CC BY
29DOI: 10.24411/2181-0443/2020-10128
ЭФФЕКТИВНЫЕ МЕТОДЫ ЛЕЧЕНИЯ И ПРОФИЛАКТИКИ ОСТРОГО
СРЕДНЕГО ОТИТА
Рахимов Солижон Комилжонович Хайдаров Илхомжон Икромжон уFлu Саидакбаров Олимхон СаидмухаммадуFли Нугманов Озодбек Журабойуг.ли
Андижанский государственный медицинский институт
Средний отит - один из самых распространенных видов заболеваний уха. Это влияет на среднее ухо, что приводит к скоплению жидкости за барабанной перепонкой. Это может привести к отеку и боли в ушах. Средний отит - воспалительное заболевание среднего уха. Существует три основных типа, один из которых - острый средний отит (ОСО), быстро развивающаяся инфекция, которая обычно вызывает боль в ушах. У маленьких детей это может привести к боли в ухе, усилению плача и нарушениям сна. Кроме того, это может вызвать потерю аппетита и жар. Второй основной тип - это, как правило, бессимптомный экссудативный средний отит (ЭСО), при котором неинфекционная жидкость обнаруживается в среднем ухе более трех месяцев. Хронический гнойный средний отит (ХГСО) - это воспаление среднего уха, в результате которого ухо опорожняется (лечится) более трех месяцев.
Ключевые слова: Средний отит, среднее ухо, ОСО, ЭСО, XrcO.
O'TKIR OTIT MEDIA KASALLIGINI DAVOLASH VA OLDINI OLISHNING EFFEKTIV METODLARI
Otit media quloq kasalliklarining eng keng tarqalgan turlaridan biridir. Bu o'rta quloqqa ta'sir qiladi, bu esa quloq pardasi orqasida suyuqlik to'planishiga olib keladi. Bu shish va quloq og'rig'iga olib kelishi mumkin. Otit media o'rta quloqning yallig'lanish kasalligidir. Uchta asosiy turi bor, biri bu o'tkir otit media (O'OM), tez boshlanadigan infektsiya bo'lib, odatda quloq og'rig'iga sabab bo'ladi. Yosh bolalarda bu quloqni tortishga, yig'lashni kuchayishiga va uyquning buzilishiga mumkin. Qo'shimcha ravishda ishtaha yo'qolishi va isitmaga ham sabab bo'lishi mumkin. Ikkinchi asosiy turi - bu odatda simptomlar bilan bog'liq bo'lmagan ekssudativ (OME) otitis media hisoblanib, bu turida uch oydan ko'proq vaqt davomida o'rta quloqda yuqumli bo'lmagan suyuqlik mavjudligi aniqlanadi. Surunkali yiringli otit media (SYOM) - bu o'rta quloqning yallig'lanishi, natijada quloq uch oydan ko'p vaqt davomida bo'shatiladi (muolaja qilinadi).
Kalit so'zlar: Otit media, o'rta quloq, O'OM, OME, SYOM.
EFFECTIVE METHODS OF TREATMENT AND PREVENTION OF ACUTE OTIT MEDIA DISEASE
Otitis media is among the most common types of ear diseases. It affects the middle ear, causing fluid buildup behind the eardrum. This can lead to swelling and an earache. Otitis media is a group of inflammatory diseases of the middle ear. One of the three main types is acute otitis media (AOM), an infection of rapid onset that usually presents with ear pain. In young children this may result in pulling at the ear, increased crying, and poor sleep. Decreased eating and a fever may also be present. The other main type is otitis media with effusion (OME), typically not associated with symptoms, although occasionally a feeling of fullness is described; it is defined as the presence of non-infectious fluid in the middle ear for more than three months
Keywords: Otitis media, middle ear, AOM, OME, CSOM.
the upper respiratory tract that alters
Acute otitis media (AOM) is a common disease, particularly in infants and young children. Almost all children experience at least one episode of AOM in the first 3 years of age, and approximately 50% experience recurrent episodes in the same period of time. AOM is mainly a bacterial disease that generally occurs on day 3 to 5 after an acute viral infection of
eustachian tube function and favours bacterial infiltration of the middle ear. Streptococcus pneumoniae (Sp), non-typable Haemophilus influenzae (ntHi), Moraxella catarrhalis (Mc) and Streptococcus pyogenes (Spy) are the agents most frequently cultured from the middle ear fluid (MEF). Generally, AOM is a mild disease but complications can
occur. The commonest complication is represented by otitis media with effusion (OME), i.e. the MEF following AOM that typically requires several weeks or more to resolve and causes temporary hearing loss to varying degrees with associated learning and behaviour problems. Tympanic membrane perforation is reported in approximately 5% of cases. Rarer but significantly more important complications include mastoiditis, facial paralysis, and intracranial bacterial infections, such as meningitis and brain abscess. Guidelines detailing the best approach to prevention and treatment of AOM have been published and continuously updated by numerous national scientific societies to reduce the risk of complications and to limit recurrences in AOM-prone children. However, research progresses very quickly, and some new potentially effective preventive or therapeutic approaches have been identified and are not discussed even in the most updated guidelines. The main aim of this narrative review is to detail what has been recently suggested as potential new therapeutic and preventive approaches to AOM.
