Treatment of acute otitis externa with ciprofloxacin otic 0.2% antibiotic ear solution.

BACKGROUND/
OBJECTIVE: An inflammation of the cutis and subcutis of the external auditory canal is a primary symptom in cases of acute otitis externa. It is usually treated locally, since this type of therapy ensures a high concentration of the drug and interacts at the site of inflammation with no systemic effects. This systematic review compares the efficacy of treatment using a ciprofloxacin 0.2% solution with other therapeutic options.
METHODS: After compiling a catalog of search terms, medical databases were searched systematically for randomized, controlled studies. This search initially yielded a total of 38 studies which were then evaluated by three independent reviewers. The number of studies was subsequently reduced to 14: six studies using a ciprofloxacin 0.2% solution, and eight studies using both 0.2% and 0.3% solutions.
RESULTS: The studies included in the review demonstrate the statistical equivalence between the ciprofloxacin solution (0.2%) and the reference products PNH (a combination of polymyxin B, neomycin sulfate and hydrocortisone), auriculum powder, and a ciprofloxacin foam with respect to the cure rate. The research groups consistently observed high in vitro activity of ciprofloxacin against Pseudomonas aeruginosa.
CONCLUSION: This systematic review confirms the hypothesis of ciprofloxacin's noninferiority in the treatment of otitis externa, in terms of the cure rate and microbiological eradication.

Introduction

Otitis externa

Inflammation of the cutis and subcutis of the external auditory canal is a primary symptom in acute otitis externa. An affected pinna can be a secondary symptom. Occasionally, the eardrum can also be inflamed.1 Inflammation of the ear can occur in an acute and a chronic form. In some cases, the clinical picture develops to a necrotizing stage. Statistically, one in ten people suffers at least once in his life from otitis externa. In 10% of cases, the inflammation is bilateral.2 Currently, many different therapies are applied to ease the symptoms. The purpose of this review is to compare the efficacy of ciprofloxacin 0.2% antibiotic ear solution with other treatment options.

General etiology

An intact auditory canal possesses the ability to cleanse itself by migrating the sloughed epithelia cells outwards with cerumen. The main function of cerumen is to protect the membrane that lines the auditory canal against inflammation. Cerumen maintains the soft consistency of the membrane and also ensures water resistance. Whether it also has an antimicrobial effect has not yet been clarified. If the cerumen is pushed from the outer part of the auditory canal toward the eardrum using a cotton swab, its effectiveness is lowered. Should bacteria then enter the ear canal, the risk of progressive bacterial growth increases. This can occur particularly in swimming pools, which is why the term “swimmer’s ear” is commonly used.3

Likewise, congenital or acquired anatomical anomalies (eg, narrow passages), the use of hearing aids, or the aforementioned radical ear and ear canal hygiene with the complete removal of cerumen or drainage can destabilize the sensitive environment and thus predispose the external auditory canal to inflammation.1

Pathogens

The pH of the external auditory canal varies between 5.0 and 5.7 and is therefore slightly acidic. Such conditions inhibit bacterial growth.1 In 1981, Brook examined the physiological, normal flora of the external auditory canal in pediatric patients. In descending order of concentration, colonization with aerobes such as Staphylococcus epidermidis, diphtheroid species, and a-hemolyzing streptococci as well as anaerobes such as propionibacterium acnes, was observed. Pseudomonas aeruginosa and Staphylococcus aureus act pathogenically against such flora and are cited in the technical literature as the main causative organisms. Sporadically, viruses and fungi can also cause otitis externa.1,4

Clinical picture

Bacterial otitis externa in its mild form can be accompanied by only minor pain and subdued swelling. In its severe form, however, the symptoms are associated with excruciating pain, otorrhea, and the complete closure of the external auditory canal. The result is conductive deafness.1

Apart from the typical acute form of otitis externa, special forms can appear such as otitis externa circumscripta, which emanates from a hair follicle inflammation, or otitis externa necroticans (“maligna”), which can take a fulminant course and therefore requires maximum, usually intravenous treatment.1,5

In the majority of published clinical studies on the treatment of otitis externa, pain, swelling, otorrhea, and redness are evaluated as typical parameters for rating the clinical signs.

