Dermatologia
www.anaisdedermatologia.org.brCONTINUING
MEDICAL
EDUCATION
Severe
bacterial
skin
infections
夽,夽夽
Sílvio
Alencar
Marques
,
Luciana
Patrícia
Fernandes
Abbade
∗FaculdadedeMedicina,UniversidadeEstadualPaulista,Botucatu,SP,Brazil Received14April2020;accepted25April2020
Availableonline16May2020
KEYWORDS Bacterialinfections; Ecthyma; Fasciitis,necrotizing; Fourniergangrene; Furunculosis; Methicillin-resistant Staphylococcus aureus
Abstract Theseverebacterialdiseasesdiscussedhereinarethosethatpresentdermatological lesionsastheirinitialmanifestations,forwhichthedermatologistisoftencalledupontogivean opinionoriseventhefirsttoexaminethepatient.Thisreviewfocusesonthosethatevolvewith skinnecrosisduringtheirnaturalhistory,thatis,necrotizingfasciitis,Fourniergangrene,and ecthymagangrenosum.Noticethatthemoredescriptiveterminologywasadopted;eachdisease was individualized,rather thanbeingreferred by thegenericterm ‘‘necrotizingsoft tissue infections’’.Duetotheirrelevanceandincreasingfrequency,infectionsbymethicillin-resistant Staphylococcusaureus(MRSA)werealsoincluded,morespecificallyabscesses,furuncle,and carbuncle, andtheirpotentialetiologiesby MRSA.Thisarticle focusesontheepidemiology, clinical dermatologicalmanifestations, methods ofdiagnosis, andtreatmentofeach ofthe diseasesmentioned.
©2020SociedadeBrasileira deDermatologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
Introduction
This article aims to review severe infectious conditions caused by bacteria that, either due to skin involvement as a primary manifestation, or due to a skin manifesta-tion that indicates severe systemic involvement, must be considered as mandatory knowledge for dermatologists,
夽 Howtocitethisarticle:MarquesSA,AbbadeLPF.Severe
bacte-rialskininfections.AnBrasDermatol.2020;95:407---17.
夽夽StudyconductedattheFaculdadedeMedicina,Universidade
EstadualPaulista,Botucatu,SP,Brazil.
∗Correspondingauthor.
E-mail:fernandes.abbade@unesp.br(L.P.Abbade).
regardlessof theirmain areaofexpertise. Currently, sev-eralauthors,particularlyinthefieldofinfectiousdiseases and surgery, prefer to use the term necrotizing soft tis-sueinfections(NSTIs),whichincludesthevariousinfections that evolve to skin necrosis, such as necrotizing fasciitis (NF), Fournier gangrene, Meleney’s synergistic gangrene (post-operative),gas gangrene, necrotizing cellulitis, and myonecrosis.1---3 However,for greater clarityand consider-ing the prevalence of these conditions, the study adopts theclassic terminology ofNF andFournier gangrene,and includes ecthymagangrenosum (EG) andcutaneous infec-tionscausedbymethicillin-resistantStaphylococcusaureus (MRSA),withemphasisonfurunculosis andabscesses.The review of thehost’s defense mechanisms,bacterial resis-tancetoantibiotics,virulence,andmicrobiome is beyond https://doi.org/10.1016/j.abd.2020.04.003
0365-0596/©2020SociedadeBrasileiradeDermatologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BYlicense(http://creativecommons.org/licenses/by/4.0/).
thescopeofthisarticle;therefore,onlytheessential mech-anismstounderstandtheetiologyandphysiopathogenesisof thediseaseunderdiscussionwereincluded.