Treatment. Administration of systemic antibiotics effective against the most common bacterial causes of AOM is the typical treatment for this disease. Amoxicillin, at the usual (50 mg/kg/day) or increased dosage (80-90 mg/kg/day) according to the sensitivity of Sp in the geographic area where AOM occurs, remains the drug of choice. Amoxicillin-clavulanic acid or cefdinir, cefpodoxime, cefuroxime and ceftriaxone are recommended in children at-risk, in those with previous treatment failure or who have experienced a recent AOM treated with amoxicillin, although apparently healed [1]. However, several reasons suggest judicious antibiotic use in patients with AOM. Up to 80% of AOM cases spontaneously resolve [2], and antibiotics given according to the recommended dosage do not reach bactericidal concentrations in 10%-15%
of patients [3], and the use of antibiotics is frequently followed by nonmarginal adverse events [4]. Finally, microbial selection and the emergence of resistance to commonly used antibiotics increases with more extensive use of these drugs [5]. All these factors explain why antibiotics are presently recommended only for selected AOM cases. The most recent version of the American Academy of Pediatrics guidelines for the diagnosis and treatment of AOM [1] indicates that treatment is mandatory in all children < 2 years with the exception of those with unilateral mild AOM and in those > 2 years with otorrhea or severe symptoms (severe otalgia or otalgia for 48 hours or longer or temperature 39°C or higher). In all the other cases, if parents agree, watchful waiting is preferred, with close follow-up and prescription of antibiotics only when the child worsens or does not improve within 48-- 72 hours of symptom onset. In general, compliance with these recommendations has led to a significant reduction in antibiotic consumption without medical problems. Unfortunately, compliance is frequently poor, and systemic antibiotics are prescribed more commonly than recommended [6-8]. Drug delivery through the trans-tympanic route has been considered to reduce all the problems related to systemic antibiotic abuse. Topical therapy has been used only to treat AOM with ear discharge, although its efficacy has not been precisely defined, and some preparations, such as those based on aminoglycosides, are excluded because of the risk of ototoxicity [9]. The instillation of antibiotics in the ear canal to treat uncomplicated AOM has not been considered, as the tympanic membrane is highly impermeable and presents a resistive barrier for the trans-tympanic diffusion of drugs. However, in recent years, a number of different drug delivery systems have been developed, and in some cases, animal studies have shown that non-invasive trans-tympanic permeation is possible, and drugs can
reach high concentrations in the middle ear without histological damage [10,11]. Ciprofloxacin has been encapsulated into spanlastic nanovesicles, and ex vivo permeation studies have demonstrated the superiority of this preparation over the commercial drops of this antibiotic [10]. Similar results were obtained with levofloxacin encapsulated into polyethylene glycol 400 decorated nanoliposomes with drug deposition inside the tympanic membrane 4.29-fold higher than that obtained with the drug solution [11]. However, despite being very attractive, topical antibiotic therapy of AOM remains a mirage. The most effective formulation of the topical preparations, the type and dosage of the drugs to be used to obtain effective MEF concentrations and the safety and efficacy of the therapy in humans with AOM are unknown, and further studies are needed before this treatment approach can enter clinical practice.
Even more difficult to translate in practice is the hypothesis put forward by some authors who see the topical application of bacteriophages (BPs) or peptides identified through the phage represents a technique to treat AOM [12]. In experimental animals, it has been demonstrated that BPs can cross the tympanic membrane and reach high concentrations in the middle ear provided that they have specific amino acid sequences displayed on their surface [13]. Administration of specifically selected BPs or antimicrobial peptides actively transported through the tympanic membrane could lead to effective AOM therapy. However, although several BP preparations have been licensed for use in humans in recent years and some attempts to use them in respiratory infections have been made [14], no study has evaluated whether non-invasive ototopical application of BPs can be effective in AOM treatment. Moreover, the use of BPs for the empirical treatment of diseases such as AOM that are potentially due to more than one bacterial pathogen
is strongly limited by the complexity of producing multivalent stable
preparations. Finally, the dose of each BP, the duration of administration, the long-term effect and the potentially adverse events, such induction of antimicrobial resistance, are not clarified [15]. However, which peptides assure the highest trans-tympanic transport and can be considered for the active delivery of drugs into the middle ear has not been established [16]. In patients with AOM for whom antibiotic administration is recommended, treatment failure can occur despite proper treatment. The presence of biofilms is a possible explanation for this problem [17]. Biofilms are multicellular bacterial communities incorporated in a polymeric matrix in which pathogens are protected from antibiotic activity by several factors [18]. The matrix provides a physical barrier to antibiotic and immunoglobulin penetration, and the pathogens themselves undergo a series of functional modifications that limit antibiotic activity. Pathogens can persist at the site of infection and periodically cause a new AOM [19]. Although all otopathogens can be associated with biofilm production and recurrent AOM, ntHi is the most important in this regard [20]. To eliminate biofilm and improve antibiotic efficacy or favour spontaneous AOM resolution, a vaccine against the majority subunit of ntHi type IV pili, pilA, was considered as a potential solution. This is because pilA is essential for ntHi virulence and biofilm formation [21]. Antibodies against this component were able to disrupt and prevent the formation of ntHI biofilms in vitro [22,23] and to solve ntHI-induced AOM in animal models [24]. Moreover, it has recently been shown that these antibodies against pilA could also inhibit formation of Mc biofilm formation, suggesting a potential positive effect in the case of ntHi and Mc combined aetiology of AOM [25]. As previously mentioned, this attractive measure is presently limited to the experimental
animals for which the use of this vaccine has also been considered for prevention of rAOM [26].
