Topical Ciprofloxacin for Non‐Perforated Acute Otitis Media: A Randomized Controlled Trial

ABSTRACT

Objective

Acute otitis media is a common pediatric infection and a leading cause of oral antibiotic prescriptions. Topical antibiotics are effective in perforated acute otitis media or tympanostomy tube otorrhea but lack evidence in intact tympanic membrane. This study evaluates adjunctive topical ciprofloxacin ear drops use when added to oral antibiotics in non‐perforated pediatric otitis media.

Methods

This prospective open‐labeled randomized controlled trial was conducted between February 2024 and December 2025 at an outpatient pediatric referral clinic. Ninety children (0–15 years) with acute otitis media and intact tympanic membranes were randomized (45 per group). Combined therapy consisted of topical ciprofloxacin ear drops plus oral amoxicillin‐clavulanic acid. Primary outcomes included time to complete pain resolution, time to fever resolution, and daily pain trajectory (Faces Pain Scale‐Revised). Time‐to‐event outcomes were analyzed according to the intention‐to‐treat principle using Kaplan–Meier methods.

Results

Combination therapy accelerated pain and fever resolution. Median time to sustained pain resolution was 3 days with combined therapy versus 5 days with oral therapy alone (RMST₁₀: 3.29 vs. 5.42 days; log‐rank p < 0.001). Median time to sustained fever resolution was 4 versus 6 days, respectively (RMST₁₀: 4.76 vs. 5.73 days; log‐rank p = 0.033).

Conclusion

Adjunctive topical ciprofloxacin combined with oral antibiotics was associated with faster pain and fever resolution in children with non‐perforated acute otitis media, without increasing adverse events, supporting a potential complementary role. These findings are hypothesis‐generating and require confirmation in larger populations before informing changes in clinical practice.

Level of Evidence

2.

In this prospective randomized controlled trial, we evaluated whether adjunctive topical ciprofloxacin ear drops improve outcomes in children with acute otitis media and intact tympanic membranes. Compared with oral amoxicillin‐clavulanic acid alone, combined therapy significantly accelerated pain and fever resolution while reducing analgesic use without increasing adverse events. Our findings support a potential complementary role for topical ciprofloxacin in selected cases of non‐perforated acute otitis media.

1. Introduction

Acute otitis media (AOM) is one of the most prevalent infections in childhood and a major driver of primary‐care consultations [1]. By 4 years of age, up to 60% of children have experienced at least one episode of AOM, and in many high‐income settings it accounts for a large proportion of antibiotic prescriptions [2, 3]. AOM is preceded by an upper respiratory tract infection, with rapid onset of otalgia, fever, irritability, and transient hearing loss that can affect child well‐being and family burden [4, 5]. Systemic antibiotics are often used early in the course of AOM to relieve symptoms and reduce the small risk of serious complications such as mastoiditis or intracranial infection [6].

AOM develops when inflammation of the nasopharyngeal and middle‐ear mucosa follows a viral upper respiratory infection. Mucosal edema and reduced mucociliary function impair Eustachian tube ventilation, creating negative middle‐ear pressure and allowing sterile fluid to accumulate [7]. Bacteria colonizing the nasopharynx can then enter the middle ear, where poor drainage and the confined bony space promote rapid bacterial growth and an inflammatory response [7, 8].

Clinically, current guidelines recommend high‐dose oral amoxicillin for most children with uncomplicated AOM, while amoxicillin‐clavulanic acid (AMC) is reserved for those with recent amoxicillin exposure or suspected infection with β‐lactamase‐producing pathogens [2, 9]. In practice, antibiotics result in a minimal impact on pain within the first 24 h, provide modest symptom improvement over the next few days, and slightly reduce the occurrence of tympanic membrane perforation and contralateral ear involvement [10]. These clinical gains are, however, weighed against some adverse effects, notably vomiting and diarrhea [10]. These limitations prompted the interest in alternative drug delivery systems aimed at achieving therapeutically effective antimicrobial concentrations within the middle ear while reducing systemic exposure [11].

