Rational antibiotic therapy: remedies and tactics

Infections - one of the main problems of ICU (may be the main reason for hospitalization of patients in the ICU or complication of other diseases), the most important predictive measure for patients. Community-based patients requiring hospitalization in the ICU and hospital infections are independent factors of mortality. They lead to an extension of inpatient treatment. Based on the foregoing, in order to improve the prognosis of patients, it is essential to develop a strategy for antibiotic therapy.

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

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

In addition, 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 ICU:

• The main disease.
• The severity of the patient's condition on the scale of assessment of acute and chronic functional changes APACHE II> 15.
• Age over 60 years.
• Diagnostic and curative invasive procedures:
  • intubation,
  • ivl,
  • catheterization of the bladder,
  • central venous catheterization.
• Use of antacids and H2-receptor blockers.
• Duration of stay in the ICU.

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

In connection with the severity of the condition of patients and the danger of infectious complications for them, antibiotic therapy should be started urgently at the first signs of the disease (without waiting for the results of bacteriological research), as delay can threaten with dangerous consequences. In their daily practice in the hospital, doctors face two groups of infectious diseases:

• out-of-hospital - emerged outside the hospital, which caused hospitalization,
• Hospital (nosocomial) - developed in a patient in a hospital.

The main differences between these groups are the types of pathogens and their antibiotic resistance. For out-of-hospital infections, a limited and fairly stable composition of the most likely pathogens, depending on the localization of the process, is characteristic. The spectrum of pathogens of hospital infections, as a rule, is less predictable. The causative agents of hospital infections are more resistant to ani antibiotics than pathogens of community-acquired infections. These differences are important for the selection of rational empirical therapy.

In hospitals, and especially in the ICU, favorable conditions have been created for the exchange of microorganisms by close contact between patients and personnel. Parallel to the background of intensive treatment, their selection takes place. As a result, a microecological situation arises with the dominance of certain strains (mostly resistant to antibiotics). They are called hospital. Clear criteria that make it possible to recognize a particular strain as hospitalized do not exist (antibiotic resistance is important, but not necessary).

When entering the hospital, the patient inevitably contacts the hospital strains of bacteria. As the length of stay in the hospital increases, the likelihood of replacing the patient's own microflora with a hospital one increases - the risk of developing infections caused by it increases. It is quite difficult to establish the exact time necessary for the patient's colonization of the patient's hospital microflora, since it depends on many factors (age, stay in intensive care units, the severity of the concomitant pathology, antibiotic therapy or prophylaxis). It is also difficult to establish a time interval when the resulting infection should be considered hospital. In most cases, the infection is regarded as hospital if it manifests its symptoms more than 48 hours after the time of hospitalization.

[1], [2], [3], [4], [5],

Epidemiology and causes of infections

To estimate the frequency of hospital infections in our country is difficult because of the lack of official registration of such diseases. In the ICU, 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 the intensive care units. According to international multicenter studies, the average prevalence of hospital infections in hospitals is 5-10%, and in the ICU it reaches 25-49%. The scientific works devoted to the study of their etiology reflect the situation in the surveyed hospitals, so their results are extrapolated to other institutions with a great deal of conventionality. Even multicenter studies are not considered exhaustive, although they are most representative.

The structure and etiology of infections in the ICU is most fully studied. According to a multi-center EPIC study conducted on one day in 1417 offices in 17 European countries (with coverage of more than 10,000 patients), 44.8% had infections, and the rate of ICU-associated patients was 20.6%. The most frequent in the ICU were pneumonia (46.9%), lower respiratory infections (17.8%) and urinary tract (17.6%), angiogenic (12%). In the etiologic structure, Gram-negative bacteria of the Enterobacteriaceae family (34.4% ), Staphylococcus aureus (30.1%), Pseudomonas aeruginosa (28.7%), coagulase-negative staphylococci (19.1%), fungi (17.1%). Many of the etiologically significant microorganisms showed resistance to traditional antibiotics, in particular, the prevalence of methicillin-resistant staphylococci was 60%, in 46% P aeruginosa was resistant to gentamicin.

