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ORIGINAL STUDIES
Topical Ciprofloxin Versus Topical
Framycetin-Gramicidin-Dexamethasone in Australian
Aboriginal Children With Recently Treated Chronic
Suppurative Otitis Media
A Randomized Controlled Trial
Amanda Leach, PhD,*† Yvonne Wood, MPH,*† Edna Gadil,*† Elizabeth Stubbs, MPH,*†
and Peter Morris, MBBS, FRACP, PhD*†‡
Background: Chronic suppurative otitis media (CSOM) affects many
children in disadvantaged populations. The most appropriate topical
antibiotic treatment in children with persistent disease is unclear.
Methods: Children with CSOM despite standard topical treatment
were randomized to 6 – 8 weeks of topical ciprofloxacin (CIP) versus
topical framycetin-gramicidin-dexamethasone (FGD). Otoscopic,
audiologic, and microbiologic outcomes were measured using standardized assessments and blinding.
Results: Ninety-seven children were randomized. Ear discharge
failed to resolve at the end of therapy in 70% children regardless of
allocation 关risk difference ⫽ ⫺2%; (95% CI: ⫺20 to 16)兴. Healing
of the tympanic membrane occurred in one of 50 children in the CIP
group and none of 47 children in the FGD group. Severity of
discharge failed to improve in more than 50% children in each
group, and mean hearing threshold (38 dB and 35 dB) and proportion of children with greater than 25 dB hearing loss (98% and 88%)
were not significantly different between the CIP and FGD groups.
Side effects were rare.
Conclusions: This study showed a similarly low rate of improvement or cure in children with persistent CSOM for both CIP and
FGD topical therapies. Complications and side effects were insufficient to cease therapy or inform prescribing of either therapy.
Key Words: chronic suppurative otitis media, randomized
controlled trial, topical antibiotics
(Pediatr Infect Dis J 2008;27: 692– 698)
Accepted for publication February 21, 2008.
From the *Menzies School of Health Research, Darwin, Australia; †Institute
of Advanced Studies, Charles Darwin University; and ‡Northern Territory Clinical School, Flinders University, Darwin, Australia.
Supported by a grant from the National Health and Medical Research
Council of Australia and the Menzies School of Health Research.
Address for correspondence: Dr. Peter S. Morris, MBBS, FRACP, PhD,
Deputy Leader, Child Health Division, Menzies School of Health Research, PO Box 41096, Casuarina, Northern Territory 0811, Australia.
E-mail: peterm@menzies.edu.au.
Copyright © 2008 by Lippincott Williams & Wilkins
ISSN: 0891-3668/08/2708-0692
DOI: 10.1097/INF.0b013e31816fca9d
692
Additional material related to this article and only published online can
be accessed on the Web by clicking on the ‘‘ArticlePlus’’ link either in
the Table of Contents or at the top of the Abstract or HTML version of
the article.
R
ural and remote Australian Aboriginal children have extremely high rates of severe otitis media1,2 reported to
develop as early as the first 3 months life. This is associated with
the very early onset of colonization by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.3
These infections can progress to perforation of the tympanic
membrane in the first year of life. In a recent survey, 24% of
all rural Aboriginal children aged 6 –30 months had a perforated tympanic membrane and nearly all were actively discharging at the time of assessment.1 Chronic suppurative
otitis media (CSOM) is now extremely uncommon in developed countries. Consequently, it is considered a preventable
disease by the World Health Organization, and perforation
rates higher than 4% are regarded as unacceptable.4
In the top end of the Northern Territory topical antibiotic drops (framycetin-gramicidin-dexamethasone) are recommended treatment for CSOM.5 Before 2007, topical quinolones were not recommended as the first-line treatment
because of uncertainty about effectiveness and concerns
about increasing antibiotic resistance.6 However, topical CIP
was already being used in some places. The use of topical
quinolones may be most effective in children who have failed
to respond to treatment with topical aminoglycosides. The
aim of the study was to assess the effectiveness and safety of
topical CIP drops compared with topical framycetin-gramicidin-dexamethasone (FGD) in children who have recently
failed to respond to recommended treatment with topical FGD.