Necrotizing
fasciitis
NFisanunusual,acute,fast-progressinginfectiousprocess thatevolves withsuperficialand evendeepmusclefascia necrosisofthesubcutaneoustissue,dermis,andepidermis, andcanprogresstosepsis,shock,anddeathinupto40%of cases.4,5 Underthename‘‘hospitalgangrene,’’this condi-tionwasdescribedinthe19thcentury,withthepublication, in 1871,of 2642 cases observed by surgeonJoseph Jones oftheConfederatearmyduringtheAmericancivilwar, as mentioned by Faraklas et al.3 In 1952, American surgeon B.Wilson coined the term necrotizing fasciitis, currently inuniversaluse,todesignatetheinfectiousprocessesthat progressthroughtheplaneofthesuperficialmuscular fas-ciaandthatevolvetonecrosisofthesubcutaneoustissues totheepidermis,andeventothedeepfasciaandmuscular plane.6
Intheabsolutemajority ofcases,NFstartsby inocula-tionofthepathogenorpathogensthroughinjurytotheskin resultingfromtrauma,perforatinginjuries,human or ani-malbites,insectbites,smallprocedures,catheterinsertion, injectionof medication or illicit drugs,and post-varicella complications, amongothers, includingcontusion without lossof continuityin theskin.7---11 The most common topo-graphiclocationofNFisthelowerlimbs,butinvolvement oftheupperlimbs(includingthehands),head,face,neck, andtrunkarenotexceptional.11---15 The conditionpresents nopredilectionfor sexorage, beingobserved inchildren and young people, but it is more frequent in adults and elderlyy.The main predisposing factors areage, diabetes mellitus,obesity,alcoholism,malnutrition, immunosuppres-sion, chronic kidney or liver disease, peripheral vascular disease,and chronic use of illicit drugs, but it may even occur in seemingly healthy individuals.10---12 Recently, NF hasbeen reportedinassociation withtheuse oftargeted therapies,suchastyrosinekinaseinhibitors;however,the cause-effect relationship inthe reportedcases is difficult to define, given the presence of several possible cofac-torsinthesepatients.16Fromanetiopathogenicstandpoint, theconditionprogressesrapidlyduetotheactionof endo-andexotoxinsproducedbytheinfectingbacterialspecies, evolving to obliterating endarteritis, local microcircula-tory thrombosis,and necrosis.4,7,12 If the condition is left untreated,is treated late, or is only treated clinically, it can evolveto toxemia,sepsis, disseminated intravascular coagulation,multipleorganfailure,anddeath.7,11,12
A widely used NF classification designates as type I thedisease caused bya synergistic association ofaerobic or anaerobic bacteria; therefore, polymicrobial necro-tizing fasciitis, which includes Group A Streptococcus, Staphylococcus aureus or other species of Staphylococci, Escherichia coli, Klebsiella spp., and, less often, other Gram-negative bacteria.4,7,17 The estimated frequency of this type Iranges from70% to80%.4 Type II NF, which is monomicrobial, isalso termed‘‘streptococcal gangrenous cellulitis.’’ItiscausedbyGroupAbeta-hemolytic strepto-cocci(alsotermedflesh-eatingbacteria),anditsfrequency
is estimated between 20% and 30% of NF cases.7,18,19 The most frequent species of Streptococcus is Streptococcus pyogenes serotypes M1 and M3, which have the ability to modify the host’s phagocytic defense response, pro-ducehemolysinsandexotoxinswithsuperantigenproperties and,consequently,induceexcessiveproliferationofT lym-phocytes and release of pro-inflammatory cytokines.7,20 These act as triggers for the streptococcal toxic shock syndrome,whichcanoccurinupto14%ofsevere strepto-coccalinfectionsandareassociatedwithhighmortality.7,19 It is important to remember that septic shock is a syn-dromicconditiontriggeredbyasevereinfectiouscondition, eitherbyGram-positiveorGram-negativebacteria,andthat resultsinthereleaseofpro-inflammatorymediators, includ-ing TNF-alpha, produced by monocytes, neutrophils, and macrophages, whichinduce vasodilation, extravasation of plasmafromthevessels,cardiacmalfunction, immunosup-pression,andmultipleorganfailure.7,20Itisnotuncommon forStaphylococcusaureusorotherspeciesofstaphylococci tobeassociatedwithstreptococcalinfection,potentiating itsdeleteriouseffects.21
Theinitialclinicalmanifestationmaybesubtleand dis-creet,witherythema,edema,andlocalheatsuggesting a pictureoferysipelaorcellulitis,whichdelaysthediagnostic suspicionrelatedtoseverity.However,pain disproportion-atetotheapparentbenignityoftheconditionisnoteworthy. As a rule, there is a rapid evolution (in 24---72h) to an erythematous-violaceouscondition;thelimitsofthelesion are lost, hemorrhagic vesicles are observed, and infiltra-tionisidentifiedbyfirmtissueinduration,edema,andpain beyondthenoticeablelimitsoftheerythema(Figs.1and2). Subsequently,areasofpallorareobserved;thepain disap-pearsor ismarkedlyreducedasaresultofthenecrosisof thelocalnervebranches.Inadditiontothese dermatologi-calsigns,generalsignsoffever,lethargy,mentalconfusion, toxemiaand,potentially,sepsisandshockareobservedin variousdegrees.Asaconsequenceofthromboembolismof thelocal/regionalmicrocirculation,thereispracticallyno bleedingduring thebiopsy procedure or localexploratory surgicalincision(Fig.3).Dependingonthedurationofthe clinical history,signsofcutaneousemphysemaanda foul-smellingdischargemaybeobservedduringtheprocedure, indicating tissue necrosis. Computed tomography (CT) or magneticresonanceimaging(MRI)areusefultodemonstrate thepresenceofsubcutaneousedema,fasciathickening, col-lectionofpurulentmaterial,andeventhepresenceofgas, an evidence of severitythat distinguishesNFfrom severe cellulitis.22---24Deepincisionalbiopsy,downtothefascia,or frozen cuts for quick analysis, may also be useful. How-ever, requesting and waiting for such procedures require time,which canbecrucialfor thesecases. Ifthe diagno-sisisnotestablishedorifappropriateinterventionsarenot instituted,signsofsepsismanifestthemselvesbetweenthe fourth andsixthday ofinfection,and maybeanticipated orpostponed.Therefore,diagnosticsuspicionbasedonthe history and clinical and dermatological examination must beraisedasearlyaspossible,prescribingbroad antibiotic coverageandindicatingsurgicaldebridement.