Therapy

Otitis externa is usually treated locally.1 Ototoxic antibiotics such as aminoglycosides should not be applied in patients with a perforated tympanic membrane. If an antibiogram has been made, the optimum antibiotic otologic drug can be determined. If none is available, “calculated antibiosis” is recommended, ie, a drug is used that is effective against the two most common pathogens S. aureus and P. aeruginosa.6 Individual decisions must be made in case of resistance. Often, an antiseptic ingredient such as aluminium acetate/ acetic acid is added to the antibiotic. Due to their acidic properties, these substances are especially suitable for lowering the pH value in the auditory canal, so that the main pathogens P. aeruginosa and S. aureus, which reach their optimal pH between 6.5 and 7.3, do not obtain perfect growing conditions or, in an ideal case, are killed.1,7

For years, glucosteroids had the reputation of primarily reducing the swelling of the auditory canal. Newer studies, however, also ascribe to them antibacterial and antifungal effects in otitis externa. Yet the number of available studies on steroidal monotherapies is still rather low.5

Nonsteroidal anti-inflammatory drugs should also be administered for pain relief.1

Ciprofloxacin

Ciprofloxacin is a synthetic antibiotic with a broad spectrum of activity and has the chemical formula C17H18FN3O3. Belonging to the group of fluoroquinolones (gyrase inhibitors), it acts as a bactericide particularly against gram-negative pathogens by inhibiting DNA replication (topoisomerase II) and interfering in the enzymatic activity of topoisomerase IV, both of which are required for the bacteria’s cell division, transcription, repair, and recombination. It is moderately effective against gram-positive pathogens, while it shows no relevant activity against fungi or parasites.8

In 75% of cases, ciprofloxacin is eliminated unchanged by renal excretion. It is also metabolized through the liver and eliminated through bile and is thus subject to enterohepatic circulation.8 Ciprofloxacin ranks among the most effective fluoroquinolones against P. aeruginosa and can also show very high in vitro activity against enterobacteria and Haemophilus influenzae. Being the only antibiotic available for oral treatment of infections caused by P. aeruginosa, it is administered in particular to treat chronic purulent otitis media, and can be applied locally and systemically to treat acute otitis externa.9

Ciprofloxacin constitutes the drug of choice for treating severe otitis externa in children and adolescents as it has been the subject of extensive investigation and is available in syrup form.10

Besides its systemic effect, ciprofloxacin is used more often topically for its local effects in the form of eye or ear drops. This fluoroquinolone thereby possesses a very broad spectrum of indications which range from complicated urinary tract infections, infections of the respiratory system, skin and bones, to severe typhoid salmonella infections, or bacterial conjunctivitis. Known side effects include gastrointestinal complaints (nausea, diarrhea, dyspepsia), disorders of the central nervous system (headache, nervousness/restlessness, dizziness, tremor, hyposmia), and skin irritations and eosinophilia.11

The undesirable effects of systemic treatment can be largely avoided through topical administration, however. A high local concentration is in fact attained, yet resorption does not occur. Therefore, itching or burning at the application site or superinfections of the ear can arise due to robust pathogens. Allergic reactions occur very rarely.10 Systemic side effects of local application occasionally include dizziness and headache.

Materials and methods

Search methods used to identify studies

The electronic databases Cochrane Ear, Nose and Throat Disorders Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE, EMBASE, and Web of Science were systematically searched for randomized, controlled studies. Using MeSH, a search term catalog was compiled with the following terms that were then entered in combinations: external ear, inflammation of the external ear, acute otitis externa, quinolone, ciprofloxacin 0.2%, ciprofloxacin, solution, ear drops, drug therapy, anti-bacterial agents, antifungal, antibiotics.

Restrictions with respect to language, publication date, or publication status were not initially made. This review was also limited to published work. The last search was started on 1 March 2011.

Patients

Patients (both children and adults) with the diagnosis of acute otitis externa were included in the review. Not included were patients who suffered from a chronic form of external otitis or otitis media.

Parameters

Symptom improvement and microbiological eradication were defined as primary outcome parameters. Time to complete disappearance of symptoms and any side effects were observed as further aspects.

Search results

Thirty-eight studies satisfied our search criteria, and we examined the abstracts of these. When this process was completed, the number of suitable studies decreased to 36; we then worked through their full texts (Figure 1). After three reviewers came to a consensus concerning further eliminations, six and eight studies, respectively, were available for this systematic review (Table 1).12–19

Figure 1

Flow chart.

