which permits unrestricted noncommercial use, provided the original work is properly

cited.
9
Therapeutics and Clinical Risk Management Dove press
open access to scientific and medical research
Open Access Full Text Article
Treatment of acute otitis externa with
ciprofloxacin otic 0.2 anti!iotic ear
solution
"e v i e w
" #$sges
# %ematian&'amani
A eichel
institute of #edical
'tatistics, informatics and
epidemiology, Faculty of
#edicine, (niversity of
)ologne, *ermany
)orrespondence+ "alph #$sges
institute of #edical 'tatistics,
informatics and epidemiology,
Faculty of #edicine, (niversity of
)ologne, ,inden!urger Allee -2,
.0/01 )ologne, *ermany
Tel +-/ 221 -23 0-.4
Fax +-/ 221 -23 0-4.
email
ralph5moesges.de
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 !ith no systemic effects. This systematic revie! compares the efficacy of
treatment using a ciprofloxacin ".#$ solution !ith other therapeutic options.
Methods: After compiling a catalog of search terms medical databases !ere searched
systemati cally for randomi%ed controlled studies. This search initially yielded a total of &'
studies !hich !ere then evaluated by three independent revie!ers. The number of studies
!as subse(uently reduced to )*+ six studies using a ciprofloxacin ".#$ solution and eight
studies using both
".#$ and ".&$ solutions.
Results: The studies included in the revie! demonstrate the statistical e(uivalence bet!een
the ciprofloxacin solution ,".#$- and the reference products ./0 ,a combination of
polymyxin 1 neomycin sulfate and hydrocortisone- auriculum po!der and a ciprofloxacin
foam !ith respect to the cure rate. The research groups consistently observed high in vitro
activity of ciprofloxacin against Pseudomonas aeruginosa.
Conclusion: This systematic revie! confirms the hypothesis of ciprofloxacin2s
noninferiority in the treatment of otitis externa in terms of the cure rate and microbiological
eradication. Keywords: otitis externa ciprofloxacin antibiotic ear solution efficacy
Introduction
Otitis
externa
Inflammation of the cutis and subcutis of the external auditory canal is a primary
symptom in acute otitis externa. An affected pinna can be a secondary symptom.
3ccasionally the eardrum can also be inflamed.
)
Inflammation of the ear can occur
in an acute and a chronic form. In some cases the clinical picture develops to a
necroti%ing stage. 4tatistically one in ten people suffers at least once in his life from
otitis externa. In )"$ of cases the inflammation is bilateral.
#
Currently many
different therapies are applied to ease the symptoms. The purpose of this revie! is
to compare the efficacy of ciprofloxacin ".#$ antibiotic ear solution !ith other
treatment options.
*eneral
etiology
An intact auditory canal possesses the ability to cleanse itself by migrating the
which permits unrestricted noncommercial use, provided the original work is properly
cited.
9
sloughed epithelia cells
out!ards !ith 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 !ater resistance. 5hether it also
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Access article
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#$sges et
al
has an antimicrobial effect has not yet been clarified. If the
cerumen is pushed from the outer part of the auditory canal
to!ard the eardrum using a cotton s!ab its effectiveness
is lo!ered. 4hould bacteria then enter the ear canal the
risk of progressive bacterial gro!th increases. This can
occur particularly in s!imming pools !hich is !hy the
term 6s!immer2s ear7 is commonly used.
&
8ike!ise congenital or ac(uired anatomical anomalies
,eg narro! passages- the use of hearing aids or the
aforementioned radical ear and ear canal hygiene !ith the
complete removal of cerumen or drainage can destabili%e
the sensitive environment and thus predispose the external
auditory canal to inflammation.
)
:athoge
ns
The p0 of the external auditory canal varies bet!een 9."
and
9.: and is therefore slightly acidic. 4uch conditions inhibit
bacterial gro!th.
)
In );') 1rook examined the
physiological normal flora of the external auditory canal
in pediatric patients. In descending order of concentration
coloni%ation !ith aerobes such as Staphylococcus
epidermidis diphthe roid species and ahemoly%ing
streptococci as !ell as anaerobes such as
propionibacterium acnes !as observed. Pseudomonas
aeruginosa and Staphylococcus aureus act pathogenically
against such flora and are cited in the technical literature as
the main causative organisms. 4poradically viruses and
fungi can also cause otitis externa.
)*
)linical
picture
1acterial otitis externa in its mild form can be
accompanied by only minor pain and subdued s!elling. In
its severe form ho!ever the symptoms are associated !ith
excruciating pain otorrhea and the complete closure of the
external auditory canal. The result is conductive deafness.
)
Apart from the typical acute form of otitis externa
special forms can appear such as otitis externa
circumscripta !hich emanates from a hair follicle
inflammation or otitis externa necroticans ,6maligna7-
!hich can take a fulminant course and therefore re(uires
maximum usually intravenous treatment.
)9
In the ma<ority of published clinical studies on the
treatment of otitis externa pain s!elling otorrhea and
redness are evaluated as typical parameters for rating the
clinical signs.
Therap
y
3titis externa is usually treated locally.
