Otitis media: an update on current pharmacotherapy and future perspectives.

Review

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Queensland on 05/28/14 For personal use only.

Otitis media: an update on current pharmacotherapy and future perspectives 1.

Introduction

2.

Epidemiology

3.

Pathophysiology/microbiology

4.

General treatment measures

5.

Conclusion

6.

Expert opinion

Nicole M Thomas & Itzhak Brook† †

Georgetown University School of Medicine, Department of Pediatric Infectious Diseases, Washington DC, USA

Introduction: Acute otitis media (AOM) is the most common childhood bacterial infection and also the leading cause of conductive hearing loss in children. Currently, there is an urgent need for developing novel therapeutic agents for treating AOM. Areas covered: Structured search of current literature. PubMed was searched for published literature in areas of pharmacotherapeutics, preventive therapies and complementary treatments for OM. The intent of this review is to provide a comprehensive evaluation of therapeutics for AOM, including preventive modalities and complementary medicine. Expert opinion: the management of AOM in young children is still evolving and depends on patterns of bacterial colonization and antimicrobial resistance in the community. The introduction of vaccinations against potential respiratory tract pathogens has altered the frequency of recovery of pathogens causing ear infections in children. Even though not all patients require antimicrobial therapy to overcome their infection, these agents improve symptoms faster and lead to fewer treatment failures. Further studies are warranted to evaluate which patients would best benefit from antimicrobial therapy. Keywords: amoxicillin, Haemophilus influenzae, otitis media, Streptococcus pneumonia Expert Opin. Pharmacother. (2014) 15(8):1069-1083

1.

Introduction

Acute otitis media (AOM) is the most frequently reported pediatric bacterial infection, with up to 85% of children experiencing an episode by the age of 3 years [1]. It is defined by rapid onset of signs/symptoms of inflammation in the middle ear such as pain, discharge, fever or irritability and bulging tympanic membrane (TM) due to an effusion or collection of fluid in the middle ear space [1-6]. It is classified according to its onset, response to therapy, duration and complications, each of which calls for a specific management plan. Generally AOM is defined as uncomplicated (no otorrhea), nonsevere (mild otalgia and temperature < 39 C) or severe (moderate-to-severe pain, pain > 48 h, with temperature > 39 C/102.2 F) [1,7]. Otitis media with effusion (OME), a different stage in the otitis media continuum, indicates asymptomatic inflammation with fluid collection in the middle ear [7,8]. It may be a result of Eustachian tube dysfunction (ETD) and precede the onset of AOM, or it may be a result of inflammatory response following AOM [9]. It does not, however, signify acute infection necessitating antibiotics. Otitis media may be further categorized as unresponsive when continued TM inflammation or acute symptoms occur despite antibiotic therapy. Residual otitis is middle ear effusion without TM inflammation or symptoms 3 -- 6 weeks after starting antibiotics, whereas persistent OM is the continued presence of middle ear effusion > 6 weeks after starting antibiotics. Finally, the term chronic OM is used to describe either 10.1517/14656566.2014.903920 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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N. M. Thomas & I. Brook

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Acute otitis media (AOM) is the most frequently reported pediatric bacterial infection and is the most common reason for antibiotic prescriptions in children. Regardless of whether antibiotics are given for AOM, pair should be assessed and managed. Treating AOM with antibiotics may decrease the time away from school/work, lessen the loss of parental sleep and are beneficial for the treatment of bilateral disease and cases with associated otorrhea. Nontoxic preparations of otorrhea (agents are highly effective and may be used as a first-line agent for otorrhea). Although systemic and topical formulations are the current mainstay of therapy, there are novel approaches to delivery of antibiotics under investigation. Preventive measures including eliminating comorbid risk factors, use of immune modulators such as vaccines and mediating the effects of respiratory viral infections are of utmost importance in reducing AOM rates. Complementary/alternative medicines may show promise for otitis media management, but quality comparison studies are limited.

This box summarizes the key points contained in the article.

chronic OME or chronic suppurative otitis (CSOM), which if untreated can cause damage to the inner ear structures, hearing loss, and delayed intellectual development (Table 1) [10]. 2.

Epidemiology

Worldwide, the annual incidence rate of AOM is estimated at 10.85% of children with over 709 million cases each year, and 51% occurring in children under 5 years old. The CSOM incidence rate is 4.76% with 31 million cases and 22.6% occurring in under-fives [11]. Additionally, OM-related hearing impairment has a prevalence of 30.82 per 10,000 and each year 21,000 people die due to complications of OM [11]. OM is the most common cause of antibiotic prescription in children, and it accounts for over $8 billion in outpatient medical care costs each year in the US alone [1,12-15]. In the US, AOM is most prevalent in children < 2 years of age, with a peak incidence in children aged between 6 and 18 months [16]. Up to 80% of children will have had at least one bout of AOM by the time they are 3 years old [13,14]. 3.

