Topical quinolone vs. antiseptic for treating ... - Wiley Online Library

Tropical Medicine and International Health volume 10 no 2 pp 190–197 february 2005

Topical quinolone vs. antiseptic for treating chronic suppurative otitis media: a randomized controlled trial Carolyn Macfadyen1, Carrol Gamble2, Paul Garner1, Isaac Macharia3, Ian Mackenzie1, Peter Mugwe3, Herbert Oburra3, Kennedy Otwombe1, Stephen Taylor2 and Paula Williamson2 1 International Health Research Group, Liverpool School of Tropical Medicine, Liverpool, UK 2 Centre for Medical Statistics and Health Evaluation, School of Health Sciences, University of Liverpool, Liverpool, UK 3 Section of Ear, Nose and Throat Diseases, University of Nairobi, Kenyatta National Hospital, Nairobi, Kenya

Summary

objective To compare a topical quinolone antibiotic (ciprofloxacin) with a cheaper topical antiseptic (boric acid) for treating chronic suppurative otitis media in children. design Randomized controlled trial. setting and participants A total of 427 children with chronic suppurative otitis media enrolled from 141 schools following screening of 39 841 schoolchildren in Kenya. intervention Topical ciprofloxacin (n ¼ 216) or boric acid in alcohol (n ¼ 211); child-to-child treatment twice daily for 2 weeks. main outcome measures Resolution of discharge (at 2 weeks for primary outcome), healing of the tympanic membrane, and change in hearing threshold from baseline, all at 2 and 4 weeks. results At 2 weeks, discharge was resolved in 123 of 207 (59%) children given ciprofloxacin, and in 65 of 204 (32%) given boric acid (relative risk 1.86; 95% CI 1.48–2.35; P < 0.0001). This effect was also significant at 4 weeks, and ciprofloxacin was associated with better hearing at both visits. No difference with respect to tympanic membrane healing was detected. There were significantly fewer adverse events of ear pain, irritation, and bleeding on mopping with ciprofloxacin than boric acid. conclusions Ciprofloxacin performed better than boric acid and alcohol for treating chronic suppurative otitis media in children in Kenya. keywords randomized controlled trial, otitis media, suppurative, fluoroquinolones, antiseptics, eardrops, instillation, drug, hearing impairment, developing countries

Introduction Chronic suppurative otitis media (CSOM) is a common cause of hearing impairment in low- and middle-income countries [Berman 1995; World Health Organization (WHO) 1998]. It is defined as chronically discharging ears (for at least the preceding 2 weeks) associated with persistent eardrum perforations. Data on prevalence of CSOM are uncommon, although one study estimated it at 1.1% in Kenyan schoolchildren (Hatcher et al. 1995). Treatment aims to eradicate infection, prevent complications, heal the tympanic membrane, and improve hearing. Treatment options include dry mopping, ear wicking, gentle syringing, or suctioning; systemic antibiotics; and topical treatment with either antiseptics or antibiotics, sometimes with steroids. A Cochrane Review published in 190

1998 (Acuin et al. 2004) concluded that topical treatment with antibiotics or antiseptics is more effective than systemic antibiotics, aural toilet alone, or no treatment at all; and topical quinolones were better than topical non-quinolone antibiotics. Antiseptic drops, such as boric acid, are cheap and listed in country guidelines of some low-income countries; e.g. in Papua New Guinea (Standard Treatment for Common Illnesses of Children in Papua New Guinea 1993). The Cochrane Review identified three small studies (n ¼ 126) comparing topical antiseptics with topical antibiotics, and did not demonstrate a difference for the outcome ‘wet ear’ (Acuin et al. 2004). Topical ciprofloxacin, a quinolone antibiotic, has recently become available, is licensed in the European Union, but is expensive: £5 per 5 ml bottle in the UK. The

ª 2005 Blackwell Publishing Ltd

Tropical Medicine and International Health

volume 10 no 2 pp 190–197 february 2005

C. Macfadyen et al. Topical quinolone vs. antiseptic for chronic suppurative otitis media

Cochrane Review found quinolones superior to other topical antibiotics for CSOM; we conducted a randomized trial to evaluate this expensive but apparently effective drug against topical antiseptics in Kenyan schoolchildren.

