choosing antibacterial therapy.

Even more important information can be obtained 24 hours after taking the pathological material and its primary culture. With a well-established laboratory and its connection with the clinic, the doctor can get an answer to the question: "Are staphylococci, enterococci, enterobacteria or P. aeruginosa involved in the infectious process?" Knowing the spectrum of natural sensitivity of the listed groups of microorganisms and the features of the spread of resistance in a specific institution, it is possible to adjust antibacterial therapy and, with a high degree of probability, ensure its adequacy.

The most accurate correction of antibacterial therapy is possible after receiving the final results of the pathogen identification and assessment of its antibiotic sensitivity.

Below are data on the spectrum of natural sensitivity of the main groups of infectious agents in the intensive care unit and on the drugs of choice for the treatment of diseases of known etiology.

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Choice of antibiotic in the treatment of infections of known etiology

The section focuses on the drugs of choice for the treatment of severe and hospital infections. Other antibacterial drugs can be used to treat community-acquired and mild forms.

Streptococcus pyogenes

The drug of choice is benzylpenicillin. Aminopenicillins are equally effective; other ß-lactams have no advantages. Acquired resistance to ß-lactams has not been described.

Alternative drugs: macrolides and lincosamides (indicated for allergies to ß-lactams).

The prevalence of acquired resistance varies across geographic regions.

Streptococcus pneumoniae

The drugs of choice are benzylpenicillin (parenterally), amoxicillin (per os) and other ß-lactams.

The prevalence of acquired resistance varies in different geographic regions. In pneumonias caused by penicillin-resistant pneumococci, benzylpenicillin and amoxicillin are effective, but in meningitis they may fail.

Alternative drugs - cephalosporins of the III-IV generation (cefotaxime, ceftriaxone, cefepime), carbapenems (for meningitis - meropenem), antipneumococcal fluoroquinolones. For meningitis caused by penicillin-resistant pneumococci, it is possible to use glycopeptides

Streptococcus agalactiae

The drugs of choice are benzylpenicillin, ampicillin, it is advisable to combine with aminoglycosides (gentamicin). Acquired resistance is a rare phenomenon.

Alternative drugs: third-generation cephalosporins, carbapenems.

Viridans streptococci

The drugs of choice are benzylpenicillin and ampicillin. In endocarditis and severe generalized infections - in combination with aminoglycosides (gentamicin). Acquired resistance is a rare phenomenon.

Alternative drugs are third-generation cephalosporins, carbapenems. In case of allergy to ß-lactams, glycopeptides can be used.

Enterococcus faecalis

The drugs of choice are benzylpenicillin or ampicillin in combination with gentamicin or streptomycin - endocarditis and severe generalized infections, ampicillin, nitrofurans or fluoroquinolones - urinary tract infections.

Acquired resistance is found to penicillins, often to aminoglycosides.

Alternative drugs: glycopeptides (it is advisable to combine with aminoglycosides), oxazolidinones.

Acquired resistance to glycopeptides among strains described in Russia is rare.

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Enterococcus faecium

The drugs of choice are glycopeptides (preferably in combination with aminoglycosides). However, treatment failures are possible.

Acquired resistance to glycopeptides among strains described in Russia is rare.

Alternative drugs oxazolidinones

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Methicillin-sensitive staphylococci

The drugs of choice are oxacillin, protected aminopenicillins, and first-generation cephalosporins.

Acquired resistance in case of sensitivity to oxacillin, simultaneous resistance to the above ß-lactams is unknown.

Alternative drugs are fluoroquinolones with increased activity against gram-positive microorganisms (levofloxacin, moxifloxacin, gatifloxacin), oxazolidinones. In severe infections and immediate-type allergies to ß-lactams, glycopeptides can be used, but their effectiveness is lower.

Methicillin-resistant staphylococci

Drugs of choice are glycopeptides. Acquired resistance: single resistant strains have been identified.

Alternative drugs are oxazolidinones. Fluoroquinolones, fusidic acid, rifampicin, co-trimoxazole, fosfomycin are sometimes effective. However, their treatment regimens are not precisely defined.

Corynebacterium diphtheriae

The drugs of choice are macrolides and lincosamides. The prevalence of acquired resistance has not been adequately studied.

Alternative drugs: benzylpenicillin, rifampicin, tetracyclines.