METHODS
Study Design
The Chronic Otitis Media Intervention Study 4 (COMIT 4) was a randomized, assessor-blinded, controlled trial
assessing the impact of topical CIP (Ciloxin) versus topical
FGD (Sofradex) in Australian Aboriginal children with chronic
suppurative otitis media (CSOM) that had persisted despite
The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
previous treatment. The intervention occurred between April
2001 and September 2001. Hearing assessments occurred in
November 2001 and December 2001. The local Human
Research Ethics Committee and the Tiwi Health Board approved the study.
Population
We conducted the study in the 3 remote Aboriginal
communities. Children 1–16 years of age who had a chronic
perforation were eligible to be enrolled in the monitoring
phase of the study. Once informed consent had been provided, children who had active CSOM were prescribed (or
continued) topical FGD 4 drops twice a day. We subsequently
randomized children who had persistent disease despite this
treatment. We excluded children from randomisation if they
were: allergic to CIP or FGD; pregnant or breast-feeding;
diagnosed with cholesteatoma; previously treated with tympanoplasty; or suffering from any other medical condition
that could interfere with participation in the study.
Randomization, Allocation Concealment,
and Blinding
A random sequence stratified by community and age
group (⬍6 years or ⱖ6 years of age) was generated using
Stata Version 7.0.7 The allocation sequence was concealed
throughout the study. Ear outcomes were also confirmed by a
third assessor (blinded to the allocation group) using video
recordings. The audiologist who performed hearing tests and
laboratory staff who processed all the swabs were also blinded to
the allocation status.
The Intervention
Children were randomly allocated after their clinical
assessment at the start of the second or third school term in
2001. Children were to receive 4 drops twice a day of either
CIP (Ciloxin) or FGD (Sofradex). We instructed staff and
families that: (1) treatment occurred after ear cleaning by dry
mopping with “tissue spears” (rolled tissue paper); and (2)
instillation of the ear drops occurred with head tilted and was
followed by pumping the tragus against the ear canal at least
10 times. The aim of these procedures was to maximize the
amount of topical treatment that reached the middle ear
space. Whenever possible, the morning treatment was supervised by the ear health team operating out of the local school
or clinic. The evening treatment was provided by the family.
The research team flew to the community for 2–3 days each
week to support the local ear health project and also attempted to check the ears each week for discharge. If the ears
were observed to be dry for at least 3 days, the treatment was
ceased. Treatment was restarted if discharge recurred. The
primary outcome assessment occurred in the last 2 weeks of
the school term. The intervention period was 6 – 8 weeks in
all children. After completing the intervention, all children
continued to receive regular care (without additional research
team support) including topical FGD if indicated.
Clinical Assessment, Swab Collection,
and Hearing Tests
All assessments were standardized. Clinical and microbiologic assessment occurred on the day of randomization, at
© 2008 Lippincott Williams & Wilkins
Topical Antibiotics for CSOM
the completion of the intervention period, and at follow-up
4 –12 weeks later. All clinical and microbiologic data were
collected by observers who were unaware of the treatment
allocation. Each child had otoscopy (Lumiview, Welch Allyn) and video-otoscopy conducted before cleaning (and after
cleaning if required). Tympanometry (Grason Stadler GSI
38) was done if their tympanic membrane was intact or their
middle ear was dry. The amount of middle ear discharge was
graded: (1) profuse— discharge visible without otoscope; (2)
moderate— discharge visible with otoscope but present in ear
canal; (3) scant— discharge visible with otoscope but limited
to middle ear space; and (4) dry—no discharge visible.
Whenever there was uncertainty about whether a middle ear
was dry or had scant discharge present, we used a second
observer to determine whether pooling of discharge was
documented on the video or whether there was sufficient fluid
present to form a droplet on a swab placed into the middle
ear. The video images were also reviewed by a second
blinded observer at a later date. Any differences in the
clinical assessment were resolved by consensus using a third
assessor. Drawings of the perforations were made at the time
of the assessment to estimate the percentage of the pars tensa
of the tympanic membrane that had been eroded (perforation
size %). Any erosion of the annulus or the pars flaccida was
not included in this estimate. The video was used to confirm
this estimate. The total perforation size (%) was calculated as
the sum of the perforation size for each tympanic membrane
divided by 2 (using 0% for intact tympanic membranes).
