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SPECIFIC FEATURES OF ANTIBIOTIC THERAPY IN PATIENTS WITH ACUTE
OBSTRUCTIVE
Abdukodirova Shakhnoza
Assistant, Department of Clinical Pharmacology, Samarkand State Medical University
Subhonov Umar Umedovich
Student of group 613, Faculty of Medicine, Samarkand State Medical University
Mukhtorov Amirjon Shokirjonovich
Student of group 511, Faculty of Pharmacy, Samarkand State Medical University
https://doi.org/10.5281/zenodo.14780569
Abstract
: Antibacterial therapy for exacerbations of chronic obstructive pulmonary
disease (COPD) is a more difficult task for many doctors than the treatment of pneumonia. Thus,
in the case of pneumonia, few people question the appropriateness of prescribing antibiotics. It is
currently believed that a clear diagnosis of pneumonia is an absolute indication for the use of
antibacterial agents. At the same time, with chronic bronchitis (CB) and COPD, many doctors are
not sure of the need and justification for prescribing antibiotics for each exacerbation of the
disease.
Keywords:
Pneumonia, diagnosis, prevention, pathogenesis, origin.
Introduction
Unlike pneumonia, the onset of COPD is not associated with infectious factors. It is a
misconception that previous respiratory infections can lead to the development of CB and COPD.
In 2004, a working group of experts from the European Respiratory Society and the
American Thoracic Society defined COPD. This term refers to a lung disease caused by a
pathological inflammatory response of the relevant structures of the bronchopulmonary tree to the
effects of inhaled particles or gases, primarily from smoking. However, there is no mention of the
role of infectious agents. Consequently, CB and COPD are not currently considered infectious
diseases.
COPD develops with long-term, several decades of exposure to air pollutants, primarily
tobacco smoke components, to the bronchopulmonary system of a susceptible person. In this case,
a large number of cytokines and intercellular inflammatory mediators are released. The recruitment
of neutrophils and subsequent increase in their functional activity, the release of a large number of
enzymes from them, primarily neutrophil elastase, cause corresponding morphofunctional changes
in the bronchopulmonary tree. Damage to the large bronchi causes chronic bronchial
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hypersecretion and, accordingly, signs of chronic disease in the form of a prolonged productive
cough. Damage to the distal parts of the bronchial tree, which do not have mucus-forming elements
in the structure of the goblet cells and bronchial glands, is characterized by capillary dilatation and
obliteration of the bronchi and bronchioles with increased resistance to air flow. Damage to lung
tissue with autolytic destruction of interalveolar septa leads to the development of panacinar
pulmonary emphysema, which further aggravates the existing dysfunction of external respiration.
Due to the development of these morphofunctional changes that accompany the evolution
of CB and COPD, a predisposition to chronic bacterial colonization of the respiratory tract
develops over time. It is known that in a healthy person, the airways located distal to the glottis
are sterile. Incidentally, microorganisms that normally colonize the oropharynx can enter them
through microaspiration and even reach the distal parts of the tracheobronchial tree. Accidental
inhalation of microbial aerosols can also occur. However, due to well-coordinated mechanisms of
defense against nonspecific infection, these microorganisms are quickly established and
eliminated, thereby maintaining the sterility of the lower respiratory tract.
At the same time, in patients with COPD, the functioning of the lower respiratory tract is
impaired - hypersecretion of mucus, increased viscosity of bronchial secretions, and impaired
mucus transport all contribute to bacterial colonization. When microorganisms enter the
respiratory tract of a person with CB or COPD, they are not destroyed, resulting in chronic
bacterial colonization.
Therefore, when discussing the relationship between infection and COPD (or CB), it is
important to remember that bacterial colonization develops against the background of pronounced
anatomical and functional changes in the tracheobronchial tree. In turn, the waste products of
microorganisms further disrupt the local defenses of the respiratory tract, which is manifested by
the loss of ciliated epithelial cilia, epithelial damage, excessive production of bronchial secretions
and a violation of its rheology, and impaired secretion. IgA. At the same time, bacterial
colonization increases, which contributes to even greater tissue damage, aggravating existing
anatomical and functional disorders. Thus, a vicious circle is closed from which patients with CB
or COPD cannot escape.