Table 1

Eligibility criteria (included studies)

Study ID	Study type	Blinding	Randomization groups	# Participants	Inclusion criteria	Exclusion criteria
Pistorius et al17	Equivalence study	No blinding	3-arm study; Group A (ciprofloxacin), Group B (ciprofloxacin + hydrocortisone), Group C (PNH)	842; 702 available for analysis (Group A: n = 239, Group B: n = 236, Group C: n = 228)	Patients >1 yearClinical signs and symptoms of external otitis within 2 days of study entry, including edema of the external auditory canal on otoscopic examination, tenderness with movement of the pinna, and ostalgia	Perforated tympanic membrane; acute otitis media; invasive malignant chronic otitis externa; dermatitis in the area of the affected ear; recent diagnosis and treatment of otitis externa (within 30 days of study entry); known fungal infection of the ear; furuncles; mastoiditis; stenosis; exostosis; tumors of the ear; significant underlying disease, including diabetes mellitus, or other immunocompromised conditions; pregnancy or lactation; allergy to carboxyquinolones, polymyxin B sulfate, neomycin sulfate, or hydrocortisone; administration of another investigational drug within 30 days of study enrolment; or previous enrolment in this study
Arnes and Dibb12	Equivalence study		2-arm study; Group A (ciprofloxacin), Group B (Terra-Cortril polymyxin B)	30Group A: n = 16Group B: n = 14	Patients ≥18 years of ageDiagnosis of otitis externa by an otorhinolaryngological practice	Pregnancy, use of systemic antimicrobial therapy, overt fungal ear infection, perforated eardrum, history of middle ear surgery, allergy to quinolone derivatives.
Roland et al19	Equivalence study (statistical noninferiority)	Observer blinded	2-arm study; Group A (ciprofloxacin + hydrocortisone), Group B (PNH + amoxicillin)	206Group A: n = 106Group B: n = 100	Patients >1 yearDiagnosis of mild, moderate or severe AOESeverity of symptoms at least “mild”AOE symptoms present >2 daysRefrain from water immersion of ear during studyGive informed consentAgree to comply with protocol requirements	AOE symptoms present <2 daysNon-intact tympanic membrane, with or without otorrheaAcute otitis media, malignant otitis externa, CSOM, mastoiditis, seborrheic dermatitis of the external auditory canal, or other suppurative noninfectious disease disordersKnown or suspected fungal, viral, or mycobacterium ear infection Diabetes, immunosuppressive disorder, renal disease, hepatitis, mononucleosis, chronic diarrhea, narcotic abuseConcomitant use of ear washes, systemic antibiotic agents, steroids, analgesics other than acetaminophen, and any preparation that might obscure study designKnown or suspected allergy to any component of study medication(s).
Drehobl et al13	Non-inferiority	Evaluator-blind	2-arm study; Group A: ciprofloxacinGroup B: PNH	628Group A: n = 319Group B: n = 309	Patients >1 year, diagnosis of acute diffuse otitis externa of <3 weeks’ duration, at least a score of 2 (moderate severity) for the symptoms otalgia, edema of the external auditory canal on otoscopic examination, and a score of at least 1 (mild severity) for the symptom otorrhea	Treatment with any investigational drug or quinolone antibiotic in the preceding 30 days; use of topical or systemic antibiotics in the preceding 7 days; use of any medication for treatment of otitis externa or otitis media in the preceding 36 hours; seborrheic dermatitis of the external auditory canal; chronic otitis externa or otorrhea of 3 weeks’ duration; known fungal infection of the ear; mastoid disease or mastoid surgery (within 60 days of study entry); tympanostomy tubes currently in place or removed within 3 months of study entry; known perforation of the eardrum or perforation within 6 months of study entry; known significant underlying disease, including diabetes mellitus, human immunodeficiency virus infection or other immunocompromised conditions; known hypersensitivity to any component of the study medications; pregnancy or lactation; previous enrolment in this study; or any other condition that might interfere with participation in the study.
Lildholdt et al15	Equivalence study	No blinding	3-arm study; Group A: ciprofloxacinGroup B: ciprofloxacin + hydrocortisoneGroup C: PNH	838	Patients with clinical signs and symptoms of acute, diffuse external otitis
Psifidis et al18	Equivalence study	No blinding	3-arm study; Group A: PNHGroup B: ciprofloxacin + hydrocortisoneGroup C: ciprofloxacin	91Group A: 32Group B: 29Group C: 30	Patients ≥18 years, external otitis for a duration of ≤3 weeks
Goldenberg et al14	Equivalence study	No blinding	3-arm study; Group A (auricularum powder), Group B (ciprofloxacin), Group C (tobramycin)	120Group A: n = 40Group B: n = 40Group C: n = 40	Patients ≥18 years, AEO diagnosed by an otolaryngologist, signed informed consent	Prior treatment with other drops or systemic antibiotics, sensitivity to any of the drugs used or their contents, or perforation of the tympanic membrane. All patients were instructed to avoid moisture and wetness of the ear during the course of their treatment.
Marom et al16	Equivalence study	Open-label	2-arm study; Group A: ciprofloxacin as foamGroup B: ciprofloxacin as solution	63Group A: n = 32Group B: n = 31	Adult men and nonpregnant, nonlactating women (≥18 years) diagnosed with unilateral AOE lasting <3 weeks of presumably bacterial origin (on the basis of otoscopy findings), pinna or tragal tenderness and an intact tympanic membrane	Known allergy to quinolones; topical or oral antibiotic therapy treatment up to 3 days before enrolment or treatment with long-acting antibiotics up to 7 days before enrolment; AOE from presumed fungal origin; ≥80% occlusion of the EAC; concurrent infection requiring systemic antimicrobial therapy; history of diabetes mellitus or immune dysfunction or current immunosuppressive therapy; seborrheic dermatitis or other dermatological disorders of the EAC; congenital abnormalities of the EAC or obstructive bony exostosis, mastoid, or other suppurative noninfectious ear disorder; presence of middle ear effusion; EAC abnormal otoscopy findings (such as abscess, polyp, or granulation tissue); any serious underlying disease; previous AOE within 30 days before enrolment; and participation in a study with investigational drug or device within 30 days before enrolment. Data were collected on age, gender, and medical and surgical history.

