The place of amoxicillin/clavulanate in treatment of community-acquired pneumonia

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Community-acquired pneumonia is a widespread infection, occupying an important place in the structure of morbidity and mortality of the population worldwide. Incidence of pneumonia in Europe is 2-15 per 1,000 persons per year . It rises to 25-44/1000 in old age and reaches 68-114/1000 in nursing home residents . In the United States, community-acquired pneumonia affects 4 million people annually. It is the cause of more than 1 mln. hospitalizations . There are also significant economic costs to society. For example, in the U.S. the annual cost of treatment is about $10 billion. per year .

The statistical average incidence of pneumonia is 10-15/1000 . The prevalence of community-acquired pneumonias among the elderly in London is 17.4/1000 .

Pneumonias (including community-acquired pneumonias) are the 6th leading cause of death . Death rate from pneumonia continues to grow everywhere. In the United States, for example, between 1979 and 1994, the number of cases of pneumonia increased by 59%. it increased by 59% . To a considerable degree it is determined by the increase of elderly people’s share in the population structure. However, age-adjusted mortality also increased by 22%, indicating the role of other factors in the changing epidemiology of pneumonia .

A variety of microorganisms can act as etiological factors of community-acquired pneumonia. The main causative agent is Streptococcus pneumoniae, which accounts for approximately 15-35% of cases of. According to a meta-analysis of 122 publications from 1966 to 1995., pneumococcal pneumonias account for about 2/3 of all deaths in community-acquired pneumonia . Frequent pathogens also include Mycoplasma pneumoniae, Chlamydia pneumoniae, Haemophilus influenzae. Together with S. pneumoniae they cause over 60% of cases . Rarer etiological factors are chlamydiae, staphylococci, Klebsiella, enterobacteriaceae, and legionella . In certain situations and in a certain patient population, community-acquired pneumonia can also be caused by other microorganisms, such as anaerobes or viruses . Thus, anaerobes (Bacteroiodas, Prevotella и Fusobacterium) are often found in children with concomitant respiratory diseases – chronic tonsillitis and sinusitis, occurring in the elderly [11,12]. Approximately 50% of patients fail to establish the etiology of community-acquired pneumonia, even with intensive research. The reason for this is the lack of a test capable of identifying all potential pathogens, the limitations of each test separately, and the possibility of mixed infection, such as a combination of typical and atypical pathogens (M. pneumoniae, C. pneumoniae, Legionella spp.), occurring in 10–40% of cases .

In the vast majority of cases, treatment is started empirically. Its success is largely determined by the correct choice of antibiotic. One of the main requirements for an antimicrobial agent for initial therapy is sufficient breadth of action, covering common pathogens. Other important criteria for antibiotic selection include: efficacy and safety proven in adequate clinical trials; favorable pharmacokinetic properties; convenient mode of administration to ensure compliance with prescribed treatment; cost-effectiveness. Given the latter criterion, in severe and moderate forms of pneumonia, an important factor is the availability of drug forms for parenteral and enteral administration, which allows for a stepwise therapy. In many countries, due to high levels of antibiotic resistance S. pneumoniae, High activity against pneumococci is added to these criteria.

One of the most satisfying the above criteria of antibacterial agents is amoxicillin/clavulanate. In addition to a broad spectrum of antibacterial action, including common Gram-positive and Gram-negative pathogens of community-acquired pneumonia, it is active against microorganisms with acquired resistance due to the production of beta-lactamases (Klebsiella spp., staphylococci, M. catarrhalis, Haemophilus spp. и E. coli), anaerobes, and is superior to benzylpenicillin and ampicillin in activity against pneumococcus.

Amoxicillin/clavulanate has high bioavailability (90%) when administered orally, generates high concentrations in the lungs and pleural fluid, penetrates quickly into sputum and accumulates in the bronchial mucosa, and the content of both components of the drug significantly exceeds the concentration required to suppress the growth of most pathogens that cause respiratory tract infections, including beta-lactamase-producing strains H. influenzae и M. catarrhalis . The advantages of amoxicillin/clavulanate include the availability of dosage forms for oral administration and intravenous administration, which allows it to be successfully used for staggered therapy, thereby reducing the period of hospitalization and financial costs of treatment.

