Primary care

Effect of recolonisation with "interfering"  streptococci on recurrences of acute and secretory otitis media in children: randomised placebo controlled trial

Kristian Roos, associate professor ^a, Eva Grahn Håkansson, research associate ^b, Stig Holm, professor ^c. 

^a Ear, Nose, and Throat Department, Lundby Hospital, 41717 Gothenburg, Sweden, ^b Department of Clinical Bacteriology, University of Umeå, 90187 Umeå, Sweden, ^c Department of Clinical Microbiology, University of Umeå

Correspondence to: K Roos kristian.roos{at}lundbysjukhus.se

	Abstract

Top Abstract Introduction Participants and methods Results Discussion References

Objective: To study the effect of recolonisation with  streptococci with the ability to inhibit the growth of otopathogens ("interfering" activity) on the recurrence of acute otitis media in susceptible children and the effect on the frequency of secretory otitis media.
Design: Double blind, randomised, placebo controlled study.
Setting: Ear, nose, and throat clinic with three doctors.
Participants: 130 children prone to otitis media aged between 6 months and 6 years, 108 of whom were eligible and followed for 3 months.
Main outcome measures: Recurrence of otitis media during follow up and a normal tympanic membrane at the last valid visit.
Interventions: Children with no recurrences during the last month received phenoxymethylpenicillin (n=22), and those with a recurrence within 1 month received amoxicillin clavulanic acid (n=86), both twice daily for 10 days. These were followed by a streptococcal or placebo solution sprayed into the nose for a further 10 days. At day 60 the same spray was started for another 10 days.
Results: At 3 months 22 children (42%) given the streptococcal spray were healthy and had a normal tympanic membrane compared with 12 (22%) of those given placebo. This difference was shown separately for recurrences of both acute otitis media and secretory otitis media.
Conclusions: Selected bacteria with the ability to inhibit the growth of common otopathogens can be used to protect against recurrent acute otitis media and secretory otitis media in children.

	Introduction

Top Abstract Introduction Participants and methods Results Discussion References

Acute otitis media is the most common bacterial infection in young children, and large amounts of antibiotics are prescribed, especially for those with recurrent episodes. The peak incidence of acute otitis media is at 1-2 years of age. The risk of developing another episode within one month after the onset of the primary infection is estimated at 35%.¹ About 5% of children are prone to otitis media, defined as six or more episodes, or recently as three or more episodes, during one year. ^{2 3} The recent definition results in a greater number of children who are considered prone to otitis media.

The most common bacteria associated with acute otitis media are Streptococcus pneumoniae, Haemophilus influenzae and, less often, Moraxella catarrhalis and group A  streptococci. These bacteria originate and spread from the nasopharynx to the middle ear cavity by way of the eustachian tube. Carlin et al showed that 75% of the bacteria associated with recurrent otitis media represented new bacterial strains.¹ The remaining 25% were from either reinfection with the same bacterial strain or treatment failures.

Secretory otitis media is the most common sequela of acute otitis media. One or more of S pneumoniae, H influenzae, or M catarrhalis are found in about 30% of patients with secretory otitis media.³

The importance of normal flora for protecting against infection in an anatomical site has recently been shown in the upper respiratory tract, and lack of bacteria with interfering activity (the ability to inhibit the growth of the common otopathogens), especially the  streptococci, has been associated with a higher incidence of reinfections in patients with streptococcal pharyngotonsillitis. ^{4 5} Lower numbers of  streptococci have been found in the nasopharynx of children who are prone to otitis media compared with those who are not prone and in those with secretory otitis media compared with healthy children.^6-8  Streptococci isolated from adenoid tissue have also been shown to have less interfering activity on pathogens associated with acute otitis media than have those isolated from the opening of the eustachian tube.⁹

We aimed to study the effect of recolonisation with  streptococci with interfering acitivity against the common otopathogens on the recurrence rate of acute otitis media. We also aimed to determine whether the frequency of secretory otitis media was affected by this treatment.

	Participants and methods

Top Abstract Introduction Participants and methods Results Discussion References

Study designFrom 1996 to 1999 we performed a double blind, randomised study with two arms on 130 children aged between 6 months and 6 years. Randomisation was undertaken by a technician with no access to information on the patients or doctors. Three ear, nose, and throat specialists at Lundby Hospital, Gothenburg, Sweden, were engaged in the study.