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Corynebacterium jeikeium

The drugs of choice are glycopeptides. The prevalence of acquired resistance has not been sufficiently studied.

Alternative drugs have not been identified.

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Listeria monocytogenes

The drugs of choice are ampicillin, preferably in combination with gentamicin. Cephalosporins are ineffective. The prevalence of acquired resistance has not been sufficiently studied.

An alternative drug is co-trimoxazole. The clinical significance of the in vitro susceptibility to macrolides, tetracyclines and chloramphenicol has not been determined.

Bacillus anthracis

The drugs of choice are benzylpenicillin and ampicillin. Cephalosporins are not very effective.

Acquired resistance: isolated reports of resistant strains have been published.

Alternative drugs: fluoroquinolones, tetracyclines, macrolides, chloramphenicol.

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Bacillus cereus

The drugs of choice are clindamycin and vancomycin. Acquired resistance has not been studied sufficiently. Alternative drugs are gentamicin and ciprofloxacin.

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Nocardia asteroides

The drug of choice is co-trimoxazole. Acquired resistance has not been sufficiently studied.

Alternative drugs: imipenem + glycopeptides, amikacin + cephalosporins, minocycline (their use is not sufficiently justified).

Neisseria meningitidis

The drug of choice is benzylpenicillin. Acquired resistance: isolated reports of resistant strains have been published.

Alternative drugs: third generation cephalosporins, chloramphenicol.

Haemophilus spp.

The drugs of choice are aminopenicillins. Acquired resistance: in some regions, resistant strains producing β-lactamases are common (their share in Russia is less than 5-6%).

Alternative drugs: third-generation cephalosporins, chloramphenicol. For localized infections - second-generation cephalosporins, protected penicillins, fluoroquinolones.

Legionella spp.

The drugs of choice are erythromycin, azithromycin or clarithromycin (preferably in combination with rifampicin). Acquired resistance is absent. Alternative drugs are fluoroquinolones, doxycycline, co-trimoxazole.

Vibrio cholerae

Drugs of choice are fluoroquinolones. Acquired resistance has been described in isolated cases.

Alternative drugs: doxycycline, co-trimoxazole.

Enterobacteriaceae

The drugs of choice for the treatment of severe infections caused by microorganisms of the Enterobacteriaceae family are β-lactam antibiotics. However, depending on the natural sensitivity of individual species, it is necessary to use different drugs. The use of aminoglycosides and fluoroquinolones is also justified. The choice of specific drugs is based on data on the localization and severity of the infection, the spread of resistance.

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Escherichia coli, Proteus mirabilis

The drugs of choice are protected aminopenicillins, cephalosporins of the II-III generation. Acquired resistance is widespread.

Alternative drugs - fluoroquinolones, aminoglycosides, fourth-generation cephalosporins, cefoperazone + sulbactam, carbapenems (their various combinations). Resistance to all alternative drugs is possible. However, the least likely is to amikacin, carbapenems (resistance to them is an extremely rare phenomenon).

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Klebsiella spp, Proteus vulgaris, Citrobacter diversus

The drugs of choice are protected aminopenicillins, cephalosporins of the II-III generation. Acquired resistance is widespread.

Alternative drugs: fluoroquinolones, aminoglycosides, cefoperazone + sulbactam, fourth generation cephalosporins, carbapenems (their various combinations).

Resistance to all alternative drugs is possible. However, the least likely is to amikacin and carbapenems (resistance to them is an extremely rare phenomenon).

Enterobacter spp, Citrobacter freundii, Serratia spp, Morganella morganii, Providencia stuartii, Providencia rettgeri

The drugs of choice are cephalosporins of the III-IV generation. Acquired resistance is widespread.

Alternative drugs: fluoroquinolones, aminoglycosides, cefoperazone + sulbactam, fourth generation cephalosporins, carbapenems (their various combinations).

Resistance may develop to all alternative drugs. However, it is least likely to develop to amikacin and carbapenems (there are isolated reports of resistant strains).

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Shigella spp.

Drugs of choice are fluoroquinolones. Acquired resistance is rare.

Alternative drugs: co-trimoxazole, ampicillin Salmonella spp., including S. typhi (generalized infections).

Drugs of choice: fluoroquinolones, third-generation cephalosporins (cefotaxime, ceftriaxone). Acquired resistance - isolated cases.