Otitis media (OM) is one of the most common infectious diseases in children and the leading cause for medical consultations and antibiotic prescription in this population. The burden of disease associated with OM is greater in developing nations and indigenous populations where the associated hearing loss contributes to poor education and employment outcomes. Current treatment and prevention is largely focused on vaccination and antibiotics. However, rates of OM, particularly in indigenous populations, remain high. With growing concerns regarding antibiotic resistance and antibiotic-associated complications, an alternative, more effective treatment is required. Otitis media (OM) refers to inflammation and/or infection in the middle ear and encompasses a continuum of acute and chronic diseases, clinically characterized by fluid in the middle ear (See Table 1 for definitions). OM is one of the most common infectious diseases in children. There are approximately 709 million cases of acute OM (acute OM (AOM)) per year worldwide, with the highest disease burden in developing nations and
indigenous populations. Although most episodes of OM resolve quickly without complication, the disease can be associated with significant health and developmental sequelae. it is estimated that approximately 21 000 people die from OM-related complications around the world each year, the highest mortality rate is in the first year of life. Complications can include mastoiditis, cholesteatoma, meningitis, brain abscess and lateral sinus thrombosis. OM often results in conductive hearing loss, which can impact on speech, language and cognitive development. In Indigenous populations, OM and its sequelae contribute to poor education and employment outcomes and greater contact with the criminal justice system [27]. The pathogenesis of OM is multifactorial and involves the adaptive and native immune systems, eustachian tube dysfunction, viral and bacterial load, and genetic and environmental factors. Otopathogens, most commonly Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae and/or respiratory viruses, colonize and proliferate in the nasopharynx (NP), where they travel up the eustachian tube to infect the middle ear and cause OM.
Table 1
Otitis Media Definitions
Type of OM
Acute otitis media (AOM) without perforation
AOM with perforation
Recurrent AOM (rAOM)
Otitis media with effusion (OME)
Chronic suppurative otitis media (CSOM)
Definition
Presence of middle ear fluid with symptoms or signs of suppurative infection, which may include otalgia, fever, irritability, vomitingor diarrhoea.
Acute suppurative infection with recent discharge from the middle ear or through a tympanostomy tube (within the past 7 days).
Recurrent bouts of AOM — three episodes in 6 months or four to five in 12 months.
Presence of middle ear fluid without symptoms or signs of suppurative infection.
A persistent discharge from the middle ear through a tympanic membrane perforation for more than 6 weeks. CSOM may include a chronic perforation with or without acute or chronic otorrhoea.
Management depends on the type and severity of OM and include watchful waiting, antibiotics and surgery. A Cochrane review which included 1483 otitis-prone children or children at increased risk of OM from around the world showed that long-term antibiotics reduced the number of episodes of AOM, with a number needed to treat of five to prevent one case of AOM. For every 12 months of antibiotic treatment per child, 1.5 episodes of AOM were prevented. None of the included studies reported on AOM with perforated tympanic membrane (AOMwP) or chronic suppurative OM (CSOM). Long-term treatment regimens with antibiotics can be difficult for families to adhere to, leading to increased risk of antibiotic-resistant pathogens. Furthermore, despite liberal use of antibiotics, the prevalence of OM, particularly in Australian Indigenous communities, remain unchanged [27].
Alternatively, attempts to prevent OM via vaccination has been widely trialed with mixed results. Pneumococcal conjugate vaccines demonstrated a modest reduction in episodes of AOM in healthy infants, and no benefit for high-risk infants or older children with a history of OM. Furthermore, disease displacement with non-vaccine S. pneumoniae serotypes and H. influenzae have been widely reported. The outcomes of vaccination targeting both S. pneumoniae and H. influenzae (PHiD-CV10) are also equivocal. In Australian Indigenous children PHiD-CV10 has resulted in some reduction in rates of suppurative OM, however these coincided with an increase in OME. In Finnish children there was a non-significant trend towards reduction in the number of AOM episodes. In contrast, implementation of PHiD-CV10 did not change the prevalence of the three main otopathogens in middle ear fluid or NP of New Zealand children with recurrent AOM or OME. OM treatment and prevention continues to provide a great challenge for researchers
and clinicians. An emerging field of research aims at treating and preventing OM using probiotics. Effective probiotic treatment is based on a comprehensive understanding the microbiota in healthy and OM states, and how this can be manipulated to treat and prevent OM. This review explores the history of successful applications of probiotics in medicine, the development of the upper respiratory tract (URT) microbiota, bacterial interference and probiotics in OM, and finally highlights future opportunities for the use of probiotics in OM.
Probiotics are "live
microorganisms which, when administered in adequate amounts, confer a health benefit on the host"[28]. In 1958, a landmark paper described the use of fecal transplantation to treat patients with Clostridium difficile enterocolitis, restoring the dysbiosis caused by antibiotics, and resulting in dramatic health improvement [29]. Despite this success, no further research was conducted on fecal transplantation for another 50 years. Recently, fecal transplantation was tested in a randomized control trial (RCT) for the treatment of C. difficile enterocolitis against vancomycin and vancomycin plus bowel lavage [30]. This study was stopped after the interim analysis. Of the 16 patients who received the fecal transplantation, 13 had resolution of symptoms after the first infusion, another two after second transfusion from a different donor. This compared to resolution of symptoms in just four of the 13 patients receiving vancomycin and three of the 13 receiving vancomycin and bowel lavage. This results has been replicated in a number of RCTs [31], and is now offered as treatment for appropriate patients. This is a striking example of where the use of probiotics has been more effective than antibiotics. Probiotics have also demonstrated impressive results when used in premature infants. Prophylactic
administration of probiotics containing Lactobacillus spp. alone or in combination with Bifidobacterium spp via enteral feeding has been shown to significantly reduced the incidence of severe necrotizing enterocolitis and all causes of mortality in preterm infants [32]. There were no reports of systemic infection with probiotic species. Probiotic prophylaxis is now routinely used in many neonatal intensive care units around the world.