At each clinical assessment, swabs of the nose and ear
discharge were taken. Aluminum shafted ENT swabs (Disposable Products, Australia) were used to collect all specimens. Nasal swabs were collected by inserting the swab
approximately 5 cm into the nose and placing it in contact
with the basal mucosal surface for a period of 5 seconds. If
the child refused a nasal swab, the child was asked to blow
their nose into a Kleenex tissue, and a swab was then used
to transfer secretions from the tissue to transport medium.
Ear discharge was collected by inserting a swab into the
middle ear space under direct vision or from as close to the
tympanic membrane perforation as possible if this was not
feasible. All swabs were placed in 1-mL skim-milk tryptone
glucose glycerol broth (STGGB), frozen at ⫺20°C in the
community within 4 hours of collection. They were transported on dry ice to our laboratory for storage at ⫺70°C
before culture.
Hearing assessment occurred in December 2001 (3– 6
months after completion of the intervention). Tests were done
in a quiet room by an audiologist who was unaware of the
allocation status of the child. Air conduction thresholds and
the air-bone gap for each ear at 500, 1000, 2000, and 4000 Hz
were determined whenever possible. The pure tone average
hearing level was calculated by averaging the air conduction
thresholds across the 4 frequencies tested in the better hearing
ear. For children who received a free field assessment (both
ears combined) the combined threshold was used. Children
with a pure tone average hearing level of ⱖ25 dB were
classified as having a significant hearing loss.
693
Leach et al
The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
Laboratory Analyses
Swabs in STGGB were thawed, mixed, and 10 ␮L
aliquots cultured on the following plates (Oxoid, Australia):
5% horse blood agar, chocolate agar, 5% horse blood agar
containing colistin and nalidixic acid, and chocolate agar plus
bacitracin, vancomycin, and clindamycin. Swabs of ear discharge were also plated onto Sabourands agar, Pseudomonas
selective agar, and MacConkey agar. Ear discharge swabs,
which initially cultured swarming Proteus spp., were filtered
to enable detection of H. influenzae; a 100-␮L aliquot was
placed on a 65-␮m nitrocellulose filter, which had been
placed directly onto BVCCA agar. After 15 minutes, the filter
was removed. Blood plates were incubated at 37°C in 5%
CO2. Pseudomonas plates were incubated at 42°C, Sabourands at room temperature for at least 2 days, and MacConkey plates at 35°C, all in air. Bacterial isolates were identified
according to standard laboratory procedures. Antimicrobial
susceptibilities of S. pneumoniae and P. aeruginosa isolates
were determined by the calibrated dichotomous susceptibility
(CDS) disc diffusion method.8 Minimum inhibitory concentrations (MICs) were determined by E-test for all pneumococci (penicillin and CIP) and Pseudomonas isolates (gentamicin and CIP). For all resistance outcomes, we report the
proportion of assessed children with nonsusceptible isolates.
Beta-lactamase production by H. influenzae and M. catarrhalis was determined using nitrocephin (Oxoid, Australia). All
bacterial isolates were stored at ⫺70°C for further investigations if required.
Outcome Measures
Clinical. The primary outcome was the proportion of all
randomized children who had clinical failure (in the worst
ear) at the end of therapy. Clinical failure was defined as
otoscopic signs of otorrhoea in the canal or middle ear space,
including otorrhoea in the canal despite healing of the tympanic membrane. The following secondary outcomes were
also analyzed: (1) Failure to improve otorrhoea (from either
profuse/moderate to scant or scant to none); (2) Failure to
heal perforation; (3) Mean change in perforation size; (4)
Failure to resolve discharge at follow up (4 –20 weeks after
completion of intervention period); (5) Hearing loss at end of
therapy—mean pure tone average threshold, and proportion
with mean hearing loss ⱖ25 dB (within 6 months after
completion of intervention period).