Abbreviations: AOE, acute otis externa; EAC, external auditory canal; CSOM, chronic suppurative otitis media.

We were denied access to the full text of two of these eight randomized controlled trials. The comprehensive publication by Lildholdt et al15 and the text by Psifidis et al18 could not be requested, which is why detailed data are missing.

Unpublished studies were not considered in this systematic review.

Background (included studies)

Treatment doses

Besides six studies that investigated a 0.2% ciprofloxacin drug, we also included two more studies that used a 0.3% ciprofloxacin product (Table 2).14,16

Table 2

Study design (included studies)

Study ID	Medications	Duration and dose	Primary endpoint	Secondary parameters	Safety
Pistorius et al17	Group A: Ciprofloxacin otic drops as hydrochloride monohydrate (0.2%)Group B: Ciprofloxacin otic drops as hydrochloride monohydrate (0.2%) plus hydrocortisone (0.1%)Group C: combination of Polymyxin B (10.000 U), neomycin sulfate (3.5 mg/mL) and hydrocortisone (0.1%)	7 daysGroup A: 3 drops twice dailyGroup B: 3 drops twice dailyGroup C: 3 drops 3 times a day (<13 years of age) or 4 drops (>13 years of age)	Clinical success (resolution or improvement of symptoms) at the end of therapy (Day 10–17)	Antimicrobial effectiveness (microbiological eradication) at the end of therapy (Day 10–17)Time until ear pain disappeared completely via visual analog scale	Medication-related adverse events
Arnes and Dibb12	Group A: Ciprofloxacin (0.2%) as ear dropsGroup B: drops containing oxytetracycline (5 mg/mL) polymyxin B (10,000 units/mL) and hydrocortisone (15 mg/mL)	7 daysGroup A: 2–3 drops twice dailyGroup B: 2–3 drops twice daily	Clinical success (complete resolution, marked improvement, slight improvement, failure, or indeterminate) at the end of therapy (Day 8)	Bacteriological assessment (eradication, persistence, recurrence, superinfection)Individual (investigator’s) assessment (completely successful, partially successful, unsuccessful, indeterminate)	Clinical side effects (adverse events)
Roland et al19	Group A: Otic solution consisting of ciprofloxacin and hydrocortisoneGroup B: Combination of PNH (polymyxin B/neomycin/ hydrocortisone) plus the antibiotic amoxicillin	Group A: 7 days, 3 drops twice dailyGroup B: 10 days, 2 drops 3 times a day (<17 years of age) or 4 drops 3 times a day (>17 years of age)	Clinical success/response to therapy (resolution) after treatment ended (Group A: Day 8, Group B: Day 11)	Microbiological eradication after treatment ended (percentage of patients with resolution of disease-specific infection)Time to end of pain Symptom severity (4-point scale for otalgia and tenderness)	Adverse events or serious adverse events
