Antibiotics in the treatment of inflammatory diseases of the paranasal sinuses

Inflammatory diseases of the paranasal sinuses are among the most common conditions encountered by clinicians of many specialties—otolaryngologists, therapists, pediatricians, and general practitioners. Virtually every acute respiratory viral infection is accompanied by catarrhal rhinosinusitis. Purulent inflammation in the paranasal sinuses develops in most clinical cases as a complication of a viral process. Pronounced edema of the nasal mucosa, subsequent blockage of the natural ostia, decreased partial pressure of oxygen, and the development of hypoxia in the sinuses create favorable conditions for the growth of bacterial flora [1].

The modern approach to treating acute bacterial rhinosinusitis includes two main directions—pathogenetic and etiotropic (antibacterial) therapy. The goals of treatment are the eradication of pathogens and restoration of sterility in the paranasal sinuses, reduction in the severity and duration of clinical symptoms, prevention of complications (orbital, intracranial, etc.), reduction of the risk of the process becoming chronic, and prevention of the selection of resistant microbial strains [5, 6].

According to the latest European guidelines for the management of acute rhinosinusitis, the use of systemic antibacterial drugs is limited to cases of severe bacterial rhinosinusitis [1]. However, data from a study conducted in the USA among general practitioners and otolaryngologists showed that, despite generally accepted recommendations, antibiotics are prescribed in over 80% of cases when a patient presents with acute rhinosinusitis [7]. Undoubtedly, antibacterial drugs are invaluable in treating infectious diseases; nevertheless, their rather broad spectrum of negative impacts on the human body cannot be dismissed. In some cases, adverse events develop during systemic antibiotic therapy—allergic and toxic reactions, antibiotic-associated diarrhea, and dysbiotic disorders of the gastrointestinal tract due to the suppression of normal flora.

Predisposing factors for adverse drug reactions with probiotic use are severe immunosuppression, prior prolonged hospitalization, surgical intervention, with the main predictor of mortality being severe underlying diseases [11]. It is also important to consider that probiotics are eliminated from the body within a few days.

Prebiotics are food substances, primarily containing non-starch poly- and oligosaccharides such as lactulose, inulin, oligofructose, and human milk oligosaccharides. These substances are practically undigested by human enzymes but serve as a food substrate for bacteria representing the obligate flora of the large intestine.

A classic prebiotic widely used in clinical practice is lactulose, which is a disaccharide synthesized from lactose (milk sugar). Lactulose consists of fructose and galactose and belongs to the group of oligosaccharides. It is hydrolyzed in the large intestine, mainly by bifidobacteria and lactobacilli.

When comparing the effects of various industrial prebiotic oligosaccharides in controlled randomized studies, it was shown that lactulose and xylooligosaccharides promote greater growth of Bifidobacterium and increased production of short-chain fatty acids compared to the prebiotic inulin [12, 13]. In this context, a new class of antimicrobial drugs – eco-antibiotics – is of definite interest.

Published results from a comparative study of the efficacy, safety, and tolerability of Ecozitrin (clarithromycin) ("AVVA RUS", Russia) and Klacid (clarithromycin) ("Abbott Laboratory Ltd.", UK) in patients with acute bacterial rhinosinusitis demonstrated that the clinical and bacteriological efficacy of these drugs is reliably comparable. However, the pharmacological composition of clarithromycin with lactulose, unlike Klacid, reduces the negative impact of antibacterial therapy on the intestinal microflora [16].

Thus, the combination of an antimicrobial drug with lactulose may help avoid complications standard for antibiotic therapy. To test this hypothesis, we conducted an open, randomized, comparative study to evaluate the efficacy and safety of the drug Ecomed, which contains azithromycin at a dose of 500 mg and lactulose in a prebiotic dose, and the drug Sumamed 500 mg in patients with acute purulent rhinosinusitis.

The study included patients who presented to the "Ear, Throat, and Nose" Clinic (Moscow) with complaints of purulent discharge, fever, and headache. Radiographic findings and rhinoscopy data indicated pus in the middle nasal meatus and/or in the nasopharyngeal vault.