The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC), proposed by Wong et al. in 2004, is a scoring systemthatcanbeausefuldiagnosticaid,despitethelack
Figure1 Necrotizingfasciitis.(A)Overviewshowingtheextentofdamageanddifferentclinicalstages.(B)Detailofthepale, erythematous-violaceous,painfuldevitalizedarea.Blisterwithhemorrhagiccontentandmarginalerythemainthestillviablearea. (C)Demonstrationofthenecessarywideningofsurgicaldebridement.
Figure2 Necrotizingfasciitisaftermanipulationoffurunculoidmyiasis.(A)Presenceofedema,milderythema,andextensive areaofnecrosis.(B)Debridementproductinwhichnecrosisfociarestillobserved.
Figure 3 Necrotizing fasciitis ofthe medialaspect of the thigh with a consolidated, devitalized lesion; upon incision, almostnobleedingwasobservedduetothrombosisofthe per-foratingvesselsfromthefasciatotheepidermis.
ofconsensusonitsspecificity. TheLRINEC usesdatafrom c-reative protein (CRP), leukogram, hemoglobin, serum sodium,creatinine,andglycemiacollectedwhenthepatient is first seen or when NF is first suspected, which are graded according totheintensity of the detected labora-toryalteration.Afinalscoreof6wouldbeequivalenttoan intermediateriskofNFandscoresequaltoorgreaterthan 8areindicativeofahigh riskofNF(Table1).25,26 In addi-tiontothis laboratory data, itis important togather the informationobtainedfrommanipulationofthelesionbya surgeoninordertopreliminarilyinciseandexposethe tis-sue,andtoevaluatethepresence ofgrossnecrosisof the fasciaandwhetherthefasciacanbeeasilydetachedfrom itssuperiorplanes.Incaseofsuspicion,biopsyandculture oftissuefragmentsshouldbeperformedandbloodculture shouldbecollectedmorethanonce.
The differentialdiagnosisincludes infectiousconditions of the skin, subcutaneous tissue and muscle, including erysipelasandsevere,bullouscellulitis,abscesses,infected hematoma,pyodermagangrenosum,pyomyositis,gas
gan-Table 1 Laboratory data indicative ofrisk for the diag-nosis ofnecrotizingfasciitis (LaboratoryRiskIndicator for NecrotizingFasciitis[LRINEC]).
Parameters Values Score(%)
Hb (g/dL) >13.5 0 11---13.5 1 <11.0 2 Leukocytes (109/L) <15 0 15---25 1 >25 2 Sodium(mmoL/L) <135 2 Creatinine(moL/mL) >1.41 2 Glucose >100 1 C-reactiveprotein >15 4
AdaptedfromWongetal.(2004).25 Thesumofscores<5,≤50%risk(lowrisk).
Between6and7=intermediaterisk;>8=75%risk(highrisk).
grene,andpostoperativeorpost-procedureinfection.The semiologicalknowledge,andthepeculiaritiesof dermato-logicalandclinicalhistoryaidedbylaboratorydata,shown intable1,raisediagnosticsuspicionandallowclinical diag-nosis.