Alternative drugs: chloramphenicol, co-trimoxazole, ampicillin.

Pseudomonas aeruginosa

Drugs of choice: ceftazidime + aminoglycosides. Acquired resistance is widespread.

Alternative drugs: protected antipseudomonal penicillins (used only in combination with aminoglycosides), ciprofloxacin, fourth-generation cephalosporins, carbapenems, polymyxin B.

Resistance to all alternative drugs may develop.

Burkholderia cepacia

The drugs of choice are carbapenems, ciprofloxacin, ceftazidime and cefoperazone, ureidopenicillins (including protected ones), co-trimoxazole and chloramphenicol. However, the treatment regimens are not sufficiently substantiated.

Acquired resistance is a fairly common phenomenon. In cystic fibrosis, strains resistant to all of the above drugs are especially common.

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Stenotrophomonas maltophilia

The drug of choice is co-trimoxazole. Acquired resistance is a relatively rare phenomenon.

Alternative drugs are ticarcillin + clavulanic acid, doxycycline and minocycline, chloramphenicol. They may have sufficient activity, but their use regimens are not sufficiently substantiated.

Strains that are resistant to alternative drugs are quite common.

Acinetobacter spp.

Drugs of choice Due to the extreme diversity of strain susceptibility, it is difficult to justify empirical therapy regimens. The most commonly suggested combinations are carbapenems or ceftazidime with aminoglycosides (mainly with amikacin), as well as fluoroquinolones with aminoglycosides. Ampicillin or cefoperazone with sulbactam (due to the latter's own antibacterial activity) may be effective.

Acquired resistance to all drugs used is widespread.

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Clostridium petrifringens

The drugs of choice are benzylpenicillin, possibly in combination with clindamycin. Acquired resistance has not been adequately studied.

Alternative drugs are almost all ß-lactams, chloramphenicol, metronidazole.

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Clostridium difficile

The drug of choice is metronidazole. Acquired resistance has not been described. An alternative drug is vancomycin.

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Actinomyces israelii and other anaerobic actinomycetes

The drugs of choice are benzylpenicillin and aminopenicillins. Acquired resistance has not been described. Alternative drugs are third-generation cephalosporins, erythromycin and clindamycin, doxycycline.

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Peptostreptococcus

The drug of choice is benzylpenicillin. Acquired resistance is not widespread.

Alternative drugs: other ß-lactams, metronidazole, clindamycin, erythromycin, doxycycline.

Bacteroides fragilis

The drug of choice is metronidazole. Acquired resistance is an extremely rare phenomenon.

Alternative drugs: clindamycin, carbapenems, cefoxitin, protected penicillins.

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Staphylococcus spp.

Currently, 34 species of staphylococci have been described. They are capable of producing a significant number of various virulence factors. The most complete "set" of them is found in strains of S. aureus. Isolation of bacteria from pathological material (with the corresponding clinical picture) almost always indicates their etiological significance.

In practice, precise species identification of other staphylococci, grouped into the "coagulase-negative" group, is often unnecessary. Such information is important for epidemiological monitoring, as well as in the case of severe infections. Isolation of coagulase-negative staphylococci from non-sterile areas of the human body usually indicates colonization or contamination with pathological material. The problem of excluding contamination arises even when isolating such microorganisms from sterile environments (blood, cerebrospinal fluid).

The spectrum of natural sensitivity of Staphylococcus spp. and acquired resistance. Staphylococci are characterized by a high level of natural sensitivity to the vast majority of antibacterial drugs (beta-lactams, aminoglycosides, fluoroquinolones, macrolides, lincosamides, tetracyclines, glycopeptides, co-trimoxazole, chloramphenicol, fusidic acid and rifampicin). However, even with such a wide range of antibiotics to choose from, in some cases the treatment of staphylococcal infections is a serious problem due to the development of antibiotic resistance in microorganisms.

Β-Lactam antibiotics

Among all antibacterial drugs, they are most active against staphylococci, but due to the widespread ability of bacteria to produce β-lactamases, natural and semi-synthetic penicillins have completely lost their clinical significance. Despite some differences in the level of microbiological activity, oxacillin, protected penicillins, cephalosporins of the first to fourth generations (except ceftazidime and cefoperazone) and carbapenems have almost the same effectiveness. The choice of a specific drug depends on the ease of use, cost and the likelihood of a mixed infectious process (involvement of gram-negative bacteria).