Patients included in the study were randomized into two groups in a 1:1 ratio – 30 patients in the observation group and 30 in the control group.

All randomized patients received the following therapy: Group 1 received Ecomed 500 mg, 1 tablet once daily for 5 days; Group 2 received the comparator drug Sumamed 500 mg once daily for 5 days. During the study, patients did not receive any other antimicrobial agents besides the study drugs, nor did they take sorbents, probiotics, or prebiotics.

Patients kept a diary in which they recorded daily body temperature, gastrointestinal (GI) symptoms (frequency of diarrhea, stool frequency and consistency, presence of flatulence, presence of abdominal pain, presence of nausea, and frequency of vomiting), and intake of the study medication.

On the 3rd day of therapy, the investigator examined the patients to monitor GI symptoms and adverse events. Upon completion of the treatment course and after 14 days (follow-up visit), patients returned to the center for a visit where a stool test for dysbiosis was performed to assess the composition of the gut microbiota. The clinical status was also assessed, including based on the data from the completed patient diaries.

All patients underwent general therapeutic and clinical laboratory examinations. The material for the intestinal dysbiosis study was feces taken from the last portion of stool obtained on the morning of the test day and on day 14 after the start of antibiotic therapy. The analysis of the nature of microorganism growth was performed on elective nutrient media (Table 1).

Even before the start of therapy, signs of intestinal dysbiosis in Lactobacillus spp. and Bifidobacterium spp. were observed in 12 (40%) and 13 (43%) of patients in Group 1, respectively. This is primarily evidenced by the fact that normal levels of lactobacilli were found in only 18 (60%) patients, and normal levels of bifidobacteria in only 17 (56.7%) patients in the main group. In the control group, normal levels of bifidobacteria were found in 21 (70%) patients and normal levels of lactobacilli in 18 (60%) patients, meaning signs of intestinal dysbiosis were present in 9-12 (30-40%) patients in the control group.

The research results are presented in Table 1.

Specifically, upon completion of treatment, on day 14, a significant increase in the number of bifidobacteria was found in 7 (23%) patients in the main group taking Ecomed, and normalization of lactobacillus levels was observed in 8 (30%) patients. In the control group of patients taking the conventional antibiotic (Sumamed), suppression of the growth of representatives of the normal flora was noted. The number of patients without detected intestinal dysbiosis in the control group was only 17 (56%), compared to 21 (70%) at the start of treatment.

Table 1 - Dynamics of Coprogram Parameters in Patients Undergoing Antimicrobial Therapy

Table 2 - Dynamics of Nasal Discharge Characteristics in the Main and Control Groups Before Treatment and on Day 14 After Treatment Completion

Table 3 - Dynamics of Nasal Discharge Intensity in the Main and Control Groups Before Treatment and on Day 14 After Treatment Completion

Patient recovery was achieved in all cases. According to the data presented in Tables 2 and 3 and Figures 2 and 3, we can conclude that the choice of antimicrobial therapy with azithromycin 500 mg once daily for 5 days is effective against acute rhinosinusitis. The indicators for the quantity and character of nasal discharge were comparable in both groups.

Therefore, the prescription of eco-antibiotics containing the prebiotic lactulose potentiates the restoration of the patient's own microbiocenosis. The addition of lactulose to the antibiotic does not in any way affect its antimicrobial activity nor negatively impact the drug's tolerability.

The inclusion of an eco-antibiotic in the antimicrobial therapy regimen mitigates the adverse events characteristic of antibiotics, which are associated with their negative impact on the state of the intestinal microbiocenosis. Eco-antibiotics prevent the development of antibiotic-associated diarrhea and do not provoke candidiasis.

Furthermore, it is very important that eco-antibiotics ensure high efficacy during antimicrobial therapy because they possess better therapeutic tolerability, thereby increasing patient adherence to treatment and enabling high compliance with the drug regimen.

In the practice of an otorhinolaryngologist, the use of eco-antibiotics is particularly promising, as on one hand, they are highly active against pathogenic microbes, and on the other hand, they have a high safety profile.

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