)
3totoxic
antibiotics
such as aminoglycosides should not be applied in patients
): )' & &
Dove press
!ith a perforated tympanic membrane. If an antibiogram
has been made the optimum antibiotic otologic drug can
be determined. If none is available 6calculated antibiosis7
is recommended ie a drug is used that is effective against
the t!o most common pathogens S. aureus and P.
aeruginosa.
=
Individual decisions must be made in case of resistance.
3ften 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
lo!ering the p0 value in the auditory canal so that the
main pathogens P. aeruginosa and S. aureus !hich reach
their optimal p0 bet!een =.9 and :.& do not obtain perfect
gro!ing conditions or in an ideal case are killed.
):
?or years glucosteroids had the reputation of primarily
reducing the s!elling of the auditory canal. /e!er studies
ho!ever also ascribe to them antibacterial and antifungal
effects in otitis externa. @et the number of available
studies on steroidal monotherapies is still rather lo!.
9
/onsteroidal antiinflammatory drugs should also be
administered for pain relief.
)
)iprofloxaci
n
Ciprofloxacin is a synthetic antibiotic !ith a broad
spectrum of activity and has the chemical formula C 0
?/ 3 . 1elonging to the g roup of fluoro(uinolones
,gyrase inhibitors- it acts as a bactericide particularly
against gramnegative pathogens by inhibiting D/A
replication ,topoisomerase II- and interfering in the
en%ymatic activity of topoisomerase IA both of !hich
are re(uired for the bacteria2s cell division transcription
repair and recombination. It is moderately effective
against gram positive pathogens !hile it sho!s no
relevant activity against fungi or parasites.
'
In :9$ of cases ciprofloxacin is eliminated unchanged
by renal excretion. It is also metaboli%ed through the liver
and eliminated through bile and is thus sub<ect to
enterohepatic circulation.
'
Ciprofloxacin ranks among the
most effective fluoro(uinolones against P. aeruginosa and
can also sho! very high in vitro activity against
enterobacteria and Haemophilus influenzae. 1eing 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.
;
Ciprofloxacin constitutes the drug of choice for treating
severe otitis externa in children and adolescents as it has
been the sub<ect of extensive investigation and is
available
in syrup form.
)"
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Dove press Acute otitis externa and ciprofloxacin
otic
1esides its systemic effect ciprofloxacin is used more
often topically for its local effects in the form of eye or ear
drops. This fluoro(uinolone thereby possesses a very broad
spectrum of indications !hich range from complicated uri
nary tract infections infections of the respiratory system
skin and bones to severe typhoid salmonella infections or
bacterial con<unctivitis. Bno!n side effects include gastro
intestinal complaints ,nausea diarrhea dyspepsia-
disorders of the central nervous system ,headache
nervousness>rest lessness di%%iness tremor hyposmia-
and skin irritations and eosinophilia.
))
The undesirable effects of systemic treatment can be
largely avoided through topical administration
ho!ever. A high local concentration is in fact attained yet
resorption does not occur. Therefore itching or burning at
the applica tion site or superinfections of the ear can arise
due to robust pathogens. Allergic reactions occur very
rarely.
)"
4ystemic side effects of local application
occasionally include di%%i ness and headache.
Materials and methods
'earch methods used to identify
studies The electronic databases Cochrane Car /ose
and Throat Dis orders Droup Trials Register The Cochrane
Central Register of Controlled Trials ,CC/TRA8-
.ubMed MCD8I/C CM1A4C and 5eb of 4cience
!ere systematically searched for randomi%ed controlled
studies. Esing Me40 a search term catalog !as
compiled !ith the follo!ing terms that !ere then
entered in combinations+ external ear inflam- mation of
the external ear acute otitis externa quinolone
ciprofloxacin 0.2% ciprofloxacin solution ear drops
drug therapy anti-bacterial agents antifungal antibiotics.
Restrictions !ith respect to language publication date
or publication status !ere not initially made. This revie!
!as also limited to published !ork. The last search !as
started on ) March #")).
:atient
s
.atients ,both children and adults- !ith the diagnosis of
acute otitis externa !ere included in the revie!. /ot
included !ere patients !ho suffered from a chronic form
of external otitis or otitis media.
:arameter
s
4ymptom improvement and microbiological eradication
!ere defined as primary outcome parameters. Time to
com plete disappearance of symptoms and any side effects
!ere
observed as further aspects.
Dove press Acute otitis externa and ciprofloxacin
otic
Results
'earch
results
Thirtyeight studies satisfied our search criteria and !e
examined the abstracts of these. 5hen this process !as
completed the number of suitable studies decreased to &=F
!e then !orked through their full texts ,?igure )-. After
three revie!ers came to a consensus concerning further
elimina tions six and eight studies respectively !ere
available for this systematic revie! ,Table )-.
)#G);
5e !ere denied access to the full text of t!o of these
eight randomi%ed controlled trials. The comprehensive
publication by 8ildholdt et al
)9
and the text by .sifidis et
al
)'
could not be re(uested !hich is !hy detailed data are
missing.
Enpublished studies !ere not considered in this
systematic revie!.
Background %included studies&
Treatment
doses
1esides six studies that investigated a ".#$ ciprofloxacin
drug !e also included t!o more studies that used a ".&$
ciprofloxacin product ,Table #-.