For children with AOM and tympanic membrane perforation or tympanostomy tubes, the underlying pathophysiology differs, as the membrane defect creates a direct passage from the external auditory canal to the middle ear. In this setting, topical quinolone‐based otic preparations deliver high antibiotic concentrations directly to the infection site with minimal systemic absorption [12, 13]. In children with AOM and otorrhea through tympanostomy tubes, topical ciprofloxacin/dexamethasone was shown to achieve faster resolution of ear discharge, higher clinical cure rates, and fewer adverse effects than oral AMC [14]. This targeted therapy combines antimicrobial and anti‐inflammatory effects to rapidly relieve symptoms while limiting systemic exposure [14].

In children with AOM without tympanic membrane perforation, however, the intact tympanic membrane functions as a barrier to drug penetration into the middle ear [15]. Traditionally, this barrier used to be mechanically breached (e.g., myringotomy) to achieve meaningful middle‐ear drug levels [15, 16]. In contrast, non‐surgical trans‐tympanic systems were shown to deliver antibiotics across an intact membrane, demonstrating that pharmacologically relevant middle‐ear concentrations may be achievable without systemic therapy [17]. Even though the intact tympanic membrane is the principal barrier to local drug delivery into the middle ear, ciprofloxacin may be able to traverse intact membranes and achieve measurable middle‐ear concentrations, providing a biological rationale for topical antimicrobial therapy in cases where the tympanic membrane is not perforated [18, 19]. Despite this rationale, clinical data on the use of standard topical antibiotic ear drops in AOM with an intact tympanic membrane are limited. Their potential role as an adjunct to oral antibiotics, particularly regarding speed of symptom resolution and reduction of systemic side effects, remains, to our knowledge, unexplored. Consequently, there is a gap between advances in understanding of AOM microbiology and middle‐ear drug delivery on one hand, and everyday clinical practice for children with non‐perforated AOM on the other. Oral antibiotics remain the default strategy, although a more localized approach might theoretically enhance symptom control in the middle ear and reduce systemic drug exposure [1, 17].

Therefore, we aim to evaluate the efficacy of combining topical antibiotic ear drops with oral antibiotic therapy in children with AOM without tympanic membrane perforation, compared with oral antibiotics alone. Specifically, we will assess differences in the speed of clinical symptom and fever resolution, pain control, and treatment tolerability. The ultimate aim of this trial is to provide preliminary, hypothesis‐generating evidence on this question, in order to inform the design of larger confirmatory studies.

2. Methods

2.1. Ethics Statement

We obtained ethical approval for this study from the Institutional Review Board (IRB) of Notre Dame des Secours University Hospital on August 1, 2023 (Reference: CR3/2023), prior to the start of enrollment in February 2024. All procedures adhered to the ethical principles of the Declaration of Helsinki. We also obtained parental informed consent for all participating children prior to enrollment. The outcomes and statistical methods reported in this manuscript correspond to those specified in the IRB‐approved study protocol.

2.2. Study Design and Setting

This is a prospective open‐label randomized controlled trial conducted at a tertiary care center with two parallel groups, primarily aiming to evaluate the effectiveness of adding topical ciprofloxacin ear drops to standard systemic therapy for AOM without tympanic membrane perforation. Because the intervention required topical administration, blinding of caregivers and investigators was not feasible. Data collection took place at outpatient general pediatric and pediatric ear, nose, and throat clinics between February 2024 and December 2025. Participants were randomly assigned in a 1:1 ratio to receive either combined therapy (ciprofloxacin ear drops administered to the affected ear with oral AMC) or standard oral therapy alone (oral AMC alone). Group allocation followed block randomization with a block size of 30 (three sequential blocks of 30 participants across the enrollment period), using a computer‐generated sequence. To maintain allocation concealment, the sequence was not released in advance, and the enrolling pediatrician was informed of each participant's assigned group individually, one participant at a time, at the point of enrollment.

Because no prior randomized trial had evaluated adjunctive topical ciprofloxacin plus oral AMC in children with non‐perforated AOM, the sample size assumptions were derived from the closest randomized trial by Dohar et al. which compared topical ciprofloxacin/dexamethasone with oral AMC in children with AOM with tympanostomy‐tube otorrhea and reported higher clinical cure with topical therapy [14]. We selected a topical quinolone without corticosteroid to isolate the potential contribution of local antibacterial therapy, as the aim of the study was a clear assessment of the role of topical antibiotic therapy as an adjunct to systemic treatment.