PatientsChildren eligible for inclusion in our study were those who had had recurrent otitis media and who had been either referred by their general practitioner or a paediatrician to the open care unit of the ear, nose, and throat department at Lundby Hospital or were directly seeking medical advice for ear pain. The children had had at least two episodes of acute otitis media during the past six months or five episodes during the past year. At the next occurrence of ear pain the children were examined, and those with a red or pale, bulging, thickened tympanic membrane were included in the study. We excluded those with penicillin allergy, serious underlying disease, immunological deficiency, a valvular heart defect, major lesions in the mouth or nose, a grommet in the ear, or chronic otitis media.

Informed written consent was obtained from one of the parents of each eligible child. The study protocol was approved by the Medical Products Agency.

Antibiotic treatmentThose children with no recurrences during the past month but who had acute otitis media were given phenoxymethylpenicillin (Kåvepenin, AstraZeneca, Sweden) 25 mg/kg bodyweight. Those children with a recurrence within the past month were given amoxicillin clavulanic acid (Spektramox, AstraZeneca) 20 mg/kg bodyweight. Both antibiotics were given twice daily for 10 days.

Spray treatmentThe streptococcal spray was made up by isolating  haemolytic streptococci from the opening of the eustachian tube of the healthy children and selecting five strains (of about 800 tested) for their superior ability to inhibit the growth of S pneumoniae, H influenzae, M catarrhalis, and S pyogenes (group A streptococci), using a method described earlier.¹⁰ The streptococci represented two strains of S sanguis, two strains of S mitis, and one strain of S oralis in equal proportions. They were freeze dried in skimmed milk, reconstituted in 0.9% sodium chloride immediately before use, and kept cold during the treatment period. The mixture corresponded to a suspension of 5×10⁸ colony forming units per millilitre. The viable counts in the bottle at the end of treatment still exceeded 5×10⁶ colony forming units per millilitre. Placebo comprised skimmed milk powder, with the same texture and colour as the spray. Parents were informed both verbally and in writing on how to give the spray, and this was demonstrated at the first visit. The bottle was given to the doctor at follow up visits to ensure that adequate amounts of spray had been given. At least five days of spray treatment (more than 50% of the suspension) had to be given for the patient to be evaluated for efficacy.

Participant flow and follow up analysis
At the first visit (day 1) the child's medical history and background data were recorded and a clinical examination was performed, including otomicroscopy (this is superior to otoscopy and allows a detailed inspection of the tympanic membrane). A nasopharyngeal swab was taken for bacteriological analysis and a 10 day course of antibiotics prescribed. Information about the study was given both in writing (signed by a parent) and verbally.

Statistics
We used Fisher's exact test and logistic regression, both bivariate and multivariate. We regarded a sample size of 130 patients, 65 in each group, as sufficient for an analysis of the clinical efficacy and safety of treatment. Earlier studies have shown that at least 50% of patients acquire new otitis media during the three months after an episode. We allowed for a drop out rate of 15%.

	Results

Top Abstract Introduction Participants and methods Results Discussion References

We excluded 5 of 137 potentially eligible patients for geographical reasons, language problems, or difficulties with follow up. Of 132 children included, 108 (82%) were eligible for analysis of efficacy (53 in the  spray group and 55 in the placebo group) and 126 (95%) for analysis of adverse events. The main reasons for not being eligible for the efficacy analysis were withdrawal from the study or refusal to start spray treatment (eight children), inadequate handling of spray (four), and antibiotic treatment being received for reasons other than acute otitis media (three). The other five patients were either lost to follow up (two), allergic to penicillin (one), or we were unable to determine whether a recurrence had occurred because they were treated by another doctor during the study (two).

The mean age of the children was 23 months. We found no significant differences between the two treatment groups for age, number of siblings, parental proneness to otitis media, allergy, duration of breast feeding, day care, or parental smoking. Recurrence was the only variable that correlated significantly with a parental history of recurrent acute otitis media during childhood. An age of less than two years was also associated with a higher recurrence rate, but this was not important. Children who had had six or more episodes of acute otitis media during the past year, or two or more during the past six months, were equally distributed between the two treatment groups, and there were no differences in efficacy outcome between these two groups. Only seven children visited another doctor for ear pain during the study.

Of the children receiving the spray, 27 (22 of whom could be evaluated) were given penicillin and 103 (86 of whom could be evaluated) amoxicillin clavulanic acid. These children were equally distributed between the spray and placebo groups.

At inclusion we isolated M catarrhalis, S pneumoniae, and H influenzae from 75 (61%), 66 (54%), and 46 (37%) of 123 children, respectively. More than one of these three species could be isolated from 66 (54%) of the children. S pneumoniae was the predominant bacteria in 50 (41%) children. No differences in distribution of the bacteria were found between the spray and placebo groups.