)*)=
The ciprofloxacin dose of the ear solutions used in the
individual studies !as comparable. The ma<ority planned a
:day application phase during !hich the study participants
applied three drops to each ear t!ice daily. Marom et al
)=
raised the dose to four drops ,".&$ ciprofloxacin- and
Doldenberg et al
)*
doubled the application period to #
!eeks. The exact dose remains unclear in the study by
Drehobl et al
)&
in !hich the study period !as also : days
!ith applications t!ice daily but the study specified the
dose as ampoule ,6vial7- rather than stating the number of
drops.
Outcomes
assessed
)linical
response
Clinical success !as in part classif ied differently
and measured at various points in times ,Table #-. In
addition the definition of treatment success varied
slightly among the studies. 4ome studies def ined
clinical success as complete recovery ,resolution- !ith
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 !ere similar. They
included edemas pain or hypersensitivity of the ear and
otorrhea.
Time to recovery 7 time to end of
pain
Time to end of pain constituted a relevant target value for
three of the studies included+
)9):);
.istorius et al
):
determined
Therapeutics and )linical "isk #anagement 2011+2
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-tudy I. -tudy tye Blinding Randomi/ation grous 0 1articiants Inclusion criteria 23clusion criteria
:istorius e=uivalence %o !linding 0&arm study> 3-2> :atients .1 year :erforated tympanic mem!rane> acute otitis
media>
et al
12
study *roup A ;ciprofloxacin<, 202 availa!le for )linical signs and symptoms of invasive malignant chronic otitis externa>
dermatitis
*roup ? ;ciprofloxacin + analysis external otitis within 2 days of study
entry,
in the area of the affected ear> recent diagnosis
hydrocortisone<, ;*roup A+ n =
20/,
including edema of the external auditory and treatment of otitis externa ;within 00 days
*roup ) ;:%@< *roup ?+ n = 204, canal on otoscopic examination,
tenderness
of study entry<> known fungal infection of the ear>
*roup )+ n = 223< with movement of the pinna, and ostalgia furuncles> mastoiditis> stenosis> exostosis>
tumors
of the ear> significant underlying disease,
including
dia!etes mellitus, or other immunocompromised
conditions> pregnancy or lactation> allergy to
car!oxy=uinolones, polymyxin ? sulfate,
neomycin
sulfate, or hydrocortisone> administration of
another investigational drug within 00 days of
study
enrolment> or previous enrolment in this study
Arnes and e=uivalence 2&arm study> 00 :atients H13 years of age :regnancy, use of systemic antimicro!ial
therapy,
9i!!
12
study *roup A ;ciprofloxacin<, *roup A+ n = 14 9iagnosis of otitis externa !y an overt fungal ear infection, perforated eardrum,
*roup ? ;Terra&)ortril *roup ?+ n = 1- otorhinolaryngological practice history of middle ear surgery, allergy to
polymyxin ?< =uinolone derivatives.
"oland e=uivalence O!server 2&arm study> 204 :atients .1 year AOe symptoms present 2 days
et al
1/
study ;statistical !linded *roup A ;ciprofloxacin + *roup A+ n = 104 9iagnosis of mild, %on&intact tympanic mem!rane, with
noninferiority< hydrocortisone<, *roup ?+ n = 100 moderate or severe AOe or without otorrhea
*roup ? ;:%@ + amoxicillin< 'everity of symptoms at least AmildB Acute otitis media, malignant otitis externa,
)'O#,
AOe symptoms present .2 days mastoiditis, se!orrheic dermatitis of the external
"efrain from water immersion auditory canal, or other suppurative
noninfectious
of ear during study disease disorders
*ive informed consent Cnown or suspected fungal, viral, or
myco!acterium
Agree to comply with protocol ear infection 9ia!etes, immunosuppressive
disorder,
re=uirements renal disease, hepatitis, mononucleosis, chronic
diarrhea, narcotic a!use
)oncomitant use of ear washes, systemic
anti!iotic
agents, steroids, analgesics other than
acetaminophen,
and any preparation that might o!scure study
design
Cnown or suspected allergy to any component of
study medication;s<.
9reho!l %on&inferiority evaluator& 2&arm study> 423 :atients .1 year, Treatment with any investigational drug or
et al
10
!lind *roup A+ ciprofloxacin *roup A+ n = 01/ diagnosis of acute diffuse =uinolone anti!iotic in the preceding 00 days>
use
*roup ?+ :%@ *roup ?+ n = 00/ otitis externa of 0 weeksD
duration, at least a score of 2
of topical or systemic anti!iotics in the preceding
2 days> use of any medication for treatment of
otitis
;moderate severity< for the externa or otitis media in the preceding 04
hours>
symptoms otalgia, edema of the se!orrheic dermatitis of the external auditory
canal>
external auditory canal on otoscopic chronic otitis externa or otorrhea of 0 weeksD
examination, and a score of at least 1 duration> known fungal infection of the ear>
mastoid
;mild severity< for the symptom otorrhea disease or mastoid surgery ;within 40 days of
study
entry<> tympanostomy tu!es currently in place or
removed within 0 months of
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9
study entry> known perforation of the eardrum
or perforation within 4 months of study entry>
known significant underlying disease, including
dia!etes 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 ,ildholdt e=uivalence %o !linding 0&arm study> 303 :atients with clinical signs and
et al
1.