Antibioticcoverageshouldbeinstitutedimmediatelyin the face of suspicion; it is not necessary to wait for a final diagnosis. The antibiotic therapy should be able to cover, albeit empirically, polymicrobial NF, acting against Gram-positive,Gram-negative,andanaerobicbacteria.An attempted analysis through systematic review, using the Cochranemethodology,didnotresultindefinitive informa-tionregarding antibiotic therapy in necrotizing infections affectingsofttissues.27Insummary,thoseauthorsconcluded that:‘‘Thereisnoempiricalantimicrobialtherapyvalidated by clinical trial. ... topics (items) should be considered,
Figure 4 Necrotizing fasciitis in a nursing infant after an attempt tosqueeze drippingmilk from thenipple. The area wasdebrideduntilthemuscleplane,withremovalofthefascia. Presenceofinfectiousactivityanareaofthechest.
amongwhichtheantimicrobialstrategyinpatientswithor withoutcomorbiditiesandinpatientswithariskfactorfor MRSAinfection.’’27
Basedonliteraturedataandthepersonalexperienceof theauthors,theuseofoneofthefollowingschemesis sug-gested:(1)Piperacillinsodium+tazobactansodium(active againstGram-positive, evenifproducers of -lactamases, active against Gram-negative, not active against MRSA), + vancomycin (active against MRSA)+clindamycin (active against Gram-positive aerobic and anaerobic bacteria).7,9,11,17---19,21 (2) Imipenem/meropenem (of the carbapenem class; active against Gram-positive, even if producers of -lactamases,active againstGram-negative, not active against MRSA)+vancomycin+clindamycin. (3) Cefepime (fourth-generation cephalosporin; active againstGram-positive, evenifproducers of -lactamases, active against Gram-negative, not active against MRSA), + vancomycin+clindamycin. The results obtained from culture/bloodcultureandantibiogrammayleadto adjust-mentsintheproposalsabove,particularlyintheassessment oftheneedtoassociateanantibioticoftheaminoglycoside classtothescheme.Ifnecessaryorconvenient,clindamycin can be replaced by metronidazole 1g every 12h, intra-venously.Itis importanttonote thatseveralof thedrugs listed above require correction for creatinine clearance when indicated; in children below 40kg or neonates, the dosemustbeadjusted.
Associated with antibacterial treatment, surgical debridement is also an essential emergency procedure (Figs.1Cand2B).Itisnotuncommonforthedermatologist tohave to convincethe emergency surgeons of the need fortheprocedure.Thedebridementmustbewide,excising all necrotic subcutaneous tissue including the fascia, and going beyond the gross necrosis as a safety margin (Fig. 4).1,2,7,11,17 It is necessary to assess whether there is associated myonecrosis and whether the involved limb mustbeamputated.Thesurgicalwoundmustremainopen andbereassessed in24h; ifnecessary,the excision must beextended, as theinfectious process and thrombosisof thelocalmicrocirculationoftenprogressdespiteantibiotic therapy.
As an adjunct treatment to broad-spectrum antibiotic therapyandsurgicaldebridement,therearereportsofthe
useof intravenousimmunoglobulin(IVIG), hyperbaric oxy-gen therapy,and negativepressuretherapy (NPT). IVIG is mentioned asa treatment in casesassociated withseptic shock, duetothepossibilityofneutralizingtheformation ofsuperantigens.28However,aretrospectivecohortstudyof 164patientsconcludedthatIVIGhadnoapparentimpacton mortalityorlengthofhospitalizationbeyondthatachieved with debridement and antibiotics.29 Regarding hyperbaric oxygen therapy, a Cochrane systematic review failed to demonstraterelevantclinicalevidencetosupportorrefute theeffectivenessofthistherapyinNF.30Theliterature fea-tures manyarticles (primarily case reports and series)on theuseofNPT,amethodusedtoacceleratehealing; how-ever, randomized clinical trials to ensure its validity are lacking.31,32 It is important to emphasize that supportive andintensivecaremeasuresmustbeavailableandusedas indicated.Withthepatient’s recovery,thesurgicalwound canberepairedbylocalgraftingwhenthebottomisclean andtissuegranulationisobserved,orbyhealingbysecond intention.17Esthetic,functional,orsocialsequelaedeserve equalefforttobereducedorsolvedinthebestpossibleway.