What should be the doctor's tactics in case of exacerbation of chronic disease or COPD?
First of all, it is necessary to determine the causes of its development.
It would be wrong to reduce the problem of exacerbations to bacterial infection alone, and
therefore it is not necessary to resort to prescribing antibacterial drugs with each exacerbation of
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CB or COPD. In addition to bacteria, exacerbations of COPD can be caused by viruses, which are
responsible for about 30-40% of cases, as well as air pollutants - in about 20% of cases.
Thus, according to the literature, 40-50% of exacerbations of COPD or COPD are caused
by bacterial infection. This, on the one hand, confirms the great importance of antimicrobial
therapy in the exacerbation of these diseases, but on the other hand, requires careful selection of
patients for such a prescription. It should be remembered that the unreasonable use of antibacterial
drugs exacerbates the problem of acquired antibiotic resistance of the main pathogens of the
respiratory tract.
If a bacteriological examination of the material taken from the respiratory tract of a patient
with COPD reveals one or another microorganism, can it be said that this is the cause of a particular
episode of exacerbation of the disease? In 1976, the results of a study by Gump et al. were
published, during which long-term observation of 25 patients with COPD was carried out. For 4
years, both during the exacerbation of the disease and during the stable course, patients visited the
doctor every 2 weeks and, if there was a productive cough, produced sputum. Then it was subjected
to bacterioscopic and cultural evaluation. A total of 1886 visits and 116 exacerbations of COPD
were recorded. The results of the study showed that with a stable course of the disease, mainly
non-typeable strains of Haemophilus influenzae (59.9% of cases) and pneumococcus (33.1% of
cases) were sown. At the same time, during the exacerbation of the disease, the same bacterial
pathogens were isolated and with approximately the same frequency.
This was the first study to seriously question the appropriateness of prescribing antibiotics
to most patients with COPD or exacerbations. If we detect the same frequency of relevant
microorganisms in bronchial secretions or sputum during periods of stable disease and during
exacerbations of COPD, and cannot distinguish chronic bacterial colonization from active ongoing
bacterial infection, what should we do? Is there a point in prescribing antibiotics?
It was not until 2004 that a definitive answer to this question was given, when studies
showed that the same types of microorganisms are found both during stable COPD and during
exacerbations. However, the fundamentally important fact is that their concentration, or in other
words, the bacterial contamination of the respiratory tract, increases hundreds or even thousands
of times during exacerbations of COPD (Sethi, 2004). It is this multiple increase in bacterial load
that initiates the inflammatory process in the respiratory tract and leads to exacerbation of the
disease.
In addition, it has been shown that during exacerbations, new strains of microorganisms
are isolated with greater frequency (Sethi et al., 2002). This applies, first of all, to H. influenzae,
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S. pneumoniae and M. catarrhalis - the main bacterial pathogens of CB and exacerbations of
COPD. When a microorganism colonizes the respiratory tract, it is recognized by the
immunocompetent cells of the patient's div and does not pose a particular danger in terms of
exacerbation of the disease. However, due to the special relationship between the micro- and
macroorganism, repeated doses of antibiotics, with or without indication, cause mutations in the
bacterial genome. As a result, the microorganism acquires new properties and "escapes" from the
immune care of the host organism, which can lead to exacerbation of the disease. Then the
macroorganism suppresses the infectious process and restores "peaceful" relations with
microorganisms, maintaining them until the next mutation occurs.
What is the role of antibacterial therapy during exacerbations of COPD? A subset of
patients in whom bacterial infection is clearly implicated in the development of an exacerbation
are indicated for antibiotic therapy. The key question is how to identify such patients among those
who present with increased cough, increased sputum volume, and new or worsening dyspnea?