Methods Study site Rural primary schools in Kisumu District, West Kenya: we visited 165 of the 186 total. The District has the highest infant (116.7/1000) and under 5-year (194.7/1000) mortality in Kenya, and ear infection is common (Ministry of Planning and National Development 2004). Participants School children aged 5 years and older, with (a) purulent, aural discharge for 14 days or longer; (b) pus in the external canal on otoscopy; and (c) perforation of the tympanic membrane. We excluded children who had been treated for ear infection or received antibiotics for any other disorder in the previous 2 weeks, or who had other ear problems (pre-existing disease, complicated otitis media, anatomical abnormalities) or allergy to study drugs. Interventions Topical eardrops were given twice daily, after dry mopping, for 10 consecutive school days (no treatment at weekends) with either ciprofloxacin eardrops (Ciloxan 0.3%; Alcon), or antiseptic eardrops (2% boric acid in 45% alcohol). Older children were appointed as ‘ear monitors’ and trained to clean and treat the infected ears, under the supervision of trained teachers, as described in Smith et al. (1996). Randomization and masking Children were randomized in a 1:1 ratio using computergenerated block randomization, stratified by school. Each treatment pack contained two bottles of randomized treatment and remained sealed until allocated to a child; packs and the bottles were identical in appearance and both treatments identical in colour and smell. Participants, carers, and outcome assessors remained blind to the treatment allocated throughout the study. Field procedures Four trained teams [each consisting of an Ear Nose and Throat (ENT) registrar, clinical officer, and a nurse


experienced in ENT] screened children by class, inviting children with CSOM and their guardians to an induction visit, usually two school days later. At induction, a child’s legal guardian(s) provided signed informed consent before assessments. After consent, but before randomization, teams performed baseline and eligibility assessments. Demographic data and a medical history were taken. Nurses established pure tone hearing threshold for air conduction, in decibels at 500 Hz, 1 kHz, 2 kHz, 4 kHz and 8 kHz, in a quiet location and by a standard technique using portable Kamplex screening audiometers (AKM KS8 MP, battery operated); they recorded ambient noise levels using sound level meters. After audiometry, registrars and clinical officers swabbed infected ears (for bacteriology and sensitivity analysis in Kisumu), then examined both ears for presence and degree of discharge, tympanic membrane perforation, and any other otoscopic findings using Earlite Kite and Heine mini otoscopes. After completing all induction assessments, eligible children were allocated their sequential treatment pack; clinical officers trained children and teachers and supervised the first dose. Every child was given a treatment record to complete to monitor treatment administration. Follow-up and outcomes Children were seen at 2 and 4 weeks to collect data. Where children were absent, we revisited the school the next day. All teams rotated schools for follow-up visits, to avoid them assessing children they had previously seen. Outcomes were (a) resolution of aural discharge; (b) healing of tympanic membrane; and (c) change in hearing threshold. The primary outcome was resolution of aural discharge at 2 weeks. We also recorded adverse events. Children with persistent discharge at week 2 were instructed to dry mop the ear(s) until week 4; those discharging at week 4 were also instructed to dry mop, and given a new bottle of eardrops and referred, with children with persistent perforation or other ear pathology, to the ENT surgeon in Kisumu. Children with other illnesses were referred to the nearby clinic or hospital. Any children referred during the study, remained in the study, and details of their referral and subsequent treatment were collected. Sample size Rates of CSOM may be higher in Kisumu than the 1.1% found other parts of Kenya, with its higher infant mortality rates (http://www.cbs.go.ke) and higher rates of ear diseases estimated by local medical staff and local surveys conducted in 2000 (Educational Assessment and Resource Centre Kisumu, and New Nyanza Provincial General Hospital 191