Microbiologic. The proportion of assessed children is used in
the analyses of microbiologic outcomes. Children for whom
a culture result could not be determined were excluded from
the analyses. The following microbiologic outcomes were
measured: the proportion of assessed children with (1) any
Pseudomonas aeruginosa, any respiratory (otitis media) bacterial pathogen (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis), (2) any bacterial pathogen
(S. pneumoniae, H. influenzae, M. catarrhalis, Streptococcus
pyogenes, Staphylococcus aureus, P. aeruginosa, Proteus spp.,
coliforms), or (3) any fungal or yeast growth in ear discharge at
the end of therapy (Table 5 available online only), and (4) any
respiratory bacterial pathogen (S. pneumoniae, H. influenzae,
M. catarrhalis, S. pyogenes) in nasal discharge at the end of
therapy (Table 5).
694
Complications and Side Effects. The proportion of assessed
children who were withdrawn from treatment because of: (1)
increased severity of disease (complication); or (2) allergy or
pain on application (side effect). The proportion of children
with (1) any S. pneumoniae or P. aeruginosa in ear discharge
with resistance to CIP at end of therapy (side effect), or (2)
change from entry to end of therapy, in the proportion of
children with any S. pneumoniae or P. aeruginosa in ear
discharge with resistance to CIP (side effect).
Modified Intention to Treat. For dichotomous or ordinal outcomes, unless otherwise stated the denominators used for analyses were all randomized children. Children not seen categorized as treatment failures (modified intention to treat). For
continuous outcomes (such as hearing threshold), subgroup
analyses other than age group, sensitivity analyses, and analyses
at follow-up, only children with assessments were included.
Subgroup Analyses. For all outcomes, the proportion of children with the outcome is specified for (1) 2 age group
categories (⬍6 years or ⱖ6 years), (2) 2 categories of ear
discharge severity (worst ear) at entry (moderate or severe or
scant), and (3) 2 bacteriological categories at entry (P.
aeruginosa culture-positive or negative in the worst ear).
Statistical Methods and Sample Size
We analyzed all data using Stata Version 9.2.7 We
based our sample size calculation on the following assumptions (1) that the proportion of children in the FGD group
with failure at the end of therapy would be 90%, and (2) a
difference of less than 25% would be unlikely to change
current clinical guidelines for management of children who
fail FGD therapy. A sample size of 102 would provide 80%
power (␣ 0.05) to detect a 25% reduction in failure to resolve
otorrhoea in the CIP group (65%) compared with the FGD
group (90%).
RESULTS
Study Participant Flow and Baseline
Characteristics
Consent was provided by parents of 97 eligible children
who were available to join the study. Fifty were allocated to
CIP and 47 to FGD. End of therapy clinical assessments were
achieved in 89 children (45 in the CIP group and 44 in the
FGC group), and microbiologic assessments were achieved in
44 and 43 children, respectively. Subsequent follow-up assessments were made for 90 children (47 CIP and 43 FGD).
For 85 children who also had assessments at the end of
therapy, the mean time to follow up assessment was 100 days
(44 CIP children) and 103 days (41 FGD children) (Fig. 1
available online only and Table 1).
Baseline characteristics for age, sex, and ear status are
presented in Table 1. Children in both groups were similar in
terms of age, severity of disease, and microbiologic culture
results.
