Antibiotic therapy for acute otitis media in children

In the general population, otitis media accounts for about 50% of all ear diseases, and among the pediatric population – 70%. The following patterns are observed: acute otitis media (AOM) is relatively rare in newborns (5%) but has a significantly more severe course. Otitis in newborns is protracted, prone to spreading beyond the middle ear cavity, and latent otoantritis often develops.

Since the main pathogens of AOM are pneumococci and Haemophilus influenzae, this must be taken into account when empirically choosing an antibiotic. Although the etiology of otitis is not linked to the clinical picture of the disease, AOM caused by pneumococci is more severe and more often accompanied by complications.

According to numerous studies conducted in our country, the most likely pathogens of otitis are S. pneumoniae, H. influenzae, S. pyogenes, and M. catarrhalis, and somewhat less frequently – S. viridans, St. aureus, S. epidermidis, and anaerobes.

In central Russia, S. pneumoniae and H. influenzae isolated in AOM maintain high sensitivity to aminopenicillins and cephalosporins: 97.0% of S. pneumoniae strains are sensitive to amoxicillin, 100% – to amoxicillin/clavulanate and cefuroxime; 98% of H. influenzae strains are sensitive to amoxicillin, 100% – to amoxicillin/clavulanate and cefuroxime [1].

The reasons for the frequent development of acute otitis media in childhood are: the inherent immaturity of protective immune mechanisms in this age group, the anatomical and physiological features of the middle ear structure, and a short, wide, and gaping auditory tube (which is normal in childhood).

Therefore, the first-line drugs for the treatment of AOM in children remain amoxicillin and amoxicillin/clavulanate.

There is no alternative to antibacterial therapy (ABT) for acute bacterial otitis media. ABT is prescribed to all children under 6 months of age, regardless of the severity of clinical manifestations, and if AOM is suspected – even when the diagnosis is not absolutely certain.

For children from 6 months to 2 years of age, ABT is prescribed in cases of a definitively established diagnosis.

The following criteria aid in making an accurate diagnosis:

• Acute, sudden onset of AOM symptoms (in most cases, this is preceded by an acute respiratory viral infection - ARVI).
• Presence of fluid in the middle ear cavities. Otoscopy reveals bulging of the tympanic membrane, limited or absent mobility (confirmed by impedance testing), and/or otorrhea.
• Otoscopy (optical pneumo-otoscopy) reveals redness of the tympanic membrane, and the clinical picture is dominated by severe pain, sleep disturbances, and feeding difficulties.
• Hearing loss, detected by audiometry or tuning fork tests (in older children).

For children aged 6 months to 2 years with diagnostic uncertainty, general observation for 72 hours is recommended, with otoscopic evaluation of AOM dynamics against the background of symptomatic therapy (pain relievers – systemic and topical, decongestants, local therapy – inhalations, ear compresses).

In children over 2 years of age, diagnosis of AOM is most successful, as their communication skills allow them to clearly indicate the painful ear, and children of this age actively participate in the treatment process.

The most common adverse consequences of antibiotic therapy in young children are gastrointestinal disorders (vomiting, diarrhea), which occur in 16% of patients [15]. Considering that gastrointestinal disturbances (vomiting, diarrhea, constipation, intestinal colic) are often already present in the symptom complex of otitis in young children, the choice of the initial antibiotic must be approached with particular responsibility. This is because an increase in diarrheal syndrome in children with AOM during antibiotic treatment may force the physician to switch to a parenteral form of antibacterial therapy, which, according to regulatory documents, can only be administered to children in a hospital setting. Consequently, an ill-considered choice of the initial antibiotic, even for moderate uncomplicated otitis media which can and should be treated on an outpatient basis, will require a change in the level of medical care, namely hospitalization, with all its possible consequences and unjustified economic costs for treating AOM.

Up to 20% of diarrhea cases can be caused by the overgrowth of C. difficile due to the suppression of the normal non-spore-forming anaerobic microflora of the large intestine. Makins et al. (2009) indicate that with the development of toxic megacolon and pseudomembranous colitis, there is a high probability of sepsis and intestinal perforation, which in some cases leads to death. The likelihood of developing pseudomembranous colitis is relatively high with the use of penicillins, fluoroquinolones, and lincosamides [10].

Antibiotic misuse not only disrupts the natural gut microbiota but also increases the risk of developing bowel diseases by an average of 50%. For example, 12% of patients diagnosed with ulcerative colitis or Crohn's disease have a history of taking more than three types of antibiotics within the last two years. For every 20 patients prescribed antibacterial drugs, there is one case of ulcerative colitis [17]. It should be noted that in 95% of cases, children with colds are prescribed several medications, with antibiotics accounting for 60% of them. Aminopenicillin use alone causes reactions such as vomiting, diarrhea, and rash in 29% of children [2, 3].

An entirely new approach to reducing gastrointestinal disturbances associated with amoxicillin/clavulanate involves the introduction of an additional component into the drug formulation, such as a prebiotic.