Similar results on the etiologic structure of infections were obtained in another study. His results also confirmed that antibiotics were prescribed for most patients in the ICU (72.9%) with a curative or prophylactic purpose. And most often - aminoglycosides (37.2%), carbapenems (31.4%), glycopeptides (23.3%), 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 in 1992-1997 showed prevalence of urinary tract infections (31%), pneumonia (27%), primary angiogenic infections (19%) in the ICU. And 87% of primary angiogenic infections were associated with central venous catheters, 86% of pneumonia with ventilation, and 95% of urinary infections with urinary catheters. The leading causative agents of pneumonia associated with ventilation were the Enterobacteriaceae (64%), P. Aeruginosa (21%), S. Aureus (20%), coagulase-negative staphylococci (36%), enterococci (16% ), S. Aureus (13%), fungi (12%) Urinary infections were dominated by fungi and Enterobacteriaceae.

Based on the primary localization of the focus of infection, one can judge the alleged etiology of the disease, which certainly serves as a reliable guide to the choice of the empirical regime of antibiotic therapy.

[6], [7], [8], [9], [10],

Principles of planning antibiotic therapy for infections

Given the complexity of the treatment of hospital infections (the severity of the condition of patients, often their polymicrobial nature, the possibility of isolating pathogens with multiple resistance to antibacterial agents in nosocomial infections), the following principles for the rational use of antibiotics in the ICU should be singled out:

• Antibiotic therapy begins immediately after the detection of infection, without waiting for the results of bacteriological research.
• The choice of starting empirical treatment regimen should be programmable, taking into account the probable spectrum of pathogens and their possible resistance (data from local monitoring of antibiotic resistance).
• Initial evaluation of the effectiveness of therapy is carried out 48-72 hours after its beginning, reducing the severity of fever and intoxication. If there is no positive effect in the specified time, then the treatment regimen is corrected.
• It is irrational and undesirable to use prophylactic antibiotics in the postoperative period or during ventilation (in the absence of clinical signs of infection).
• The administration of antibiotics is carried out in accordance with official instructions. The main routes of administration are intravenous, intramuscular, oral. Other pathways (intraarterial, endolymphatic, intra-abdominal, endotracheal, etc.) have no proven advantages over traditional ones.

The choice of an antibacterial drug can be carried out based on the established etiology of the disease and the susceptibility of the pathogen to antibiotics - etiotropic therapy. In situations where the causative agent is unknown, the drug is administered on the basis of an empirical approach. In the latter case, the antibiotic is selected on the basis of a well-known list of microorganisms that cause infection of a specific localization, and knowledge of the main trends of antibiotic resistance of the most probable pathogens. It is clear that in the clinical practice most often before the specification of the etiology of the disease the doctor is forced to use an empirical approach.

In severe infections, one should adhere to the principle of maximum starting empirical therapy - the administration of drugs acting on the maximum number of potential pathogens of the disease localization. To adhere to this principle is especially necessary in the treatment of NPIVL, peritonitis, severe sepsis. Since it is established that in case of inadequate initial therapy, the risk of a lethal outcome significantly increases (for example, for NPIVL it increases by 3 times).

Under adequate empirical antibacterial therapy is understood:

• at the chosen mode there is an influence on all potential pathogens,
• when choosing an antibacterial drug, the risk of multidrug resistance of pathogens is taken into account,
• The treatment regimen should not promote selection in the separation of resistant strains.

Empirical and targeted etiotropic antibacterial therapy

Conducting rational antibacterial therapy of hospital infections in the ICU is impossible without modern knowledge about the etiological structure of diseases and antibiotic resistance of their pathogens. In practice, this means the need to identify the pathogen by microbiological methods, determining its antibiotic sensitivity. Discuss the selection of the optimal antibacterial drug can only be after the above studies.

However, in practical medicine, the situation is not so simple, and even the most modern microbiological methods often fail to give the doctor a quick answer or even clarify the causative agent of the disease. In such a case, knowledge comes to the aid of the most probable pathogens of specific forms of hospital infections, the spectrum of natural antibiotic activity and the level of acquired resistance to them in a given region and in a specific hospital. The last condition is most important when planning antibiotic therapy of hospital infections in the ICU, where the level of acquired resistance is highest. Since insufficient equipment of microbiological laboratories and low level of standardization of studies on antibiotic sensitivity assessment do not allow to form a real picture of the epidemiological situation in the medical institution and to develop weighted treatment recommendations.

The etiology of infectious diseases is the main factor determining the strategy and tactics of antibiotic therapy. In connection with the impossibility of rapid diagnosis of bacterial infections and evaluation of the antibiotic susceptibility of their pathogens, the appointment of antibiotic therapy in intensive care usually occurs empirically.

Despite a significant variety of infectious agents in the intensive care unit, only a limited number of bacterial species play a leading role in their aetiology. On the grounds of the common nature of the spectra of natural sensitivity to antibacterial drugs and the mechanisms of their resistance, they can be grouped 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 Enterobacteriaceae family,
4. Pseudomonas aeruginosa.