Assuming a clinically meaningful difference in resolution rates of 85% versus 65%, with a 2‐sided α of 0.05 and 80% power, the minimum required sample size was estimated at 44 participants per group. We enrolled 45 children in each group.

2.3. Inclusion and Exclusion Criteria

Children were eligible for inclusion if they were between 0 and 15 years of age and had a clinical diagnosis of AOM according to the American Academy of Pediatrics criteria, which require a bulging or erythematous tympanic membrane with reduced mobility and an acute onset of symptoms such as otalgia, fever, or irritability [20, 21]. Only children with an intact tympanic membrane and no evidence of perforation were considered, and none could have received systemic or topical antimicrobial therapy within the preceding 72 h. Caregivers had to be able to ensure a 10‐day follow‐up by telephone.

Children with chronic suppurative otitis media, recurrent otitis media with effusion, tympanic membrane perforation, as well as otitis externa were excluded. Children who had a history of ear surgery, had any craniofacial syndromes affecting Eustachian tube function, or a known allergy to beta‐lactams or quinolones were also excluded.

2.4. Data Collection Tools and Procedures

2.4.1. Drug Regimens

Children in the combined‐therapy group received topical ciprofloxacin drops, 3 drops to the affected ear twice for 10 days, in addition to oral AMC 90 mg/kg/day for the amoxicillin component, divided twice daily, for 10 days. Children in the standard oral therapy group received oral AMC at the same dose and duration. All medications were prescribed by the treating physician according to standard weight‐based pediatric dosing.

Analgesic and antipyretic use followed a defined trigger: paracetamol (15 mg/kg every 6 h) and ibuprofen/non‐steroidal anti‐inflammatory drugs (NSAIDs) (10 mg/kg every 8 h) were administered for pain relief or when temperature exceeded 38°C, per standard weight‐based pediatric dosing. Parents recorded daily use of each medication as administered or not administered.

2.4.2. Questionnaire and Monitoring Forms

Diagnosis was established clinically by a general pediatrician using otoscopy. Formal assessment of tympanic membrane motility was not performed.

Data were collected using a 10‐day monitoring booklet completed daily by parents under investigator guidance. All randomized participants completed follow‐up and received their assigned intervention. Efficacy analyses included all randomized participants according to their assigned treatment group, consistent with the intention‐to‐treat principle.

The booklet captured baseline characteristics, including the child's age, sex, birth weight, prematurity status, history of asthma or other chronic conditions, and any previous ear, nose and throat surgeries. Daily pain was then assessed using the Faces Pain Scale‐Revised (FPS‐R) (rated on a scale of 0 to 10), with parents recording the child's pain score each day for the full 10‐day period [22]. We note that the FPS‐R was developed and validated as a child self‐report instrument for approximately ages 4 to 16 years; in this cohort, the majority of participants were younger, and pain was necessarily assessed by parental proxy rather than child self‐report [22]. Temperature was recorded daily by parents using an oral thermometer, as the peak temperature over each 24‐h period. The number of days until fever resolution was also noted.

Parents also recorded all analgesic and antibiotic administration, including the use of NSAID, paracetamol, and adherence to oral AMC as well as ciprofloxacin ear drops if taken. Every 3 days, parents evaluated symptom progression, rating ear tugging, excessive crying, irritability, sleep difficulty, activity or playfulness, appetite changes, and perceived fever as mild, severe, or absent. This checklist corresponds closely to the AOM‐severity of symptom instrument, a validated parent‐reported outcome measure for young children with AOM [23]. Adverse events were documented by checking the presence of vomiting, diarrhea, abdominal pain, bloating, rash, itching, swelling, or otorrhea.

To support accurate reporting, investigators conducted daily phone interviews to verify entries and confirm treatment compliance. When necessary, children were reassessed in the clinic by the senior authors.