Fournier
gangrene
In 1883, the French dermatologist Jean-Alfred Fournier (1832---1914), headoftheDepartmentof Dermatologyand SyphilographyattheHôpitalSaintLouisdeParis,reported aninfectionandrapidevolutiontonecrosisoftheperineum andscrotuminfivepatients;hetermedthisevolution gan-grènefoudroyantedelaverge,i.e.,rapidgangreneofthe penis.33,34Currently,thisconditionisrecognizedasavariant ofnecrotizing fasciitiswithan initialandspecificlocation in theperineum,genitalia, or perianalregion,and isnow knownasFourniergangrene.34 Itisan uncommondisease, whosemortalityratesrangefrom7.5%to22.5%ofcasesin different series.34---36 Itcan be confinedto thescrotum or extendtowardtheperineum,penis, pubis,andabdominal wall.Althoughmorefrequentinmales,whoaccountfor52% to100%ofcasesindifferentseries,itcanalsobeobservedin females.34---36 Theagegroupmostaffectedisthatabove50 yearsofage,butcasesinchildrenandadolescents,although very rare, have been described.34---36 In a review study of 40casesdiagnosedinBrazil,theauthorsidentifieddiabetes mellitusasthemaincomorbidity,presentin70%ofpatients, followedbysystemicarterialhypertension(35%),heart dis-ease(15%),anddyslipidemiaandobesityin7.5%.37Alcohol abuseandmalnutritionarealsomentionedaspredisposing factors. The triggering factors are varied; prior infection of the urinary tract, perianal infection, surgical manip-ulation (including postectomy), penile prosthesis, genital trauma (includingpenis-enlargement fillings), and scrotal traumaarelistedasthemostimportantandfrequent.34---39 Inwomen,traumas,microtraumasrelatedtohairremoval, episiotomy,andinfectionofthevulvarregionandperineum arementioned.34,35
Theetiologyispolymicrobialinmostcases,rangingfrom 54% to 80% in different series. The most common infec-tious agentisEscherichia coli,but bacteriaofthe genera Streptococcus,Bacteroides,Enterobacter,Staphylococcus, including MRSA, Enterococcus, Pseudomonas,
Corynebac-Figure5 Fourniergangreneonthevulvaafterhairremoval.Presenceofedema,erythema,andsignsofnecrosis.
terium, Klebsiella, or even Candida albicans are also common.Suchagentscanactaloneorinassociation.35,40---42 Fourniergangreneprogressesthroughthesuperficialand deepplanesoftheurogenitalandanogenitalfascia.34 The sequence of events mirrors that of classic cutaneous NF: infection,vascularocclusion,infarction,andtissue necro-sis.Theconditionprogressesveryquicklyinmales,asColles’ fasciaoftheperineum,Dartos’fasciaofthepenisand scro-tum, and Scarpa’s fascia of the anterior abdominal wall formacontinuum,allowingtheinfectiontoprogressthrough theseplanes.7,34
The initial condition is erythema and edema with increasedvolumeand,asinclassicalNF,isaccompaniedby painthatisdisproportionaltotheclinicalappearance.34,35,37 The sequence of dermatological signs can be described as edema, swelling, poorly defined erythema, violaceous erythema, and finally pallor and cutaneous necrosis, also identifiedincasesofvulvarlesions(Fig.5).
Clinical evaluation and diagnostic suspicion must be raisedasearlyaspossibleandtheinterventionmustnotwait for histological or microbiological confirmation. Although the diagnostic referral can be dermatological, the inter-ventionisurological,gynecological,andsurgical,aimingto removealldevitalizedtissue,andcombinedwithantibiotic coveragetargetedattheaforementionedpathogens.35,40---42 The antibiotic prescription cannot be mild: it must be intravenous and canbe summarized, as mentioned above for the NF, as the following options: (1) Piperacillin sodium+tazobactan sodium, + vancomycin+clindamycin. (2) Imipenem/meropenem+vancomycin+clindamycin. (3) Cefepime+vancomycin+clindamycin. As with NF, clin-damycin can also be replaced by metronidazole. Such measures,evidently,mustbeassociatedwithanalgesiaand care in an intensive care unit (ICU) setting. The progno-sis is variable.In a seriesof 40 cases in Brazil, mortality was 22.5% and was strongly correlated with the pres-enceofsepsisat hospitaladmissionandthe lengthofICU stay; theseresults wereverysimilar tothoseobservedin a recent study from Korea with 41 patients, where the mortality rate was22.0%.37,41 In a wideliterature review that compiled 1726 cases, the observed mortality rates ranged from 3% to 45%, with a median of 16%, and was mostly associated with sepsis and diabetes.35 Such data show the extreme importance of early diagnosis, spe-cialized intervention, and support in an intensive care unit.
Figure6 EcthymagangrenosumduetoPseudomonas aerug-inosa: multiple lesions at different stages of evolution in a patient undergoing chemotherapy for myeloproliferative dis-ease.