The listed pathogens are sources of more than 80% of cases of urinary and respiratory tract infections, intra-abdominal and surgical intervention, and angiogenic infections. For infections of different localization, some features of etiology are characteristic. For example, angiogenic infections are most often caused by staphylococci, and urinary tracts are caused by gram-negative microorganisms, enterococci practically do not affect the respiratory tract. For intra-abdominal and wound infections, the greatest etiological diversity is characteristic.

The data given can serve as the first reference for the selection of empirical antibiotic therapy. Very simple and, in some cases, extremely useful research is the smear microscopy from the focus of infection. Unfortunately, this simple method in most institutions is paid very little attention, despite the fact that information about the prevalence of gram-positive or gram-negative flora is extremely important for the choice of antibiotic therapy.

Even more important information can be obtained one day after taking the pathological material and its primary culture. With well-established work of the laboratory, its connection with the clinic, the doctor can receive an answer to the question "Do staphylococci, enterococci, enterobacteria or P. Aeruginosa participate in the infectious process?" Knowing the spectrum of natural sensitivity of these groups of microorganisms and the specific features of the spread of resistance in a particular 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 obtaining the final results of identification of the pathogen and evaluation of its antibiotic susceptibility.

Below are the data on the spectrum of natural sensitivity of the main groups of pathogens of infections in the ICU and on the drugs of choice for the treatment of diseases of known etiology.

[11], [12], [13], [14], [15], [16]

The choice of an antibiotic in the treatment of infections of known etiology

The section focuses on the means of choice for the treatment of severe and hospital infections. For the treatment of community-acquired and light forms, other antibacterial drugs can be used.

Streptococcus pyogenes

The drug of choice is benzylpenicillin. Equally effective aminopenicillins, other ß-lactams do not have advantages. Acquired resistance to ß-lactams is not described.

Alternative preparations of macrolides and lincosamides (shown when allergic to ß-lactams).

The prevalence of acquired sustainability varies in different geographic regions.

Streptococcus pneumoniae

Preparations for the selection of benzylpenicillin (parenteral), amoxicillin (per os) other ß-lactams.

The prevalence of acquired sustainability varies in different geographic regions. With pneumonia caused by penicillin-resistant pneumococci, benzylpenicillin and amoxicillin are effective, with meningitis - failures are possible.

Alternative drugs - cephalosporins III-IV generations (cefotaxime, ceftriaxone, cefepime), carbapenems (with meningitis - meropenem), antipnevmokokkovye fluoroquinolones. With meningitis caused by penicillin-resistant pneumococci, the use of glycopeptides

Streptococcus agalactiae

Preparations for the selection of benzylpenicillin, ampicillin, it is advisable to combine with aminoglycosides (gentamicin). Acquired stability is a rare occurrence.

Alternative preparations cephalosporins of the third generation, carbapenems.

Greasy streptococci

Preparations for the selection of benzylpenicillin, ampicillin. With endocarditis and severe generalized infections - in combination with aminoglycosides (gentamicin). Acquired stability is a rare phenomenon.

Alternative preparations cephalosporins of the third generation, carbapenems. When allergic to ß-lactams, glycopeptides can be used.

Enterococcus faecalis

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

Acquired resistance is encountered to penicillins, often to aminoglycosides.

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

Acquired resistance to glycopeptides among the strains described in Russia is a rarity.

[17], [18], [19], [20], [21], [22]

Enterococcus faecium

Preparations for the selection of glycopeptides (better - in combination with aminoglycosides). However, failures in treatment are possible.

Acquired resistance to glycopeptides among the strains described in Russia is a rarity.

Alternative preparations of oxazolidinones

[23], [24], [25], [26]

Methicillin-sensitive staphylococci

Preparations for the choice of oxacillin, protected aminopenicillins, cephalosporins of the first generation.

Acquired resistance with sensitivity to oxacillin is not simultaneous resistance to the ß-lactams listed above.

Alternative preparations fluoroquinolones with increased activity against gram-positive microorganisms (levofloxacin, moxifloxacin, gatifloxacin), oxazolidinones. In severe infections and allergies of immediate type, it is possible to use glycopeptides for ß-lactams, but their effectiveness is lower.

Methicillin-resistant staphylococci

Preparations for the selection of glycopeptides. Acquired resistance identified single resistant strains.