To determine potential candidates for probiotic therapy in OM, a comprehensive understanding of the development of the healthy URT microbiota is required. The URT is colonized by commensal flora during birth. Soon afterwards the URT microbiota rapidly changes to develop niche-differentiation. Henceforth, one of several microbial profiles develop, defined by dominant key species. Profiles dominated by early colonization with Moraxella and Corynebacterium/ Dolosigranulum are more stable than those dominated by Haemophilus or Streptococcus, and appear to protect against URT infections (URTI). The healthy URT microbiota has greater richness and diversity when compared to patients with pneumonia, URTIs and AOM [29-34]. For example, healthy children had twice (n=15) the number of operations taxonomic units (OTUs) identified in the URT compared to children with pneumonia (n=8). Resident microbial flora contributes to the protection of the host against pathogen proliferation, but is also integral to the development of a competent immune system. Experiments using germ-free mice have demonstrated the importance of the bacterial microbiota on mediation of immune cell differentiation and subsequent modulation of inflammation. It is now well established that birth via caesarian section is related to a higher risk of inflammatory disease, where the immune system have difficulties distinguishing self from non-self or where
external antigens elicit an over the top response such as seen in food allergy, atopy, allergic rhinitis, and asthma. There is speculation that the respiratory microbiota, shaped by method of delivery, may be contributing to this disruption to the developing immune system. Disruption of the respiratory microbiota can impact local immunity, infection susceptibility and the development of chronic respiratory inflammatory diseases. It is believed that there is a critical period in infancy/childhood when the influence of microbes on the developing immune system establishes a system of homeostasis, this is likely to happen during the first year of life. The local administration of probiotics in the upper airways in infancy/childhood may enable the development of a stable, resilient microbiota, and promote the establishment of a healthy immune system with the ability to distinguish self from non-self as well as deliver a measured response to external antigens [35,36].
Prevention. As the respiratory microbiota of children with recurrent AOM (rAOM) differs from that of healthy subjects, it was proposed that the administration of probiotics could restore normal upper respiratory tract microbial composition, thus reducing the risk of AOM development. However, although a recent study seems to indicate that the administration of Lactobacillus salivarius PS7, a probiotic with specific activity against otopathogens, could be effective in reducing the risk of new AOM episodes in otitis-prone children [41], the real importance of oral pre- and probiotics for AOM prophylaxis remains debatable. The results of studies are conflicting, frequently showing no effect on AOM development. A clear example in this regard was reported by Cohen et al. who conducted a double-blind, placebo-controlled trial in a group of 224 otitis-prone children aged 7 to 13 months. These patients were randomly assigned to receive follow-up formula
supplemented with probiotics (Streptococcus thermophilus NCC 2496, Streptococcus salivarius DSM 13,084, Lactobacillus rhamnosus LPR CGMCC 1.3724 and prebiotics (Raftilose/ Raftiline) or follow-up formula alone. During the following 12 months, a similar number of AOM cases was diagnosed in both groups (249 and 237 in treated and untreated subjects, respectively; incidence rate ratio [IRR] 1.0, 95% confidence interval [CI] 0.8-1.2. Moreover, the incidence of lower respiratory tract infections (IRR 0.9, 0.71.2) and prescription of antibiotic courses (IRR 1.0, 95% CI: 0.8-1.2) were similar, highlighting the ineffectiveness of the supplementation. Equally debatable are the results of the studies that have evaluated the impact on rAOM of nasopharyngeal administration of probiotics. Several years ago, Roos et al. [42] reported that nasal spraying of selected strains of a-haemolytic Streptococci could reduce the risk of streptococcal tonsillitis in children with a history of previous episodes of this disease. Based on this evidence, it was thought that similar results could also be obtained in the prevention of rAOM, provided that pharyngeal recolonization was made by means of probiotics effective against otopathogens. However, presently, definitive conclusions on the real efficacy of this prophylactic measure cannot be drawn. Many of the studies have significant methodological limitations. Data were frequently collected with open studies with a high risk of selection bias and no control of either the persistence of the probiotic in the upper respiratory tract or its impact on the respiratory microbiota. Moreover, even when study methods were at relatively low risk of bias, the results were conflicting or not completely satisfactory. Roos et al. used a nasal spray containing a mixture of Streptococcus mitis, S. sanguinis, and Streptococci oralis and reported that the rate of recurrence among the treated patients was
significantly lower than in the group of those receiving placebo (42% vs 22%; p = 0.02). In contrast, Tano et al. [41] who administered S. mitis, S. sanguinis, and S. oralis by nasal spray did not find any significant difference in the rate of new episodes of AOM between the two groups of the studied children. Finally, in a randomized double-blind placebo-controlled trial enrolling children with rAOM, nasal spray administration of Streptococcus salivarius 24SMB, a strain capable of producing bacteriocin-like substances with significant activity against AOM pathogens was studied [42,43]. The proportion of children who did not suffer from new episodes of AOM during the study period was lower among treated patients than among controls, but the difference did not reach statistical significance (15% vs 30%; p = 0.075). However, when the analysis was limited to children who were colonized by Streptococcus salivarius 24SMB, differences became highly significant (p = 0.03), showing that colonization with the used probiotics was essential for AOM prevention. Unfortunately, colonization was shown in approximately 50% of the cases with a high risk of failure of prophylaxis. On the other hand, local probiotic prophylaxis is a complex procedure that is at high risk of poor compliance by parents. Prophylaxis must last several months. Preparations must be maintained in the fridge for a long period. Probiotics must be sprayed in both nostrils by adequately trained parents for a few days each month for some consecutive months. Moreover, the probiotic or the mixture of probiotics with the greatest efficacy has not yet been identified, the dose and the schedule of administration are not precisely defined, and the duration of the supposed protection is not quantified. All of these limitations indicate that the local use of probiotics to prevent AOM is far from being considered an established measure of intervention in otitis-prone children.