However, the use of β-lactam antibiotics is possible only if staphylococci do not have another resistance mechanism - an additional penicillin-binding protein. A marker of such a mechanism is resistance to oxacillin. According to historical tradition, S. aureus with such a resistance mechanism retained the name methicillin-resistant (Methicillin Resistant Staphylococcus aureus - MRSA), despite the fact that methicillin has long been practically excluded from medical practice.

If resistance to oxacillin is detected, treatment of staphylococcal infections with β-lactams is discontinued.

An exception is the cephalosporin antibiotic ceftobiprole. It is capable of suppressing the activity of the penicillin-binding protein of staphylococci.

An important feature of MRSA is the high frequency of associated resistance to antibacterial drugs of other groups (macrolides and lincosamides, aminoglycosides, tetracyclines and fluoroquinolones).

For a long time, MRSA was considered to be exclusively hospital pathogens (their prevalence in many intensive care units in Russia is over 60%). However, recently the situation has changed for the worse: microorganisms increasingly cause severe community-acquired skin and soft tissue infections, as well as destructive pneumonia.

Glycopeptide antibiotics (vancomycin, teicoplanin, and a number of other drugs at various stages of development) are considered the drugs of choice for the treatment of MRSA infections. However, currently available glycopeptides (vancomycin and teicoplanin) exhibit only bacteriostatic action against staphylococci (a significant disadvantage compared to β-lactams). In cases where glycopeptides were prescribed for various reasons to treat infections caused by methicillin-sensitive staphylococci, their clinical efficacy was lower than that of β-lactams. These facts allow us to consider this group of antibiotics as suboptimal for the treatment of staphylococcal infections.

Resistance to glycopeptides among MRSA was not detected for a long time, but since the second half of the 90s of the last century, reports have been published on strains with a reduced level of sensitivity to them. The mechanism of resistance has not been deciphered completely. It is difficult to estimate the frequency of spread of such strains due to methodological difficulties in their detection, however, it is obvious that the effectiveness of vancomycin is sharply reduced in the infections they cause. There are also isolated reports on the isolation of MRSA with a high level of resistance to vancomycin (transfer of resistance genes from enterococci).

Oxazolidinones

The only drug in the group is linezolid. It has high activity and is effective against all staphylococci, regardless of resistance to other antibiotics. It is considered a serious alternative to glycopeptides in the treatment of infections caused by MRSA. Linezolid may be the drug of choice for the treatment of infections caused by staphylococcal strains with reduced sensitivity to glycopeptides.

Fluoroquinolones

The drugs of this group have different activity against staphylococci: ciprofloxacin and ofloxacin are relatively low but clinically significant, while levofloxacin, moxifloxacin, gemifloxacin and other new fluoroquinolones are more active. The clinical and bacteriological efficacy of levofloxacin against staphylococcal infections has been well proven. However, as noted above, MRSA often exhibits associated resistance to them.

Drugs of other groups

Fusidic acid, co-trimoxazole and rifampicin are also effective against staphylococci. However, no detailed clinical trials have been conducted to evaluate them. Since resistance to all of the listed drugs develops fairly quickly, it is advisable to combine them (for example, co-trimoxazole and rifampicin). Such combinations are especially promising in the treatment of mild infections caused by MRSA.

Given the above facts, it is obvious that when developing tactics for empirical therapy of staphylococcal infections in each specific department, it is necessary to take into account data on the frequency of spread of MRSA.

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Enterococcus spp.

Enterococci were placed in a genus separate from streptococci in 1984. Within the genus Enterococcus, there are more than 10 species, most of which rarely cause human disease. Among clinical isolates, 80-90% are E faecalis and 5-10% are E faecium, while other species play a limited role. In intensive care unit (ICU) practice, enterococcal angiogenic infections, often associated with catheters, are of most importance. In wound infections, enterococci are usually part of microbial associations and do not play a significant independent role. Their role in the pathogenesis of intra-abdominal infections has not been precisely established, but specific antienterococcal therapy does not improve treatment outcomes. Enterococcal urinary tract infections are usually associated with catheters and resolve spontaneously after their removal or with the use of narrow-spectrum drugs.

