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SideEffects
Irritation,erythema, anddrynessinitiallycanoccurwithfirsttimeuse.Alternatingdayswheninitiating
therapycanberecommended.
SpecialConsiderations
Thisagentisamilder,lessirritatingtopicalthanmostBPOpreparations.Itsusealongwithamoisturizer
priortoapplicationpreventsoverdryingandirritation.
Dapsone
MechanismofAction
Drugproperties ofdapsone(Aczone)include bothantiinflammatoryandantibacterialactivity, although
theexactmechanismofactionisnotwellunderstood.
Dosage
Dapsoneisappliedoncedailywithotheracneagentsortwicedailyasasingleagent.Itisadministrated
tobothadolescentsandmiddle-agedfemales.
Contraindications
Hypersensitivitytoanyingredientshasbeennoted.
SideEffects
A rare but potentially lethal side effect is methemogloinemia. This condition results in an abnormal
productionofredbloodcellprotein,whichdeliversoxygenthroughoutthebody.
SpecialConsiderations
Cautionmustbe exercised when using dapsonewith topical BPOproductsdue to theformationof an
orange-browndiscoloration.Thisiseasilywipedawaybutmaybeconcerninginitially.Oraldapsonehas
been indicated in dose-related hemolysis in patients with a glucose-6-phosphate dehydrogenase
deficiency.
TopicalAntibiotics
Topical antibiotics may be prescribed when comedolytic antibacterials are either not effective or not
toleratedandsystemicantibioticsarenotdesired.TopicalantibioticsinhibitthegrowthofC.acnes and
decreasethenumberof comedones, papules, andpustules. Clindamycin1% (Clindagel)issupplied in
solutions, saturated pads, lotions, and gels. Rarely, topical clindamycin has been implicated in
pseudomembranouscolitisandregionalenteritis. Thepractitionershouldadvisepatientstodiscontinue
therapy if diarrheadevelops. Toavoidresistanceand toimproveresults, thepractitioner maysuggest
washing with BPO and then applying clindamycin. The combination of BPO and clindamycin used
together has been shown to prevent drug resistance and improve results. Now a novel topical foam
minocycline4%(Amzeeq)formulationisavailablebyprescriptionandappliedoncedaily.
OralAntibiotics
MechanismofAction
Whenimprovement cannot be achieved withtopical therapy,oral antibioticsmaybeconsidered. Oral
antibiotics are indicated for inflammatory acne because they suppress C. acnes, as well as inhibit
bacteriallipases,neutrophilchemotaxis,andfollicularplugging.
Tetracycline
Althoughtetracyclineisrarelyusedfirstlineduetogastrointestinal(GI)upset,itsderivativesdoxycyline
andminocyclineareusedfor treatinginflammatoryacne.Newerweight-based once-dailyformulations
minocycline(Ximino)areavailable,aswellasasmall-to-swallowdoxycycline(Targadox),providinga
widerangeofoptions.
Dosage
Doxycyclineandminocylinedosesareadministeredat50,75,100,and200mg/dandaretaperedto100
mg/d after improvement occurs. Clinical improvement takes at least 3 to 4 weeks. Ximino, brand
minocycline, is available as 45, 90, and 135 mg tablets taken once daily as weight-based options.
Targadoxisavailablein50-mgtablets.
Contraindications
Thecontraindicationnotedishypersensitivitytoproductscontainingtetracyclineanditsby-products.
SideEffects
Thesideeffectsofthetetracyclineclassincludephotosensitivity,gastricirritation,blooddyscrasias,and
pseudotumorcerebri(benignintracranialhypertension).Cautionshouldbeexercisedintreatingpatients
whohaverenalfailureorwhoareconcurrentlytakingdigoxinbecausetetracyclinemayincreaseserum
digoxinlevels.
SpecialConsiderations
Tetracyclinepermanentlystainstheteethinchildren,soitshouldnotbeprescribedforpatientsyounger
than12 years ofage.Moreover,thedrugisa teratogen.Itmayalsodecrease theeffectiveness oforal
contraceptives. Therefore, caution should be exercised when prescribing it for sexually active female
patients.Patienteducationshouldincludedirectionstoavoidconcurrentingestionofdairyproducts,iron
preparations, and antacids which decrease absorption. Ideally, the medication should be taken on an
emptystomach.
