Otitis Media: The Options Are Gelling

29. November 2016
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Otitis media is frequently treated in infants and young children by using antibiotics. However, the side effects and the long duration of treatment lessen compliance. A hydrogel which is applied just once to the eardrum in a case of illness is about to change that.

It all frequently starts with a runny nose, with sneezing and headaches. The viral infection can suddenly be followed by incipient ear pain, a pressure sensation in the ear, fluid build-up in the middle ear, fever and general poor health. 80 percent of middle ear infections are specifically caused by migratory viruses. They make their way from the nasopharynx, through the Eustachian tube into the middle ear. In addition, the viral infection causes air circulation disorders with negative pressure in the middle ear. In only one out of five cases is the illness triggered by pathogenic bacteria. Middle ear infection is one of the most common diseases of infants and young children.

The disease peaks between six and eighteen months of age. By about the age of seven, each child has experienced at least one acute otitis media case. Reason for this high incidence is that the Eustachian tube is more vulnerable to it. In young children, the Eustachian tube is shorter and wider toward the nasopharyngeal space than in the adult.

When are antibiotics useful?

A guideline for the treatment of acute otitis media is currently not available in Germany. The US guideline from the American Academy of Pediatrics therefore serves as a means of orientation. According to it, in the instance of uncomplicated unilateral otitis media giving a course of antibiotics to children over six months without there being underlying disease is not necessary.

This can be treated to begin with solely using decongestant nose drops and painkillers. In the instance of unilateral non-severe otitis, an antibiotic should, according to the guideline, only be given to children under six months of age (grade B-(“should be”)-recommendation). If both ears are affected, an age limit of two years applies.

Moderate to strong ear pain, fever over 39 °C, a persistent, purulent ear discharge, risk factors such as Down syndrome or a cleft lip and palate, as well as pain that has been occurring for at least 48 hours, are further indications for antibiotic therapy. The first choice recommended by the guideline is amoxicillin. Children who are younger than 24 months must be treated for ten days; with older children a five to seven-day therapy is sufficient.

Especially with young children, taking the antibiotics for several days proves however to be a challenge. The long duration of treatment and poor compliance may affect the effectiveness of the therapy and promote the development of antibiotic resistance. In addition, children often suffer from side effects such as diarrhoea, vomiting or skin reactions. Daniel Kohane and colleagues at the Boston Medical Center and Boston Children’s Hospital have now developed a hydrogel through which both adverse effects and the risk of antibiotic resistance and the duration of treatment are minimised.

Gel consists of polymer, ciprofloxacin and three permeatio enhancers

Because of its broad spectrum of activity, the scientists decided to carry out their experiments with the antibiotic ciprofloxacin. However, since ciprofloxacin – like many other drugs – cannot penetrate the eardrum and thus cannot be used alone, for example in the form of ear drops, the team needed other substances: the local anaesthetic bupivacaine (0.5 percent), sodium lauryl sulfate (one per cent) and the terpene limonene (two percent).

These three substances (permeation enhancer) make the eardrum permeable, so that about four times as much ciprofloxacin (one percent solution) passes to the other side. The third component, the hydrogel, consists of a polymer mixture. It forms a stable deposit from which the antibiotic is released for over seven days. To be able to apply the gel on the eardrum, it first needs to exist in liquid form. Once it has however been placed in the ear, it should set and form a gel. The polymer must not be removed but will have degraded within three weeks.

161129_Antibiotika_Hydrogel

The hydrogel with antibiotic is applied directly to the eardrum. © Kohane Group, Boston Children’s Hospital

Cure rate of 100 percent

The researchers tested their new hydrogel on chinchillas. For this, they administered Haemophilus influenzae bacteria directly into the ears of the animals. The researchers then divided the animals into three groups: the control group was not treated. The “solution” group received the antibiotic ciprofloxacin as a one percent solution and the “hydrogel” group received the gel-ciprofloxacin-“permeation enhancer” mixture administered directly into the ears. In contrast to the untreated control group, in which all animals were still suffering from a middle ear infection a week later, in the “solution” group 60 percent of the animals were healthy. The reason why the antibiotic alone also seems to work, the authors stated, was that infected eardrums are approximately five to thirty times more permeable to drugs. And that remains the case although they are five times thicker than when “healthy”. Nonetheless a cure rate of about 60 percent is not satisfactory. In addition, human eardrums are about ten times thicker than those of chinchillas, on account of which it is very likely less antibiotic can penetrate it.

When the scientists treated chinchillas with the hydrogel, the infection had disappeared within 24 hours in all animals. Further tests showed that the concentration of ciprofloxacin one week after this application still remained higher than the minimum inhibitory concentration. The minimum inhibitory concentration is the smallest amount of active ingredient that prevents the propagation of pathogens. None of the animals suffered a relapse.

If the antibiotic was dropped into the ear without hydrogel alone, the active agent was already undetectable after only three days. The subsequent hearing test showed that the hydrogel only minimally impaired hearing – comparable to the effect of ear wax in the ears. After about three weeks the gel breaks down and one can, say the authors, hear normally again.

How do things look with regard to toxicity?

Permeation enhancers are supposed to make the stratum corneum of the tympanic membrane more permeable. According to researchers, the special combination of bupivacaine, sodium lauryl sulfate and limonene is nevertheless not harmful. As tests showed, ciprofloxacin and the three permeation enhancers did indeed increase cytotoxicity in-vitro, nonetheless the chinchillas tolerated the substance well: their eardrums, which were excised seven days after treatment, were similar in thickness to that of healthy individuals and showed no injured tissue, no necrosis or inflammatory cells.

According to the scientists, all three permeation enhancers were approved by the Food and Drug Administration (FDA) as excipients and the polymer was chemically only slightly modified from a substance that had already been approved by the FDA. Next, the researchers plan to study the hydrogel for potential side effects.

Possible minimisation of antimicrobial resistance

“The hydrogel was biocompatible in the ear. Ciprofloxacin was not able to be systemically detected (in the blood), which validates the localised delivery of the agent”, the authors write in their study. “This fast gelling hydrogel could improve compliance, reduce side effects and prevent systemic dissemination of antibiotics associated with one of the most common childhood diseases. The development of antimicrobial resistance could possibly also be minimised through this”.

A slightly more fluid gel, for example in the form of ear drops, would be desirable for use in babies and toddlers. This is because, according to the study, the test animals first had to be sedated before the scientists were able to apply the gel to the eardrum using a catheter. Whether the mixture of hydrogel, antibiotic and “permeation enhancer” can be used for the treatment of otitis media, therefore, remains to be seen. Finally, local antibiotics also have the disadvantage of potential allergisation and could, for example, induce allergic contakt eczema in the ear canal. The authors however believe in their method and have already had their results provisionally patented.

Original publication:

Treatment of otitis media by transtympanic delivery of antibiotics
Yang et al.; Science Translational Medicine, doi: 10.1126/scitranslmed.aaf4363

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