Spectrum of natural susceptibility of Enterococcus spp. and acquired resistance. Of the known drugs, some ß-lactams, glycopeptides, rifampicin, macrolides, chloramphenicol, tetracyclines (doxycycline), nitrofurantoin, and fluoroquinolones have antienterococcal activity. However, the clinical significance of rifampicin, macrolides, and chloramphenicol in the treatment of infections has not been determined. Tetracyclines, nitrofurantoin, and fluoroquinolones are used only for the treatment of enterococcal urinary tract infections.

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SS-Lactam antibiotics

Among them, benzylpenicillin, aminopenicillins, ureidopenicillins (the greatest experience has been accumulated for piperacillin) and carbapenems have antienterococcal activity. All cephalosporins lack it. It is important to note that the natural sensitivity to ß-lactams in the two main types of enterococci is different. E. faecalis is usually sensitive, and E. faecium is resistant. Neither ureidopenicillins nor carbapenems have advantages over ampicillin. The drugs of this group exhibit only bacteriostatic activity against enterococci; to achieve a bactericidal effect, they must be combined with aminoglycosides.

Glycopeptides

Glycopeptide antibiotics (vancomycin and teicoplanin) are traditionally considered the drugs of choice in the treatment of enterococcal infections caused by strains resistant to ß-lactam antibiotics. However, glycopeptides, like ß-lactams, have only a bacteriostatic effect on enterococci. To achieve a bactericidal effect, glycopeptides should be combined with aminoglycosides.

Resistance to glycopeptides among enterococci began to be noted in the mid-80s of the last century; in recent years, such strains have also appeared in Russia.

Oxazolidinones

Linezolid is the only drug available in Russia for the treatment of infections caused by vancomycin-resistant enterococci (VRE).

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Family enterobacteriaceae

The family of enterobacteria includes more than thirty genera and several hundred species of microorganisms. Of primary clinical significance are bacteria of the genera Escherichia, Klebsiella, Enterobacter, Citrobacter, Serratia, Proteus, Providencia, Morganella. There is considerable evidence confirming the etiological significance of the listed microorganisms. In each specific case of their isolation from primarily non-sterile areas of the human body, their significance must be assessed with the utmost seriousness.

The spectrum of antibiotic sensitivity of enterobacteria and acquired resistance. The natural sensitivity of individual members of the family to antibiotics varies. However, the basis of treatment is ß-lactams, fluoroquinolones and aminoglycosides.

SS-Lactams

Depending on the spectrum of natural sensitivity to them, enterobacteria are divided into several groups:

• Escherichia coli, Proteus mirabilis are resistant to all ß-lactam antibiotics, except for natural and semi-synthetic penicillinase-stable penicillins. However, in intensive care units, semi-synthetic penicillins (amino-, carboxy- and ureidopenicillins) and first-generation cephalosporins are rarely used due to the widespread resistance to them. Thus, depending on the severity and nature of the infection (hospital or community-acquired), the drugs of choice for empirical treatment of infections caused by microorganisms of the group in question are inhibitor-protected penicillins or second- to fourth-generation cephalosporins.
• Klebsiella spp., Proteus vulgaris, Citrobacter diversus have a narrower spectrum of natural sensitivity. It is limited to cephalosporins of II-IV generations, inhibitor-protected penicillins and carbapenems.
• Enterobacter spp., Citrobacter freundii, Serratia spp., Morganella morganii, Providencia stuartii are typical hospital pathogens, one of the most difficult groups to treat with ß-lactam antibiotics. The spectrum of their natural sensitivity is limited to cephalosporins of the III-IV generations, carbapenems and such drugs as ticarcillin + clavulanic acid and piperacillin + tazobactam.

The basis of treatment of enterobacterial infections in the intensive care unit is cephalosporins of the third and fourth generations. For a long time, it was believed that carbapenems, protected penicillins and cephalosporins (cefoperazone + sulbactam) are reserve drugs, but at present this approach should be revised. Due to the extremely widespread in Russia mechanism of resistance in the form of extended-spectrum ß-lactamases (EBLS), which destroy all cephalosporins, the effectiveness of such drugs in the treatment of infections in the intensive care unit has been sharply reduced.

Carbapenems (imipenem, meropenem and ertapenem) are most effective against infections with enterobacteria producing BERS, while cefoperazone + sulbactam are less effective. Currently, the ability to synthesize ESBL is widespread mainly among pathogens of hospital infections. Moreover, it is impossible to predict their prevalence in a specific institution or even department without conducting special microbiological studies.