Drehobl et al13	Group A: Cetraxal (ciprofloxacin otic solution 0.2%)Group B: PNH otic solution; neomycin sulfate (3.5 mg/mL neomycin base), polymyxin B (10 000 U) and hydrocortisone (1%)	7 daysGroup A: 1 vial twice daily (morning and evening)Group B: 4 drops 3 times daily (for patients >13 years of age) or 3 drops (for patients <13 years of age) (morning, afternoon, evening)	Clinical success (proportion of patients with clinical cure) after follow-up period (day 15–17).Clinical cure was defined as a score of 0 for otalgia, edema, and otorrhea	Clinical success (proportion of patients with clinical cure) at the end of treatment (Day 8–10)Clinical improvement (defined as a score of 0 or 1 for otalgia, edema, and otorrhea), resolution of otalgia, and clinical + microbiologic cure at the end of treatment and after the follow-up period	Drug-related adverse events
Lildholdt et al15	Group A: Ciprofloxacin (0.2%) otic solutionGroup B: Combination of ciprofloxacin (0.2%) otic solution and hydrocortisone (0.1%)Group C: Suspension of polymyxin B-neomycin sulfate (3.5 mg/mL)-hydrocortisone (1%)	7 daysGroup A: 3 drops twice dailyGroup B: 3 drops twice dailyGroup C: 4 drops 3 times a day	Clinical success (resolution or improvement) maintained at follow-up about 3 weeks later	Median time to end of ear painEvaluation of ear cultures
Psifidis et al18	Group A: Combination of polymyxin B (10,000 U/mL), neomycin (3.5 mg/mL), and hydrocortisone (10 mg/mL)Group B: Combination of 0.2% ciprofloxacin (2 mg/mL) and hydrocortisone (10 mg/mL)Group C: Ciprofloxacin (0.2%) alone	7 daysGroup A: 3 drops 3 times dailyGroup B: 3 drops twice dailyGroup C: 3 drops twice daily	Clinical success (complete resolution of external otitis) at the end of the follow-up period (Day 21–35)	Microbiological effectiveness (eradication, persistence, superinfection)	Adverse events
Goldenberg et al14	Group A: Auricularum powder (dexamethasone 10 mg, oxytetracycline HCl 90,000 U, polymyxin B sulfate 100,000 U, nystatin 1,000,000 U; Trima, Serolam Laboratories, Germany)Group B: Ciprofloxacin 0.3% (Ciloxan, Alcon Laboratories, Fort Worth, TX)Group C: Tobramycin (Tobrex, Alcon Laboratories)	14 daysGroup A: 1 application twice dailyGroup B: 3 times a dayGroup C: 3 times a day	Clinical success (rate of cure) at Day 3–4 after initial treatment	Clinical success (rate of cure) at Day 14Microbiological effectiveness	Adverse events
Marom et al16	Group A: Foam Otic Cipro, 0.3% ciprofloxacin foam-based formulationGroup B: Ciloxan, 0.3% solution-based ciprofloxacin	7 daysGroup A: One application twice dailyGroup B: 4 drops twice daily	Clinical response/cure defined as resolution (absence of AOE-related signs and symptoms) or improvement (presence of AOE-related minor signs or symptoms, with no further therapy required) at the end of therapy (Day 8–14)	Otorrhea cessationPain relief	Adverse events

Abbreviation: AOE, acute otis externa.

The ciprofloxacin dose of the ear solutions used in the individual studies was comparable. The majority planned a 7-day application phase, during which the study participants applied three drops to each ear twice daily. Marom et al16 raised the dose to four drops (0.3% ciprofloxacin), and Goldenberg et al14 doubled the application period to 2 weeks. The exact dose remains unclear in the study by Drehobl et al13 in which the study period was also 7 days, with applications twice daily, but the study specified the dose as ampoule (“vial”) rather than stating the number of drops.