This issue became clear in the late 80s of the last century. A study conducted in Winnipeg,
Canada, showed that patients with COPD exacerbations are a heterogeneous group of patients
(Anthonisen et al., 1987). They differ from each other in the severity of clinical signs of
exacerbation. To classify such patients, 3 types of COPD exacerbations were identified, each
subsequent type of which is weaker than the previous one in terms of the severity of clinical
manifestations. Type I exacerbation is characterized by the presence in the patient of all three
clinical criteria for exacerbation of the disease: the appearance or intensification of shortness of
breath, an increase in sputum volume, the appearance of purulent sputum or its purulent nature.
The presence of any two signs in various combinations corresponds to type II exacerbation of
COPD, and only one - type III.
The same study showed that the effectiveness of antimicrobial therapy for COPD was
highest in type I exacerbations of the disease (significantly higher compared with placebo). Less
effective antibacterial therapy was noted in type II exacerbations, the difference between the
effectiveness of antibiotics and placebo was small. In type III exacerbations, the effect of taking
antibacterial drugs was comparable to placebo.
This study also showed that the severity of clinical symptoms during COPD exacerbations
depends on the etiological factor, with the most severe exacerbations being associated with
bacterial infection. It is precisely such exacerbations that are an indication for the appointment of
antimicrobial chemotherapy. The more severe the clinical manifestations of the disease, the more
unjustified, and sometimes dangerous, the prescription of antibiotics becomes.
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Many studies and meta-analyses have shown that prescribing antibiotics for each
exacerbation of COPD provides a small benefit compared with placebo. Only with type I
exacerbations is the superiority of antibiotics over placebo clear and unconditional. This
superiority is manifested not only in a decrease in the severity of clinical symptoms, but also in a
clear reduction in mortality during severe COPD exacerbations (Puhan et al., 2007).
The European Respiratory Society (2005) recommendations state that the presence of
purulent sputum in both type I and type II exacerbations is a prerequisite for prescribing antibiotic
therapy for COPD exacerbations. These recommendations are supported by the results of a study
by Stockley et al. (2007), which showed that the frequency of isolation of the main bacterial
pathogens of respiratory diseases depends on the nature of the sputum.
So, according to modern recommendations, antibacterial drugs should be prescribed for:
– patients with exacerbation of type I disease;
Patients with type II exacerbation of COPD, one of the clinical signs of which is the
production of purulent sputum;
- with severe exacerbation of COPD, accompanied by the development of acute respiratory
failure (ERS guidelines, 2005).
Even 10 years ago, most guidelines for the treatment of COPD (European Respiratory
Society, American Thoracic Society, British Thoracic Society, etc.) emphasized that antibiotics
during exacerbations should be prescribed according to indications, giving preference to available
inexpensive drugs. However, it was not indicated what the exact indications for the appointment
of antibacterial therapy should be.
More recent recommendations (GOLD 2001, 2003) have defined indications for antibiotics
as: shortness of breath, cough, increased sputum volume, and the appearance and increase of
purulent sputum. It is emphasized that the choice of antibiotic should be made taking into account
local data on the sensitivity of the main bacterial pathogens that cause most exacerbations of COPD
- H. influenzae, S. pneumoniae and M. catarrhalis. Today, there are many antibacterial drugs with
sufficient activity against these microorganisms. Which antibiotic should you prefer?