In children given the spray the rate of recurrence during the three months of follow up was significantly reduced compared with those given placebo. Overall, 22 (42%) of the children given spray experienced no acute otitis media during the study and had a normal tympanic membrane at the last valid visit compared with 12 (22%) of the children given placebo (table). Furthermore, 10 (31%) of the 32 children without recurrence who were given the spray had secretory otitis media at the last valid visit compared with 15 (56%) of the 27 children in the placebo group.

Of the 130 children included, 22 in the spray group had adverse events compared with 25 in the placebo group. One child in the placebo group got pneumonia and spray treatment was stopped, and another child in the same group stopped treatment owing to an adverse event.

	Discussion

Top Abstract Introduction Participants and methods Results Discussion References

Heredity and age under 2 years are important factors in recurrent otitis media.¹¹ Passive smoking, breast feeding, number of siblings, type of day care, and allergy have also been implicated, but studies of these are not as conclusive.

We found a 50% rate of recurrence of acute otitis media within three months of an episode in children who are prone to otitis despite adequate antibiotic treatment. We also found a high frequency of secretory otitis media. Up to 78% of the children treated with antibiotics and placebo either had a recurrence or still had secretory otitis media after three months. Antibiotic prophylaxis, either long term seasonal treatment or intermittent treatment in relation to viral infection, is used to reduce the frequency of new episodes of acute otitis media in children with recurrent otitis. ^{12 13} Such treatments have, however, been questioned because of the increasing antibiotic resistance of respiratory tract pathogens. Placement of a tympanostomy tube has been practised and seems to effectively prevent recurrent otitis media in these children.¹³ The procedure, however, carries a risk, is costly, needs to be performed under general anaesthesia, and has complications and sequelae related to the tympanic membrane.¹⁴ Vaccination against pneumococci and H influenzae seems to have little impact on the frequency of acute otitis media in children under 2 years.

People who lack interfering  streptococci seem to have more streptococcal throat infections than those with interefering  streptococci on their tonsils. ^{4 5} Furthermore, patients with recurrent streptococcal pharyngotonsillitis have fewer recurrences after recolonisation with a mixture of four  streptococcal strains with good growth inhibiting activity of group A streptococci. ^{15 16}

Nasopharyngeal cultures from children who are prone to otitis or secretory otitis media show low numbers of  streptococci with interfering activity against common pathogens of acute otitis media. We therefore tried to recolonise children prone to recurrent acute otitis media with a mixture of five strains of interfering  streptococci. This resulted in a significantly decreased number of recurrences of acute otitis media in the treated children compared with those given placebo. This difference was also seen in the children with secretory otitis media at the last valid visit.

The results of ecological recolonisation studies, both in patients with streptococcal pharyngotonsillitis and in children with recurrent otitis media, have emphasised the importance of a normal balance between microorganisms in the upper respiratory tract.  Streptococci were used in these studies, but it has recently been shown that other bacteria such as Prevotella and Peptostreptococcus species have interfering activity on pathogens in the upper respiratory tract and could therefore be candidates for ecological interventions.⁷ Most antibiotics used to treat infections in the upper respiratory tract have an impact on the normal bacterial flora, including the dominating  streptococci. As these bacteria are part of the body's natural defence, treatment with antibiotics abates this part of the defence system and thus facilitates colonisation with pathogenic bacteria. Paradoxically, repeated courses of antibiotics might contribute to recurrent infections in children who are prone to otitis. Restoration of the normal flora would therefore be the logical way to inhibit further recurrences.

In conclusion, recolonisation with  streptococci with inhibitory activity against common pathogens of otitis media significantly diminishes the recurrence rate of this condition in susceptible children. This is also true for secretory otitis media, often arising as a complication of acute otitis media.

Although the number of failures is still high, treatment with  streptococci could be of considerable value owing to the high incidence of acute otitis media and secretory otitis media in children. Such treatment would also reduce the intake of antibiotics.

	Acknowledgments

Lundby Hospital supported the clinical part of the study by giving access to necessary staff. The authors of this study have been cooperating for over 15 years in the study of recurrent infections in the upper respiratory tract and the present study is a continuation of earlier studies on bacterial interference done by the authors.

Contributors: KR, EGH, and SH formulated the study hypothesis, discussed core ideas, designed the protocol, and evaluated the data. KR coordinated the study and included most of his patients in the study. SH supervised the bacteriological part of the study. EGH was responsible for the selection of interfering  streptococci and prepared the streptococcal suspension together with Marie Eklund. Hanna Eklöf monitored the study. Eva Lydén and Carl von Sydow included patients from Lundby Hospital. Hans Stenlund, University of Umeå, was responsible for the statistical analysis. The Medical Products Agency in Uppsala approved the design and suggested minor changes.