Pathophysiology/microbiology

It is commonly known that more children present with OM during the winter months, when respiratory viral infections due to pathogens such as respiratory syncytial virus (RSV) and rhinovirus, and other viruses associated with the ‘common cold’, are present in the community [8,17-20]. These infections adversely affect Eustachian tube function and predispose to middle ear inflammation [6,9,20,21]. Additionally, 1070

anatomy plays a role in increased susceptibility to infection as younger children have shorter, more compliant and more horizontally placed auditory tubes. This prevents drainage of middle ear secretions and results in negative pressure in the middle ear space. This pressure further predisposes the child to periodic aspiration of contaminated bacterial nasopharyngeal secretions, which may result in bacterial infection [9,21,22]. There are multiple conditions that cause auditory tube dysfunction and predispose children to recurrent or persistent OM. As previously mentioned, young age (1 -- 3 years old) and frequent viral respiratory infections are key factors. Additionally, conditions including allergic and vasomotor rhinitis, hypothyroidism, gastroesophageal reflux, immune deficiencies, genetic conditions with craniofacial abnormalities (including Trisomy 21), cleft palate, obstructing adenoids, sino-pulmonary diseases such as cystic fibrosis, presence of cochlear implants, and nasopharyngeal tumors increase the risk of AOM [8,9,12,23]. Environmental factors that increase susceptibility include the presence of siblings, bottle feeding or propping, use of pacifiers, passive exposure to cigarette smoke and other pollutants, as well as daycare [8]. Infants with their first episode of AOM in the first 2 -- 3 months of life are more likely to have recurrent or chronic OM during the first year, and those with OM during infancy were more likely to develop allergic eczema and asthma [1,8]. Otitis media may be caused by both bacteria and viruses, and coinfection is not uncommon. Polybacterial infection has been seen in up to 55% of cases, with bacterial and viral coinfections occurring in up to 70% [8,24,25]. Synergism has been identified in viral upper respiratory infection (URI) and otitis media, as well as with bacterial OM co-pathogens [26]. Infection is thought to be a result of a preceding or coinciding viral URI, which creates an environment of ETD and resultant growth, adhesion, and invasion of pathogenic bacteria (which colonize the nasopharynx) into the middle ear [19,24,27,28]. Although studies have shown how respiratory viruses increase susceptibility to bacterial infection [28-32], it is not absolutely clear as to whether the viruses are the primary cause of AOM or whether they just promote bacterial super infection by impairing Eustachian tube function and other host immune and nonimmune defenses [6,20,32]. What is known is that bacterial AOM with viral coinfection has higher concentrations of some inflammatory mediators than bacterial AOM alone [33-35]. RSV, a well-known cause of respiratory tract infections, has been strongly associated with an increased odds ratio of Streptococcus pneumoniae and Haemophilus influenzae AOM [36,37]. Recent data have implicated RSV induction of pro-inflammatory cytokines in causing immune modulation and downregulation of IFN-g, which may possibly be linked to an increased risk in development of AOM [28,36]. Additionally, the presence of virus in the middle ear space may interfere with antibiotic eradication of bacterial pathogens and predispose to unresponsive OM [34]. Another suggested factor may be the presence of biofilms in otitis

Expert Opin. Pharmacother. (2014) 15(8)

Table 1. Definitions.


AOM Uncomplicated AOM [1,7,134]

Otitis media without the presence of otorrhea

Nonsevere AOM [1,7,134]

Mild pain Fever < 39 C Intense erythema or mild bulging of the TM

Severe AOM [1,7,134]

Moderate-to-severe pain Duration of pain > 48 h Fever ‡ 39 C Moderate-to-severe bulging of the TM

OME [7,8,134]

Asymptomatic Fluid collection in middle ear

Persistent OM [9,10]

Infection despite adequate antibiotics

Residual OM [9,10]

Continued presence of middle ear effusion for 3 -- 6 weeks following antibiotic therapy

Chronic OM Chronic OM with effusion [10]

Persistent effusion > 6 weeks

Chronic suppurative OM [10,134]

Chronic otorrhea Leads to damage of structures and potential hearing loss

AOM: Acute otitis media; OME: Otitis media with effusion; TM: Tympanic membrane.



media. These sessile colonies of bacteria act as a virulence factor and adhere to and persist on endothelial surfaces. They have been demonstrated in S. pneumoniae, H. influenzae, and chronic suppurative Pseudomonas aeruginosa OM, and may lead to resistance to chemotherapy and host immune responses, as well as serve as a reservoir for recurrent infection and contribute to chronic OME and CSOM [23,28,38-40]. Overall microbiological findings from recent studies looking at middle ear aspirates from children with AOM detected a pathogen in up to 96% of cases. Polymerase chain reaction (PCR) has dramatically increased the rates of viral detection. The most common viruses associated with AOM are RSV, influenza virus, and adenovirus, as well as human metapneumovirus and enteroviruses [6,25,28,34,35,37,41]. The bacterial causes of AOM in early infancy may differ from those in later life. There is risk of infection from Gram-negative enterics in infants who are under 6 weeks of age and have been or are in a NICU [42]. In healthy infants, AOM in the first 3 months of life is often caused by pathogens similar to those causing AOM in older children [42,43]. The most common bacterial pathogens in children are S. pneumoniae, non-typeable Hemophilus influenzae (NTHi), and Moraxella catarrhallis [18,28,41,44-46]. In children prone to ear infections, the organisms are still predominantly S. pneumoniae and NTHi; however, they often have higher antibiotic resistance [41]. Staphylococcus aureus, including methicillinresistant strains, has also been isolated, especially since the implementation of pneumococcal conjugate vaccine (PCV7) vaccine [47], and Alloiococcus otiditis is another pathogen felt to play a role in otitis media [48]. Bullous myringitis, once believed to be due to mycoplasma infections, has been shown to be more commonly caused by S. pneumoniae, NTHi, and M. catarrhalis, [49-51], whereas AOM associated with conjunctivitis is more likely caused by NTHi [52]. Group A betahemolytic streptococcus is not a common cause of otitis media, but when present, it is usually seen in older children. It also seems to be associated with greater inflammation and complications compared with other bacterial pathogens [53]. In mixed bacterial infections, the most frequent co-infecting organisms are S. pneumoniae and nonencapsulated H. influenzae [45,54]. In patients with perforated OM and suppuration, or those with tympanostomy tubes in place and suppuration, the organisms recovered include S. pneumoniae, H. influenzae, M. catarrhalis, and, in chronic cases, S. aureus, P. aeruginosa, and Gram-negatives such as Proteus species, Escherichia coli, or Klebsiella species [55,56]. Vaccines have played a major role in the variation of otopathogens over time. Wide use of the conjugate pneumococcal vaccine PCV7 since 2000 has had a significant impact on not only the reduction of the seven serotypes of S. pneumoniae included in the vaccine in immunized children, but also in adults aged 20 -- 35 and 65 years and older [57]. With this, a resultant shift in pathogen dominance from PCV7 strains of S. pneumoniae to NTHi, as well as nonPCV7 S. pneumoniae pathogens (especially serotypes 19A 1072