The basis of the tactics of empirical therapy of infections caused by ESBL producers is knowledge of their prevalence in a particular institution, as well as a clear distinction between community-acquired and hospital-acquired pathology.

• In case of community-acquired, even extremely severe infections, cephalosporins of the third and fourth generations will most likely be quite effective.
• In hospital infections, the use of cephalosporins is possible with a low frequency of ESBL in the institution, as well as in patients without the following risk factors: long-term hospitalization, previous antibacterial therapy, concomitant diseases.
• For hospital-acquired infections in settings with a high incidence of ESBL, especially in patients with the risk factors listed above, the drugs of choice are carbapenems or cefoperazone + sulbactam.

Drugs of other groups

Aminoglycosides and fluoroquinolones are significantly inferior to ß-lactams in their effectiveness in treating infections in intensive care units.

First of all, it should be noted that the use of aminoglycosides as monotherapy is inappropriate. Moreover, there is currently no data confirming the need for their use in combination with ß-lactams. Since the effectiveness of such combinations is not higher than monotherapy with ß-lactams.

Monotherapy of enterobacterial infections in intensive care units with fluoroquinolones is quite possible, although their use is less justified than that of ß-lactams. It should be noted that the "new" fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin) do not exceed traditional drugs of this group (ciprofloxacin and ofloxacin) in their antimicrobial activity against enterobacteria and effectiveness. Almost complete cross-resistance is observed to all fluoroquinolones. Quite often, fluoroquinolones are used in combination with ß-lactams, but the justification for such combinations is also insufficient. A significant limitation for the use of fluoroquinolones is the very high frequency of associated resistance with ß-lactams: up to 50-70% of enterobacterial strains producing ESBL are also resistant to fluoroquinolones.

Pseudomonas aeruginosa

Pseudomonas aeruginosa is a member of the genus Pseudomonas. Along with the genera Burkholderia, Comamonasu and some others, it is in turn a member of the family Pseudomonadaceae. Representatives of this taxonomic group are free-living, undemanding to cultivation conditions, aerobic gram-negative rods. They are classified as so-called non-fermenting bacteria (not capable of fermenting glucose). The Enterobacteriaceae family (E. coli, etc.) is classified as "fermenting" microorganisms. Pseudomonadaceae is characterized by an oxidative metabolism.

Antibiotic susceptibility spectrum

Some ß-lactams, aminoglycosides, fluoroquinolones, and polymyxin B have clinically significant antipseudomonal activity.

SS-Lactams

Carbapenem antibiotics exhibit the greatest activity against P. aeruginosa (meropenem is somewhat more active in vitro than imipenem, while ertapenem is inactive). Next in descending order of activity are fourth-generation cephalosporins (cefepime), aztreonam, third-generation cephalosporins (ceftazidime, cefoperazone), ureidopenicillins (primarily piperacillin), ticarcillin, and carbenicillin. It should be emphasized that common cephalosporins (cefotaxime and ceftriaxone) are virtually devoid of antipseudomonas activity.

Acquired resistance to ß-lactams is a very common phenomenon among P. aeruginosa. Its main mechanisms are hyperproduction of its own chromosomal ß-lactamases, development of methods that ensure the removal of antibiotics from the internal environment of bacterial cells, and a decrease in the permeability of external structures as a result of complete or partial loss of porin proteins. Acquired ß-lactamases of various groups (most often the OXA group) are also common among P. aeruginosa.

The diversity of resistance mechanisms results in a significant diversity of possible phenotypes. The vast majority of strains circulating in the ICU are currently resistant to carbenicillins and piperacillin, which almost completely deprives these drugs of any value. Quite often, P. aeruginosa retains sensitivity to the combination of piperacillin + tazobactam.

Ceftazidime and cefepime are currently considered the main antipseudomonas drugs. There is incomplete cross-resistance between them. There are strains that are resistant to one of the indicated antibiotics, but sensitive to the other. Among pseudomonads, resistance to carbapenems is the least common, and there is no complete cross-resistance between imipenem and meropenem. There may be cases when the microorganism is not sensitive to carbapenems, but the use of ceftazidime or cefepime is effective. In such a situation, planning empirical therapy for pseudomonad infections is possible only on the basis of local data on the characteristics of antibiotic resistance of microorganisms in a particular institution.