study *roup A+ ciprofloxacin symptoms of acute,
*roup ?+ ciprofloxacin + diffuse external otitis
hydrocortisone
*roup )+ :%@
:sifidis
et al
13
e=uivalenc
e study
%o !linding 0&arm study>
*roup A+
:%@
/1
*roup A+ 02
:atients H13
years, external
otitis for a *roup ?+ ciprofloxacin +
hydrocortisone
*roup ?+ 2/
*roup )+ 00
duration of I0 weeks
*roup )+ ciprofloxacin
*olden!erg e=uivalence %o !linding 0&arm study> 120 :atients H13 years, :rior treatment with other drops or systemic
et al
1-
study *roup A ;auricularum *roup A+ n = -0 AeO diagnosed !y an otolaryngologist, anti!iotics, sensitivity to any of the drugs used
powder<, *roup ?+ n = -0 signed informed consent or their contents, or perforation of the tympanic
*roup ? ;ciprofloxacin<, *roup )+ n = -0 mem!rane. All patients were instructed to avoid
*roup ) ;to!ramycin< moisture and wetness of the ear during the
course
of their treatment.
#arom e=uivalence Open&la!el 2&arm study> 40 Adult men and nonpregnant, Cnown allergy to =uinolones> topical or oral
et al
14
study *roup A+ ciprofloxacin *roup A+ n = 02 nonlactating women ;H13 years< anti!iotic therapy treatment up to 0 days !efore
as foam *roup ?+ n = 01 diagnosed with unilateral AOe lasting enrolment or treatment with long&acting
anti!iotics
*roup ?+ ciprofloxacin 0 weeks of presuma!ly !acterial
origin
up to 2 days !efore enrolment> AOe from
presumed
as solution ;on the !asis of otoscopy findings<, fungal origin> H30 occlusion of the EA)>
concurrent
pinna or tragal tenderness and infection re=uiring systemic antimicro!ial therapy>
an intact tympanic mem!rane history of dia!etes mellitus or immune
dysfunction
or current immunosuppressive therapy>
se!orrheic
dermatitis or other dermatological disorders of
the eA)> congenital a!normalities of the eA)
or o!structive !ony exostosis, mastoid, or other
suppurative noninfectious ear disorder> presence
of
middle ear effusion> EA) a!normal otoscopy
findings
;such as a!scess, polyp, or granulation tissue<>
any
serious underlying disease> previous AOe within
00 days !efore enrolment> and participation in
a study with investigational drug or device within
00 days !efore enrolment. 9ata were collected
on
age, gender, and medical and surgical history.
4bbreviations: AOe, acute otis externa> eA), external auditory canal> )'O#, chronic suppurative otitis media.
#$sges et
al
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Therapeutics and )linical "isk #anagement
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+able " 'tudy design ;included studies<
-tudy I. Medications .uration and dose 1rimary endoint -econdary arameters -a6ety
:istorius *roup A+ 2 days )linical success Antimicro!ial effectiveness #edication&
et al
12
)iprofloxacin otic drops *roup A+ ;resolution or ;micro!iological related
adverse
as hydrochloride 0 drops twice daily improvement of eradication< at the end events
monohydrate ;0.2< *roup ?+ symptoms< at the of therapy ;9ay 10712<
*roup ?+ 0 drops twice daily end of therapy Time until ear pain
)iprofloxacin otic drops *roup )+ ;9ay 10712< disappeared completely
as hydrochloride 0 drops 0 times a day via visual analog scale
monohydrate ;0.2< plus ;10 years of age<
hydrocortisone ;0.1< or - drops
*roup )+ ;.10 years of age<
com!ination of
:olymyxin ? ;10.000 (<,
neomycin sulfate ;0.. mgFm,<
and hydrocortisone ;0.1<
Arnes and *roup A+ 2 days )linical success ?acteriological
assessment
)linical side
9i!!
12
)iprofloxacin ;0.2< *roup A+ ;complete resolution, ;eradication, persistence, effects
;adverse
as ear drops 270 drops twice daily marked
improvement,
recurrence, superinfection< events<
*roup ?+ *roup ?+ slight improvement, individual ;investigatorDs<
drops containing 270 drops twice daily failure, or assessment ;completely
oxytetracycline ;. mgFm,< indeterminate< successful, partially
polymyxin ? ;10,000
unitsFm,<
at the end of successful, unsuccessful,
and hydrocortisone ;1.