Alternative preparations of oxazolidinones. Sometimes fluoroquinolones, fusidic acid, rifampicin, co-trimoxazole, phosphomycin are effective. However, the treatment regimens are not exactly defined.

Corynebacterium diphtheriae

Preparations for the selection of macrolides and lincosamides. The prevalence of acquired resistance has not been studied enough.

Alternative preparations benzylpenicillin, rifampicin, tetracyclines.

[27], [28], [29], [30], [31], [32], [33]

Corynebacteriumjeikeium

Preparations for the selection of glycopeptides. The prevalence of acquired resistance has not been studied enough.

Alternative drugs are not defined.

[34], [35], [36], [37], [38], [39]

Listeria monocytogenes

Drugs for choosing ampicillin, better in combination with gentamicin. Cephalosporins are ineffective. The prevalence of acquired resistance has not been studied enough.

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

Bacillus anthracis

Preparations for the selection of benzylpenicillin, ampicillin. Cephalosporins are not very effective.

Acquired resistance published single reports on the detection of resistant strains.

Alternative preparations fluoroquinolones, tetracyclines, macrolides, chloramphenicol.

[40], [41], [42]

Bacillus cereus

Drugs for the selection of clindamycin, vancomycin. The acquired stability has not been studied enough. Alternative preparations gentamycin, ciprofloxacin.

[43], [44], [45], [46], [47], [48], [49], [50],

Nocardia asteroides

The drug of choice is co-trimoxazole. The acquired stability has not been studied enough.

Alternative preparations imipenem + glycopeptides, amikacin + cephalosporins, minocycline (their use is insufficiently justified).

Neisseria meningitidis

The drug of choice is benzylpenicillin. Acquired resistance published single reports on the detection of resistant strains.

Alternative preparations cephalosporins of the third generation, chloramphenicol.

Haemophilus spp.

Preparations for the choice of aminopenicillins. Acquired resistance in some regions is widespread resistant strains producing β-lactamases (their share in Russia is less than 5-6%).

Alternative preparations cephalosporins of the third generation, chloramphenicol. With localized infections - cephalosporins of the second generation, protected penicillins, fluoroquinolones.

Legionella spp.

Drugs for the selection of erythromycin, azithromycin or clarithromycin (better in combination with rifampicin). Acquired resistance is absent. Alternative preparations fluoroquinolones, doxycycline, co-trimoxazole.

Vibrio cholerae

Drugs for the selection of fluoroquinolones. Acquired resistance describes single cases.

Alternative drugs doxycycline, co-trimoxazole.

Enterobacteriaceae

Drugs of choice in the treatment of severe infections caused by microorganisms of the Enterobacteriaceae family are β-lactam antibiotics. However, depending on the natural sensitivity of certain species, different drugs must be used. The use of aminoglycosides and fluoroquinolones is also justified. The choice of specific drugs based on data on the localization and severity of infection, the spread of resistance.

[51], [52], [53]

Escherichia coli, Proteus mirabilis

Preparations of choice protected aminopenicillins, cephalosporins II-III generation. Acquired resistance is widespread.

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

[54], [55], [56], [57], [58], [59]

Klebsiella spp, Proteus vulgaris, Citrobacter diversus

Drugs of choice protected aminopenicillins, cephalosporins II-III generation. Acquired resistance is widespread.

Alternative preparations fluoroquinolones, aminoglycosides, cefoperazone + sulbactam, cephalosporins of the IV generation, carbapenems (their various combinations).

To all alternative drugs, the formation of resistance is possible. However, the least likely - to amikacin, carbapenems (resistance to them - an extremely rare phenomenon).

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

Preparations for the choice of cephalosporin III-IV generation. Acquired resistance is widespread.

Alternative preparations fluoroquinolones, aminoglycosides, cefoperazone + sulbactam, cephalosporins of the IV generation, carbapenems (their various combinations).

To all alternative drugs, the formation of resistance is possible. However, the least likely - to amikacin, carbapenem (there are isolated reports of resistant strains).

[60], [61], [62], [63], [64]

Shigella spp.

Drugs for the selection of fluoroquinolones. Acquired stability - isolated cases.

Alternative preparations of co-trimoxazole, ampicillin Salmonella spp., Including S. Typhi (generalized infections).

Preparations for the selection of fluoroquinolones, cephalosporins of the third generation (cefotaxime, ceftriaxone). Acquired stability - isolated cases.

Alternative drugs are chloramphenicol, co-trimoxazole, ampicillin.

Pseudomonas aeruginosa

Preparations for the choice of ceftazidime + aminoglycosides. Acquired resistance is widespread.