and 15) occurred and the relative proportion of AOM due to M. catarrhalis also increased [41,44,46,54,58,59]. Of note, these ‘replacement’ pneumococcal serotypes have been noted to be increasingly resistant to penicillins [44,54,59]. Routine PCV13 immunization (conjugate S. pneumoniae vaccine with six additions to the PCV7 serotypes) was introduced in 2010, and early trend reports for invasive disease are promising. Kaplan et al. showed that invasive pneumococcal infections (including mastoiditis) decreased 42% overall and 53% for children < 24 months of age in 2011 compared with the number of cases from 2007 to 2009 [60]. When looking specifically at serotypes, the number of 19A isolates in 2011 dropped by 58% compared with the average number of 19A isolates in 2007 -- 2009, and although the total number of nonPCV13 serotypes remained fairly stable, there was a slight increase in serotype 33F. Phase IV observational studies evaluating the effect and impact of PCV13 on ear infections in children are currently recruiting subjects [61,62]. As it is anticipated that the effectiveness will be similar to that observed following PCV7, it will be interesting not only to determine the resulting prevalence of S. pneumoniae AOM but also the significance of serotype 33F since the introduction of PCV13. As nature likes to fill a void, one can certainly anticipate further changes in the pathogen profile of otitis media due to the vaccine [44,59,60,63,64]. 4.

General treatment measures

Treatment of otalgia Pain is often associated with AOM. The American Academy of Pediatrics (AAP), which has recently published new guidelines on the diagnosis and management of AOM, strongly recommends an assessment and treatment of any ear pain, regardless of whether antibiotics are prescribed [22]. Analgesics can provide pain relief within 24 h of onset, and they should be provided as long as clinically needed. Various pharmacotherapeutics have been used, most commonly oral ibuprofen, acetaminophen, and paracetamol (outside the US) [65,66]. Topical otic drops, which include those with anesthetics such as lidocaine, benzocaine, procaine, and naturopathic products, are another option for pain in children without perforation. A randomized, double-blind placebo-controlled trial examined the use of topical lignocaine (aka lidocaine) versus saline for otalgia associated with nonperforated AOM. They demonstrated a 50% reduction in reported pain with the lignocaine at 10 and 30 min, but not at 20 min after application [67]. A Cochrane database review from 2006, which was subsequently updated in 2011 (and which included the aforementioned article), however concluded that there is limited evidence that ear drops are effective at 30 min and unclear if results from these studies are a result of the natural course of illness, placebo effect of receiving treatment, soothing effect of any liquid in the ear, or the drops themselves [68]. Additionally, a review by Wood et al. reviewed four trials assessing benzocaine in combination with antipyrine (an 4.1



Otitis media: an update on current pharmacotherapy and future perspectives

anti-inflammatory), lidocaine, tetracaine, and herbal extracts for pain, and concluded that although these agents may be safe and effective, further studies are still required to conclusively demonstrate their utility [69]. Of note, Auralgan otic drops, which contain antipyrine, benzocaine, and dehydrated glycerin, were removed from the market in 2011 due to lack of FDA approval and inadequate labeling [70]. Homeopathic agents (usually a combination of marigold [Calendula flores], garlic [Allium sativum], mullein [Verbascum thapsus], St. John’s wort [Hypericum perforatum], lavender, and vitamin E) have also been used [71], and although a 2004 Cochrane data base review reported them as ‘modestly therapeutic’, a 2011 Cochrane update found the evidence to be insufficient to comment on their effectiveness [68]. Taylor and Jacobs more recently assessed the effect of a commonly used homeopathic otic drop combination consisting of Pulsatilla, Chamomilla, Sulphur, Calcarea carbonica, Belladonna, and Lycopodium for use as an adjunct in a nonblinded/nonplacebo-controlled trial, and found moderate efficacy in treating otalgia early in the course of infection [72]. As stated throughout, further evaluation is certainly needed to elicit the efficacy of all otototopic agents. In cases of extreme pain, narcotics with codeine or another morphine analog may be effectively used, although the risk of side effects such as respiratory depression must be weighed against the benefit of acute pain relief [22]. Tympanostomy/ myringotomy has also been successfully used for pain relief, but as procedures with potential side effects, and the need for a qualified skillset, they are not first line for pain relief [7]. Ultimately, pain management should be used with consideration of the risk/benefit ratio of the medication, as well as parent/patient preference. 4.2 4.2.1