2.5. Outcome Measures

The primary outcomes of the study were time to pain resolution, time to fever resolution, and daily pain trajectory as assessed by the FPS‐R scale. Time to pain resolution was defined as the number of days from enrollment to the first day on which the daily pain score reached 0 and remained at 0 through day 10 of follow‐up (sustained resolution). Participants who did not meet this criterion by day 10 were right‐censored at day 10.

Time to fever resolution was defined as the number of days from enrollment to the first day on which the daily peak temperature fell below 37.5°C and remained below that threshold through day 10. Participants who did not meet this criterion by day 10 were right‐censored at day 10. The secondary outcomes included the severity of associated symptoms such as irritability, ear tugging, crying, sleep difficulty, and appetite changes, the incidence of adverse events involving gastrointestinal, dermatologic, or local ear reactions, as well as the need for medical re‐evaluation or escalation of therapy.

2.6. Statistical Analysis

Collected data were entered into Microsoft Excel, verified for completeness and consistency, and analyzed using SPSS v26.0. We generated descriptive statistics for baseline and outcome variables. Then, we summarized categorical data as counts and percentages, and continuous variables as mean ± standard deviation (SD). We examined the distribution of continuous variables by calculating skewness and kurtosis coefficients, considering values ranging between −1 and +1 of acceptable univariate normality.

We compared baseline characteristics between groups using independent‐samples Student's t‐tests for normally distributed continuous variables. When homogeneity of variances was violated, we used Welch's t‐test [24]. For non‐normally distributed continuous variables, we applied the Mann–Whitney U test [25]. Categorical variables were compared using Pearson's chi‐square test or Fisher's exact test, as appropriate.

We analyzed the primary time‐to‐event outcomes using Kaplan–Meier estimation with the event and censoring definitions specified above. All 90 randomized participants were included and analyzed according to their originally assigned treatment group, consistent with the intention‐to‐treat principle. Because no participant crossed over, discontinued treatment, or was lost to follow‐up, the intention‐to‐treat and per‐protocol populations were numerically identical (n = 45 per group). Participants who had not experienced the corresponding event by day 10 were retained in the analysis as administratively right‐censored observations. We reported Kaplan–Meier median resolution times, restricted mean survival time through day 10 (RMST₁₀), log‐rank tests for between‐group comparisons, and day‐by‐day numbers at risk, events, and censored observations.

Daily pain trajectories, symptom scores, and analgesic use patterns were evaluated using mixed‐effects longitudinal models. Daily proportions requiring antalgics were compared using chi‐square tests. Adverse event incidence was compared using Fisher's exact tests. Statistical significance was set at p < 0.05.

3. Results

3.1. Study Population

A total of 90 children had unilateral AOM meeting all predefined inclusion and exclusion criteria. All of these were randomized and analyzed to their assigned treatment group (intention‐to‐treat population, n = 45 per group). No participant was excluded after randomization, crossed over to the other treatment group, discontinued the assigned intervention, or was lost to follow‐up. Therefore, the intention‐to‐treat and per‐protocol populations were identical. None of these enrolled participants had asthma, chronic systemic disease, previous ENT surgery, or craniofacial abnormalities known to predispose to recurrent AOM, and therefore baseline health status was globally comparable between both study groups. Of the 90 children, 45 received combined therapy with oral AMC plus topical ciprofloxacin, and 45 received oral AMC alone (Figure 1).

FIGURE 1.

CONSORT flow diagram of formally assessed and randomized study participants.

The mean age was 26.0 ± 21.4 months (range 4–108 months), with no significant difference between groups (26.1 ± 21.3 vs. 26.0 ± 21.9 months, respectively, p = 0.99). A total of 53.3% were male, with similar sex distribution between groups. Baseline demographic and clinical characteristics were comparable between groups, including age, sex distribution, prematurity status, and baseline pain score (6.4 ± 2.8 vs. 5.9 ± 3.0, p = 0.43). Mean baseline FPS‐R pain scores were 6.4 ± 2.8 in the combined‐therapy group and 5.9 ± 3.0 in the oral‐therapy‐alone group (p = 0.43). Mean baseline peak temperature was 38.6°C ± 0.5°C and 38.9°C ± 0.7°C, respectively (p = 0.01) (Table 1).