Outcomes assessed

Clinical response

Clinical success was, in part, classified differently and measured at various points in times (Table 2). In addition, the definition of treatment success varied slightly among the studies. Some studies defined clinical success as complete recovery (resolution) with complete freedom from symptoms. In others, it included mild symptoms, but a distinct improvement from the initial value. In principle, the symptoms and signs typical for the disease and used in the evaluation were similar. They included edemas, pain, or hypersensitivity of the ear, and otorrhea.

Time to recovery – time to end of pain

Time to end of pain constituted a relevant target value for three of the studies included:15,17,19 Pistorius et al17 determined this parameter via the Visual Analog Scale; Lildholdt et al15 and Roland et al19 rated pain perception in diary entries on a scale of 0–4.

Goldenberg et al14 evaluated pain intensity at two set times: Day 3–4 and Day 14.

An alternative approach to analyzing pain was chosen by Marom et al16 who, instead of the time to end of pain, evaluated the basic development of pain perception based on daily entries via the visual analog scale.

Microbiological response

With the exception of one study, the microbiological effectiveness of the study medication, among others, was measured as the secondary outcome measure.16

Upon inclusion of the patients, samples were taken to determine the causative organisms. This procedure was repeated at the end of treatment (or alternatively after a follow-up period). The classification scheme was defined differently in the individual studies:

Drehobl et al13 divided the samples into “no exudates observed”, “exudate was present, but there was no growth on culture”, “exudate was present, and culture showed some pathogen growth at baseline or patient’s response was clinical failure”, or “exudate was present, and culture showed one or more new pathogens” and assessed them at the end of treatment and also after a follow-up period. Patients who tested positive for bacteria at the beginning of the study and then tested negative later during the study came into the category “microbial cure.”

Arnes et al12 Pistorius et al17, and Psifidis et al18 defined outcome critaria from “eradication” to “superinfection” or “reinfection” and examined the microbiological activity at the end of treatment and after follow-up. The change or the reduction of pathogenic infections could be determined in this way for each group and each pathogen.

In contrast, Lildholdt et al15 in their study evaluated the number of persisting cultures after the end of treatment, which was also relevant for Goldenberg et al14 that is, whether and to what extent bacterial proliferation still existed after therapy was completed.

Adverse events

In the majority of the studies, adverse events were evaluated as an expression of safety. Four studies specified such events additionally13,16,17,19 by explicitly analyzing medication-related adverse events; three studies evaluated clinical side effects/adverse events in general.12,14,18 Whether adverse events were of relevance in the study by Lildholdt et al remains unclear.

Timing of outcome assessment

The relevant point in time at which the primary and secondary outcome measures were assessed differed among the studies. Whereas in some studies the data were included in the analysis directly after the application phase was completed, others defined the time after a follow-up phase as decisive for the analysis. In only one case, the data from Day 3–4 formed the basis of the analysis.14

In the studies that conducted an analysis with data directly after treatment had ended, the point in time varied between Day 8 and Day 17. In the studies that collected data relevant to the target value after a follow-up phase, the time span ranged from Day 15 to Day 35.

Study results

Clinical cure

The included studies demonstrate the statistical equivalence between ciprofloxacin (0.2%) and the reference product PNH (Table 3). Some studies investigated the cure rate after completion of treatment.12,17,19 Here, the rate for patients whose condition fell into the category “clinical resolution” or “improvement” ranged between 93% and 100%. Studies that evaluated the outcome parameters after a follow-up period showed cure or improvement rates between 86.6% and 96.7%.13,15,18 Consequently, comparably high success rates for the ciprofloxacin 0.2% drug were determined in these studies.