Treatment of infection Systemic antibiotics

Otitis media remains the most common condition for which antibiotics are prescribed for children in the US [1,12]. The reason for treating with antibiotics is based on the high prevalence of bacteria in the middle ear effusion [35]. Although treating with antibiotics does not appear to immediately decrease otalgia and many cases of AOM will resolve without them, they have been shown to decrease the time away from school/work, may lessen the loss of parental sleep, and have demonstrated benefit for treatment of bilateral disease and cases with associated otorrhea [73-80]. Additionally, treatment has been shown to reduce the incidence of TM perforation and contralateral AOM episodes [79]. Recent randomized clinical trials in young children show differences in clinical improvement of 26 -- 35% with antibiotic therapy over placebo [4,5]. Based on studies that have evaluated the benefits and pitfalls of the wait-and-see approach for the care of AOM, newly defined treatment options have been outlined in detail in the AAP’s recently published guidelines on the management and diagnosis of otitis media (Figure 1) [22]. For children over 2 years old with unilateral nonsevere

AOM without otorrhea, they outline two potential courses of action. Antibiotics may be given at the time of diagnosis or the provider and family may choose a period of observation (with provision of symptomatic relief), and initiation of antibiotics only if the symptoms worsen or fail to improve within 48 -- 72 h [5,22,73,79,81,82]. Observation as an initial management for AOM in cases as described above has been proven not to increase suppurative complications, if follow-up is available and antibiotics are given for recalcitrant cases [4]. It is important to point out that the guidelines do not suggest that one can delay treatment of any and all episodes of otitis media, however, as a failure to do so would risk a return to the increase in complications seen prior to the discovery of antibiotics [22]. If antibiotics are chosen, the decision should be based on the most likely bacterial pathogen and its susceptibility to the antibiotic, as well as the absorption of the drug into the area of concern (right bug, right drug, and right location). Additional factors include cost, convenience of administration (i.e., frequency of administration), acceptability (taste, texture, formulation such as liquid vs pill, vs chewable tab), and side effects. Length of treatment course depends on the patient’s age and severity of infection. Currently, a 10-day course is recommended for children < 2 years old with AOM and those with severe symptoms (perforation/complications), whereas a 7-day regimen may be considered for those from 2 to 5 years with mild/moderate infection and 5 -- 7 days course for those over 6 years old [5,83]. The current drug of choice for AOM remains high-dose amoxicillin, 80 -- 90 mg/kg/day divided 2 -- 3 times a day [4,5,74]. This is due to not only to its efficacy against the most common pathogens, but its palatable taste, cost, and low incidence of side effects. Studies looking at treatment of AOM indicate that 83 -- 87% of isolates of S. pneumoniae are susceptible to amoxicillin [84-86]. Using the higher dose allows drug concentrations in the middle ear fluid to exceed the MICs of intermediately resistant (MIC 0.12 -1 mcg/ml), and some highly resistant S. pneumoniae (MIC > 2 mcg/ml) [87]. Of note, maximum dosing for obese patients has not been addressed with regard to high-dose amoxicillin dosing. As childhood obesity has risen, dosing based on weight (without a max) would result in higher doses than the recommended adult dose. Although there is a study looking at prescribing practices----one that shows that the children with higher weights often received lower mg/kg dosing, there is not a consensus as to what maximum dose specifications should be [88]. Some isolates of NTHi are b-lactamase producers, resulting in penicillin resistance. Casey et al. looked at middle ear effusions in a local community from 2008 to 2010 and found that anywhere from 16.7 to 56.2% of the isolates of NTHi produced b-lactamase. This would suggest that 43.8 -- 83.3% the cases of H. influenzae isolates may be susceptible to high-dose amoxicillin [44]. Additionally, studies looking at


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NTHi isolates from non-otic sources have reported 52 -- 82% susceptibility to high-dose amoxicillin [84,89-91]. On the other hand, M. catarrhalis is universally b-lactamase-positive, and as such, a b-lactamase inhibitor would be indicated for treatment. Data show that it has stable resistance patterns and is susceptible to amoxicillin/clavulanate, as well as most other classes of antibiotics used for the treatment of AOM [28,91]. Despite its b-lactamase production, there is evidence of clinical resolution of M. catarrhalis-associated AOM in children treated with amoxicillin alone [92]. Because of this finding and because cultures are often not obtained in the diagnosis of AOM, it is not considered unreasonable at this time to initiate therapy with amoxicillin, even in light of the risk of M. catarrhalis infection [92]. With newly changing microbial profiles expected with the PCV13 vaccine, it will be important to determine whether M. catarrhalis becomes more prevalent as a cause of AOM. The first-line therapy in patients who are allergic to amoxicillin are the second- or third-generation cephalosporins. These include cefuroxime axetil (30 mg/kg/day divided b.i.d.), cefpodoxime proxetil (10 mg/kg/day divided b.i.d.), cefdinir (14 mg/kg/day), which has the best taste out of the three, and can be dosed as either b.i.d. for 5 days or once a day for 10 days, or intramuscular ceftriaxone (50 mg/kg 1-consider repeat dose within 5 -- 7 days) [93,94]. Recent studies looking at cross-reactivity between penicillin and second-/third-generation cephalosporins show that the degree is negligible [93]. Macrolides may be considered if a severe allergy is present, but the efficacy against both H. influenzae and S. pneumoniae are limited. A trial looking at single 60 mg/kg dose of azithromycin extended release did show near equivalent effectiveness to a 10-day course of high-dose amoxicillin/clavulanate (80.5 vs 84.5% cure rates) for AOM; however, a meta-analysis of clinical trials comparing amoxicillin or amoxicillin/clavulanate with azithromycin or clarithromycin demonstrated an increased risk of clinical failure with the use of these macrolides [89,95,96]. Amoxicillin is not recommended if it has been taken in the past month, if there is coinciding purulent conjunctivitis (suggesting infection with NTHi), or if there is persistent or recurrent infection that is unresponsive to amoxicillin [22]. In these cases, treatment with an antibiotic that has additional b-lactamase coverage would be a better choice [91]. Highdose amoxicillin--clavulanate (90 mg/kg/day amoxicillin with 6.4 mg/kg/day clavulanate) has been shown to have excellent success in eradicating 96% of isolates of S. pneumoniae from the middle ear, as well as 100% in vitro efficacy against H. influenzae [91]. Additionally, it has been found to have higher efficacy than azithromycin and cefdinir [97]. In a blinded headto-head comparison of high-dose amoxicillin/clavulanate (80 mg/kg/days 10 days) versus cefdinir (14 mg/kg/day 5 days) in 330 children, Casey demonstrated that amoxicillin/clavulanate had superior efficacy (86 vs 71%) [98]. Secondor third-generation cephalosporins are effective against b-lactamase producers, and although the single dose of 1074