Sun protection should be encouraged due to sun sensitivity. Long-term use of these agents is not
recommendedduetodrugresistance.Changeoftherapytooralisotretinoinifnotimprovedafter three
monthsoforalantibiotictherapyshouldbeconsidered.Difficult-to-treatacnemayalsorespondtoother
lessoftenusedantibioticsincludingbutnotlimitedtocephalexin(Keflex)orsulfamethoxazole/trimethoprim(BactrimDS)whenotheragentshavenotdemonstratedimprovement.
Trimethoprim/Sulfamethoxazole
Trimethoprim/sulfamethoxazole has been used successfully in patients with acne refractory to other
antibioticsandingram-negativeacne.
OtherSystemicDrugs
Sarecycline(Seysara)
Dosage
Sarecycline (Seysara) was approved in 2018 and is available as 50-mg tablets. This tertracyclinederivedantibioticiseffectiveformoderatetosevereacnevulgaris.
Erythromycin
Erythromycinanditsderivativesarealternativeswhentetracyclinefailsorisnottolerated.Theycanalso
be used when the patient is younger than age 12. A common side effect is GI upset. There are drug
interactionswithdigoxin,theophylline,andcyclosporine.
Dosage
Availableindosesof250,333,500,and1,000mg/d,erythromycincanbeaseffectiveastetracycline.It
ishelpfulintreatingthoseindividualswithtetracyclineallergy.
OtherSystemicDrugs
RetinoicAcidDerivatives:Isotretinoin
MechanismofAction
Isotretinoin (formerly Accutane, now Absorica) has changed the management of acne therapy. It is
reservedforpatientswithseverenodulocysticacnewhenothertreatmentshavefailed.Isotretinoinisa
retinoic acid derivative. Although the exact mechanism is unknown, it decreases sebum production,
follicularobstruction,andthenumberofskinbacteria.Italsohasanantiinflammatoryaction.
Dosage
Isotretinoinisgivenatadoseof0.5to1mg/kg/d.Therapycontinuesfor20to24weeks.Iftherapyneeds
toberepeated,6monthsshouldelapsebeforerestartingthedrug.Isotretinoinisavailablein10-,20-,and
40-mgcapsulesusuallytwicedaily.
Contraindications
Becauseisotretinoinisassociatedwithseriousbirthdefects,onlyprescribers registeredintheiPledge
programmayprescribe thedrug.Thisprogramwasestablishedto preventpregnancyfor thecourse of
therapy and 1 month after. Female patients are required to consent to pregnancy prevention and/or
contraceptionwhileondrugtherapy.
AdverseEvents
The most significant adverse effect of isotretinoin is teratogenicity. A 25-fold increase in fetal
abnormalitieshasbeendocumented.Evenwithoutexternalabnormalities,approximately50%ofchildren
exposedtoisotretinoininutero hadsubnormalintelligence.Approximately25% ofpatientsexperience
cholesterolandtriglycerideelevations.
SpecialConsiderations
Itisrecommendedthatthisdrugbeprescribedbyadermatologist.Twonegativepregnancytests1month
apartpriortoinitiationofthedrugarerequired.RegistrationwiththeiPledgeprogramismandatory,and
monthlypregnancyscreeningshouldbeperformedwhileonthisdrug.Obtainingmonthlypregnancytests
duringtherapyismandatoryforallfemalepatientsofchildbearingpotential.
Beforeinitiatingtherapy,baselineCBC,chemistryprofile,fastingtriglyceride,andcholesterollevels
shouldbeobtained.Inaddition,arepeatCBCandachemistryprofile shouldthenbeobtained1month
afterthestartoftherapyandaftereachdosageadjustment.Pregnancyshouldbeavoidedatleast1month
after therapy is discontinued. Pseudotumor cerebri has been reported when isotretinoin therapy is
combined with oral antibiotics, that is, tetracycline. Almost all patients report dry skin and mucous
membranes,includingcheilitis,severedryskin,anddifficultywearingcontactlenses.Othersideeffects
includemusculoskeletalachesandcornealopacities.Therapyshouldnotbeinitiatedinadolescentswho
havenotcompletedgrowingduetoconcernregardingprematureclosureoftheepiphyses.