Alternative preparations protected antipseudomonadal penicillins (used only in combination with aminoglycosides), ciprofloxacin, cephalosporins of the IV generation, carbapenems, polymyxin B.

Perhaps the development of resistance to all alternative drugs.

Burkholderia cepacia

Drugs for the selection of carbapenems, ciprofloxacin, ceftazidime and cefoperazone, ureidopenicillins (including protected ones), co-trimoxazole and chloramphenicol. However, treatment regimens are not well founded.

Acquired resistance is quite common. In cystic fibrosis, strains that are resistant to all these drugs are especially common.

[65], [66], [67], [68], [69], [70]

Stenotrophomonas maltophilia

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

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

It is often enough to meet strains resistant to alternative drugs.

Acinetobacter spp.

Drugs of choice in connection with the extreme variety of sensitivity of strains, the justification of regimes of empirical therapy is difficult. The most common combinations are carbapenems or ceftazidime with aminoglycosides (mainly with amikacin), as well as fluoroquinolones with aminoglycosides. It may be effective to prescribe ampicillin or cefoperazone with sulbactam (due to the antibacterial activity of the latter).

Acquired resistance to all drugs used is widespread.

[71], [72], [73], [74], [75], [76], [77], [78], [79],

Clostridium petfringens

Preparations for the selection of benzylpenicillin, possibly in combination with clindamycin. The acquired stability has not been studied enough.

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

[80], [81], [82], [83], [84], [85], [86], [87], [88]

Clostridium difficile

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

[89], [90], [91], [92], [93]

Actinomyces israelii and other anaerobic actinomycetes

Preparations for the selection of benzylpenicillin, aminopenicillins. Acquired resistance is not described. Alternative preparations cephalosporins of the third generation, erythromycin and clindamycin, doxycycline.

[94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104]

Peptostreptococcus

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

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

Bacteroidesfragilis

The drug of choice is metronidazole. Acquired stability is extremely rare.

Alternative drugs clindamycin, carbapenems, cefoxitin, protected penicillins.

[105], [106], [107], [108], [109], [110],

Staphylococcus spp.

34 types of staphylococci are currently described. They are capable of producing a significant number of diverse virulence factors. The most complete "set" is found in strains of S. Aureus. The isolation of bacteria from a pathological material (with an appropriate clinical picture) almost always indicates their etiological significance.

In the precise species identification of staphylococci of other species, united in the group of "coagulase-negative", in practice, it is often not necessary. Such information is important for epidemiological monitoring, as well as for serious 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 exclusion of contamination arises even when such microorganisms are isolated from sterile media (blood, liquor).

The spectrum of natural sensitivity of Staphylococcus spp. And acquired resistance. Staphylococci have 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 great opportunities for the choice of antibiotics in some cases, the treatment of staphylococcal infections is a serious problem, which is associated with the formation of antibiotic resistance in microorganisms.

β-Lactam antibiotics

Among all antibacterial drugs, they are most active against staphylococci, but due to the wide spread among bacteria of the ability to produce β-lactamases, natural and semisynthetic penicillins are completely devoid of clinical significance. Despite some differences in the level of microbiological activity, oxacillin, protected penicillins, cephalosporins of I-IV generations (except ceftazidime and cefoperazone) and carbapenems have practically the same efficacy. The choice of a particular drug depends on the ease of use, cost and likelihood of a mixed infectious process (participation of gram-negative bacteria).

However, the use of β-lactam antibiotics is possible only in the absence of staphylococcus another mechanism of resistance - an additional penicillin-binding protein. A marker of this mechanism is resistance to oxacillin. According to the historical tradition, S. Aureus with a similar mechanism of resistance retained the name Methicillin Resistant Staphylococcus aureus (MRSA), despite the fact that methicillin has long been virtually excluded from medical practice.

With the identification of resistance to oxacillin, the treatment of staphylococcal infections with β-lactams is discontinued.

An exception is the cephalosporin antibiotic ceftobiprol. It is able to suppress 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 state pathogenic pathogens (the frequency of their spread in many ICUs of Russia is more than 60%). However, recently the situation has changed for the worse microorganisms increasingly cause severe out-of-hospital infections of the skin and soft tissues, as well as destructive pneumonia.