injectable ceftriaxone is effective against penicillin-susceptible S. pneumoniae and b-lactamase producing NTHi and Moraxella, a 50 mg/kg/day 3 day regimen adds further coverage against penicillin-resistant S. pneumoniae [94]. Clindamycin is useful against penicillin-resistant S. pneumoniae and MRSA, but not NTHi or M. catarrhalis, so it is generally recommended for use in combination with a second- or thirdgeneration cephalosporin, or if a specific susceptible organism has been identified via culture of middle ear effusion [91,99]. Multidrug-resistant S. pneumoniae serotype 19A has been found to be susceptible to levofloxacin and linezolid, neither of which is FDA-approved for treatment of AOM [91]. A multicenter blinded, noninferiority, randomized comparative study looked at levofloxacin versus amoxicillin/ clavulanate in 1650 children with recurrent or persistent AOM [100]. Clinical cure rates were 72.4% in the levofloxacin group and 69.9% in the amoxicillin/clavulanate group. Levofloxacin was not considered inferior, and there were no differences in the incidence of adverse events. These alternative antibiotics may need to be considered in recalcitrant cases where culture of fluid from tympanocentesis shows no other approved alternative [58,91,100]. S. pneumoniae is resistant to tetracyclines, trimethoprimsulfamethoxazole and erythromycin-sulfisoxazole. Although the latter two were previous regimens frequently utilized for AOM, neither are currently recommended for usage. Recent studies utilizing antibiotics for AOM include very few new prospective trials comparing alternate antibiotics to the usually prescribed amoxicillin and recent trials looking at antibiotic efficacy vs placebo have not used amoxicillin but rather amoxicillin/clavulanate [4,5]. Hoberman et al. conducted a randomized, double-blind, placebo-controlled evaluation of the efficacy of high-dose amoxicillin/clavulanate (90 mg/kg/day) treatment on AOM in 291 patients aged 6 -- 23 months of age. They found that symptoms over the first 7 days were lower for the children treated with antibiotics versus placebo and that treatment failure by day 4 -- 5 was 4% in the treatment group versus 23% in the placebo group, and failure by day 10 -- 12 was much higher (51 vs 16%) in the placebo group. In a comparison of outcome in unilateral versus bilateral AOM, clinical failure rates by day 10 -- 12 in children with unilateral AOM were 9% in those treated with amoxicillin/clavulanate versus 41% in those treated with placebo (RD, 32%; NNT = 3) and 23 vs 60% (RD, 37%; NNT = 3) in those treated with bilateral AOM. According to these results, antimicrobial treatment of AOM was more beneficial than in previous studies that used less stringent diagnostic criteria [4]. Ta¨htinen’s group conducted a randomized, double-blind, placebo-controlled, intention-to-treat study of low-dose amoxicillin/clavulanate (40 mg/kg/day) versus placebo in 319 patients from 6 to 35 months of age [5]. They found that treatment failure occurred in 18.6% of the treatment group versus 44.9% of the placebo group (NNT = 3.8, p < 0.001). Additionally, they determined that there was no significant difference in use of pain or fever



Middle ear effusion

Fever > 39°C Pain ≥ 48 hours Moderate/ severe bulging?

Yes

Purulent conjunctivitis or amoxicillin in last 30 days or penicillin allergy?

Moderate/ severe ADM

Yes

Other antibiotic (Abx)

No

No

Amoxicillin

Pain ≥ 48 hours intense erythema or mild bulging?

Yes

Yes 6 – 24 months old? No

Parental desire for antibiotic?

No

No


Yes Unilateral infection?

Serous Otitis Media


Yes

Other antibiotic

No

No


Yes

Amoxicillin

Yes Other antibiotic

No

Observation

Improved 48 – 72 hours?

Yes

Continue observation

Amoxicillin No


> 24 months old?

Yes Other antibiotic

No

Amoxicillin

Figure 1. Acute otitis media algorithm infants/children > 6 m [22]. AOM: Acute otitis media.

therapy (84.2% of the amoxicillin--clavulanate group, 85.9% of the placebo group), but the parents of children in the placebo group missed more days of work. Overall there was a benefit of antibiotics over placebo at the end of treatment (Figure 1) (p < 0.001) [5]. Finally, it is noteworthy that no trials on new antibiotics have been published. As a result, we have to make the best use of the antibiotics currently available. Topical therapies If TM perforation with otorrhea has occurred, topical antibiotics are recommended as first-line agents [101] due to the ability to provide a high concentration of antibiotic directly into the middle ear. This however may be an unreliable method if there is a large amount of suppuration due to the inability to ensure the sufficient antibiotic will actually penetrate the middle ear. Administration of quinolone otic drops (ofloxacin, ciprofloxacin), with or without steroids, may be utilized and have been found to be safe for administration in the middle ear, although they are fairly expensive in comparison to other therapies [101-104]. Aminoglycoside otic drops (especially gentamicin), however, are generally not indicated due to the concerns associated with vestibular ototoxicity [102]. A 2012 study looking at distortion product otoacoustic emission (DPOAE) (a method of detecting ototoxic changes before cochlear damage is detectable by 4.2.2