TABLE 1.

Sociodemographic and baseline clinical characteristics.

	Combined therapy (n = 45)	Oral therapy alone (n = 45)	Total (n = 90)	p
Sociodemographic variables
Age (months), mean ± SD	26.1 ± 21.3	26.0 ± 21.9	26.0 ± 21.4	0.99
Male sex, n (%)	25 (55.6%)	23 (51.1%)	48 (53.3%)	0.83
Clinical baseline variables
Weight (kg), mean ± SD	13.1 ± 4.0	12.9 ± 5.4	13.0 ± 4.7	0.83
Baseline pain score (FPS‐R, day 1), mean ± SD	6.4 ± 2.8	5.9 ± 3.0	6.2 ± 2.9	0.43
Baseline peak temperature (°C, day 1), mean ± SD	38.6 ± 0.5	38.9 ± 0.7	38.7 ± 0.6	0.01

Regarding baseline illness severity, 21 of 45 children (46.7%) in the combined‐therapy group and 20 of 45 (44.4%) in the oral‐therapy‐alone group presented with severe pain, defined as an FPS‐R score ≥ 8/10. In contrast, high fever (≥ 39°C) was present in 10 of 45 children (22.2%) in the combined‐therapy group compared with 26 of 45 (57.8%) in the oral‐therapy‐alone group, indicating an imbalance in baseline fever severity between treatment groups.

3.2. Pain Evolution and Time to Resolution

Pain scores were similar between groups on day 1 but differed significantly thereafter. Starting day 2, children receiving combination therapy had consistently lower mean FPS‐R pain scores compared with those receiving oral therapy alone, with the greatest differences observed between days 3 and 5 (all p < 0.001). Time to sustained pain resolution was analyzed using Kaplan–Meier methods. Sustained pain resolution occurred earlier in the combined‐therapy group, with a median time to resolution of 3 days compared with 5 days in the oral‐therapy‐alone group. RMST₁₀ was 3.29 days in the combined‐therapy group and 5.42 days in the oral‐therapy‐alone group (Table 2). The Kaplan–Meier distributions differed significantly between treatment groups (log‐rank p < 0.001) (Figure 2).

TABLE 2.

Time‐to‐event analysis of sustained pain and fever resolution.

Outcome	Combined therapy (n = 45)	Oral therapy alone (n = 45)	RMST10 difference a	p
Sustained pain resolution	Median, 3 days; RMST10, 3.29 days; 45 events, 0 censored	Median, 5 days; RMST10, 5.42 days; 42 events, 3 censored (6.7%)	−2.13 days	< 0.001
Sustained fever resolution	Median, 4 days; RMST10, 4.76 days; 44 events, 1 censored (2.2%)	Median, 6 days; RMST10, 5.73 days; 43 events, 2 censored (4.4%)	−0.97 days	0.033

^a RMST₁₀ difference = combined therapy minus oral therapy alone; negative values indicate a shorter average time without sustained symptom resolution in the combined‐therapy group.

FIGURE 2.

Kaplan–Meier curves for time to complete pain resolution and time to fever normalization.

All 45 participants receiving combined therapy achieved sustained pain resolution during the 10‐day follow‐up. In the oral‐therapy‐alone group, 42 of 45 participants achieved sustained pain resolution, whereas 3 participants (6.7%) had not met the sustained‐resolution criterion by day 10 and were administratively right‐censored at that time. By day 4, 42 of 45 children (93.3%) in the combined‐therapy group had achieved sustained pain resolution compared with 19 of 45 (42.2%) in the oral‐therapy‐alone group. Day‐by‐day numbers at risk, events, and censored observations are presented in Table S1.

3.3. Fever Resolution

Despite the small but statistically significant baseline temperature difference between groups (Table 1), both groups met identical diagnostic criteria for febrile AOM, and the absolute difference was only 0.3°C.