In most cases, AOM is a bacterial disease usually preceded by a viral infection. Consequently, to prevent recurrent AOM in otitis-prone children, the use of available vaccines against respiratory viruses and bacteria is strongly recommended. Unfortunately, although several viruses can cause upper respiratory disease that triggers bacterial superinfection, only one viral vaccine is presently available, and the prevention of viral infections favouring AOM is strongly limited. Moreover, although effective in reducing total influenza burden, influenza vaccines are significantly less effective than the other vaccines commonly used to prevent infectious diseases, particularly in younger children and the elderly [44]. Moreover, influenza virus antigenic drift is extremely common, and strong protection vaccines must be updated almost every year with a very complicated and costly process. Furthermore, when an antigenic shift occurs, previously prepared vaccines are almost completely useless, and pandemic develops [45]. Regarding protection offered against AOM, a Cochrane Review [46] that has pooled data from 4 randomized controlled trials involving 3,184 <6 children years has shown that influenza vaccine administration was associated with a small reduction in AOM occurrence (risk ratio [RR] 0.84, 95% CI 0.69-1.02) without a difference according to the type of vaccine. Moreover, a subgroup analysis revealed a reduction in the number of antibiotics prescribed for AOM in immunized children (2 studies, 1,223 children; RR 0.70, 95% CI 0.590.83). This value was considered insufficient per se to recommend the use of influenza vaccines to prevent AOM without considering the global advantages of influenza immunization. Fortunately, it is highly likely that in the future, prevention of viral infections that precede AOM can be significantly improved. A number of universal influenza vaccines are in an advanced stage of development [47]. Moreover,
several vaccines against other common respiratory viruses have been studied [48-50].
As Sp is the most important bacterial cause of AOM, the use of pneumococcal conjugate vaccines (PCV) has been considered as a fundamental measure for AOM prevention since the availability of the first PCV, the heptavalent preparation (PCV7). PCV7 contained serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, which were chosen from the most common causes of invasive pneumococcal disease (IPD) in the USA. However, although highly effective, PCV7 administration to infants and young children was associated with the so-called replacement phenomenon, i.e. the emergence of infections due to pneumococcal serotypes not included in the vaccine [51]. To overcome this problem, several PCVs containing a greater number of serotypes were developed and they have been effectively used in millions of children since licensure [52]. Among them, those including 10 and 13 serotypes were licensed for use in humans. In both of these vaccines, serotypes contained in PCV7 were maintained, and serotypes 1, 5, and 7F were added. Moreover, in PCV13, serotypes 3, 6A, and 19A were also included. However, whereas PCV7 and PCV13 had the same carrier protein (a nontoxic mutant of diphtheria toxin, CRM197), PCV10 was prepared using different carriers for the various serotypes (ntHi protein D, diphtheria toxoid, and tetanus toxoid). The presence of a component of ntHi cells is considered an additional advantage because it could evoke antibodies against this pathogen, thus increasing the global protective efficacy of PCV10 [53]. However, regarding AOM, the use of PCVs was generally associated with a reduction of disease incidence, although the magnitude of the preventive effect was significantly greater in observational studies than in randomized controlled trials [54]. Several factors could explain
this difference. First, the possibility that in observational studies, the use of broad case definitions and reporting of AOM could have caused an incorrect estimation of the real incidence of the disease before PCV use. Moreover, child characteristics, local variability of pneumococcal serotype circulation, type of PCV and schedule of administration could have significantly influenced the results [55,56]. Unfortunately, serotype replacement was shown worldwide after PCV10 and PCV13 introduction. The phenomenon was shown for all pneumococcal diseases, including AOM. In a study carried out in Iceland [57], it was shown that the introduction of the 10-valent vaccine led to a significant increase in the number of pneumococcal serotypes not included in this vaccine that could be detected in the MEF of children with AOM compared with the period before PCV introduction. In particular, cases due to serotypes 6C, 15B/C, 23A, and 23B increased significantly. In Spain [58], the analysis of the serotype distribution of Sp causing AOM after PCV13 introduction showed that together with a decrease in the rate of vaccine serotypes, an increase of non-vaccine serotypes was shown, although differences were detected between studied regions. In Barcelona, serotype 11A emerged, whereas serotype 23B was the most important pathogen in Gipuzkoa. In Switzerland [59], patients with AOM diagnosed between 2004 and 2015, before the introduction of PCVs and after that of PCV7 (2007) and PCV13 (2011) were studied. The role of Sp as the cause of AOM progressively declined with the use of PCVs, but non-vaccine serotypes tended to emerge in Europe as well as in USA, with serotypes 11, 15 and 23 being the most common. Serotype replacement was also evidenced when complicated AOM was studied. In two USA studies carried out after PCV7 [60] and PCV13 [61] introduction, it was shown that although both vaccines were effective in reducing the number of mastoiditis cases due to vaccine serotypes, a substantial