Table 3

Results

Study ID	Clinical response		Time to end of pain	Microbiological response
	Definition	Numbers		Bacteriological assessment	Effectiveness
Pistorius et al17	Clinical resolution or improvement	Group A: 93%Group B: 90%Group C: 87%	Group A: 4.7 daysGroup B: 3.8 daysGroup C: 4.1 days	Pseudomonas aeruginosa: 67%	Bacteriological eradication (including presumed eradication)Group A: 92%Group B: 95%Group C: 87%
Arnes and Dibb12	Complete success, partial success, unsuccessful, indeterminate	Complete successGroup A: 14 (87.5%)Group B: 5 (35.7%)Partial successGroup A: 2 (12.5%)Group B: 4 (28.6%)Unsuccessful or indeterminateGroup A: 0Group B: 5 (35.7%)		P. aeruginosaGroup A: 6 (37.5%)Group B: 7 (50%)	EradicationGroup A: 15 (93.75%)Group B: 7 (50%)PersistenceGroup A: 1 (6.25%)Group B: 7 (50%)SuperinfectionGroup A: 1 (6.25%)Group B: 0
Roland et al19	Cured or improved 7 days after treatment ended	Group A: 94.3%Group B: 89.8%	Group A: 6 daysGroup B: 6 days		EradicationGroup A: 67 (95.7%)Group B: 53 (89.8%)SuperinfectionGroup A: 1 (1.4%)Group B: 2 (3.4%)FailureGroup A: 2 (2.9%)Group B: 4 (6.8%)
Drehobl et al13	Clinical cure of otitis symptoms after follow-up (score 0 for otalgia, edema, and otorrhea)	Group A. 86.6%Group B: 81.1%			P. aeruginosaGroup A: 87.5%Group B: 78.6%Staphylococcus aureusGroup A: 72.7%Group B: 75.9%
Lildholdt et al15	Resolution or improvement after followup period (3 weeks later)	Group A: ~95%Group B: ~95%	Median: 4.8 days (no statistically significant difference)	P. aeruginosa: 64%	Persisting P. aeruginosaGroup A: 9 (8.7%)Group B: 11 (9.4%)Group C: 22 (21.4%)
Psifidis et al18	Complete resolution of external otitis	Group A: 84.4%Group B: 100%Group C: 96.7%		P, aeruginosaGroup A: 18 (56.3%)Group B: 13 (44.8%)Group C: 11 (36.7%)	EradicationGroup A: 72%Group B: 83.3%Group C: 93.8%PersistenceGroup A: 12%Group B: 5.6%Group C: 6.3%SuperinfectionGroup A: 16%Group B: 11.1%Group C: 0%
Goldenberg et al14	Cured at day 3–4 after initial treatment	Group A: 86%Group B: 77%Group C: 56%		P.: 86 (72%)S. aureus: 22 (18%)Proteus mirabilis: 6 (5%)Coagulase-negativeStaphylococcus: 6 (5%)	P. aeruginosaGroup A: 0Group B: 0Group C: 10%S. aureusGroup A: 0Group B: 2.5%Group C: 0Staphylococcus coagulase-negativeGroup A: 0Group B: 5%Group C: 10%
Marom et al16	Resolution (absence of signs and symptoms) or improvement (presence of symptoms with no further therapy required)	PP population Resolution Group A: 25 (86.2%) Group B: 22 (78.6%) Improvement Group A: 4 (13.8%) Group B: 6 (21.4%) ITT population Resolution + improvement Group A: 93.6% Group B: 93.8%

Abbreviations: ITT, intention-to-treat; PP; per-protocol.

Similar results were ascertained in the studies that investigated a higher concentration of ciprofloxacin (0.3%).14,16 In the study by Goldenberg et al14 about 77% of patients who were treated with ciprofloxacin fulfilled the definition of cure on Day 3–4. After 14 days, the rate reached 100%. Marom et al16 found study participants in the per-protocol population to be 100% symptom-free at the end of a 7-day treatment phase. In the intent-to-treat population, complete resolution was observed in 93.6% of the patients in the ciprofloxacin group at the same point in time.

Microbial cure

The authors consistently identified high in vitro activity of ciprofloxacin against P. aeruginosa with high eradication rates of 83.3% to 95.7% and rare cases of persisting organisms or superinfections (Table 3).

Psifidis et al18 and Pistorius et al17 who, besides ciprofloxacin 0.2%, also tested a combination of ciprofloxacin 0.2% and hydrocortisone 0.1%, observed that the addition of hydrocortisone raised the eradication rate even further.

In the treatment of patients who had an infection with S. aureus bacteria, ciprofloxacin proved effective in 72.7% of patients.

Adverse events

No adverse events occurred in some studies,12,18,19 but in others, incidents that could be attributed to the medication took place at a rate of 3%–6% in the groups treated with ciprofloxacin (Table 4). The majority of studies spoke exclusively of mild side-effects, with similar frequencies in the individual groups; premature discontinuation was rarely reported. Drehobl et al13 and Pistorius et al17 name headache, earache, and itching at the site of application as the main symptoms that could be linked to the trial medication.