	Footnotes

Funding: The study was supported by the Swedish National Board for Industrial and Technical Development and the Teknikbro Foundation and grants from Samariten Foundation, Stockholm.

Competing interests: We have been involved in the interference between potentially pathogenic bacteria and apathogens in the upper respiratory tract for many years. This has resulted in several theses at the University of Umeå and Gothenburg. This study is a continuation of ongoing scientific studies covering the upper respiratory tract. We believe that bacterial interference is of importance for the normal defence system and has a clinical impact. We hope that it might be routinely applied as an alternative, or supplement, to antibiotic treatment in the future. We have therefore applied for a patent in some countries for the bacterial strains used in the study.

	References

Top Abstract Introduction Participants and methods Results Discussion References

1.	Carlin S, Marchant C, Shurin P, Johnson C, Murdell-Panek D, Barenkamp S. Early recurrence of otitis media: reinfection or relapse. J Pediatr 1987; 110: 20-25[CrossRef][Medline].
2.	Ingvarsson L, Lundgren K, Stenström C. Occurrence of acute otitis media in children: cohort studies in an urban population. Ann Otol Rhinol Laryngol 1990; suppl 149: 17-18.
3.	Stenfors L-E, Räisinen S. Occurrence of Streptococcus pneumoniae and Haemophilus influenzae in otitis media with effusion. Clin Otolaryngol 1992; 17: 195-199[Medline].
4.	Roos K, Grahn E, Holm SE. Evaluation of beta-lactamase activity and microbial interference in treatment failures of acute streptococcal tonsillitis. Scand J Infect Dis 1986; 18: 313-319[Medline].
5.	Grahn E, Holm SE. Bacterial interference in the throat during a streptococcal tonsillitis outbreak in an apartment house area. Zbl Bact Hyg A 1983; 256: 72-79.
6.	Bernstein J, Faden H, Dryja D, Wactawski-Wende J. Micro-ecology of the nasopharyngeal bacterial flora in otitis-prone and non-otitis-prone children. Acta Otolaryngol (Stockh) 1993; 113: 88-92[Medline].
7.	Brook I, Yocum P. Bacterial interference in the adenoids of otitis media-prone children. Pediatr Infect Dis J 1999; 18: 835-837[CrossRef][Medline].
8.	Fujimori I, Hisamatsu K, Kikushima K, Goto R, Murakami Y, Yamada T. The nasopharyngeal flora in children with otitis media with effusion. Eur Arch Otorhinolaryngol 1996; 253: 260-263[Medline].
9.	Tano K, Olofsson C, Grahn Håkansson E, Holm SE. In vitro inhibition of S. pneumoniae, non-typeable H. influenzae and M. catarrhalis by alpha-hemolytic streptococci from healthy children. Int J Pediatr Otorhinolaryngol 1999; 47: 49-56[CrossRef][Medline].
10.	Grahn E, Holm SE, Roos K, Ekedahl C. Interference of alpha-hemolytic streptococci isolated from tonsillar surface, on hemolytic streptococci, Streptococcus pyogenes, a methodological study. Zbl Bact Hyg A 1983; 254: 459-468.
11.	Stenström C, Ingvarsson L. Otitis-prone children and controls: a study of possible predisposing factors. 1. Heredity, family background and perinatal period. Acta Otolaryngol (Stockh) 1997; 117: 87-93[Medline].
12.	Casselbrant ML, Kaleida P, Rockette H, Paradise J, Bluestone C, Kurs-Lasky M, et al. Efficacy of antimicrobial prophylaxis and tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial. Pediatr Infect Dis J 1992; 11: 278-286[Medline].
13.	Prellner K, Foglé-Hansson M, Jörgensen F, Kalm O, Kamme C. Prevention of recurrent acute otitis media in otitis-prone children by intermittent prophylaxis with penicillin. Acta Otolaryngol (Stockh) 1994; 114: 182-187[Medline].
14.	Tos M, Stangerup SE. Hearing loss in tympanosclerosis caused by grommets. Arch Otolaryngol Head Neck Surg 1989; 115: 931-935.
15.	Roos K, Holm SE, Grahn E, Lind L. Alpha-streptococci as supplementary treatment of recurrent streptococcal tonsillitis: a randomized placebo-controlled study. Scand J Infect Dis 1993; 25: 31-35[Medline].
16.	Roos K, Holm SE, Grahn E, Lagergren L. Recolonization with four selected alpha-streptococcal strains in the treatment of recurrent streptococcal tonsillitisa placebo-controlled randomized multicentre study. Scand J Infect Dis 1996; 28: 459-462[Medline].

(Accepted 29 September 2000)