Fever normalization occurred earlier in children receiving combined therapy. The median time to sustained fever resolution was 4 days in the combined‐therapy group compared with 6 days in the oral‐therapy‐alone group. RMST₁₀ was 4.76 and 5.73 days, respectively, and the Kaplan–Meier distributions differed significantly between treatment groups (log‐rank p = 0.033) (Figure 2).

Of the 45 participants receiving combined therapy, 44 achieved sustained fever resolution during follow‐up, while 1 participant (2.2%) had not achieved sustained resolution by day 10 and was administratively right‐censored. In the oral‐therapy‐alone group, 43 of 45 participants achieved sustained fever resolution, while 2 participants (4.4%) were censored at day 10. Day‐by‐day numbers at risk, events, and censored observations are reported in Table S1.

3.4. Analgesic Use

Analgesic consumption decreased more rapidly in the combination group. Mixed‐effects longitudinal modeling demonstrated significant group‐by‐time interactions for both NSAID (p = 0.007) and paracetamol (p = 0.017), indicating a faster reduction in symptomatic medication requirements among children receiving adjunctive topical therapy (Figure 3).

FIGURE 3.

Daily proportion of children requiring non‐steroidal anti‐inflammatory drugs and paracetamol during 10‐day follow‐up.

Although complete cessation of antipyretics converged toward the end of follow‐up in both groups, cumulative exposure and longitudinal trajectory analyses confirmed a significantly lower symptomatic medication burden in the combination group. Analgesic use in both declined to zero by day 8.

3.5. Adverse Events

No serious adverse events were reported in either group. Minor gastrointestinal or dermatologic symptoms were infrequent and comparable between groups (Table 3). No cases required treatment escalation or resulted in tympanic membrane perforation.

TABLE 3.

Adverse events during the 10‐day follow‐up.

Adverse event	Combined therapy (n = 45)	Oral therapy alone (n = 45)	p
Diarrhea/vomiting	18 (40%)	22 (48.9%)	0.525
Rash, itching and/or swelling	0 (0%)	7 (15.6%)	0.012
Ear itching	5 (11.1%)	3 (6.7%)	0.714

4. Discussion

In this randomized controlled trial, adjunctive topical ciprofloxacin accelerated pain and fever resolution in children with AOM and intact tympanic membranes. To our knowledge, it represents one of the first evaluations of topical antibiotics as adjuncts in non‐perforated AOM [1]. Our findings demonstrate that combining topical ciprofloxacin ear drops with oral AMC led to faster recovery in terms of pain and fever resolution and reduced analgesic needs.

Children receiving combined topical ciprofloxacin and oral AMC achieved faster pain resolution in our exploratory trial. This aligns with the results of Dohar et al. who reported a shorter median time to cessation of otorrhea with topical ciprofloxacin/dexamethasone compared with oral AMC in children with AOM and tympanostomy tubes, along with higher cure rates [14]. The biological plausibility and mechanism underlying this observation cannot be determined from this study, which did not include pharmacokinetic or microbiological sampling of the middle ear. Prior ex vivo and formulation work demonstrated that quinolone antibiotics can cross the tympanic membrane under experimental conditions and that topical ciprofloxacin/dexamethasone improves outcomes in AOM with tympanostomy‐tube otorrhea, which motivated our hypothesis [17, 18].

Fever normalized faster in the combination group, with lower temperatures during follow‐up compared with the oral‐only controls. Although a small statistically significant baseline difference of approximately 0.3°C was noted between groups at day 1, this difference was modest and unlikely to account for the sustained divergence in fever trajectories over subsequent days. This more rapid normalization is biologically reasonable. Fever in AOM reflects systemic cytokine release triggered by middle‐ear bacterial proliferation and local inflammation [26]. Effective antimicrobial therapy reduces bacterial load, which in turn suppresses pro‐inflammatory mediators, leading to earlier fever normalization [27]. Adjunctive topical ciprofloxacin may enhance this process by achieving high local concentrations at the tympanic membrane‐middle ear interface [28]. An interesting contrast is provided by Hullegie et al. who reported lower earlier resolution fever with topical antibiotic‐corticosteroid eardrops compared with oral antibiotics in children with AOM and ear discharge [1]. This could be explained by the fact that, in contrast to ours, Hullegie et al. study evaluated topical therapy as a replacement for systemic treatment in perforated AOM and was prematurely terminated with a small sample size [1].