Primary Outcome Measure
Failure to Resolve Otorrhoea at End of Therapy (Intention
to Treat). There were 35 of 50 (70%) children in the CIP
group and 34 of 47 (72%) in the FGD group who had
© 2008 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
Secondary Outcome Measures
TABLE 1. Participant Characteristics at
Commencement of Therapy
Mean age (SD) (yr)
Range
Age ⬍6 yr
Male sex
Mean age (SD) in years at 1st perforation‡
Range
Mean (SD) perforation size (%) at entry
No. (%) of children with following ear
outcomes at commencement of
therapy
Moderate or profuse discharge
Bilateral perforation
Bilateral discharge (ⱖscant)
Mean perforation size ⬎25%
Mean perforation size in worst
ear ⬎25%
Pseudomonas aeruginosa
culture-positive§
P. aeruginosa ciprofloxacin non-sus¶
P. aeruginosa gentamicin non-sus¶
Respiratory bacteria
Streptococcus pneumoniae
Haemophilus influenzae
Fungi or yeast
Topical Antibiotics for CSOM
CIP*
n ⫽ 50
FGD†
n ⫽ 47
7.7 (3.2)
1–14
17 (34%)
17 (34%)
0.85 (0.9)
0.1– 4.6
30 (20)
7.8 (3.7)
1–15
18 (38%)
20 (43%)
0.83 (0.6)
0.1–3.2
31 (23)
38 (76%)
36 (72%)
30 (60%)
27 (54%)
34 (68%)
34 (72%)
33 (70%)
23 (49%)
22 (47%)
27 (57%)
31 (65%)
27 (60%)
0
13 (26%)
13 (27%)
2 (4%)
12 (25%)
8 (17%)
0
12 (26%)
10 (22%)
1 (2%)
9 (20%)
10 (22%)
*Topical CIP (Ciloxin), 4 drops twice a day after cleaning.
†
Topical FCD (Sofradex), 4 drops twice a day after cleaning.
‡
For this outcome, CIP (n ⫽ 45) and FGD (n ⫽ 46).
§
For this outcome, CIP (n ⫽ 48) and FGD (n ⫽ 45).
¶
Non-susceptible MIC ⱖ1.0 ␮g/mL.
SD indicates standard deviation.
Clinical Outcomes at the End of Therapy. Otorrhoea failed to
improve in 26 of 50 children in the CIP group and 28 of 47
children in the FGD group 关RD ⫽ ⫺7%; (95% CI: ⫺27 to
12), Table 3兴. The effect size was similar for children less than
age 6 and for children older than age 6, for children with
moderate/profuse versus scant otorrhoea, and for children with
or without P. aeruginosa in ear discharge at commencement of
therapy (subgroups not shown). Perforations persisted at the end
of therapy in 49 of 50 children in the CIP group and in all
children in the FGD group. The mean change in perforation size
was around ⫺2% in both groups. Differences between treatment
groups were not significant for any of the subgroups age,
severity of discharge or P. aeruginosa in ear discharge commencement of therapy (subgroups not shown).
Persistent Otorrhoea at 12–28 Weeks Follow-Up. More children in the CIP group (86%) than in the FGD group (74%) had
persistent otorrhoea after 12–28 weeks of commencing therapy;
this difference was significant for older children 关RD ⫽ 26%;
(95% CI: 5– 47)兴. Degree of discharge severity and P. aeruginosa in ear discharge at commencement of therapy did not
significantly change the effect size (subgroups not shown).
Hearing Outcomes
otoscopic signs of otorrhoea in the canal or middle ear space
at the end of therapy 关risk difference (RD) ⫽ ⫺2%; (95%
confidence interval (CI): ⫺20 to 16); Table 2兴. There was no
substantial difference between treatment groups for children
aged less than 6 years or older children. Differences between
CIP and FGD were similar to the overall difference and were
nonsignificant for subgroups defined by severity of discharge
or presence of P. aeruginosa in discharge at commencement
of therapy.
Differences in hearing outcomes were nonsignificant
and not different for subgroups age group, discharge severity
or P. aeruginosa at commencement of therapy. Of 73 children who had hearing loss assessed, the mean hearing threshold was 38 dB for 41 children in the CIP group and 35 dB for
32 children in the FGD group 关mean difference ⫽ 3 dB; (95%
CI: ⫺1 to 6)兴. The proportion of children with a hearing
threshold greater then 25 dB was 93% overall and was similar
for both treatment groups 关RD ⫽ 10%; (95% CI: ⫺2 to 22)兴.
Microbiologic Outcomes
There were significant treatment group differences for
several microbiologic outcomes (Table 4, available online
only).