mgFm,<
therapy ;9ay 3< indeterminate<
"oland *roup A+ *roup A+ )linical successF #icro!iological eradication Adverse
events
et al
1/
Otic solution consisting 2 days, response to therapy after treatment ended or serious
of ciprofloxacin and 0 drops twice daily ;resolution< after ;percentage of patients adverse
events
hydrocortisone *roup ?+ treatment ended with resolution of
*roup ?+ 10 days, ;*roup A+ 9ay 3, disease&specific infection<
)om!ination of :%@ 2 drops 0 times a day *roup ?+ 9ay 11< Time to end of pain
;polymyxin ?FneomycinF ;12 years of age< 'ymptom severity
hydrocortisone< or - drops 0 times a
day
;-&point scale for otalgia
plus the anti!iotic ;.12 years of age< and tenderness<
amoxicillin
9reho!l *roup A+ 2 days )linical success )linical success 9rug&related
et al
10
)etraxal ;ciprofloxacin otic *roup A+ ;proportion of ;proportion of patients adverse
events
solution 0.2< 1 vial twice daily patients with clinical with clinical cure< at the
*roup ?+ ;morning and evening< cure< after follow&up end of treatment ;9ay 37
10<
:%@ otic solution> *roup ?+ period ;day 1.712<. )linical improvement
neomycin sulfate - drops 0 times daily )linical cure was ;defined as a score of 0
;0.. mgFm, neomycin !ase<, ;for patients .10 years defined as a score or 1 for otalgia, edema,
polymyxin ? ;10 000 (< of age< or 0 drops of 0 for otalgia, and otorrhea<, resolution
and hydrocortisone ;1< ;for patients 10 years edema, and otorrhea of otalgia, and clinical +
of age< ;morning, micro!iologic cure at the
afternoon, evening< end of treatment and after
the follow&up period
,ildholdt *roup A+ 2 days )linical success #edian time to end
et al
1.
)iprofloxacin ;0.2< *roup A+ ;resolution or of ear pain
otic solution 0 drops twice daily improvement< evaluation of ear cultures
*roup ?+ *roup ?+ maintained at
)om!ination of 0 drops twice daily follow&up a!out
ciprofloxacin ;0.2< *roup )+ 0 weeks later
otic solution and - drops 0 times a day
hydrocortisone ;0.1<
*roup )+
'uspension of polymyxin
?&neomycin sulfate
;0.. mgFm,<&
hydrocortisone ;1<
;Continue
d<
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'#
Dove press Acute otitis externa and ciprofloxacin
otic
+able " ;Continued<
-tudy I. Medications .uration and dose 1rimary endoint -econdary arameters -a6ety
:sifidis *roup A+ 2 days )linical success #icro!iological Adverse
events
et al
13
)om!ination of *roup A+ ;complete effectiveness ;eradication,
polymyxin ? ;10,000 (Fm,<, 0 drops 0 times daily resolution of persistence,
superinfection<
neomycin ;0.. mgFm,<, *roup ?+ external otitis<
and hydrocortisone 0 drops twice daily at the end of the
;10 mgFm,< *roup )+ follow&up period
*roup ?+ 0 drops twice daily ;9ay 2170.<
)om!ination of 0.2
ciprofloxacin ;2 mgFm,< and
hydrocortisone ;10 mgFm,<
*roup )+
)iprofloxacin ;0.2< alone
*olden!erg *roup A+ 1- days )linical success )linical success Adverse
events
et al
1-
Auricularum powder *roup A+ ;rate of cure< at ;rate of cure< at
;dexamethasone 1 application 9ay 07- after 9ay 1-
10 mg, oxytetracycline twice daily initial treatment #icro!iological
@)l /0,000 (, polymyxin ? *roup ?+ effectiveness
sulfate 100,000 (, nystatin 0 times a day
1,000,000 (> Trima, 'erolam *roup )+
,a!oratories, *ermany< 0 times a day
*roup ?+
)iprofloxacin 0.0
;)iloxan, Alcon ,a!oratories,
Fort worth, TG<
*roup )+ To!ramycin
;To!rex, Alcon ,a!oratories<
#arom *roup A+ 2 days )linical responseF Otorrhea cessation Adverse
events
et al
14
Foam Otic )ipro, 0.0 *roup A+ cure defined as :ain relief
ciprofloxacin One application resolution ;a!sence
foam&!ased formulation twice daily of AOe&related signs
*roup ?+ *roup ?+ and symptoms< or
)iloxan, 0.0 - drops twice daily improvement
solution&!ased ciprofloxacin ;presence of AOe&
related minor signs
or symptoms, with
no further therapy
re=uired< at the end
of therapy ;9ay 37
1-<
4bbreviation: AOe, acute otis externa.
this parameter via the Aisual Analog 4caleF 8ildholdt et
al
)9
and Roland et al
);
rated pain perception in diary
entries on a scale of "G*.
Doldenberg et al
)*
evaluated pain intensity at t!o set
times+ Day &G* and Day )*.
An alternative approach to analy%ing pain !as chosen
by Marom et al
)=
!ho instead of the time to end of pain
evaluated the basic development of pain perception based
on daily entries via the visual analog scale.
#icro!iological
response
5ith the exception of one study the microbiological
effectiveness of the study medication among others !as
measured as the secondary outcome measure.
)=
Epon inclusion of the patients samples !ere taken to
determine the causative organisms. This procedure !as
repeated at the end of treatment ,or alternatively after a
follo!up period-. The classification scheme !as defined
differently in the individual studies+
Drehobl et al
)&
divided the samples into 6no exudates
observed7 6exudate !as present but there !as no gro!th
on culture7 6exudate !as present and culture sho!ed some
patho gen gro!th at baseline or patient2s response !as
clinical failure7 or 6exudate !as present and culture
sho!ed one or more ne! pathogens7 and assessed them at
the end of treatment and also after a follo!up period.