To answer this question, it is necessary to find evidence of the clinical superiority of one
antibacterial drug over another. One of the publications (Destache et al., 1999) presents the results
of a comparison of three lines of drugs that are not equal in terms of in vitro efficacy, but were
previously considered clinically equivalent. Among the first-line drugs are amoxicillin,
cotrimoxazole, tetracyclines, erythromycin; II - oral cephalosporins, including cefuroxime,
cefaclor; III - azithromycin, amoxicillin/clavulanate, ciprofloxacin. One of the criteria for the
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effectiveness of therapy was the relapse-free period - the period without exacerbation of the
disease. It is this criterion that indicates the degree of microbial eradication. The study showed that
the duration of the relapse-free period when using first-line drugs was 17 weeks, second-line - 22
weeks, and against the background of azithromycin, amoxicillin/clavulanate and ciprofloxacin -
34 weeks. First-line drugs were ineffective in 19% of cases, second-line in 16%, and third-line in
6.5%. In 2007, the results of a meta-analysis were presented (Dimopoulos et al., 2007), which
compared different antibiotics for CB or COPD exacerbation. The effectiveness of 2 antibacterial
therapies was assessed
: I – amoxicillin, ampicillin, pivampicillin, co-trimoxazole, doxycycline; II – protected
aminopenicillins, new macrolides, 2nd-3rd generation cephalosporins, fluoroquinolones. The
drugs were shown to have the same efficacy in terms of mortality and pathogen eradication, as
well as a comparable safety profile (adverse events, diarrhea). However, the clinical efficacy of
therapy was significantly higher when second-line antibiotics were prescribed.
Thus, at the present stage, according to the results of numerous controlled studies, it is
recommended to use mainly three classes of antibiotics for the antibacterial treatment of COPD
exacerbations: macrolides, respiratory fluoroquinolones, and protected aminopenicillins.
A meta-analysis by Siempos et al. (2007) compared the efficacy of these three classes of
antibacterial drugs in COPD exacerbations. Their results showed that macrolides, respiratory
fluoroquinolones, and protected β-lactams prescribed for COPD exacerbations have comparable
clinical efficacy.
At first glance, macrolides seem far from ideal drugs for the treatment of exacerbations of
COPD due to their low activity against Haemophilus influenzae. Indeed, the “old” macrolides, in
particular erythromycin, have sufficient activity against pneumococcus and moraxella, but are
ineffective against Haemophilus influenzae. And only with the advent of azalides, interest in the
use of macrolides for exacerbations of COPD and COPD, where the frequency of infection with
Haemophilus influenzae is high, has increased significantly. This is due to the fact that
azithromycin has a higher antihemophilic activity than erythromycin. The minimum inhibitory
concentration (MIC) of azithromycin against Haemophilus influenzae is 2 mg / l, which is 4 times
lower than the MIC of erythromycin (Dorca et al., 2004).
In addition, the high clinical efficacy of azithromycin, including antihemophilic, is
associated not only with a low MIC of the drug in the blood serum, but also with its specific
pharmacokinetics. With the help of appropriate carrier cells, such as neutrophils and macrophages,
azithromycin is delivered specifically to the site of infection, where its concentration increases
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many times compared to the serum concentration. This explains the paradox of azithromycin -
moderate activity in vitro and proven high efficacy in vivo. It is currently believed that not the
concentration of the antibiotic in the blood serum, but also at the site of infection is of great
importance. In the case of CB and COPD, this is primarily bronchial secretions and lung
parenchyma.
The concentration of azithromycin in the tissues and fluids of the lower respiratory tract is
much higher than that of other macrolides, which explains the low rate of therapeutic failure when
azithromycin is prescribed for exacerbations of CB and COPD.
In the above studies on the effectiveness of antibacterial therapy for exacerbations of
COPD, one of the important criteria for treatment was not taken into account - its duration. If we
analyze the numerous literature data, then in almost every publication there is an ambiguous text
- it is recommended to prescribe antibiotics for 7, 10, 14 or more days. At the same time, it is
known that the duration of antimicrobial therapy is associated with compliance (patient adherence
to the prescribed treatment). And in the case of exacerbations of COPD, the patient's refusal to
follow medical recommendations leads to a significant deterioration of the disease. The unique
pharmacokinetics of azithromycin allows the drug to be used in a short course for exacerbations
of CB and COPD. A number of studies have shown that the effectiveness of a 3-day course of
treatment with azithromycin for exacerbations of CB and COPD is not inferior to 7-10-day courses
of other antibacterial drugs, and at the same time, a short course of azithromycin therapy ensures
high patient compliance with treatment.
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