TABLE 2. Primary Outcome: Failure to Resolve Otorrhoea at End of Treatment
(Intention to Treat Analysis)
Outcome
Failure to resolve
otorrhoea
Failure to resolve
otorrhoea
Subgroup
All
Overall
71%
⬍6 yr
74%
ⱖ6 yr
69%
Moderate or severe discharge
at entry
Scant discharge at entry
71%
Any P. aeruginosa in ear
discharge at entry
No P. aeruginosa in ear
discharge at entry
72%
69%
71%
CIP*
(n ⫽ 50)
FGD†
(n ⫽ 47)
RD Difference
关95% CI兴
35/50
70%
13/17
76%
22/33
67%
27/38
71%
8/12
67%
21/31
68%
12/17
71%
34/47
72%
13/18
72%
21/29
72%
24/34
71%
10/13
77%
19/27
70%
13/18
72%
⫺2% (⫺20 to 16)
4% (⫺25 to 33)
⫺6% (⫺29 to 17)
0.4% 关⫺21 to 21兴
⫺10% 关⫺45 to 25兴
⫺3% 关⫺26 to 21兴
⫺2% 关⫺32 to 28兴
*Topical CIP (Ciloxin), 4 drops twice a day after cleaning.
†
Topical FGD (Sofradex), 4 drops twice a day after cleaning.
© 2008 Lippincott Williams & Wilkins
695
The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
Leach et al
TABLE 3. Secondary Outcomes: Failure to Improve Otorrhoea at End of Treatment,
Failure to Heal Perforation at End of Treatment, Change in Perforation Size at End of
Treatment, and Failure to Cure at the Follow-Up Examination
Outcome
Subgroup
Overall
Failure to improve otorrhoea
All
56%
Failure to heal perforation
All
99%
All
All
⫺2.4
80%
⬍6 yr
89%
ⱖ6 yr
76%
‡
Change in perforation size
Persistent otorrhoea at 12–28
wk follow up
†
CIP*
(n ⫽ 50)
FGD
(n ⫽ 47)
Difference
RD or MD 关95% CI兴
26/50
52%
49/50
98%
⫺2.10%
43/50
86%
14/17
82%
29/33
88%
28/47
60%
47/47
100%
⫺2.80%
35/47
74%
17/18
94%
18/29
62%
⫺7% 关⫺27 to 12兴
⫺2% 关⫺6 to 2兴
0.7% 关⫺2.2 to 3.6兴
12% 关⫺4 to 27兴
⫺12% 关⫺33 to 9兴
26% 关5 to 47兴
*Topical CIP (Ciloxin), 4 drops twice a day after cleaning.
†
Topical FGD (Sofradex), 4 drops twice a day after cleaning.
‡
For this outcome, CIP (n ⫽ 45) and FGD (n ⫽ 43).
P. aeruginosa. At the end of intervention, P. aeruginosa was
cultured from the ear discharge of 6 of 45 (13%) children in
the CIP group and 18 of 44 (41%) in the FGD group 关RD ⫽
⫺27%; (95% CI: ⫺45 to ⫺10)兴. The differences between
treatment groups were consistent with overall differences for
subgroups age ⬎6 years, scant discharge, and presence of P.
aeruginosa at commencement of therapy. Statistically significant differences between treatment groups were seen for
younger children 关RD ⫽ ⫺32%; (95% CI: ⫺55 to ⫺9)兴 or if
discharge was scant 关RD ⫽ ⫺58%; (95% CI: ⫺89 to ⫺26)兴.
Failure to eradicate P. aeruginosa could not be attributed to
resistant strains. Seven isolates (6 from 58 older children)
were resistant to gentamicin (MIC ⬎1.0); 3 in the CIP group
and 4 in the FGD group 关RD ⫽ ⫺2%; (95% CI: ⫺14 to 9)兴.
One of the 6 isolates from 45 CIP patients was CIP resistant
(MIC ⬎1 ␮g/mL) and none of the 18 isolates from the 44
FGD patients was CIP resistant.