.atients !ho tested positive for bacteria at the beginning of
the study and then tested negative later during the study
came into the category 6microbial cure.7
+able ! "esults
-tudy I. Clinical resonse +ime to
Microbiological resonse
.e6inition 7umbers
end o6 ain
Bacteriological
assessment
266ectiveness
:istorius et al
12
)linical resolution *roup A+ /0 *roup A+ -.2 days Pseudomonas ?acteriological
or improvement *roup ?+ /0 *roup ?+ 0.3 days aeruginosa+ 42 eradication
*roup )+ 32 *roup )+ -.1 days ;including presumed
eradication<
*roup A+ /2
*roup ?+ /.
*roup )+ 32
Arnes and 9i!!
12
)omplete success, )omplete success P. aeruginosa eradication
partial success, *roup A+ 1-
;32..<
*roup A+ 4 ;02..< *roup A+ 1.
;/0.2.<
unsuccessful, *roup ?+ . ;0..2< *roup ?+ 2 ;.0< *roup ?+ 2 ;.0<
indeterminate :artial success :ersistence
*roup A+ 2 ;12..< *roup A+ 1 ;4.2.<
*roup ?+ - ;23.4< *roup ?+ 2 ;.0<
(nsuccessful or 'uperinfection
indeterminate *roup A+ 1 ;4.2.<
*roup A+ 0 *roup ?+ 0
*roup ?+ . ;0..2<
"oland et al
1/
)ured or *roup A+ /-.0 *roup A+ 4 days eradication
improved *roup ?+ 3/.3 *roup ?+ 4 days *roup A+ 42 ;/..2<
2 days after *roup ?+ .0 ;3/.3<
treatment ended 'uperinfection
*roup A+ 1 ;1.-<
*roup ?+ 2 ;0.-<
Failure
*roup A+ 2 ;2./<
*roup ?+ - ;4.3<
9reho!l et al
10
)linical cure of *roup A. 34.4 P. aeruginosa
otitis symptoms *roup ?+ 31.1 *roup A+ 32..
after follow&up *roup ?+ 23.4
;score 0 for Staphylococcus
aureus
otalgia, edema, *roup A+ 22.2
and otorrhea< *roup ?+ 2../
,ildholdt et al
1.
"esolution
or
improvemen
t after follow&
*roup A+ /.
*roup ?+ /.
#edian+ -.3 days
;no statistically
significant
difference<
P. aeruginosa+ 4- :ersisting P.
aeruginosa *roup A+
/ ;3.2< *roup ?+
11 ;/.-< up period *roup )+ 22 ;21.-<
;0 weeks later<
:sifidis et al
13
)omplete resolution *roup A+ 3-.- P, aeruginosa eradication
of external otitis *roup ?+ 100 *roup A+ 13 ;.4.0< *roup A+ 22
*roup )+ /4.2 *roup ?+ 10 ;--.3< *roup ?+ 30.0
*roup )+ 11 ;04.2< *roup )+ /0.3
:ersistence
*roup A+ 12
*roup ?+ ..4
*roup )+ 4.0
'uperinfection
*roup A+ 14
*roup ?+ 11.1
*roup )+ 0
*olden!erg et al
1-
)ured at day *roup A+ 34 P.+ 34 ;22< P. aeruginosa
07- after *roup ?+ 22 S. aureus+ 22 ;13< *roup A+ 0
initial treatment *roup )+ .4 Proteus mirabilis+ 4
;.<
*roup ?+ 0
)oagulase&negative *roup )+ 10
Staphylococcus+ 4
;.<
;Continued<
+able ! ;Continued<
-tudy I. Clinical resonse +ime to
Microbiological resonse
.e6inition 7umbers
end o6 ain
Bacteriological
assessment
266ectiveness
S. aureus
*roup A+ 0
*roup ?+ 2..
*roup )+ 0
Staphylococcus
coagulase&
negative *roup
A+ 0
*roup ?+ .
*roup )+ 10
#arom et al
14
"esolution ;a!sence
of signs and symptoms<
or improvement
;presence of symptoms
with no further therapy
re=uired<
1< ::
population
"esolutio
n
*roup A+ 2.
;34.2< *roup ?+
22 ;23.4<
improvement
*roup A+ -
;10.3< *roup ?+
4 ;21.-<
2< iTT population
"esolution +
improvement
*roup A+
/0.4
*roup ?+
/0.3
4bbreviations: iTT, intention&to&treat> ::> per&protocol.
Arnes et al
)#
.istorius et al
):
and .sifidis et al
)'
defined
outcome critaria from 6eradication7 to 6superinfection7 or
6reinfection7 and examined the microbiological activity at
the end of treatment and after follo!up. The change or the
reduction of pathogenic infections could be determined in
this !ay for each group and each pathogen.
In contrast 8ildholdt et al
)9
in their study evaluated the
number of persisting cultures after the end of treatment
!hich !as also relevant for Doldenberg et al
)*
that is
!hether and to !hat extent bacterial proliferation still
existed after therapy !as completed.
Adverse
events
In the ma<ority of the studies adverse events !ere
evaluated as an expression of safety. ?our studies specified
such events additionally
)&)=):);
by explicitly analy%ing
medication related adverse eventsF three studies evaluated
clinical side effects>adverse events in general.
)#)*)'
5hether adverse events !ere of relevance in the study by
8ildholdt et al remains unclear.