Ablackboxwarningwasaddedin2002,warningofanincreaseinaggressiveorviolentbehaviorsin
patients;consentisrequiredthroughtheiPledgeagreementforallpatients(maleandfemale)regarding
depressivesymptoms.
OtherMedications
TopicalCombinations
MarketedasBenzamycin,thecombinationoferythromycin3%andbenzoylperoxide5%ingelbasemay
increase compliance when a topical antibiotic is needed in addition to one or more other topical
medications.Thegelisapplied onceor twice daily. Althoughtheproductrequires refrigeration,small
quantitiesmaybetransferredtoanothercontainerforupto10days,whichtendstopromotetherapeutic
adherence.
Similarly,acombinationofclindamycin1%andBPO5%gel(BenzaClinGel,DuacGel)isavailable.
UnlikeBenzamycin,theseproductshaveashelflifeof3monthsatroomtemperatureanddonotrequire
refrigeration.Additionally, newer topicalagentsareavailable withvaryingpercentagesofeachactive
agent. This allows for increased use in different skin types, especially those with more sensitive
complexion.Clindamycin1.2%/Tretinoin0.25% (Veltin,Ziana),Adapalene0.1%/BPO2.5%(Epiduo),
and Adapalene 0.3%/BPO 2.5% (Epiduo forte) are just a few of the options now available. Other
benefitstousingcombinationproductsincludereducingsideeffectsandpreventingdrugresistancewith
theindividualproducts.
HormonalTherapy
Oralcontraceptivescanbeusedinwomenwhenconventionaltopicalandsystemictherapieshavefailed.
This will be discussedinChapter55. Oral contraceptives thatcontainethinylestradiol,levonorgestrel,
andnorgestimateordrospirenoneareeffectiveinthetreatmentofacne.Someotheroral contraceptives
mayexacerbateacne.Relativetoothertherapies,oralcontraceptivesareinexpensive.Theyreduceboth
come-donal andinflammatoryacnes and are worthconsidering for women who are alreadytaking or
consideringtakingsystemiccontraceptives.
Spironolactone
MechanismofAction
Originally marketed to treat hypertension, spironolactone (Aldactone) is a potassium-sparing weak
diureticandandrogenblocker. It is areliable optionfor treatmentinadultwomenwithcyclicpainful
hormonalacne,particularlyatthejawline.Long-termeffectivenessandtolerabilityhaveproventhisagent
tobeareliableandsafeoption.Althoughnolongerrequired,annuallaboratorymonitoringforpotassium
levelsmaybeperformed.Educationregardingconcernsfor hyperkalemia shouldbe discussed priorto
therapy.Pregnancypreventionisimportantwhileusingthisdrugtherapy.Usually,improvementisevident
within3monthsofuse.
Dosage
Startingdosagecanbe25to50mgandthencanbeincreasedifnecessarytomaximum200mg/d.Longtermusehasproveneffectiveinmanagingadultfemaleacne.
SideEffects
GIupsetmaybeexperiencedinadditiontodrymouthanddizziness.Gynecomastiaandirregularmenses
havealsobeenreportedaspossiblesideeffects.
SelectingtheMostAppropriateAgent
Themostimportantconsiderationinselectingatherapeuticregimenismatchingtheseverityoftheacneto
theappropriatepharmacologicagent(Figure15.1andTable15.4).
First-LineTherapy
Thefirstlineoftherapyforcomedonalacneistopicalmedication.Topicalcomedolyticsencouragefaster
turnover of the surface skin. The addition of bacteriocidal or topical antibiotics enhances results for
patientswithclosedcomedonesandpustules.
FIGURE15–1Treatmentalgorithmforacne.
TABLE15.4
RecommendedOrderofTreatmentforAcne
Order Agent Comments
Firstline Topicaltherapy Improvementtakes
~6weeks.