Amoxicillin/clavulanate is well tolerated. According to clinical trials, side effects are rare (8-14%), are mild and do not usually require discontinuation of treatment. When taken orally, they manifest themselves mainly in gastrointestinal. Their frequency is significantly reduced when the drug is taken with food. Allergic reactions (erythema, urticaria) are very rare.

High activity against pneumococci, Haemophilus influenzae and staphylococci, along with good tolerability, served as a reason for including amoxicillin/clavulanate in the majority of international and domestic standards for treatment of community-acquired pneumonia and bronchitis in adults and children. In clinical trials it is used as a standard reference drug in determining the effectiveness of new antibiotics in patients with bronchopulmonary diseases. Currently, amoxicillin/clavulanate is regarded as the leading drug in the treatment of community-acquired respiratory tract infections and as one of the most active antibiotics against S. pneumoniae, including strains with reduced sensitivity to penicillins .

Expert committees dealing with problems of management of community-acquired pneumonia in the context of the development of pneumococcal «epidemics», recommend amoxicillin/clavulanate as a first-line drug for adults and children [24,25]. The basis for this is, first, the results of experimental studies showing that the drug’s activity against S. pneumoniae with varying degrees of sensitivity to penicillin . According to a large collaborative international study (The Alexander Project) among a large number of studied antibiotics only amoxicillin/clavulanate and ceftriaxone created concentrations in blood serum and tissues needed to inhibit 90% of pathogens with moderate and high resistance to penicillin . Second, the activity of amoxicillin/clavulanate against resistant strains of S. pneumoniae can be increased by increasing the dose of the drug . Third, the results of randomized clinical trials suggest that amoxicillin/clavulanate is effective in approximately 90% of patients with pneumococcal pneumoniae, in t.ч. caused by penicillin- and cephalosporin-resistant strains of the microorganism . Fourth, data from large studies on antibiotic resistance also indicate that the level of resistance to S. pneumoniae to amoxicillin/clavulanate is significantly lower than to other antibiotics. Thus, in a study conducted in Spain – In a country that is home to penicillin-resistant clones S. pneumoniae , where the level of antibiotic resistance is highest, resistance to amoxicillin/clavulanate was 3.68%, while resistance to penicillin – 32.11%, azithromycin – 24.41%, cefpodoxime – 32.44%, cefuroxime – 34.11% and cefaclor – 69,9% . Similar results were obtained in a national multicenter prospective study in Portugal, in which 1,071 strains of S. pneumoniae, isolated in patients with community-acquired lower respiratory tract infections . Amoxicillin/clavulanate exhibited the highest activity in vitro among the antibiotics studied against S. pneumoniae, H. influenzae и M. catarrhalis.

According to experts, inhibitor-protected aminopenicillins, which include amoxicillin/clavulanate, are best suited for empirical antibacterial therapy of community-acquired pneumonia that requires hospitalization for the severity of the patient . Since they are not active against pathogens of atypical pneumonia (mycoplasmas, chlamydia, legionella), it is recommended to combine inhibitor-proof aminopenicillins with macrolides when the latter are suspected.

Amoxicillin/clavulanate is assigned a significant place by the scientific community of pulmonologists in practical recommendations for diagnosis, treatment and prevention of community-acquired pneumonia in adults . Oral medication is considered the drug of choice in the outpatient treatment of community-acquired pneumonia, both in patients with non-serious pneumonia under 60 years of age without comorbidities and over 60 years of age and/or with comorbidities. Hospitalized patients with community-acquired pneumonia are recommended intravenous drug administration or step therapy (intravenous administration followed by switch to oral administration when the condition stabilizes). When the patient is stable and the pneumonia is not severe, oral amoxicillin/clavulanate can be administered immediately. For severe pneumonia, the combination of intravenous amoxicillin/clavulanate with intravenous macrolide is recommended as the regimen of choice.

