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

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Amoxicillin and pneumonia

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 Moscow 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 (Table.). 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.