Ecthyma
gangrenosum
Thefirstmentionof ecthymagangrenosum(EG) appeared in1897inanarticlebyLFBarkeronclinicalmanifestations relatedtoaninfectioncausedbyBacciluspyocyaneus,which at the time was the denomination for the current Pseu-domonasaeruginosa.43Thename‘‘ecthymagangrenosum,’’ whichappearedin1951in apublicationbyRHBroughton, has since been of universal use and implies, conceptu-ally,the state of sepsis by P. aeruginosa.44 As knowledge evolved,EGbecameassociatedwithotherGram-negative, Gram-positivebacteria, and evenfungi, especially of the generaCandidaandFusarium.7,45Someauthorsreferto
non-P.aeruginosa casesasecthymagangrenosum-like,butthe main messageis that thedermatological manifestation is practicallyidenticaland,for diagnosticsuspicion,thefirst interventionshouldbedirectedtoP.aeruginosa whilethe etiologyofthediseaseisinvestigated.45,46
Clinically,it is characterized by the rapid evolution of alocalized lesion,initially vesiculobullousor papulonodu-lar,inanerythematous,edematousbackground,evolvingin 12---24htolocalsignsofskinnecrosisandanulceronecrotic lesion.45---49 These dermatological clinical manifestations correspondtotheinvasionofthevenulesbytheinfectious agent,withconsequentdamageofthevascularwall, induc-tionofthrombosisinthearterioles,inflammationprocess, edemaandvascularobstruction,andlocalizedskinnecrosis. Thelesionsaregenerallysmallinnumber,buttheycanbe multipleandatdifferentstagesofevolution(Figs.6---8).The
Figure7 Ecthymagangrenosum.Detailoftheinjuryobserved inFig.6.Presenceofrecent,clearlynecroticlesions.
Figure8 EcthymagangrenosumduetoPseudomonas aerug-inosa. Detail of ulceronecrotic lesion and active border, erythematous-edematous,infiltrated.
Figure9 EcthymagangrenosumduetoPseudomonas aerugi-nosainaninfantwithhithertounknownprimaryneutropenia. Erythema, edema, infiltration, necrotic lesion, and recent ulceratedlesion.
preferredlocationsaretheperineum,buttocks, inguinocru-ralfold(Fig.9),interglutealcleft,anddistalextremities, butlesionscanaffect any area,includingthe head,face, andneck.45,48---51Thegeneralclinicalpictureassociatedwith skin lesions may already indicate fever, toxemia, or sep-sis; it may even be observed in previously asymptomatic oroligosymptomaticpatients.52,53Thedifferentialdiagnosis ofskinlesionsshouldincludelesionsofseveresmallvessel leukocytoclasticvasculitis,sepsisskinlesions,disseminated vascular coagulation, and septic emboli associated with endocarditis. Although meningococcemia is mentioned in the literature as a differential of EG, purpura fulminans lesionsaredistinct:theyarepurpuric,net-likerashes with-outblisters.54,55
Inareviewstudyof167casesofEGreportedinthe lit-erature retrievedin PubMed, MEDLINE, and ScienceDirect between1975and2014,theauthorsidentifiedthatin73.6% of the total cases the agent was P. aeruginosa, in 17.3% anotherbacterium,andin9%theetiologywasfungal.Itis noteworthy that EG wasa manifestation of sepsis in only 58.5% of the cases where the agent wasP. aeruginosa.45 Thesedataarerelevant,astheydemonstratethatstarting theempiricaltreatmentaimingatPseudomonasisthe cor-rectconductwhile the realetiology is notidentified,and that EG can be a manifestation of bacteremia associated withastillstableclinicalpicture.
EG affects any age group, but childhood as a whole deserves particularattention, asthe youngerthepatient, thegreatertheseverityoftheprognosis.45,47,49
The predisposing factor is often immunosuppression and/orneutropenia,primaryorsecondarytochemotherapy. In patients with lymphoproliferative diseases undergo-ing chemotherapy, fungal etiology must be considered with a certain priority.45,49---51 In general, the most prevalent underlying diseases or clinical situations are: leukemia/lymphoma, other malignancies, severe burns, transplant patients, and patients on immunosuppressive therapy.45,49---51Inmorethanonecase,EGwasatelltalesign ofsevereinfectionbyP.aeruginosainthecontextofprimary neutropeniahithertohidden.47,49
Inthefaceofclinicalsuspicion,theetiologicaldiagnosis reliesonbloodcultureandcultureforbacteriaandfungiin a biopsyfragmentof thelesion, whichis collectedat the edgeoftheulcerorinanon-necroticarea.Theantibiogram ismandatoryandshouldnotbedismissed.Simultaneously, an eventualfocusfor theemissionofbacteremia mustbe identified,payingspecialattentiontothelungs.