Any Respiratory Bacterial Pathogen in Ear Discharge at
End of Therapy. Respiratory bacterial pathogens were cultured from 26% ear discharge specimens; 9 of 45 (20%) CIP
recipients and 14 of 44 (32%) FGD recipients 关RD ⫽ ⫺12%;
(95% CI: ⫺30 to 6)兴. S. pneumoniae was in 7% specimens
and H. influenzae in 21%; H. influenzae was less common in
ear discharge specimens from the CIP group (16%) than the
FGD group (27% positive). Significantly fewer respiratory
bacteria were detected in the CIP group if discharge at entry
was scant 关RD ⫽ ⫺25%; (95% CI: ⫺49 to ⫺0.5)兴. One CIP
resistant pneumococcus (serotype 23F) was isolated from a
CIP group child.
Other Bacterial Pathogens and Fungi in Ear Discharge at
End of Therapy. Staphylococcal spp. were isolated from 76%
children at end of therapy in both groups. Swarming Proteus
spp. were recovered from 0% of the CIP group and 36% of
the FGD group 关RD ⫽ ⫺36%; (95% CI: ⫺51 to ⫺22)兴.
Differences were similar for younger and older children.
Fungi or yeasts were more common in the CIP group (69%)
than the FGD group (36%) at the end of therapy 关RD ⫽ 33%;
(95% CI: 13–52)兴; this difference was greatest for young
children 关RD ⫽ 42%; (95% CI: 10 –74)兴 and for children with
scant discharge at entry 关RD ⫽ 56%; (95% CI: 22–90)兴.
696
Microbiologic Outcomes—Nasal Carriage at the End of
Therapy. No significant difference in nasal carriage of pneumococci, H. influenzae, M. catarrhalis, or S. pyogenes was
found between the 2 treatment groups (Table 5, available
online only). Carriage of any one of these pathogens was very
high in these children and was similar in the CIP group (95%)
to the FGD group (93%). One pneumococcus (serotype 19F)
from the CIP group was resistant to CIP.
Complications and Side Effects. No child was withdrawn
from treatment because of increased severity of disease,
allergy, or pain on application. Resistant S. pneumoniae or P.
aeruginosa were rare. One of 18 P. aeruginosa isolates and
one of 6 S. pneumoniae isolates (in the CIP group) had CIP
MICs ⱖ1.0 ␮g/mL. The proportion of children with at least
one CIP resistant pathogen (MIC ⱖ1.0 ␮g/mL) cultured from
ear discharge changed from 0% before therapy to 2% at the
end of therapy.
DISCUSSION
In 3 small remote communities with approximately 600
children 3 to 16 years of age, we identified 171 (29%)
children with a history of discharging ears. Of these, 110 had
persistent CSOM despite treatment provided by the schoolbased ear health programs. These children were eligible to
participate in a treatment trial. Unfortunately, of the one-third
of the children who achieved dry ears by the end of the
intervention period, many had relapsed before the end of the
school year. The low cure rate seen in this study explains why
CSOM remains such an enormous problem in remote Aboriginal communities.
Important differences were noticed for several of the
microbiologic outcomes; P. aeruginosa and swarming Proteus spp. were cultured less often from children in the CIP
group, and there was a trend towards less H. influenzae in the
CIP group; fungi or yeasts were more common in the CIP
group. Staphylococcal spp. and overall bacterial pathogen
recovery were not different between the 2 treatment groups.
Follow-up at 12–28 weeks indicated further increase in the
proportion of children who failed to resolve ear discharge
© 2008 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
(80% overall). Although this deterioration is disappointing, it
further stresses the challenges of long-term interventions for
Australian Aboriginal children living in remote settings.
Age group, severity of discharge, and culture of P.
aeruginosa at baseline did not significantly affect the differences between CIP and FGD groups for failure to resolve
otorrhoea (primary outcome) at the end of treatment. The
reduction in P. aeruginosa in CIP group compared with FGD
关RD ⫽ 27%; (95% CI: ⫺45 to ⫺10)兴 confirmed that compliance with treatment was sufficient to change the microbiology of the infection.