Amoxicillin/clavulanate is the drug of choice for the treatment of community-acquired lower respiratory tract infections in special clinical situations, including.ч. in patients with alcohol abuse, diabetes mellitus, destructive and abscessed, the potential pathogens of which are Enterobacteriaceae, S. aureus, K. pneumoniae and anaerobes . It is also recommended for patients with community-acquired pneumonia, running in the background of chronic obstructive pulmonary disease, etiological factors of which are H. influenzae, S. pneumoniae и M. catarrhalis, as well as with pneumonia developed with influenza and other viral infections. The results of a recent study have clearly demonstrated the rationality of amoxicillin/clavulanate for the treatment of anaerobic infections and related complications, such as lung abscess and necrotizing pneumonia . Amoxicillin/clavulanate are also among the drugs of choice for the treatment of pneumonia in individuals living in organized communities (nursing homes, orphanages, etc.).д.) .

Amoxicillin/clavulanate is FDA Category B for the risk of pregnancy, t.е. Studies in animals have not revealed any risk of adverse effects of the drug on the fetus . There are no reports of toxic effects of amoxicillin/clavulanate on the human fetus. Thus, it is not contraindicated for the treatment of community-acquired pneumonia in pregnant women.

Pharmacoeconomic data based on the results of randomized, double-blind studies involving a total of more than 2,000 patients indicate that amoxicillin/clavulanate is more cost-effective for lower respiratory tract infections than erythromycin, cefuroxime, ampicillin, and cefaclor .

Thus, despite the changing epidemiological situation, amoxicillin/clavulanate continues to be one of the most effective agents for treatment of community-acquired pneumonia in different categories of patients.

Antibiotics for pneumonia: the whole truth

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A hundred years ago, pneumonia was justifiably considered an extremely dangerous disease, because it often resulted in the death of the patient. The disease is still a threat today. But thanks to the advent of antibacterial drugs, its danger has been greatly reduced. When used properly as prescribed by a doctor, antibiotics ensure recovery and prevent complications of pneumonia. Conversely, uncontrolled use of these drugs can cause irreparable harm to a patient’s health.

What is pneumonia

A lung disease, mostly infectious, that affects the alveoli (the end sections of the lungs) and interferes with gas exchange at the lung level.

  • Chest pain
  • Cough with sputum
  • Fatigue
  • Shortness of breath, difficulty breathing
  • High fever

Symptoms occur in both mild and severe forms. This depends on the type of microorganism that caused the disease, the age of the patient and the general state of health. In adults who do not have serious pathologies, the disease runs easier. It is most dangerous for young children, the elderly, and people with weakened immune systems.

When pneumonia is suspected, laboratory tests of blood and sputum, chest X-ray. For a more detailed examination, a CT scan (computed tomography) of the lungs is used. If the diagnosis is confirmed, the doctor prescribes antibiotics. Their use is necessary to prevent further development of the infection and to prevent complications.

General principles of antibiotic therapy

Treatment begins as soon as the diagnosis is confirmed radiologically. Doctors use broad-spectrum antibiotics for therapy. After the exact determination of the microbial pathogen in the sputum, the treatment plan may be adjusted: the drug to which the identified microorganism is most sensitive is prescribed.

Also, replacement of one antibacterial agent with another is carried out if:

  • After taking the medication, no improvement occurs within 3 days.
  • Significant side effects have occurred from the use of a particular remedy.
  • The antibiotic is too toxic for a certain group of patients (children, pregnant women).

Decrease in fever, reduction of dyspnea, signs of intoxication, amount of sputum 72 hours after the start of treatment indicates the correct prescription of the drug.

Types of antibiotics for treating pneumonia

When prescribing drugs of this group, it is taken into account:

  • Type of pneumonia (cerebral pneumonia, aspiration pneumonia, focal pneumonia, prick pneumonia)
  • Age of the patient
  • The severity of the condition

New generation antibiotics are considered to be the most effective. They have the advantage of fast action on pathogens, fewer side effects, and better patient tolerance. Modern drugs have a long duration of action, so they are taken only 1-2 times a day. While 1st and 2nd generation antibacterials – Up to four.