conventional audiometry) found that children who received neomycin/polymyxin B/hydrocortisone otic (Cortisporin) suspension following tympanostomy tubes did not have any differences in the DPOAE amplitudes compared with control [104]. The authors concluded that this combination of otic therapy, which has been used for years in the US, is most likely safe to use. A Cochrane database study looking at the efficacy of otic drops in suppurative OM found better results for topical quinolone antibiotics compared with oral antibiotics [105]. The effects of topical nonquinolone antibiotics without steroids were less clear compared with systemic treatment. They also reported no benefit to adding systemic treatment to topical antibiotics and determined that the risk for acute adverse events such as nausea, vomiting, and allergic reactions to be negligible with topical therapy. There are currently no topical otic agents approved for otomycosis; however, there are animal studies, a Russian study (abstract only in English), and anecdotal evidence of using off-label topical antifungals with success [102,106]. Corticosteroids (hydrocortisone, dexamethasone) have been used in combination with ear drops for years because of their anti-inflammatory effects. The risk of toxicity however is debatable. Some data indicate that they are safe and effective, and even may have a protective effect on the cochlea, whereas some animal studies have shown that topical application of hydrocortisone may lead


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to hearing impairment [102,103]. Although there are studies evaluating the effects of topical ophthalmic corticosteroid therapy on pituitary--adrenal function, there are no studies evaluating systemic effects from topical otic hydrocortisone. Wall et al. conducted a review looking at 47 studies related to the use of ciprofloxacin/dexamethasone otic suspension [103]. They found that it is safe and effective with regard to clinical cures and microbiological eradication of pathogens in the treatment of AOM in patients with tympanostomy tubes. They also discussed clinical reports of low-treatment failure rates and reported clear evidence for the positive effect of dexamethasone when added to ciprofloxacin for the topical treatment of ear infections. Additionally, three prospective randomized controlled studies showed that when used for suppurative otitis, cipro/dex combination drops were better than ciprofloxacin or ofloxacin drops alone, better-treatedassociated granulation tissue, and were more effective than oral amoxicillin [107-109]. Vasocidin ophthalmic solution has been successfully used in the past for the treatment of AOM with otorrhea; however, it has been found to cause middle ear mucosal irritation (but no ototoxicity) [102]. Topical antiseptics are generally not recommended as a number of them have been found to be ototoxic. Cresylate, VoSol, gentian violet, and chlorhexidine all have studies showing toxicity if introduced into the middle ear [102]. Jinnouchi et al. evaluated the use of a modified Burow’s solution (13% aluminum acetate) and found that it was effective and nonototoxic (via audiogram only) for the management of suppurative OM [110]. Loock recently conducted a small randomized controlled trial comparing the use of a one-time dose of boric acid powder, acetic acid ear drops, or a standard regimen of topical ciprofloxacin eardrops in suppurative OM for use in the developing world [111]. Although the reported efficacy was found to be statistically equivalent to quinolone, safety for use in the treatment of otorrhea will need to be established. Overall, nonototoxic preparations of ototopical agents are highly effective and may be used as a first-line agent for otorrhea. Of note, there are clinical trials studying the use of spray bacteriotherapy. Nasal spray with probiotic bacteria (e.g., Streptococcus sanguinis or Lactobacillus rhamnosus) showed significant therapeutic effects, including complete or significant recovery from serous OM [112]. Other therapies Although systemic and topical formulations are the current mainstay of therapy, there are novel approaches to delivery of antibiotics. Daniel et al. looked at the feasibility of a biodegradable modified release antibiotic pellet capable of destroying biofilms in chronic OME [113]. They tested their pellets containing rifampin and clindamycin via an in vitro model and found continued bacterial inhibition for 3 weeks. Although still in development, this may be a promising new therapeutic modality for the treatment of OM. 4.2.3

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Balatsouras et al. evaluated the impact of leukotriene inhibitor therapy on the clinical course of OME in children with asthma and OME. They found a statistically significant beneficial effect on the clinical course of OME in the children who were on montelukast. [114]. Schoem et al., however, studied a leukotriene inhibitor in a small study of 38 children between 2 and 6 years of age. Early in the study it became apparent that the montelukast regimen was not having any effect. An interim analysis performed on the 38 patients showed clearance of effusion in only 3 of the patients receiving montelukast and 4 of the controls. Based on this early trend, the study was terminated by the funding sponsor [115]. As it is known that asthma/atopy are comorbid conditions associated with AOM, it may be reasonable to evaluate their effectiveness in prevention as opposed to the treatment of AOM. Systemic oral antihistamine and decongestants have not been shown to be effective in the management of AOM, and decongestants are actually contraindicated for use in young children [9,116]. There are little published data to support their use in children, and additionally there are no data supporting the use of vasoconstrictors such as phenylephrine for children. Although there have not been any recent prospective randomized trials looking at the effects, a Cochrane review first published in 2003, and updated in 2008 on the treatment of AOM, and a Cochrane review in 2006 on their effectiveness for OME did not show any benefit [117,118]. Prevention of infection Prevention of infection is of outmost importance. Eliminating known or suspected environmental or comorbid risk factors, such as decreasing cigarette smoke, increasing breast feeding, limiting pacifier use beyond 6 months of age, avoiding daycares with large populations, and managing conditions that increase the risk of AOM such as gastroesophageal reflux and allergy symptoms, may be beneficial in reducing the number of episodes. Vaccines are particularly effective in the reduction of AOM, and with the aforementioned association between AOM and respiratory viruses ensuring vaccination with pneumococcal conjugate vaccine, as well as annual influenza vaccine is imperative. Additionally, mediation of the effects of viral respiratory infections has a positive impact on AOM incidence. A recent randomized, double-blind controlled trial found an 85% decrease in the incidence of otitis media in young influenza-infected children who were treated within 48 h of infection with oseltamavir [119]. Prophylaxis with low-dose amoxicillin for 3 -- 6 months followed by intermittent therapy at the first sign of a URI was previously recommended for recurrent OM [120]. This was based on studies that showed that antibiotic prophylaxis decreased the frequency of recurrent OM by 50% [121]. The current AAP guidelines, however, have now included a recommendation NOT to prescribe prophylactic antibiotics, but rather offer tympanostomy tubes as an option [22]. This is 4.3