However, the greatest threat to the entire system of antibacterial therapy is the ability of pseudomonads to synthesize metallo-ß-lactamases (such strains are quite common in Russia), which has appeared relatively recently. The peculiarity of these enzymes is the ability to hydrolyze almost all ß-lactams, including carbapenems. In such cases, aztreonam sometimes retains activity.

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Aminoglycosides

All aminoglycosides available in Russia (gentamicin, tobramycin, netilmicin and amikacin) exhibit approximately the same activity against P. aeruginosa. The MIC of amikacin is slightly higher than that of other representatives of the group, but its doses and, accordingly, concentrations in the blood serum are also higher. The strains of P. aeruginosa common in Russia most often exhibit resistance to gentamicin and tobramycin, and rarely to amikacin. The patterns of cross-resistance to aminoglycosides are quite complex and in practice almost any variant can be encountered. Having data on the sensitivity of a microorganism to three aminoglycosides, it is impossible to predict with complete certainty the sensitivity to the fourth.

Aminoglycosides are not used as monotherapy for pseudomonas infections. However, unlike enterobacterial diseases, in infections caused by P. aeruginosa, the use of combinations of ß-lactams and aminoglycosides is quite widespread and quite justified (especially against the background of neutropenia).

Fluoroquinolones

Among all available fluoroquinolones, ciprofloxacin has the highest activity against P. aeruginosa. However, pharmacodynamic calculations indicate that to obtain a reliable clinical effect, its daily dose should be more than 2.0 g, which is higher than the permissible values.

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Multiple resistance

An extremely difficult problem for antibacterial therapy is the so-called panresistant strains of P. aeruginosa. They are resistant to all ß-lactams, aminoglycosides and fluoroquinolones. Such strains, as a rule, retain sensitivity only to polymyxin B. One of the possible approaches to the treatment of infections caused by such microorganisms may be a quantitative assessment of sensitivity and the choice of a combination of two or more antibiotics demonstrating the lowest MIC values, but the effectiveness of such an approach in the clinic has not been sufficiently studied.

Duration of antibacterial therapy

Antibacterial therapy is administered until stable positive changes in the patient's condition are achieved and the main symptoms of infection disappear. Due to the absence of pathognomonic signs of a bacterial infection, it is difficult to establish absolute criteria for its termination. Usually, the question of stopping antibiotic therapy is decided individually based on a comprehensive assessment of the change in the patient's condition. However, the general criteria for the adequacy of antibacterial therapy are as follows:

• disappearance or reduction in the number of microorganisms in the material obtained by an invasive method from the main source of infection,
• negative blood culture results,
• absence of signs of systemic inflammatory response and infection-induced organ dysfunction,
• positive dynamics of the main symptoms of infection,
• persistent normalization of body temperature (maximum daytime <37.5 °C).

The persistence of only one sign of bacterial infection (fever or leukocytosis) is not considered an absolute indication for continuing antibacterial therapy. Since studies have shown that during the stay of patients in the intensive care unit on mechanical ventilation, achieving normal temperature, disappearance of leukocytosis and sterilization of the tracheal mucosa are unlikely even with adequate antibacterial therapy. Isolated subfebrile body temperature (maximum daytime <37.9 °C) without chills and changes in the peripheral blood may be a manifestation of post-infectious asthenia or abacterial inflammation after surgery, polytrauma, which does not require continuing antibacterial therapy. The persistence of moderate leukocytosis (9-12x10 ⁹ /l) without a shift in the leukocyte formula to the left and other signs of bacterial infection is assessed similarly.

The usual duration of antibacterial therapy for hospital infections of various localizations is 5-10 days. Longer periods are undesirable due to the development of possible complications of treatment, the risk of selection of resistant strains and the development of superinfection. In the absence of a stable clinical and laboratory response to adequate antibacterial therapy within 5-7 days, additional examination (ultrasound, CT, etc.) is necessary to search for complications or a source of infection in another localization.

Longer periods of antibacterial therapy are necessary for infections of organs and tissues where therapeutic concentrations of drugs are difficult to achieve, therefore, there is a higher risk of persistence of pathogens and relapses. Such infections primarily include osteomyelitis, infective endocarditis, secondary purulent meningitis. In addition, for infections caused by S. aureus, longer courses of antibacterial therapy (2-3 weeks) are usually also recommended.