Secondline Oralmedications Monitorin6weeks
Thirdline Isotretinoinorrefer Prescribewithcaution
todermatologist towomenof
childbearingage
Second-LineTherapy
Patientswhoseacnedoesnotrespondtotopicaltherapymayneedoralmedications.Thepractitionermay
initiatetreatment withoralantibiotics inadditionto topical medications for more severepapulocystic
acne.Oralcontraceptivesareausefulandcost-effectivealternativeforsexuallyactivewomen.
Third-LineTherapy
Isotretinoinisreservedforthemostsevereformsofnodulocysticacne.Specialcaremustbetakenwhen
prescribingthisagentforwomenwhocanbecomepregnant.Practitionerswhoarenotregisteredinthe
iPledge program or who cannot comply with the necessary monitoring and follow-up may feel more
comfortablereferringthepatienttoanindividualwhois,forevaluationandtreatment.
SPECIALPOPULATIONCONSIDERATIONS
Pediatric
Because of the risk of dental enamel defects and bone growth retardation, the use of tetracycline is
contraindicatedinchildrenyounger thanage12. Growthretardationinchildrenwhohave notreached
adultheightisassociatedwithisotretinoinuse.Childrenmayalsoexperienceincreasedarthralgias and
backpainwiththeuseofisotretinoin.
WomenofChildbearingAge
Women of childbearing age who are using isotretinoin or tazarotene gel must not become pregnant
becauseoftheteratogenicityofbothproducts.Practitionersmaysuggestthatalong-actingcontraceptive,
such as Depo-Provera, be used. If pregnancy occurs, the patient must be counseled accordingly.
Tetracycline,alsoconsideredteratogenic,maydecreasetheeffectivenessoforalcontraceptives.Women
takingthisantibioticshouldrelyonalong-actingcontraceptiveorabarriermethodtopreventpregnancy.
Topicalretinoicacidisnotrecommendedforuseinpregnantwomenornursingmothers.
Ethnic
Azelaicacidmaycausehypopigmentationinpatientswithdarkskin.
MONITORINGPATIENTRESPONSE
Follow-upshouldbescheduledmonthlytomonitorthepatient’sresponsetotherapy,providereassurance,
andencourageadherenceto therapy. Monthlyvisits provide the opportunity to adjustmedicationsand
dosagesasthepatient’sacnerespondstotreatment.Theidealmanagementislong-termtopicaltherapy.If
isotretinoinisprescribed,laboratorytestsshouldbeobtainedbeforetherapyand1monthintotherapy,as
describedpreviously.
PATIENTEDUCATION
DrugInformation
Thepractitionermayshowthepatienthowtoapplytopicalpreparationscorrectlytopreventexcessive
irritation (Box 15.1). An important consideration in prescribing topical therapyis thatmany gels and
solutionscontainsignificantamountsofalcohol.Ifapatientissensitivetoalcohol-basedpreparationsor
isexperiencingsignificantdrynessdespitelowconcentrationsofactiveingredients,thepractitionermay
consider switching to a preparation thatdoes not containalcohol, such as a creamor aqueousgel or
lotion.
Box15.1 GeneralPrinciplesforApplyingTopicalAcnePreparations
• Initiate therapy with a lower concentration of active ingredient and then work up to a higher
concentrationastolerated.
•Chooseaproductwithalowerpercentageofalcoholforpeoplewithsensitiveskin.
•Applytheproducttoclean,dryskin.Allowatleast20minutestoelapsebetweenwashingtheface
andapplyingthemedication.
•Usethesmallestamountofmedicationnecessaryforcoverage.
•Applyin“dots”overthedesiredareaandthengentlymassageintoskin.
•Applyonedryingagentinthemorningandanotherintheeveningtoavoidexcessiveirritation.
Nutritionalfactorsmayplayanimportantroleinthepathogenesisofacne.Adietwithalowglycemic
load, higherinproteinthancarbohydratesandfats,candecreaselesioncountsinacnevulgaris. Alow
glycemic–load diethasalso beenassociated witha reduction incalorie intake,body mass index,and
insulin resistance. Improved insulin sensitivity leads to a decrease in androgen production and a
concordantimprovementinthesymptomsofacnevulgaris.