Timing of outcome
assessment
The relevant point in time at !hich the primary and
second ary outcome measures !ere assessed differed
among the studies. 5hereas in some studies the data !ere
included in the
analysis directly after the application phase !as completed
others defined the time after a follo!up phase as decisive
for the analysis. In only one case the data from Day &G*
formed the basis of the analysis.
)*
In the studies that conducted an analysis !ith data
directly after treatment had ended the point in time varied
bet!een Day ' and Day ):. In the studies that collected
data relevant to the target value after a follo!up phase the
time span ranged from Day )9 to Day &9.
'tudy
results
)linical
cure
The included studies demonstrate the statistical
e(uivalence bet!een ciprofloxacin ,".#$- and the
reference product ./0 ,Table &-. 4ome studies
investigated the cure rate after completion of
treatment.
)#):);
0ere the rate for patients !hose
condition fell into the category 6clinical resolution7 or
6improvement7 ranged bet!een ;&$ and )""$. 4tudies
that evaluated the outcome parameters after a follo!up
period sho!ed cure or improvement rates bet!een '=.=$
and ;=.:$.
)&)9)'
Conse(uently comparably high success
rates for the ciprofloxacin ".#$ drug !ere determined in
these studies.
4imilar results !ere ascertained in the studies that inves
tigated a higher concentration of ciprofloxacin ,".&$-.
)*)=
In
+able 5 Adverse
events
-tudy I. 4dverse events Medication8related 42 +ye and severity 1remature
discontinuation
:istorius et al
12
*roup A+ 44 *roup A+ 4 @eadache, ear pain, *roup A+ 1
;20< *roup ?+ . pruritus mainly mild or *roup ?+ -
*roup ?+ 20 *roup )+ . moderate in severity *roup )+ 0
;2.<
*roup )+ ..
;20<
Arnes and 9i!!
12
%one
"oland et al
1/
*roup A+ 4 *roup A+ 0 #ostly not serious 11 ;in most
cases
;..2< *roup ?+ 1 ;1 !reast cancer< otitis media<
*roup ?+ . ;1.0<
;.<
9reho!l et al
10
*roup A+ 11 ear pruritus, headache, *roup A+ 0
;0.3< ear discomfort, application *roup ?+ 0
*roup ?+ 11 site painF!urning mostly
;0.4< of mild intensity
,ildholdt et al
1.
:sifidis et al
13
%one
*olden!erg et al
1-
%one
#arom et al
14
*roup A+ 2 *roup A+ - Otalgia, tinnitus, pruritus, *roup A+ 1
;21< ;12< + 1 serious Ae diarrhea, headache, *roup ?+ 0
*roup ?+ . *roup ?+ 1 ;0< throat pain
;14<
the study by Doldenberg et al
)*
about ::$ of patients !ho
!ere treated !ith ciprofloxacin fulfilled the definition of
cure on Day &G*. After )* days the rate reached )""$.
Marom et al
)=
found study participants in the perprotocol
population to be )""$ symptomfree at the end of a :day
treatment phase. In the intenttotreat population complete
resolution
Results of the
!as observed in ;&.=$ of the patients in the ciprofloxacin
group at the same point in time.
#icro!ial
cure
The authors consistently identified high in vitro activity of
ciprofloxacin against P. aeruginosa !ith high eradication
rates of '&.&$ to ;9.:$ and rare cases of persisting organ
isms or superinfections ,Table &-.
.sifidis et al
)'
and .istorius et al
):
!ho besides cipro
database search
(abstracts read)
N = 38
Full texts
processed
N = 36
Studies
relevant for the
review
N = 6
9igure , Flow chart.
Exclusion criteria
J No ciprofloxacin
J !ron" concentration
of ciprofloxacin
J #ni$al testin"
J No R%&
Exclusion criteria
J No ciprofloxacin
J !ron" concentration
of ciprofloxacin
Studies relevant for the
review
(extension of the
inclusion criteria to
ciprofloxacin '(3))
N = 8
floxacin ".#$ also tested a combination of ciprofloxacin
".#$ and hydrocortisone ".)$ observed that the addition
of hydrocortisone raised the eradication rate even further.
In the treatment of patients !ho had an infection !ith
S. aureus bacteria ciprofloxacin proved effective in
:#.:$ of patients.
Adverse
events
/o adverse events occurred in some studies
)#)');
but in
oth ers incidents that could be attributed to the medication
took place at a rate of &$G=$ in the groups treated !ith
cipro floxacin ,Table *-. The ma<ority of studies spoke
exclusively of mild sideeffects !ith similar fre(uencies in
the individual groupsF premature discontinuation !as
rarely reported. Drehobl et al
)&
and .istorius et al
):
name
headache earache and itching at the site of application as
the main symptoms that could be linked to the trial
medication.
"isk of
!ias
The greatest susceptibility to systematic distortions of the
study results constituted the insufficient blinding of the
included studies. 5hile t!o study groups explicitly men
tioned using nonblinding
)=)'
four other authors made no
comment !hatsoever in this regard.
)#)*)9)'
1ased on the
fact that blinding !as not addressed ho!ever it is to be
assumed that blinding did not occur and the studies !ere
openlabel. In the study by Drehobl et al
)&
the evaluator at
least !as blinded and only Roland et al
);
conducted an
observer>investigator blinded study.