increase in nonvaccine serotypes occurred, partly explaining the increase in mastoiditis incidence shown during the immunization periods. Finally, in Italy [62], where the aetiology of AOM complicated by tympanic membrane perforation was studied, it was shown that after 5 years from the introduction of PCV13, approximately 27% of these cases were due to Sp and that 77.1% of the detected strains were not included in the administered vaccine, independent of age and the previous history of recurrent AOM. Serotypes 15A/F, 11A/ D, and 24 A/B/F were the most common non-PCV13 serotypes. To limit the new serotype replacement, new pneumococcal vaccines were studied, and some of them are in an advanced stage of development. In some cases, the addition of some of the emerging serotypes, always conjugated with a carrier protein, has been considered the best solution to improve protection offered by the presently available PCVs. In other cases, vaccines based on reverse vaccinology, i.e. the evaluation of the genome of an organism to identify novel antigens and epitopes that might constitute vaccine candidates, were developed [63]. Finally, vaccines based on whole pneumococcal cells were considered a potential effective solution. Among the new PCVs, the one for which the greatest number of paediatric data is available is the 15-valent preparation in which, to the same serotypes already present in PCV13, serotypes 22F and 33F were added using CRM197 as carrier protein for all serotypes [64]. Two variants, one unadjuvanted and one with aluminium, are in development. Both were found to be safe and well tolerated as PCV13. However, their clinical efficacy on AOM incidence is not known, as studies in this regard were never carried out. Available data seem to indicate that PCV15 cannot substantially modify the current incidence of AOM due to the emerging pneumococcal strains. Serotypes 22F and 33F were included in PCV15 as they were frequently associated
with IPD. However, they are rarely found in the MEF of children with AOM, confirming the differences in aetiology between IPD and AOM already observed in the past [65]. Moreover, a recent study [66] in which the immunogenicity of adjuvanted and unadjuvanted PCV was compared to that of PCV13 in infants showed that, although adjuvanted formulation evoked greater antibody response than the unadjuvanted PCV15, both preparations were noninferior to PCV13 for 10 of the 13 common serotypes but were inferior for 6A, 6B, and 19A. For these serotypes, the minimal protective serum concentration of 0.35 Mg/mL that WHO experts have recommended for the evaluation of the clinical performance of new PCVs was achieved in a significantly lower number of PCV15-treated infants than in those receiving PCV13 [67].
Conclusion: Several new measures have been suggested to reduce systemic antibiotic abuse in AOM therapy and prophylaxis. For therapy, the administration of preparations containing antibiotics, BPs or peptides can allow trans-tympanic passage of effective anti-otopathogen measures and the use of vaccines or immunoglobulins can disrupt
biofilm. All of these treatment hypotheses are very attractive and deserve attention, but the development of preparations for use in humans remains in the early stages, and at the moment, there is no possibility of their use in clinical practice. The best solution to reduce antibiotic use and related problems is compliance with expert recommendations that accurately select AOM cases for which antibiotics are truly needed and suggest watchful waiting for mild AOM cases, particularly in children < 2 years. Similar conclusions can be drawn for the measures suggested for AOM prophylaxis. New vaccines are in development, but even when they have been tested in humans, no study has ever evaluated their efficacy in AOM prevention. Even more underdeveloped are the measures based on the use of probiotics by nasal spray. In this case, reconstitution of normal respiratory microbiota and its effect on the risk of AOM development must still be demonstrated. Reduction of AOM recurrences remains strictly related to the presently available prophylactic measures. We hope, this article will be at least a little motivation for further research.
REFERENCES:
1. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013;131:e964-999.
2. Palmu AA, Herva E, Savolainen H, et al. Association of clinical signs and symptoms with bacterial findings in acute otitis media. Clin Infect Dis. 2004;38:234-242.
3. Pichichero ME, Reed MD. Variations in amoxicillin pharmacokinetic/ pharmacodynamic parameters may explain treatment failures in acute otitis media. Paediatr Drugs. 2009;11:243-249.
4. Tahtinen PA, Laine MK, Huovinen P, et al. A placebo-controlled trial of antimicrobial treatment for acute otitis media. N Engl J Med. 2011;364:116-126.
5. Johnson CE, Belman S. The role of antibacterial therapy of acute otitis media in promoting drug resistance. Paediatr Drugs. 2001;3:639-647.
6. Thompson PL, Gilbert RE, Long PF, et al. Has UK guidance affected general practitioner antibiotic prescribing for otitis media in children? J Public Health (Oxf). 2008;30:479-486.
7. Marchisio P, Tagliabue M, Klersy C, et al. Patterns in acute otitis media drug prescriptions: a survey of Italian pediatricians and otolaryngologists. Expert Rev Anti Infect Ther. 2014;12:1159-1163.
8. Haggard M. Poor adherence to antibiotic prescribing guidelines in acute otitis media-obstacles, implications, and possible solutions. Eur J Pediatr. 2011;170:323-332.
9. Venekamp RP, Prasad V, Hay AD. Are topical antibiotics an alternative to oral antibiotics for children with acute otitis media and ear discharge? BMJ. 2016;352:i308.
10. Al-Mahallawi AM, Khowessah OM, Shoukri RA. Enhanced non invasive trans -tympanic delivery of ciprofloxacin through encapsulation into nano-spanlastic vesicles: fabrication, in-vitro characterization, and comparative ex-vivo permeation studies. Int J Pharm. 2017;522:157-164.
11. Abdelbary AA, Abd-Elsalam WH, Al-Mahallawi AM. Fabrication of levofloxacin polyethylene glycol decorated nanoliposomes for enhanced management of acute otitis media: statistical optimization, trans-
tympanic permeation and in vivo evaluation. Int J Pharm. 2019 Mar 25;559:201-209. • An interesting study performed with the aim to encapsulate levofloxacin (LFX) into polyethylene glycol 400 (PEG 400) decorated nanoliposomes (PNLs) as an approach for drug delivery through the intact tympanic-membrane
12. Mittal R, Parrish JM, Soni M, et al. Microbial otitis media: recent advancements in treatment, current challenges and opportunities. J Med Microbiol. 2018;67:1417-1425.