Treatment should immediately target the most likely etiology, i.e., intravenous antibiotic coverage against P. aeruginosa, with the use of aminoglycosides, preferably amikacinat a dose of7.5---15mg/kg/dayIVor IM, divided intwoorthreeinfusions/applications.45,48 Inchildren,the recommended dose is 15---20mg/kg per day, witha max-imum dose of 1.5g, divided into IV infusions every eight hoursorIMevery12/12h.Thereisaneedfordose adjust-mentinsituationsofalteredcreatinineclearance.Theuse ofcarbapenemsisalsopossible.Ifimipenemischosen,the recommendeddoseis1---2g/dayIVinfusedeverysixhours. Inchildrenweighinglessthan40kg,therecommendeddose is15---25mg/kg/dayIV,dividedintoinfusionsevery6h,with amaximumtotaldoseof2g/day.Imipenemdosecorrection is required for patients withrenal failurewith creatinine clearancebelow50mL/min.Meropenemisthemostwidely used and recommended carbapenem at a dose of up to 6g/day, IV, divided into infusions every 6h. For children under 40kg, the dose is limited to20---40mg/kg per infu-sion,everyeighthours.Inpatientswithrenalimpairment, thedose shouldalsobecorrectedin lightofthe patient’s creatinine clearance. As for possible adverse effects, the potentialfornephrotoxicityandototoxicityassociatedwith aminoglycosidesingeneralisnoteworthy.
Surgicaldebridement ofthe lesionis auseful adjuvant methodinEG,butitisnotasessentialasinNFandFournier gangrene.45
EGprognosisdependsonthepatient’sgeneralcondition, immunological status,underlying disease and, in cases of
Skin
infections
caused
by
methicillin-resistant
Staphylococcus
aureus
(MRSA)
Inthe1880s,AlexanderOgstonfirstdetected Staphylococ-cusaureusfromapurulentabscessexudatelocatedonthe legofapatientand,in1884,FriedrichJuliusRosenbach for-mallyisolatedthisbacterium.57S.aureusisaGram-positive bacterium coccus thatis well adapted tothehuman host andthe healthcare environment.It ispart ofthe normal humanmicrobiota,oftenfoundontheskin,especiallythe armpit,inguinalregion,andinthenasalcavity,witha preva-lenceofaround25---30%.It isoneofthe mainagents that causeendocarditis,bacteremia,pneumonia,osteomyelitis, andskinandsofttissueinfections(SSTI),triggeringmildto fatalconditions.58
S. aureus has quickly become one of the main causes of hospital-related infections. Initially a bacterium sensi-tive to penicillin, resistance was observed in the 1940s, mediatedbythe-lactamase blaZgene.In 1960,thefirst semi-synthetic anti-staphylococcal penicillins were devel-opedand strains of MRSA were observed withinone year oftheirfirstclinicaluse.59,60
Until the 1980s, MRSA infections occurred in patients with known predisposing factors such as hospitalization, presenceofaninvasivedevice,historyofsurgery, hemodial-ysis, immunosuppression,or residence in a nursing home. Subsequently,MRSAinfectionswerereportedinhealthy pop-ulationswithoutriskfactors,i.e.,withnorecenthistoryof contactwithhospitalsorhealthservices,withanincrease inthe numberofreports inthe2000s.61 The MRSAstrains that caused infections in patients without the previously describedriskfactorswereshowntobedifferentfromthose in hospitals, giving rise to the term community-acquired MRSA (CA-MRSA).62 To differentiate hospital strains, the termhospital-acquiredMRSA(HA-MRSA)wasaddedforthose relatedtohealthcareservices.63
Resistance to methicillin occurs due to chromosomal segments present in some strains of S. aureus that carry the methicillin resistance gene (mecA), called SCCmec (staphylococcalchromosomecassettemec),beingdistinct in HA-MRSA (SCCmec types I, II, and III) and CA-MRSA (SCCmec types IV---XI).64 MecA expression conferred resis-tancetotheavailable-lactamantibiotics,whileresistance tonon--lactamantibiotics commonlyassociatedwith HA-MRSAisduetoavarietyofmechanisms.63Thefirstreportsof CA-MRSAinLatinAmericaweredescribedin2002and2003 insouthernBrazil.65
Essentially, CA-MRSA infections differ from HA-MRSA infectionsbythreemaincharacteristics:first,theaffected populations are younger and generally healthier, with no previously defined risk factors; second, presence of epidemicclones,classifiedasUSA300orUSA400;third, CA-MRSAclonescontainaresistancemechanism producedvia SCCmecIVa(presentin84%ofCA-MARSstrains)with produc-tionofPanton-Valentineleukocidin(PVL),whichdetermines greattissuedestruction,leadingtosevereSSTIandnecrotic
Figure10 MRSAfurunculosis.A healthy42-year-oldpatient withseveralabscessesandfuruncles.PositivecultureforMRSA withproductionofPanton-Valentineleukocidin(PVL).