Each group of antibacterials is effective against a specific type of pathogen. Thus, to combat pneumococci, the penicillin series is used. For pneumonia caused by chlamydia and mycoplasmas, prescribe macrolides, fluoroquinols. And cephalosporins destroy E. coli.

How the treatment is carried out

With a mild and moderate course of the disease, treatment at home is allowed. Therapy is carried out with antibiotics in tablets, capsules, in the form of suspension or syrup. In severe and complicated forms, injections are prescribed. If the disease is very severe, in the first days the drugs are administered intravenously, and later – intramuscular . And only after the condition improves, the patient is transferred to tablets. This change from one form of medicine to another is called «stepwise » course of treatment.

Antibacterials are prescribed for at least 7 days. Depending on the result of control radiological examination, then they are either cancelled or the treatment course is prescribed with the new antibiotics.

Antibiotics in the treatment of viral pneumonia

To treat viral pneumonia, completely different drugs are used than in the treatment of other forms of this disease. This is due to the fact that its causative agents are viruses that are not sensitive to antibacterial drugs. Therefore, their use is not only useless, but also dangerous. Using antibiotics incorrectly as prescribed causes the development of resistance in pathogenic bacteria. And when medications are really needed, they may not have the right effect. Antibiotics are used only if the pneumonia is mixed or if purulent complications develop.

Why antibiotics are ineffective

The decrease in the effectiveness of drugs is caused by:

  • Resistance of microorganisms to the particular drug prescribed for treatment
  • Frequent change of antibacterials, so that pathogenic microbes get used to them
  • Improperly chosen dosage

Most often such cases occur in patients who often self-medicate and take antibiotics without a doctor’s prescription.

Treatment of pneumonia cannot do without antibiotics. Today, it is the only effective measure to eliminate the microorganisms that caused the disease. But therapy should always be conducted under medical supervision. Self-administered and often improperly selected drugs, cause side effects, cause complications and extend the treatment period.

Antibiotics stop working: pneumonia and sepsis sets in. Antimicrobial resistance

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Polls show that about 35% of people believe that antibiotics kill viruses. Such drug ignorance costs lives: bacteria are becoming more and more resistant to medication. As a result, each year worldwide from antimicrobial resistance (antimicrobial resistance, resistance of bacteria to antibiotics — note. ed.) Approximately 700,000 people are dying.

Sepsis and Antimicrobial Resistance. Addiction of bacteria to antibiotics leads to both high mortality and economic decline.

Global losses due to antibiotic resistance were about $400 million of GDP in 2018, could rise to $8 trillion by 2050. Today 700,000 people around the world die each year from resistance, and from cancer — About 8 million 200 thousand. By 2050, the number of deaths from the effects of antimicrobial resistance will rise to 10 million per year.

Fewer and fewer new antibiotics appear on the market each year. Whereas in 1984 there were 18, in 1998 — 12, by 2012 that number had dropped to 4–5 per year.

Sepsis and pneumonia: prevention and treatment problems

As a result of increased antimicrobial resistance, the number of patients, such as pneumonia. In a severe case of the course of the disease occurs blood poisoning (sepsis), then saving the lives of patients — It takes several days.

In severe pneumonia, patients on IVH die in 64% of cases. To prevent sepsis it is necessary to administer antibiotics at least in the first four hours. Thus, if an antibiotic is administered in the first two to three hours, the lethality in sepsis increases one and a half times. If at the fifth or sixth hour of the disease, the mortality rate will already increase by half. The likelihood is minimal, of course, in the first hour of administering the drug.

While a number of bacteria were resistant to four groups of antibiotics in the 1980s, five were still effective. Lethality was in the order of 10–20%. From 2010 to the present time almost all antibiotic groups have become resistant to Klebsiella, except for three. As a result, patients infected with this bacterium had a fatality rate of 40–60%.

Antimicrobial resistance causes problems for clinics.

Among them — rapid spread of antimicrobial resistant bacteria by patients in the department, which significantly increases the risk of mortality of patients.

To change the situation, it is necessary to introduce the rational use of antibiotics and containment of resistance into the practice of medical organizations and programs.