Moreover, while cumulative NSAID dose, mean daily use, and mixed‐effects longitudinal trajectories were lower in the combination group, Kaplan–Meier analysis for complete cessation of NSAIDs was not statistically significant. This could be explained by the parental behaviors in managing their children. Caregivers frequently administer antipyretics prophylactically and continue them even when the fever subsides, partly in order to avert potential symptom recurrence [29, 30]. Additionally, adherence to fixed dosing as prescribed by clinicians, including nighttime administration despite clinical improvement, prolongs analgesic exposure beyond the point of therapeutic need [31].

Adverse events were minor and comparable between groups and no serious events were noted. Minor gastrointestinal symptoms were common in both groups, consistent with the known side‐effect profile of systemic AMC [32]. No cases required treatment escalation, and no tympanic membrane perforations occurred during follow‐up, suggesting that the addition of topical therapy does not increase systemic adverse events [31, 33]. However, the trial was not powered for formal safety‐equivalence testing, and these findings should not be interpreted as evidence of equivalent safety between the two regimens.

4.1. Clinical Implications

Adjunctive topical ciprofloxacin ear drops with oral AMC were associated with earlier symptomatic recovery in children with non‐perforated AOM, particularly with respect to pain resolution and reduced analgesic requirements. Although topical antibiotics are currently used primarily for cases with tympanic membrane perforation or tympanostomy tubes, our exploratory findings suggest that adjunctive topical therapy in selected non‐perforated cases warrants further investigation. These findings should not be interpreted as supporting changes in current treatment guidelines, shorter systemic antibiotic courses, or antibiotic‐stewardship strategies. This single‐center trial was exploratory, and its sample size and design were not intended to establish such clinical recommendations.

The precise mechanism remains to be confirmed experimentally, as middle‐ear drug concentrations and microbiological outcomes were not assessed. Thus, future studies should incorporate validated age‐appropriate symptom measures, microbiological endpoints, middle‐ear fluid sampling where feasible, and short‐ and long‐term recurrence assessment to determine whether adjunctive topical ciprofloxacin has a reproducible clinical role in non‐perforated AOM.

4.2. Limitations

This study presents a few limitations. Pain was assessed using a parent‐completed rating adapted from the FPS‐R, a scale validated for child self‐report from approximately age 4 years. Given that the majority of the participants were younger than 4 years, pain scores reflect parental proxy assessment rather than validated child self‐report for most participants. Additionally, the single‐center outpatient setting may limit generalizability, while the absence of tympanocentesis prevents microbiological confirmation of pathogens, potentially masking variability in treatment response by etiology. Residual confounding may persist despite randomization as there was a slight difference in baseline temperature (0.3°C), although other baseline characteristics were well matched. Formal assessment of tympanic membrane motility was not performed, and the proposed mechanism of trans‐tympanic drug penetration, inferred from previous experimental studies, was not directly evaluated. In addition, a history of previous episodes of AOM was not prospectively collected and therefore could not be compared between treatment groups. Finally, the trial was not prospectively registered in a public clinical‐trials registry, despite prospective IRB approval and the existence of an approved study protocol before enrollment.

5. Conclusion

In conclusion, this study showed that adjunctive topical ciprofloxacin ear drops combined with oral amoxicillin‐clavulanic acid were associated with faster pain and fever resolution in children with acute otitis media and intact tympanic membranes without increasing adverse events. These findings support further evaluation of adjunctive topical therapy as a potential complementary approach in selected non‐perforated cases. Larger trials incorporating microbiological endpoints are warranted to confirm these findings and better define the clinical role of this therapeutic approach.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Numbers at risk, events, and censoring for sustained pain and fever resolution during the 10‐day follow‐up.

Ghadban E., Boutros T., Romani D., and Dunya G., “Topical Ciprofloxacin for Non‐Perforated Acute Otitis Media: A Randomized Controlled Trial,” Laryngoscope Investigative Otolaryngology 11, no. 5 (2026): e70612, 10.1002/lio2.70612.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.