13. Kurabi A, Pak KK, Bernhardt M, et al. Discovery of a biological mechanism of active transport through the tympanic membrane to the middle ear. Sci Rep. 2016;6:22663.
14. Chang RYK, Wallin M, Lin Y, et al. Phage therapy for respiratory infections. Adv Drug Deliv Rev. 2018;133:76-86.
15. El-Shibiny A, El-Sahhar S. Bacteriophages: the possible solution to treat infections caused by pathogenic bacteria. Can J Microbiol. 2017;63:865-879.
16. Kurabi A, Schaerer D, Chang L, et al. Optimisation of peptides that actively cross the tympanic membrane by random amino acid extension: a phage display study. J Drug Target. 2018;26:127-134.
17. Bakaletz LO. Bacterial biofilms in the upper airway—evidence for role in pathology and implications for treatment of otitis media. Paediatr Respir Rev. 2012;13:154-159.
18. Flemming HC, Wingender J. The biofilm matrix. Nat Rev Microbiol. 2010;8:623-633.
19. Cope EK, Goldstein-Daruech N, Kofonow JM, et al. Regulation of virulence gene expression resulting from Streptococcus pneumoniae and nontypeable Haemophilus influenzae interactions in chronic disease. PLoS One. 2011;6:e28523.
20. Haggard M. Otitis media: prospects for prevention. Vaccine. 2008;26((Suppl. 7)):G20-G24.
21. Jurcisek JA, Bookwalter JE, Baker BD, et al. The PilA protein of nontypeable Haemophilus influenzae plays a role in biofilm formation, adherence to epithelial cells and colonization of the mammalian upper respiratory tract. Mol Microbiol. 2007;65:1288-1299.
22. Mokrzan EM, Ward MO, Bakaletz LO. Type IV pilus expression is upregulated in nontypeable Haemophilus influenzae biofilms formed at the temperature of the human nasopharynx. J Bacteriol. 2016;198:2619-2630.
23. Novotny LA, Jurcisek JA, Jr WMO, et al. Antibodies against the majority subunit of type IV pili disperse nontypeable Haemophilus influenzae biofilms in a LuxS-dependent manner and confer therapeutic resolution of experimental otitis media. Mol Microbiol. 2015;96:276-292.
24. Novotny LA, Clements JD, Goodman SD, et al. Transcutaneous immunization with a band-aid prevents experimental otitis media in a polymicrobial model. Clin Vaccine Immunol. 2017;24:e00563- 16.
25. Mokrzan EM, Novotny LA, Brockman KL, et al. Antibodies against the majority subunit (PilA) of the type IV pilus of nontypeable Haemophilus influenzae disperse Moraxella catarrhalis from a dual-species biofilm. MBio. 2018;9:e02423-18.
26. Lappan R, Imbrogno K, Sikazwe C, et al. A microbiome case-control study of recurrent acute otitis media identified potentially protective bacterial genera. BMC Microbiol. 2018;18:13.
27. Coleman, A., & Cervin, A. (2018). Probiotics in the treatment of otitis media. The past, the present and the future. International Journal of Pediatric Otorhinolaryngology. doi:10.1016/j.ijporl.2018.10.023.
28. FAO/WHO, Guidelines for the Evaluation of Probiotics in Food. City: FAO/WHO, 2002.
29. Eiseman B, Silen W, Bascom GS, Kauvar AJ. 1958. Surgery 1958; 44: 854-859.
30. van Nood E, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JFWM, Tijssen JGP, Speelman P, Dijkgraaf MGW, Keller JJ. 2013. New Engl. J. Med. 2013; 368: 407-415.
31. Moayyedi P, Yuan Y, Baharith H, Ford A. 2017. Med. J. Aust. 2017; 207: 166-172.
32. AlFaleh K, Anabrees J. 2014. Cochrane Database of Systematic Reviews 2014.
33. Dominguez-Bello MG, Costello EK, Contrera M, Mgris M, Hidalgo G, Fierer N, Knight R. 2010. Proc. Natl. Acad. Sci. U S A 2010; 107: 11971-11975.
34. Bosch AATM, Levin E, van Houten MA, Hasrat R, Kalkman G, Biesroek G, de Steenhuijsen Piters WAA, de Groot PKCM, Pernet P, Keijer BJF, Sanders EAM, Bogaert D. 2016. EBioMedicine 2016; 9: 336-345.
35. Biesbroek G, Tsivtsivadze E, Sanders E, Montijn R, Veenhoven R, Keijer BJF, Bogaert D. 2014. Am. J. Respir. Crit. Care Medicine 2014; 190: 1283-1292.
36. Biesbroek G, Bosch AATM, Wang X, Keijer BJF, Veenhoven R, Sanders E, Bogaert D. 2014. Am. J. Respir. Crit. Care Medicine 2014; 190: 298-308.
37. Sakwinska O, Bastic Schmid V, Berger B, Bruttin A, Keitel K, Legpage M, Moine D, Ngom Bru C, Brüssow H, Gervaix A. 2014. J. Clin. Microbiol. 2014; 52: 1590-1594.
38. Pettigrew M, Laufer A, Gent J, Kong Y, Fennie K, Metlay J. 2012. Appl. Environ. Microbiol. 2012; 78: 6262-6270.
39. Sato S, Kiyono H. 2012. Curr. Opin. Virol. 2012; 2: 225-232.
40. Brugman S, Perdijk O, van Neerven RJJ, Savelkoul HFJ. 2015. Arch. Immunol. Ther. Exp. 2015; 63: 251-268.
41. Lappan R, Imbrogno K, Sikazwe C, et al. A microbiome case-control study of recurrent acute otitis media identified potentially protective bacterial genera. BMC Microbiol. 2018;18:13.