(NNPGH) ENT Clinic, Kisumu, unpublished data; and Dr David Odeny, personal communication) – we therefore used a higher estimate than that of Hatcher et al. 1995, but more conservative than the local Kisumu estimates, 15.1%, which were judged to be overestimated as they were based on 900 students screened in three schools selected following high referral numbers to the education assessment and rehabilitation centre in Kisumu and rates may not be limited to CSOM. Assuming a prevalence of 2%, and a total of 46,116 children in 186 schools in February 2002 (Office of the District Education Officer 2002), we estimated that 920 children would be potentially eligible for the study. Assuming 750 agreed to participate and an estimated 50% resolution rate at 2 weeks in the antiseptic group (Acuin et al. 2004), we calculated the study would have a power of 79% to detect the defined minimum clinically worthwhile absolute difference in resolution rates of 10%, at a twosided significance level of 5%. An interim analysis was carried out for the first 200 study participants to check the estimated resolution rate for the control group. The results indicated a resolution rate at 2 weeks of 0.31 (95% CI 0.22–0.40) in the boric acid group. Although the original estimate of 0.5 was excluded from the confidence interval, further sample size calculations assuming, in turn, the limits of this interval to be the true proportion (i.e. 0.22 and 0.40 respectively), showed our original numbers would still be sufficient to provide approximately 80% power to detect an absolute difference of 10% in either of these scenarios. Thus our target sample size seemed compatible with the plausible estimates for the control group resolution rate from our interim analysis. As this calculation did not involve any comparison between the two groups, the overall type 1 error rate is unaffected (Wittes et al. 1999). Statistical methods (analyses) All analyses followed the intention-to-treat principle and were conducted using SAS v8.2 2001. For bilateral disease, resolution and healing were considered to occur when both ears were resolved or healed. We also carried out sensitivity analyses defining bilateral resolution and healing to have occurred when either or both ears resolved or healed. For audiometry readings, a single reading was taken from the diseased ear in unilateral cases, whilst the average across the two ears was calculated for bilateral disease. Hearing threshold was recorded in dBHL and was averaged across the 500 Hz, 1 kHz, 2 kHz and 4 kHz frequency range. For resolution and healing outcomes, ciprofloxacin was compared with boric acid using the relative risk (RR) and 95% confidence interval. We assessed the statistical signi192

ficance using the Pearson’s chi-square statistic. We used logistic regression for resolution at 2 weeks, to assess whether the age of the child, bilateral disease, length of current CSOM episode and degree of perforation at induction affected the relative treatment effect. Results are expressed as odds ratio (OR). For audiometry, analysis of covariance (ancova) was undertaken for hearing threshold, according to the study protocol. The WHO classifications were also used to describe hearing impairment levels and Fisher’s exact test was used consider changes between levels. We report adverse events, notably local symptoms such as pain, irritation or bleeding (for example on mopping), as a secondary outcome. Ethical approval We obtained ethical approval from the Ministries of Education and Health, the Provincial Ethical Review Committee, the Kenyatta National Hospital Institutional Review Board in Kenya, and the Liverpool School of Tropical Medicine Research Ethics Committee in the UK. We received consent for the study from local education and medical staff, from head teachers of the schools, who informed students, and parents. We obtained informed parental consent from eligible children’s legally acceptable representatives. Results We conducted the study in 165 of the 186 Kisumu rural primary schools in the May to August 2002 school term. Twenty-one schools were not reached in the time available. We reviewed 39 266 children at the screening visit, plus an additional 575 children seen at the induction visit. We found eligible children in 141 schools, and randomized a total of 427 children (Figure 1). At the week 4 visit, three subjects in the boric acid group and one in the ciprofloxacin group were seen 1 week late. Seven children received some or all of the wrong treatment because of switching with other participants’ bottles at allocation or during treatment (Figure 1). All participants were analysed in the group they were initially randomized to. The groups were comparable with respect to baseline data (Table 1). Outcomes Resolution of aural discharge is higher with ciprofloxacin at 2 and 4 weeks (Table 2). Sensitivity analyses allowing for varying outcome definition in bilateral disease did not significantly affect the results. The estimated treatment