due to the increased antimicrobial resistance [46] and cost versus benefit (only a modest decrease in AOM, only seen while on the antibiotic) of prophylaxis. Surgical intervention, on the other hand, has been shown to decrease the pain associated with infection, with resultant decrease clinic/ER visits, family anxiety, and risk of conductive hearing loss [122,123]. The use of intranasal preparations, including steroids, antihistamines, and decongestants, and even surfactant to improve Eustachian tube function, and therefore also prevent development of OM, has also been documented throughout the literature. Rashid conducted a comprehensive review of the efficacy of intranasal steroids, antihistamines, decongestants, and saline for the treatment of ETD [21]. Although the data were often conflicting, it was concluded that the use of nasal steroids and antihistamines may be an effective and safe treatment for ETD, whereas the data are lacking in support of intranasal decongestants and saline. Additionally, it was added that these medications may be effective when properly administered in such a way as to deliver the medications directly into the Eustachian tube orifice. Karagama et al. conducted a study evaluating different positions and modes of delivery (spray vs drops) of intranasal medication. They found that these factors were critical in maximizing delivery of the medication and that they should be factored in when evaluating efficacy of nasal medications [33]. At this time, decongestants and antihistamines are not recommended as further evidence is required to support intranasal treatment for ETD, and therefore prevention of OM. The same applies for systemic oral antihistamine and decongestants as they also have not been shown to be effective in the prevention of AOM, and as mentioned previously, decongestants are contraindicated for use in young children [9,116]. There are two recent animal studies looking at the use of surfactant for ETD and otitis media and have shown faster recovery times and quicker resolution of effusions [9]. Additionally, Duplessis et al. examined the effects of oxymetazoline, acetylcysteine, pseudoephedrine, and pulmonary surfactant on ET function in Navy divers within a hyperbaric chamber. All divers who received placebo had decreased ET function after multiple dives. Whereas only the oxymetazoline group had statistically significant effects, the surfactant did produce decreases in ET opening pressure on the postdive tests compared with the placebo [124]. Complementary/alternative medicine There are a number of complementary therapies for the prevention of AOM, including herbal eardrops, homeopathic treatments (i.e., chamomile, echinacea, and belladonna), xylitol, use of probiotics, acupuncture, and chiropractic modalities, but not many have scientific studies evaluating their efficacy. A 2011 Cochrane review examined the evidence for the use of xylitol in preventing recurrent AOM and found four studies that met the criteria for analysis [125]. Overall, it demonstrated a statistically significant reduction (25%) in 4.4

the risk of occurrence of AOM among healthy children in the xylitol group compared with the control group (relative risk 0.75; 95% CI: 0.65 -- 0.88; RD -0.07; 95% CI: -0.12 to -0.03). Chewing gum and lozenges containing xylitol appeared to be more effective than syrup; however, it emphasized that children younger than 2 years who are the greatest risk of developing AOM cannot safely use lozenges or chewing gum. Additionally, compliance is a potential problem. Xylitol was not shown to be effective for treatment, and although it has been shown to decrease biofilm production by S. pneumoniae, [126], in order to prevent infection, dosing was required 3 -- 5 times each day throughout the respiratory illness season. Sporadic or as-needed use was not shown to be effective. Of note, there is currently a National Institutes of Health sponsored study underway evaluating the efficacy of viscous xylitol solution for OM prophylaxis [127]. There are a few studies looking at the use of probiotics for the prevention of OM [71,128,129]. Although the evidence is conflicting, recent data seem to show promise. Three studies examining the use of milk/formula supplemented with probiotics both showed preventive effects compared with placebo [130,131]. Hatakka et al. randomized a group of children to receive a probiotic capsule or placebo daily for 24 weeks [132]. Although there was a large dropout rate, they found probiotics did not reduce the occurrence or recurrence of otitis media. They also obtained nasopharyngeal samples at three points in time and showed no reduction in the presence of S. pneumoniae or H. influenzae but an increased prevalence of M. catarrhalis. Stecksen-Blicks et al. showed milk supplemented with probiotics and fluoride consumed once daily, 5 days a week, for 21 months, had preventive effects on otitis media (0.4 days of otitis media vs 1.3 days of otitis media, p < 0.05) [130]. Rautava et al. looked at probiotics in infants by supplementing formula for infants younger than 2 months compared with placebo supplementation daily until the age of 12 months [131]. There was a significant reduction in the number of episodes of otitis media in the first 7 months of life (22 vs 50%; risk ratio [RR] 0.44 [95% CI: 0.21 -- 0.90]; p = 0.014) and a decrease in the amount of antibiotics prescribed (31 vs 60%; RR 0.52 [95% CI: 0.29 -- 0.92]; p = 0.015). These conflicting reports highlight the need for further research in this area. Finally, zinc supplementation has been described as another possible adjunct to decreasing OM incidence. However, a 2010 Cochrane database review of zinc supplementation for OM prevention indicated that the evidence was inconclusive and that further research was needed [133]. 5.