Glycopeptide antibiotics (vancomycin, teicoplanin and a number of other drugs at different stages of development) are considered as a means of choice for the treatment of infections caused by MRSA. However, currently available glycopeptides (vancomycin and teicoplanin) show only bacteriostatic action against staphylococci (a significant disadvantage in comparison with β-lactams). In cases where glycopeptides for various reasons were prescribed for the treatment of infections caused by methicillin-susceptible 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 has not been detected for a long time, however, since the second half of the 1990s, reports of strains with a reduced level of sensitivity to them have begun to be published. The mechanism of stability is not deciphered. It is difficult to estimate the frequency of spread of such strains because of the methodological difficulties in their detection, however it is obvious that with the infections they cause, the effectiveness of vancomycin is dramatically reduced. 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 of the group is linezolid. It has a high activity and is effective against all staphylococci, regardless of resistance to other antibiotics. It is considered as a serious alternative to glycopeptides in the treatment of infections caused by MRSA. Linezolid can be a means of choice for the treatment of infections caused by strains of staphylococci with reduced sensitivity to glycopeptides.

Fluoroquinolones

Preparations of this group have different activity against staphylococci ciprofloxacin and ofloxacin - relatively low, but clinically significant, levofloxacin, moxifloxacin, hemifloxacin and other new fluoroquinolones - more. The clinical and bacteriological efficacy of levofloxacin in staphylococcal infections is well established. However, as indicated above, in MRSA, they are often associated with resistance.

Preparations of other groups

Effective against staphylococcus is also fusidic acid, co-trimoxazole and rifampicin. However, detailed clinical trials for their otsekke not conducted. In connection with the fact that all the listed drugs quickly develop resistance, they are advisable to combine (for example, co-trimoxazole and rifampicin). Such combinations are particularly promising in the treatment of mild infections caused by MRSA.

Given these facts, it is obvious that when developing tactics for the empirical therapy of staphylococcal infections in each specific compartment, one should take into account the frequency of MRSA spread.

[111], [112], [113]

Enterococcus spp.

Enterococci were isolated from the streptococcus genus in 1984. Within the genus Enterococcus, more than 10 species are isolated, most of them extremely rarely cause human diseases. Among the clinical isolates, 80-90% are in E faecalis and 5-10% in E faecium, other species play a limited role. In the practice of ICU, enterococcal angiogenic infections, often associated with catheters, are most important. With wound infections, enterococci, as a rule, are part of microbial associations and do not play a significant independent role. Their significance in the pathogenesis of intra-abdominal infections is not accurately established, however, specific anti-enterococcal therapy does not improve the results of treatment. Enterococcal urinary tract infections are usually associated with catheters and pass after their removal either spontaneously or with the use of narrow-spectrum drugs.

Spectrum of natural sensitivity Enterococcus spp. And acquired resistance. Of the known drugs, some ß-lactams, glycopeptides, rifampicin, macrolides, chloramphenicol, tetracyclines (doxycycline), nitrofurantoin, and fluoroquinolones are known to have anti-enterococcal activity. However, the clinical significance of rifampicin, macrolides and chloramphenicol in the treatment of infections is uncertain. Tetracyclines, nitrofurantoin and fluoroquinolones are used only for the treatment of enterococcal urinary tract infections.

[114], [115], [116], [117], [118]

ß-Lactam antibiotics

Among them, benzylpenicillin, aminopenicillins, ureidopenicillins (the greatest experience is accumulated for piperacillin) and carbapenems have anti-enterococcal activity. All cephalosporins are devoid of it. It is important to note that the natural sensitivity to ß-lactams in two main species of enterococci is different E. Faecalis are usually sensitive, and E. Faecium are stable. Neither ureidopenicillins nor carbapenems have advantages over ampicillin. Preparations of this group have only bacteriostatic activity against enterococci, they must be combined with aminoglycosides to achieve a bactericidal effect.

Glycopeptides

Glycopeptide antibiotics (vancomycin and teicoplanin) have traditionally been considered as a drug of choice in the treatment of enterococcal infections caused by strains resistant to ß-lactam antibiotics. However, glycopeptides, as well as ß-lactams, possess only bacteriostatic action against enterococci. To achieve a bactericidal effect, glycopeptides should be combined with aminoglycosides.

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

Oxazolidinones

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

[119], [120], [121], [122], [123], [124],

Family enterobacteriaceae

The family of enterobacteria includes more than thirty genera and several hundred species of microorganisms. The main clinical importance is the bacteria of the genera Escherichia, Klebsiella, Enterobacter, Citrobacter, Serratia, Proteus, Providencia, Morganella. There are numerous data confirming the etiological significance of these microorganisms. In each case, their isolation from the primarily non-sterile areas of the human body to assess their significance must be approached with all seriousness.