Antibiotics used to treat inflammatory diseases of the upper respiratory tract simultaneously affect beneficial bacteria in the large intestine, particularly Lactobacillus acidophilus and Bifidobacterium bifidum. These bacteria are not only necessary for adequate digestion, detoxification, absorption, production of vitamins and hormones, and cancer prevention, but they are also part of the first line of defense against pathogenic microflora. The elimination of symbiotic bacteria creates preconditions for the development of resistant yeast infections and disruption of the normal biocenosis throughout the GI tract, ranging from oropharyngeal candidiasis with taste distortion to antibiotic-associated diarrhea (AAD) with the proliferation of C. difficile in the intestines [4]. The likelihood of colonization of the upper respiratory tract and gastrointestinal tract by highly virulent and multidrug-resistant St. aureus also increases [2].

According to a survey of 5,978 specialists from 35 cities in the Russian Federation, the problem of dyspeptic and dysbiotic disorders is relevant for 100% of therapists, 84% of pediatricians, 97% of gastroenterologists, and 56% of otorhinolaryngologists.

The impossibility of refusing antibiotics for infections with a high risk of serious septic complications, including diseases such as otitis and sinusitis (especially in young children), has necessitated an alternative approach.

Lactulose in its crystalline anhydrous form is characterized by an extremely high degree of purity compared to ordinary lactulose in syrup. Importantly, lactulose in prebiotic doses does not interact with the structure of the antibiotic and, consequently, does not affect its pharmacokinetics or clinical efficacy. The introduction of lactulose promotes an increase in the concentration of bifidobacteria and lactobacilli in the large intestine, with the colony of bifidobacteria increasing a thousandfold, leading to enhanced immunity [5, 8]. Eco-antibiotics are available in the most in-demand antibiotic groups, such as: aminopenicillins, protected aminopenicillins, macrolides, and fluoroquinolones.

To evaluate the efficacy and tolerability of the drug Ecoclav® compared to the drug Augmentin® when administered via an equivalent regimen for the treatment of children diagnosed with "Unilateral or bilateral acute otitis media of moderate or severe severity," as well as to assess the impact of the drugs Ecoclav® and Augmentin® on the indigenous (healthy) intestinal microflora.

Study Tasks

1. To analyze the clinical picture of acute otitis at the time of presentation, considering the state of the gastrointestinal tract, and to evaluate these changes dynamically.
2. To conduct laboratory microbiological studies of the nasopharynx, pharynx, and intestine at different stages of treatment in the comparison groups.
3. To perform instrumental studies in the comparison groups confirming the effectiveness of antibiotics combined with lactulose-anhydrous on the course of otitis and the state of the gastrointestinal tract.

Study Design

A prospective, open-label, randomized study involving 60 patients aged 3 to 5 years. All patients were divided into 2 groups of 30 people each. Microbiological examination of the nasopharyngeal and oropharyngeal mucosa was performed in 26 individuals from each group. Patients in the main group received the eco-antibiotic Ecoclav (amoxicillin/clavulanate + lactulose anhydrous) for 7 days at a dose of 45 mg/kg of body weight per day, divided into 2-3 doses. The study used the pediatric form of Ecoclav (powder for oral suspension, containing 250 mg amoxicillin + 62.5 mg clavulanic acid/5 ml), approved for use in children from the first days of life. Patients in the control group received Augmentin (amoxicillin/clavulanate) (powder for oral suspension 156 mg/5 ml) according to the standard regimen. The diagnosis of otitis in all children was established based on medical history, presenting complaints, and the results of optical otoscopy.

Two groups of specialists participated in the study: otorhinolaryngologists, whom the children with AOM directly visited, and gastroenterologists from the District Diagnostic Center of the Southern Administrative District of Moscow (Head of Department – V.V. Yezhova).

Additional instrumental studies used included:

• Impedance tympanometry.
• Acoustic reflex testing. 
• Otoacoustic emissions. 
• Audiometry (as indicated).

All patients underwent microbiological tests:

• Cultures from the nasopharynx, taken under the control of a rhinoscope (diameter 2.7 mm, viewing angle 30°, Eleps, Russia); samples were taken from the deep sections of the pharyngeal opening of the auditory tube using ultra-thin swabs.
• Cultures from the oropharynx.

These studies were conducted on the day of presentation, on days 7-10, and on day 30 from the start of treatment.

Before the start of the study, gastroenterologists performed an anamnestic assessment of the gastrointestinal tract status of all patients. When indicated, examinations were performed according to medical standards (microbiological examination of stool with determination of antibiotic and phage susceptibility on day 1 and day 7 from the start of treatment).

For an objective assessment of drug tolerability, the following instrumental methods were also included in the study protocol: esophagogastroduodenoscopy (EGD), abdominal ultrasound, and a urease test.