Patientsshouldbecautionedtoavoidusingexcessiveamountsoftopicalmedicationsinthehopethatit
will speed improvement. Instead, irritation will most likely be the result, and that may discourage
continuationoftherapy.
Patienceisthekeytoresolutionofacne.Adolescentslookingforaquickcuremaybedisappointed,so
thepractitionershoulddiscussrealisticexpectationsforimprovementwiththepatient.Allformsofacne
therapyrequireaminimumof4to6weeksbeforeresultsareseen.Itisimportanttoprovideappropriate
follow-upandencouragementandtohavethepatientreturnforevaluationandrefinementofthetreatment
program.
Patient-OrientedInformationSources
TheWebsiteswww.acne.organdwww.nih.gov/medlineplus/acne.html(asitefromtheNationalInstitutes
ofHealth)provideinformationaboutacneandtreatment.
COMPLEMENTARYANDALTERNATIVEMEDICINE
Zincisinvolved inthemaintenance ofskinhealthandimmunefunction,local hormoneactivation,and
production of retinol-binding protein. It has shown some bacteriostatic action against C. acnes and
inhibitoryactionontheproductionofretinol-bindingprotein.
Anotherproductthathasbeenshowntoimproveacneseverityisteatreeoil.Ithaslessskinirritation
thanbenzoylperoxide.Asolutionof5%to15%isappliedoncedaily.
Witchhazelisinexpensiveandlessdryingthanalcoholandcanbeusedasatonerforthoseindividuals
with oily skin. Nicotinamide is a member of the vitamin B group. More specifically, a form of B
3
complexisavailableina4%topicalcreamoranoraldietarysupplement.Nicomideisagenericvitamin
that includes zinc, copper, and folic acid taken once or twice daily. It is believed to decrease
inflammationintheskinwhichsubsequentlyreducesacnelesions.
ROSACEA
Occasionallymistakenforacnevulgaris,rosaceais anacneiformdisorder thatbegins inmidlife(ages
30–50).Itisestimatedthatrosaceaaffectsover16millionpeoplebytheNationalRosaceaSociety.The
rashissymmetricandlimitedtothecentralpartoftheface.Fair-skinnedpeoplewithatendencytoblush
aremoreoftenaffected.Althoughrosaceaismorelikelytodevelopinwomen,menwhoareaffectedmay
haveamoresevereformofthedisorder.Rosaceaisnotfrequentlyseeninskinofcolorbutdoesoccur.
CAUSES
Rosaceadoes nothaveaclearcause.Varioustheoriessuggestbacterialinfection,fungalinfection,mite
(Demodex folliculorum) infestation, menopausal changes, and more recently Helicobacter pylori
infection.Sunexposure,heat,excessivewashing,andirritatingcosmeticsmayexacerbaterosaceaalong
withothertriggerssuchasalcohol,hormones,stress,andspicyfoods.
PATHOPHYSIOLOGY
Early vascular rosacea consists of simple erythema in response to cold exposure. Extravascular fluid
accumulates.Asaresult,bloodflowtothesuperficialdermisincreases.Persistenttelangiectasiaoccurs
lateinthevascularstageofthedisorder.Duringthisperiod,ocularinvolvementmaydevelop,consisting
ofmild conjunctivitis, dryeyes,burning,blepharitis,andoccasionallykeratitis andcorneal ulceration.
Thesecondstageofrosacearepresentslymphatic failure.Itresultsinepidermalepithelialhyperplasia
andpilosebaceous gland hyperplasia with fibrosis, inflammation, and telangiectasia. Clinical changes
include persistent erythema, telangectasia, papules, and pustules. Rhinophyma, the characteristic deep
inflammation and connective tissue hypertrophy of the nose, may begin to develop during this stage.
Rhinophymaisalmostexclusivelyseeninmenolderthanage40andistreatableonlybylaserorsurgery.
Late-stage rosacea is recognized by persistent deep erythema, dense telangiectases, papules, pustules,
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