Spectrum of antibiotic susceptibility of enterobacteria and acquired resistance. The natural sensitivity to antibiotics of individual members of the family is different. However, the basis of treatment - 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 have resistance to all ß-lactam antibiotics, except natural and semi-synthetic penicillinase-resistant penicillins. However, in the ICU, semisynthetic penicillins (amino, carboxy- and ureidopenicillins) and cephalosporins of the first generation do not use much in connection with the widespread spread of 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 the microorganisms of the group under consideration are inhibitor-protected penicillins or cephalosporins of the II-IV generation.
• 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 complex groups for treatment with ß-lactam antibiotics. The spectrum of their natural sensitivity is limited by cephalosporins of III-IV generations, carbapenems and such drugs as ticarcillin + clavulanic acid and piperacillin + tazobactam.

The basis for the treatment of enterobacter infections in the ICU is cephalosporins of III-IV generations. For a long time it was believed that carbapenems, protected penicillins and cephalosporins (cefoperazone + sulbactam) are reserve drugs, but this approach should now be revised. Due to the extremely wide spread in Russia of the mechanism of resistance in the form of ß-lactamases of the extended spectrum (BIRS), which destroy all cephalosporins, the effectiveness of such drugs in the treatment of infections in the ICU is drastically reduced.

The maximum effectiveness of infections with enterobacteria producing BIRS, carbapenems (imipenem, meropenem and ertapenem), a smaller - cefoperazone + sulbactam. Currently, the ability to synthesize ESBL is widespread, mainly among pathogens of hospital infections. Moreover, it is impossible to predict their prevalence in a particular institution or even a department without special microbiological research.

The basis for the tactics of empirical therapy of infections caused by BLBC producers is knowledge of their prevalence in a particular institution, as well as a clear separation of community and hospital pathology.

• With out-of-hospital even extremely severe infections, cephalosporins of III-IV generations are likely to be quite effective.
• In case of hospital infections, the use of cephalosporins is possible at a low incidence of BLDS in the institution, as well as in patients without the following risk factors, prolonged hospitalization, previous antibiotic therapy, concomitant diseases.
• For hospital infections in institutions with a high prevalence of LDRD, especially in patients with the above risk factors, the drugs of choice are carbapenems or cefoperazone + sulbactam.

Preparations of other groups

Aminoglycosides and fluoroquinolones on the effectiveness of treatment of infections in the ICU are significantly inferior to ß-lactams.

First of all, it should be noted that the use of aminoglycosides as monotherapy is inexpedient. Moreover, at the present time there is 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 enterobacter infections in the ICU with fluoroquinolones is quite possible, although their use is justified worse than ß-lactams. It should be noted that the "new" fluoroquinolones (levofloxacin, moxifloxacin, hemifloxacin) do not exceed the traditional drugs of this group (ciprofloxacin and ofloxacin) because of their antimicrobial activity against enterobacteria and efficacy. To all fluoroquinolones, almost total cross resistance is observed. Quite often, fluoroquinolones are used in combination with ß-lactams, but the validity of such combinations is also insufficient. A significant limitation for the use of fluoroquinolones is the very high frequency of associated resistance with ß-lactams to 50-70% of strains of enterobacteria producing BLBS, and are resistant to fluoroquinolones.

Pseudomonas aeruginosa

Pseudomonas aeruginosa is a part of the genus Pseudomonas. He, along with the genera Burkholderia, Comamonasu by some others, in turn is part of the family Pseudomonadaceae. Representatives of this taxonomic group are free-living, aerobic gram-negative rods that are not exacting to cultivation conditions. They are referred to as the so-called non-fermenting bacteria (not capable of fermenting glucose). The "fermenting" microorganisms include the family Enterobacteriaceae (E. Coli, etc.). Pseudomonadaceae is characterized by an oxidative metabolism.

Spectrum of antibiotic sensitivity

Some ß-lactams, aminoglycosides, fluoroquinolones, as well as polymyxin B, have a clinically significant antipseudomonas activity.

ß-Lactams

The most active against R. Aeruginosa are carbapenem antibiotics (meropenem in vitro is somewhat more active than imipenem, and ertapenem is inactive). Further, in order of decreasing activity, cephalosporins of the fourth generation (cefepime), aztreonam, cephalosporins of the third generation (ceftazidime, cefoperazone), ureidopenicillins (primarily piperacillin), ticarcillin and carbenicillin follow in descending order of activity. It should be emphasized that common cephalosporins (cefotaxime and ceftriaxone) are virtually devoid of anti-pseudomonas activity.