42. Cárdenas N, Martín V, Arroyo R, et al. Prevention of recurrent acute otitis media in children through the use of lactobacillus salivarius PS7, a target-specific probiotic strain. Nutrients. 2019;11:E376.
43. Marchisio P, Santagati M, Scillato M, et al. Streptococcus salivarius 24SMB administered by nasal spray for the prevention of acute otitis media in otitis-prone children. Eur J Clin Microbiol Infect Dis. 2015;34:2377-2383.
44. Krammer F, Palese P. Advances in the development of influenza virus vaccines. Nat Rev Drug Discov. 2015;14:167-182.
45. Houser K, Subbarao K. Influenza vaccines: challenges and solutions. Cell Host Microbe. 2015;17:295-300.
46. Norhayati MN, Ho JJ, Azman MY. Influenza vaccines for preventing acute otitis media in infants and children. Cochrane Database Syst Rev. 2017 Oct 17;10: CD010089.
47. Vemula SV, Sayedahmed EE, Sambhara S, et al. Vaccine approaches conferring cross-protection against influenza viruses. Expert Rev Vaccines. 2017;16:1141-1154.
48. Villafana T, Falloon J, Griffin MP, et al. Passive and active immunization against respiratory syncytial virus for the young and old. Expert Rev Vaccines. 2017;16:1-13.
49. Glanville N, Johnston SL. Challenges in developing a cross-serotype rhinovirus vaccine. Curr Opin Virol. 2015;11:83-88.
50. Fougeroux C, Holst PJ. Future prospects for the development of cost-effective adenovirus vaccines. Int J Mol Sci. 2017;18:E686.
51. Weinberger DM, Malley R, Lipsitch M. Serotype replacement in disease after pneumococcal vaccination. Lancet. 2011;378:1962-1973.
52. Scott P, Rutjes AWS, Bermetz L, et al. Pneumococcal conjugate vaccines: a systematic review of data from randomized controlled trials and observational studies of childhood schedules using 7-, 9-, 10- and 13-valent vaccines; [cited 2019 Apr 25].
53. Esposito S, Principi N. Safety and tolerability of pneumococcal vaccines in children. Expert Opin Drug Saf. 2016;15:777-785.
54. Vojtek I, Nordgren M, Hoet B. Impact of pneumococcal conjugate vaccines on otitis media: A review of measurement and interpretation challenges. Int J Pediatr Otorhinolaryngol. 2017;100:174-182.
55. Ben-Shimol S, Givon-Lavi N, Leibovitz E, et al. Near- elimination of otitis media caused by 13-valent pneumococcal conjugate vaccine (PCV) serotypes in southern Israel shortly after sequential introduction of 7-valent/13 -valent PCV. Clin Infect Dis. 2014;59::1724-1732.
56. Pichichero M, Kaur R, Scott DA, et al. Effectiveness of 13-valent pneumococcal conjugate vaccination for protection against acute otitis media caused by Streptococcus pneumoniae in healthy young children: a prospective observational study. Lancet Child Adolesc Health. 2018;2:561-568.
57. Quirk SJ, Haraldsson G, Erlendsdottir H, et al. Effect of vaccination on pneumococci isolated from the nasopharynx of healthy children and the middle ear of children with otitis media in Iceland. J Clin Microbiol. 2018;56:e01046-18.
58. Morales M, Ludwig G, Ercibengoa M, et al. Changes in the serotype distribution of Streptococcus pneumoniae causing otitis media after PCV13 introduction in Spain. PLoS One. 2018;13:e0209048.
59. Allemann A, Frey PM, Brugger SD, et al. Pneumococcal carriage and serotype variation before and after introduction of pneumococcal conjugate vaccines in patients with acute otitis media in Switzerland. Vaccine. 2017;35:1946-1953.
60. Halgrimson WR, Chan KH, Abzug MJ, et al. Incidence of acute mastoiditis in Colorado children in the pneumococcal conjugate vaccine era. Pediatr Infect Dis J. 2014;33:453-457.
61. Kaplan SL, Center KJ, Barson WJ, et al. Multicenter surveillance of Streptococcus pneumoniae isolates from middle ear and mastoid cultures in the 13-valent pneumococcal conjugate vaccine era. Clin Infect Dis. 2015;60:1339-1345.
62. Marchisio P, Esposito S, Picca M, et al. Serotypes not Included in 13-valent pneumococcal vaccine as causes of acute otitis media with spontaneous tympanic membrane perforation in a geographic area with high vaccination coverage. Pediatr Infect Dis J. 2017;36:521-523.
63. Rappuoli R, Bottomley MJ, D'Oro U, et al. Reverse vaccinology 2.0: human immunology instructs vaccine antigen design. J Exp Med. 2016;213::469-481.
64. Skinner JM, Indrawati L, Cannon J, et al. Pre-clinical evaluation of a 15-valent pneumococcal conjugate vaccine (PCV15-CRM197) in an infant-rhesus monkey immunogenicity model. Vaccine. 2011;29:8870-8876.
65. Pichichero ME Pneumococcal whole-cell and protein-based vaccines: changing the paradigm. Expert Rev Vaccines. 2017;16::1181-1190.
66. Greenberg D, Hoover PA, Vesikari T, et al. Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) in healthy infants. Vaccine. 2018;36:6883-6891.
67. Feavers I, Knezevic I, Powell M, et al. Challenges in the evaluation and licensing of new pneumococcal vaccines, 7-8 July 2008, Ottawa, Canada. Vaccine. 2009;27:3681-3688.