Assessed for eligibility (n = 39 841*) *39, 266 at screen + 575 at induction

Diagnosed with CSOM (n = 548*) *489 at screen + 59 at induction Children with CSOM not entered trial (n = 121) • Invited but absent at induction (n = 19) • Declined to give consent (n = 2) • Did not meet inclusion criteria (n = 100)* Dry perforation (n = 40) Other diagnoses (n = 19) Other medications (n = 21) Too young (n = 14) Other reasons (n = 22) *16 children met two exclusion criteria Randomised (n = 427)

(n = 216) Allocated to ciprofloxacin • (n = 212) Received cipro only • Received cipro and boric (n = 3) • Received boric only (n = 1)

(n = 211) Allocated to boric acid • Received boric acid only (n = 208) • Received boric and cipro (n = 2) • Received cipro only (n = 1)

Treat 10 schooldays (twice daily) Child to child approach Week 2 follow-up

Week 2 follow-up

Attended

(n = 207)

Attended

Absent but not withdrawn

(n = 3)

Absent but not withdrawn

(n = 2)

Absent and withdrawn at week 2

(n = 6)

Absent and withdrawn at week 2

(n = 5)

• •

Lost to follow-up (n = 5) Consent withdrawn (n = 1)

• •

Week 4 follow-up (n = 200) Attended: Withdrawn at week 2 (n = 6) Absent and withdrawn at week 4 (n = 10) •

Lost to follow -up

(n = 10)

(n = 204)

(n = 5) Lost to follow-up Consent withdrawn (n = 0)

Week 4 follow-up Attended Withdrawn at week 2 Absent and withdrawn at week 4 •

Lost to follow -up

(n = 202) (n = 5) (n = 4)

(n = 4)

Figure 1 Flow of participants through the study.

effect for resolution of discharge did not differ substantially after adjusting for age of the child, bilateral disease, length of current CSOM episode and degree of perforation at induction, using logistic regression: at 2 weeks, the results,


expressed as OR, 95% CI were 3.13, 2.09–4.69 (unadjusted); 3.16, 2.04–4.93 (adjusted); and at 4 weeks were 2.86, 1.91–4.27 (unadjusted); and 2.91, 1.88–4.50 (adjusted). 193




Antibiotic (Cipro)

Antiseptic (Boric)

Characteristic

N*

N*

Total randomized

216

211

Age [mean (SD) (range)]

215

Male [n (%N)]

216

11.0 (3.15) (5.1–19.0) 128 (59)

211 211

11.3 (3.15) (4.1–19.3) 123 (58)

Bilateral [n (%N)]

216

48 (22)

211

58 (27)

Weeks since start of current episode [median (IQR)]

196

8 (4–16)

194

8 (4–20)

Start of current episode [n (%N)] Ear ache Cough or cold Fever Other Not known

216

Any treatment ever received for ear problems [n (%N)]

214

117 (55)

210

122 (58)

Audiometry [mean (SD) (range)]

212

41.0 (13.3) (16.9–100)

209

42.3 (13.4) (11.3–100)

Table 1 Baseline comparison

211 127 (59) 75 (35) 61 (28) 50 (23) 39 (18)

126 (60) 75 (36) 54 (26) 65 (31) 26 (12)

Degree of perforation [n (%N)] Unilateral disease (diseased ear) Small Medium Large Total Bilateral disease (both ears) Both small Both medium Both large Both total One small, one medium One small, one total One medium, one large One large, one total

166

149 28 70 56 11

(17) (42) (34) (7)

47

22 61 56 10

(15) (41) (38) (7)

56 5 (11) 14 (30) 11 (23) 5 (11) 4 (9) 1 (2) 5 (11) 2 (4)

4 (7) 18 (32) 17 (30) 2 (4) 5 (9) 0 8 (14) 2 (4)

* N is the number available or eligible for each characteristic. Table 2 Resolution of aural discharge at 2 and 4 weeks Antibiotic (cipro) [n/N (%)]

Antiseptic (boric)à [n/N (%)]

RR (95% CI)

P-value

Resolution at 2 weeks 1. Both ears resolve 2. Either or both ears resolve

123/207 (59.4) 132/207 (63.8)

65/204 (31.9) 77/202 (38.1)

1.86 (1.48–2.35) 1.67 (1.36–2.05)