Acquired resistance to ß-lactams - a very common phenomenon among P. Aeruginosa. Its main mechanisms are the hyperproduction of intrinsic chromosomal ß-lactamases, the 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. Among P. Aeruginosa, the acquired ß-lactamases of various groups (most often OXA groups) are also common.

The variety of mechanisms of resistance leads to a significant variety of possible phenotypes. The overwhelming majority of strains circulating in the ICU are now resistant to carbenicillins and piperacillin, which almost completely deprives these drugs of any significance. Frequently, P. Aeruginosa retains sensitivity to the combination of piperacillin + tazobactam.

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

However, the most threatening for the entire system of antibacterial therapy is the relatively recent ability of pseudomonads to synthesize metal-ß-lactamases (similar strains are quite common in Russia). A feature of these enzymes is the ability to hydrolyze virtually all β-lactams, including carbapenems. In such cases, it sometimes retains activity to aztreonam.

[125], [126], [127], [128], [129]

Aminoglycosides

All aminoglycosides available in Russia (gentamycin, tobramycin, netilmicin, and amikacin) exhibit approximately the same activity against P. Aeruginosa. MIC of amikacin is slightly higher than in other group members, however, its doses and, accordingly, serum concentrations are also higher. In the strains of R. Aeruginosa common in Russia, resistance to gentamicin and tobramycin is most often met, and rarely to amikacin. The patterns of cross resistance to aminoglycosides are quite complex and practically any variants can be found in practice. Having data on the sensitivity of the microorganism to three aminoglycosides, it is impossible to predict with full certainty the sensitivity to the fourth.

Aminoglycosides are not used as monotherapy agents for pseudomonasal infections. However, unlike enterobacter diseases, with the infections caused by P. Aeruginosa, the use of combinations of ß-lactams and aminoglycosides is fairly widespread and quite justified (especially against neutropenia).

Fluoroquinolones

Among all available fluoroquinolones, ciprofloxacin is the most active against P. Aeruginosa. However, pharmacodynamic calculations suggest that to obtain a reliable clinical effect, its daily dose should be more than 2.0 g, which is higher than the allowable values.

[130]

Multiple stability

An extremely complex problem for antibacterial therapy is the so-called pan-resistant strains of P. Aeruginosa. They are resistant to all ß-lactams, aminoglycosides and fluoroquinolones. Such strains tend to retain sensitivity only to polymyxin B. One possible approach to treating infections caused by such microorganisms can be a quantitative assessment of sensitivity and the choice of a combination of two or more antibiotics showing the lowest MIC values, however the effectiveness of such an approach in the clinic insufficiently studied.

The duration of antibiotic therapy

Antibacterial therapy is performed until stable positive changes in the patient's condition and the disappearance of the main symptoms of infection. In connection with the absence of pathognomonic signs of bacterial infection, absolute criteria for its termination are difficult to establish. Usually, the issue of stopping antibiotic therapy is solved individually based on a comprehensive assessment of the patient's condition change. However, the general criteria for the sufficiency of antibiotic therapy are as follows:

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

Preservation of only one sign of bacterial infection (fever or leukocytosis) is not considered an absolute indication for the continuation of antibiotic therapy. Since studies have shown that during the stay of patients in the ICU on artificial ventilation, the normal temperature, the disappearance of leukocytosis and sterilization of the mucous membrane of the trachea are unlikely even against the background of adequate antibiotic therapy. Isolated subfebrile body temperature (maximum daily <37,9 ° C) without chills and changes in peripheral blood may be a manifestation of postinfection asthenia or abacterial inflammation after surgery, polytrauma, which does not require the continuation of antibacterial therapy. Similarly, conserving moderate leukocytosis (9-12x10 ⁹ / L) without shifting the leukocyte formula to the left and other signs of bacterial infection are also considered.

Usual terms of antibacterial therapy of hospital infections of different localization - 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 persistent clinico-laboratory response to adequate antibacterial therapy for 5-7 days, an additional examination (ultrasound, CT, etc.) is needed to search for complications or a hotbed of infection of another localization.

Longer terms of antibiotic therapy are needed for organ and tissue infections where therapeutic drug concentrations are difficult to achieve, hence there is a higher risk of persistence of pathogens and relapses. Such infections include, first of all, osteomyelitis, infective endocarditis, secondary purulent meningitis. In addition, longer courses of antibiotic therapy (2-3 weeks) are usually recommended for infections caused by S. Aureus.