Conclusion

Otitis media is the most common childhood bacterial infection and also the leading cause of conductive hearing loss in children. Unfortunately, the management of AOM in young children is not straightforward. Studies indicate that antibiotic treatment improves symptoms faster and leads


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to fewer treatment failures, yet they also show that not all young children require antibiotic treatment to recover. Ultimately the decision on who requires treatment and who can be observed is critical. One must weigh the benefits of treatment, including economic effects and prevention of sequelae, with the possible side effects and potential increase in resistant organisms. Additionally, despite an obvious need for prophylactic measures, development of highly effective vaccines for OM and other preventive therapies still remains a great challenge. What is evident is that the development of novel therapeutic strategies is urgently needed for treating OM. 6.

Expert opinion

Although the management of AOM continues to evolve, further studies are certainly warranted in this clinical area. There needs to be continuous re-evaluation of the ‘wait-andsee’ approach for mild AOM. The two large studies looking at treatment versus placebo showed statistically better outcomes with treatment. Additionally, evaluation of the economic burden associated with absenteeism due to AOM illustrates a significant impact, and this negative aspect of the watchful waiting approach may render it less effective overall. According to the US Bureau of Labor Statistics, the mean salary for an 8-h work day in the US is $192.08. With over 9 million cases of AOM reported each year, a 1-day absence would amount to a loss of over $1.7 billion each year. This highlights the need to ensure the right children for delay in therapy are identified and that there are clear and concise algorithms for guiding the treatment of OM. It may be reasonable to evaluate a middle ground, with the use of shortened courses of antibiotic therapy in lieu of watchful waiting. As ear infections clearly interfere with a family’s daily routine, decreasing the use of antibiotics should not be prioritized at the family’s expense. Regarding which antibiotic to use for treatment, clinical experience suggests that amoxicillin/clavulanate may be better than amoxicillin overall for effective therapy; however, amoxicillin is touted as the firstline antibiotic for AOM. This is felt to be due to the high cost and higher side effect profile of amoxicillin/clavulanate. There are currently no comparison studies looking at the use of amoxicillin for the treatment of uncomplicated AOM. The recommendation to use amoxicillin as first-line therapy should be based on placebo-controlled studies evaluating its efficacy against the current prevalent pathogens, as well as a head-to-head superiority study comparing highdose amoxicillin versus amoxicillin/clavulanate. Additionally, there is a definite need to further evaluate and clarify the safety and efficacy of topical analgesic drops, especially in young children. Of course, there is always the need for the new development of safe and effective antibiotics, especially with the increasing prevalence of multidrug-resistant pathogens. These new antibiotics will require randomized controlled superiority studies against the currently available 1078

medications, along with evaluation of dosing regimens and length of therapy. In addition to new antibiotics, which may be difficult to develop, research into alternate delivery systems with and without an intact TM would be of great benefit and further research in complementary and alternative medicine could provide an entire new spectrum of evidence-based therapy. Well-designed randomized controlled trials of the usefulness of complementary and alternative medicine in AOM are required, especially because a large number of families already use these for treatment. A suggested initial approach would be to compare them with placebo, and if shown to be effective, conduct head-to-head superiority trials with antibiotics. Preventive approaches to management also warrant further evaluation. Additional research needs to be conducted to understand how prophylactic agents can reduce the incidence of AOM. It will be of benefit to obtain a better understanding of the relationship between respiratory viruses and otitis media, and the impact they have on immunity. This understanding may allow for innovative modalities for the prevention of AOM. Additionally, further evaluation of agents for respiratory virus prevention and treatment, including antivirals, the efficacy of immune modulators (i.e., vaccines, IFN-a 2, IFN-b, probiotic and prebiotic agents), and naturopathic treatments are needed. Although the PCV7 vaccine has shown great benefit, and randomized trials of influenza virus vaccine have shown that prevention of antecedent viral infection has impacted the incidence of influenza associated AOM, there needs to be continued research into the development of respiratory viral and even combination viral/bacterial vaccines. Also, it will be important to evaluate the impact of PCV 13 vaccination. If it reduces multidrug-resistant pneumococcal serotype circulation, it may decrease the need for high-dose amoxicillin or amoxicillin/clavulanate in the future. Finally, it is also important to further evaluate and establish the role of comorbid conditions on the development of AOM. Improved understanding and management of diseases such as gastroesophageal reflux and allergic rhinitis may decrease the incidence of OM in these populations.

Acknowledgements Christine Tydingco and Amanda Bray for assistance with the table/algorithm.

Declaration of interest The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Air Force, Department of Defense, or the US government. Title 17 U.S.C. 105 provides that “copyright protection under this title is not available for any work of the United States Government”. Title17 U.S.C. 101 defines a US government work as “a work prepared by a military service member or employee of the United States government as part of that person’s official duties”. The authors have no relevant affiliations



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Affiliation

Hatakka K, Blomgren K, Pohjavuori S, et al. Treatment of acute otitis media with probiotics in otitis-prone children-a double-blind, placebo-controlled


134. Available from: http://otitismedia. hawkelibrary.com

Nicole M Thomas1 MD & Itzhak Brook†2 MSc MD † Author for correspondence 1 Uniformed Services University of the Health Sciences, Department of Pediatrics, Bethesda, MD, USA 2 Georgetown University School of Medicine, Department of Pediatric Infectious Diseases, 4431 Albemarle st. NW, Washington DC, USA E-mail: [email protected]

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