In the Ecoclav group, there were 27 children with acute catarrhal otitis media of moderate severity and 3 children with severe purulent perforated otitis (90% and 10%, respectively). In the Augmentin group, there were 26 children with catarrhal otitis and 4 with purulent perforated otitis (86.7% and 13.3%, respectively).

Instrumental examination (impedance tympanometry) of 26 patients in the main group (Ecoclav®) established that 76.9% of patients had exudate (Type B). Eustachian tube dysfunction was noted in 23.1% (Type C). Furthermore, the acoustic reflex was absent in 80% of the children. 56% of the children did not pass the otoacoustic emissions test. Of the 16 children who underwent audiometric testing, first-degree hearing loss was diagnosed in 75%, second-degree in 6.25%, and 18.75% of patients had normal hearing.

Accordingly, in the comparison group (Augmentin), studies were performed on 28 children. 63.3% of patients had exudate, and dysfunction was present in 20%; 16.7% of children had Type A. The acoustic reflex was absent in 28.6% of children. 37.9% of patients did not pass the otoacoustic emissions test. First-degree hearing loss was diagnosed in 4 out of 7 examined children (according to audiometry data).

Thus, the two groups were practically identical in terms of the main clinical parameters of otitis, age, and gender indicators.

Upon completion of the 7-day course of antibiotic therapy, a follow-up examination of 26 patients in the Ecoclav® group revealed the presence of exudate (Type B) in 14% of children, Eustachian tube dysfunction (Type C) was determined in 38.4%, and hearing normalization, according to impedance tympanometry, was noted in 46.1% of children. The absence of an acoustic reflex was observed only in 19% of children. The otoacoustic emissions test was passed by 84.4%, and accordingly, 15.6% did not pass. Hearing normalized in 86% of children (according to audiometry data).

Upon examining 26 patients in the Augmentin group after 7 days, the presence of exudate in the ear (Type B) was recorded in 7.7% of children, Eustachian tube dysfunction (Type C) was detected in 50%, and hearing normalization, according to impedance tympanometry, was noted in 43.3% of children. The absence of an acoustic reflex was observed in 11.5% of children. The otoacoustic emissions test was passed by 91%, and 8% of patients did not pass. Of the 18 examined, hearing normalized in 88% of children (according to audiometry data).

An examination of 26 patients from the main group was conducted on day 30 after the start of treatment. Exudate in the ear persisted in 11.5% of children, and Eustachian tube dysfunction was observed in 7.7%. Hearing normalization – Type A – was noted in 88.8% of children. The acoustic reflex was absent in 15.3%; all patients passed the otoacoustic emissions test. According to audiometry performed on 20 children, hearing normalization was noted in 100%.

In the comparison group, 26 patients also participated in the examination on day 30 after the start of treatment. Exudate was detected in 7.7% of children, and Eustachian tube dysfunction (Type C) was observed in 15.4%. Hearing normalization – Type A – was recorded in 76.9% of children. The acoustic reflex was absent in 11.5%; 2 patients (7.7%) did not pass the otoacoustic emissions test. First-degree hearing loss (according to audiometry data) was present in 3 out of 19 examined (15.7%); hearing had normalized in the remaining children (84.2%).

The microbiological examination included determining the composition of the microflora in the nasopharynx and oropharynx before the start of treatment and at various times after its completion. Data on the levels of S. pneumoniae, H. influenzae, M. catarrhalis, and St. aureus are presented. The presented data show that the effect of antibiotic application varied.

The efficacy of the drug Ecoclav® against all the listed pathogens was high – by the end of treatment, it was not possible to detect these microorganisms in the nasopharynx.

At the same time, in the comparison group after the course of antibiotic therapy, M. catarrhalis and St. aureus were detected in 3.57% of patients. It is important to note here that treatment with Augmentin did not affect the frequency of St. aureus occurrence in patients, whereas the use of Ecoclav allowed for the elimination of this pathogen, despite its initial frequency being higher (7.7% in the main group vs. 3.57% in the comparison group).

After 30 days, nasopharyngeal culture data revealed a significant difference in results: St. aureus was detected in 26% of cases in the main group, compared to 35.7% in the comparison group.

As the results of oropharyngeal cultures showed, the use of Ecoclav resulted in a pronounced sanitizing effect. On day 7 from the start of treatment, colonization by St. aureus in the oropharynx was not detected in the Ecoclav group, whereas in the Augmentin group, this pathogen was detected in 10.7% of patients. After the end of antibiotic therapy, natural colonization of the oropharyngeal mucosa occurs, including by St. aureus. The degree of such colonization is proportional to the degree of damage to the normal flora resulting from antibiotic therapy. Thirty days after treatment with Ecoclav, oropharyngeal colonization by St. aureus was detected in only 27% of patients, whereas after Augmentin therapy, St. aureus was detected more frequently – in 35% of cases.

Table 1. Microflora of the Nasopharynx and Oropharynx at Various Time Points from the Start of Antibiotic Therapy

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