Although CSOM is regarded as an extremely difficult
condition to treat in all populations, a number of clinical trials
of quinolone antibiotics (including CIP) with activity against
Pseudomonas aeruginosa have described high cure rates. Cochrane reviews of interventions for CSOM9 found that topical
quinolone antibiotics were more effective than systemic
quinolone antibiotics at clearing discharge at 1–2 weeks
关RD ⫽ 33%; (95% CI: 20 – 47)兴. In a second review, topical
quinolone antibiotics without steroids were similar to topical
nonquinolone antibiotics without steroids 关RD ⫽ 11%; (95%
CI: ⫺30 to 9)兴.10
Similarly, a recent evidence summary11 found 3 randomized controlled trials that compared topical quinolone
antibiotics with topical nonquinolone antibiotics. They reported that all the studies found no significant difference in
the proportion of people who still had a wet ear on otoscopy
at the end of treatment. These reviews did not include the
most recent randomized, double blind comparison of topical
CIP versus topical FGD in Australian Aboriginal children
with persistent discharge for at least 2 weeks.12 After 9 days
treatment, the children available for follow-up were more
likely to have dry ears if they received topical CIP 关42 of 55
(76%) versus 29 of 56 (52%); RD ⫽ 25%; 95% CI: 7– 42兴.
The number of children swabbed at follow-up was not reported although 2 isolates (S. pneumoniae and Comamonas
acidovorans) were resistant to CIP. These outcomes are
encouraging but may have been affected by the relatively
large proportion of the randomized children that was lost to
follow-up (24%) or had missing clinical data (56%). The high
cure rate after only 9 days of treatment is very different to
the clinical experience of staff working in remote communities. It is possible that these children may have had new
discharge through a previously dry perforation (or less severe
infections) and this may have increased the effectiveness of
topical CIP.
Implications for Research. Our study emphasizes the challenges of treating CSOM in remote Aboriginal communities.
Long-term therapies are difficult and high rates of failure are
discouraging. Microbiologic assessments have shown some
important differences between the topical agents used in this
study. Although P. aeruginosa is reportedly the primary
pathogen of CSOM, we found multiple pathogens, including
H. influenzae, Proteus spp., and Staphylococcal spp., to be
involved. Given the uncertainty about the role of different
pathogens, clinical trials should assess microbiologic outcomes whenever this is feasible. Further clinical trials that
evaluate combined therapies in children with persistent
CSOM are also needed. In this population, delivering topical
© 2008 Lippincott Williams & Wilkins
Topical Antibiotics for CSOM
antibiotic treatment for weeks to months can be difficult.
Programs that aim to enhance the adherence, frequency, and
duration of treatment may result in better outcomes and
should be evaluated.
Implications for Practice. Our study found that there was no
substantial benefit in using topical CIP rather than FGD in
CSOM in remote Aboriginal children who had persistent
disease despite previous treatment. We found no significant
increase in frequency of infection caused by CIP resistant P.
aeruginosa or S. pneumoniae. Ototoxicity was not an outcome measured in this study, but we did not find any differences
in conductive hearing loss or development of significant
sensorineural hearing loss in the FGD group compared with
CIP group. However, the need for more prolonged or intense
treatment with topical antibiotics means that the potential for
ototoxicity remains a concern.
Ear health programs in remote Aboriginal communities
should recognize that children with persistent CSOM will
need prolonged courses of treatment and ongoing follow-up
over several months. Modest benefits are possible but are
relatively labor intensive. Greater efforts to prevent the onset
of CSOM, including prompt treatment with close follow-up
when acute otitis media with perforation occurs, are essential
components of any ear health program in this population.
ACKNOWLEDGMENTS
We thank the families, schools, and health clinic who
participated and assisted in this randomized controlled trial.
It would not have been possible without the support of the
Tiwi Health Board and the Tiwi for Life Program. We also
thank our colleagues who all made important contributions to
the planning and conduct of the study: Jemima Beissbarth,
Kim Hare, Brooke Harrington, Christine Lienert, Gabrielle
McCallum, Peter Silberberg, and Mary-Anne Tipungwuti.
Joseph McDonnell assisted with data analysis.
REFERENCES
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© 2008 Lippincott Williams & Wilkins
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