Table 4

Adverse events

Study ID	Adverse events	Medication-related AE	Type and severity	Premature discontinuation
Pistorius et al17	Group A: 66 (23%)Group B: 70 (25%)Group C: 55 (20%)	Group A: 6%Group B: 5%Group C: 5%	Headache, ear pain, pruritus mainly mild or moderate in severity	Group A: 1Group B: 4Group C: 3
Arnes and Dibb12	None
Roland et al19	Group A: 6 (5.7%)Group B: 5 (5%)	Group A: 0Group B: 1 (1.0%)	Mostly not serious (1 breast cancer)	11 (in most cases otitis media)
Drehobl et al13		Group A: 11 (3.8%)Group B: 11 (3.6%)	Ear pruritus, headache, ear discomfort, application site pain/burning mostly of mild intensity	Group A: 3Group B: 3
Lildholdt et al15
Psifidis et al18	None
Goldenberg et al14	None
Marom et al16	Group A: 7 (21%)Group B: 5 (16%)	Group A: 4 (12%) + 1 serious AEGroup B: 1 (3%)	Otalgia, tinnitus, pruritus, diarrhea, headache, throat pain	Group A: 1Group B: 0

Risk of bias

The greatest susceptibility to systematic distortions of the study results constituted the insufficient blinding of the included studies. While two study groups explicitly mentioned using non-blinding,16,18 four other authors made no comment whatsoever in this regard.12,14,15,18 Based on the fact that blinding was not addressed, however, it is to be assumed that blinding did not occur and the studies were open-label. In the study by Drehobl et al13 the evaluator at least was blinded, and only Roland et al19 conducted an observer/investigator-blinded study.

In addition, the randomization procedure remained unclear in a large proportion of the studies. Although all were randomized, controlled studies according to the publications, the randomization process was mentioned in only three studies.12,16,19

Another deficit with reference to the included studies was the absence of two full texts. We could only draw on the information from the abstracts by Lildholdt et al15 and Psifidis et al18 because we were denied access to the complete, comprehensive material.

Discussion

The outcome measure “clinical success” consistently shows higher success rates in patients treated with the fluoroquinolone, than in the control groups. At the same time, the authors point out – in addition to the effectiveness of the active ingredient – the absence of any ototoxicity and the low systemic exposure caused by ciprofloxacin.

In summary, clinical equivalence can be determined for both of the treatment possibilities ciprofloxacin/hydrocortisone and PNH plus amoxicillin in adults and children. However, low systemic exposure, the absence of ototoxicity, and the smaller dose speak clearly for treatment with ciprofloxacin.

Ciprofloxacin stands out due to its low rate of side effects. Adequate safety is thereby given with this fluoroquinolone.

For this reason, ciprofloxacin is not only non-inferior to other classes of antibiotics but also to antibiotic drugs that are combined with glucocorticoids.

Studies that evaluated microbiological activity come to the conclusion that the organism P. aeruginosa represents the main pathogen in the investigated population having acute otitis externa. The authors consistently ascertained high in vitro activity of ciprofloxacin against P. aeruginosa.

Special attention must be paid to patient compliance in the included studies. The lower the required application rate of the otologic drug, the more probable it is that the patients adhere to therapy and apply the medicine regularly. Thus we can conclude that patients requiring fewer daily drug administrations will comply more closely with the treatment plan.

When considering the bias, and consequently the results, we should pay particular attention to a certain distortion: due to the different daily application rates of the otologic drugs used, double-blinding of the study could not always be achieved.

The possibility of including a much larger number of clinical studies in this review would have existed if the question at hand had also applied to ciprofloxacin 0.3% solution.

Other studies not included in this review combined ciprofloxacin 0.2% solution with the glucosteroid dexamethasone, which can be categorized as a glucocorticoid belonging to the active substance class two to three analogous to the classification of therapeutic index of topical dermatotherapy, and is thus to be considered potent.20

These combination drugs were in turn tested against “conventional” combination drugs such as PNH. The efficacy of ciprofloxacin could be therefore increased.

Conclusion

The studies included in this review demonstrate the statistical equivalence of ciprofloxacin (0.2%) and the reference product PNH, and thereby confirm the hypothesis of non-inferiority in terms of the cure rate and microbiological eradication. The efficacy of ciprofloxacin 0.2% antibiotic ear solution can be acknowledged.