In addition the randomi%ation procedure remained
unclear in a large proportion of the studies. Although all
!ere randomi%ed controlled studies according to the pub
lications the randomi%ation process !as mentioned in only
three studies.
)#)=);
Another deficit !ith reference to the included studies
!as the absence of t!o full texts. 5e could only dra! on
the information from the abstracts by 8ildholdt et al
)9
and
.sifidis et al
)'
because !e !ere denied access to the
complete comprehensive material.
.iscussion
The outcome measure 6clinical success7 consistently
sho!s higher success rates in patients treated !ith the
fluoro (uinolone than in the control groups. At the
same time the authors point out G in addition to the
effectiveness of the active ingredient G the absence of any
ototoxicity and the lo! systemic exposure caused by
ciprofloxacin.
In summary clinical e(uivalence can be determined
for both of the treatment possibilities ciprofloxacin>
hydrocortisone and ./0 plus amoxicillin in adults and
children. 0o!ever lo! systemic exposure the absence of
ototoxicity and the smaller dose speak clearly for
treatment !ith ciprofloxacin.
Ciprofloxacin stands out due to its lo! rate of side
effects. Ade(uate safety is thereby given !ith this
fluoro(uinolone.
?or this reason ciprofloxacin is not only noninferior to
other classes of antibiotics but also to antibiotic drugs that
are combined !ith glucocorticoids.
4tudies 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.
4pecial attention must be paid to patient compliance
in the included studies. The lo!er the re(uired application
rate of the otologic drug the more probable it is that the
patients adhere to therapy and apply the medicine
regularly. Thus !e can conclude that patients re(uiring
fe!er daily drug administrations !ill comply more closely
!ith the treatment plan.
5hen considering the bias and conse(uently the
results !e should pay particular attention to a certain
distortion+ due to the different daily application rates of the
otologic drugs used doubleblinding of the study could not
al!ays be achieved.
The possibility of including a much larger number of
clinical studies in this revie! !ould have existed if the
(uestion at hand had also applied to ciprofloxacin ".&$
solution.
3ther studies not included in this revie! combined
cipro floxacin ".#$ solution !ith the glucosteroid
dexamethasone !hich can be categori%ed as a
glucocorticoid belonging to the active substance class t!o
to three analogous to the clas sification of therapeutic index
of topical dermatotherapy and is thus to be considered
potent.
#"
These combination drugs !ere in turn tested against
6conventional7 combination drugs such as ./0. The
efficacy of ciprofloxacin could be therefore increased.
Conclusion
The studies included in this revie! demonstrate the
statistical e(uivalence of ciprofloxacin ,".#$- and the
reference product ./0 and thereby confirm the hypothesis
of noninferiority in terms of the cure rate and
microbiological eradication. The efficacy of ciprofloxacin
".#$ antibiotic ear solution can be ackno!ledged.
.isclosure
The authors report no conflicts of interest.
Re6erences
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and
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ochrane #atabase Syst $e". #")"F,)-+CD""*:*".
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%m )am Physician. #"")F=&,9-+;#:G;&=.
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+
ange,andte pharma(ologie. 1erlin 0eidelberg+ 4pringer AerlagF #""9.
;. 8emmer 1 1rune B ,0rsg.-. Pharma(otherapie + (linische pharma-
(ologie. 0eidelberg+ 4pringer Medi%in AerlagF #"":.
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hydrocortisone combination treatment. urr 4ed $es &pin.
);;&F)&,&-+)'#G)'=.
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".#$ versus polymyxin 1neomycinhydrocortisone in the
treatment of acute diffuse otitis externaM. urr 4ed $es &pin.
#""'F#*,)#-+
&9&)G&9*#.
)*. Doldenberg D Dol% A /et%er A Loachims 0N. The use of otic
po!der in the treatment of acute external otitis. %m 3 &tolaryngol.
#""#F#&,&-+
)*#G)*:.
)9. 8ildholdt T Dehanno . Behrl 5 8eiberman A. 3titis
externa treated by topical antibiotics. &tolaryngol Head 'ec(
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)):,#-+.))=.
)=. Marom T @elin R Doldfarb A et al. Comparison of safety and
efficacy of foambased versus solutionbased ciprofloxacin for acute
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neomycin hydrocortisone otic suspension in the treatment of acute
diffuse otitis externa. 2nfect #is lin Pract. );;;+','-+&':G&;9.
)'. .sifidis A /ikolaidis . Tsona A et al. The efficacy and safety of
local ciprofloxacin in patients !ith external otitis+ a randomi%ed
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#&.
);. Roland .4 1elcher 1. 1ettis R et alF Cipro 4tudy Droup. A single
topical agent is clinically e(uivalent to the combination of topical and
oral antibiotic treatment for otitis externa. %m 3 &tolaryngol. #""'F
#;,*-+#99G#=).
#". /eurodermitis Bontakek%em. 4tiftung 5arentest.
http+>>!! ! .test.de> themen>gesundheit O
k osmetik>medikamente> v omPar%t>aPhautPhaare>aP
ek%emPneurode r mitis>aPek%emPneurode r mitis>besp r.med >. Accessed
April #9 #")).
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