pneumonia.66---69ItisimportanttohighlightthattheSCCmec IVpathway promotesresistance to-lactamantibiotics in general,butnottootherantibiotics,unlikeHA-MRSA infec-tions,whichgenerallyshowresistancetovariousclassesof antibiotics.70
Although CA-MRSA infection is not associated withthe riskfactorsforHA-MRSA,somegroupsareathigherriskfor developinginfectionbythisbacterialagent,suchasyoung adults,those incarcerated, African-Americans, illicit drug users,athletes,indigenous people,peoplewithHIV/AIDS, andmenwhohavesexwithmen.71
CA-MRSA is predominantly related to SSTI of varying degreesofseverity;itsometimesalsocausespneumoniaand severeandfatalboneandjointinfections.58,72
The termSSTI is generic andcan beappliedtoa wide varietyofinfectionsincludingimpetigo,folliculitis, furuncu-losis,cellulitis,andabscesses.Thefocusofthisreviewwill beoncasesoffurunculosisandabscesses,duetothe char-acteristicformationofpurulentcollectionsandexudation, whichareoftencausedbyMRSA.73
Furunclesmainlyaffectareasrichinhairfollicles,such asthearmpitsandtheglutealregion,withtheformationof abscessesinthehypodermis.Hairfolliclesarethegateway toS.aureus,favoringitsdevelopment.Itusuallypresentsas anerythematous,painful,andfloatingnodule,withpustules onthe surfaceand a drainage point.A single or multiple concomitantlesionscanbeobserved(Fig.10).
Carbuncle is thecoalescence oftwoor more furuncles in the same locus, with multiple drainage sinus tracts, which tends to extend more deeply into the hypoder-mis (Fig.11).Systemic symptomsare usuallypresent and
Figure11 Carbuncleinapatientwithinsulin-dependent dia-betesmellitus.Aninfiltratederythematous-winecoloredlesion, ulceratedwithareasofnecrosisandpurulentsecretion. regionallymphadenopathycanbeobserved.Carbunclecan appearanywhere with hair; however, it is more common intheposteriorcervicalregion,back,andthighs.74 Predis-posingfactorsforthedevelopmentoffuruncles,including recurrentfuruncle,areeczema,diabetesmellitus,alcohol use,malnutrition,immunodeficiency,obesity,poorhygiene, chronicMRSAcolonization,hyperhidrosis,andanemia.75
Cutaneousabscessesarefocalcollectionsofpuslocated in the dermis and hypodermis, which usually present as painful,erythematousnodules,oftensurmountedbya pus-tule and with an erythematous-edematous border. They oftenpresent withfloatingpoints or signsof spontaneous drainage.Intheearlystages andindeeper presentations, they may not show the classic fluctuation sign. In asso-ciation, cellulitis that extends radially from the purulent focusmaybeobserved.73 S.aureus is isolatedin approxi-mately60---75%ofcasesofuncomplicatedskinabscesses,of which50---70%areMRSA.Coagulase-negativestaphylococcus isthenextmostisolatedspecies,followedbyavarietyof -hemolyticstreptococcalspecies.76Riskfactorsforrecurrent abscesses include intramuscular injections; hair removal fromlegs,armpits,pubisandscalp;andprevious coloniza-tionorinfectionwithCA-MRSA.
The diagnosis of furunculosis andabscess is essentially clinical, but ultrasound can be a useful complement in casesof abscesseswhere fluctuationis absent or difficult tolocate.77 When possible, sampling of purulent exudate forcultureandantibiogramshouldbeperformedinorderto betterguidetheconduct.
Thetreatmentofisolatedandsmallfurunclescanbe per-formedwithtopicalantibiotics,fusidicacid,ormupirocin, three times a day, for seven to ten days. Early squeez-ing of the lesion should be avoided; however, surgical drainage must be performed in the fluctuation phase. As for larger furuncles, carbuncle, and abscesses, incision and drainage are strongly recommended when they are inthefluctuationphase.78 Incision and drainageinvolvea single linear incision, followed by blunt dissection. Nee-dle aspiration has been shown to be generally inferior to incision and drainage of abscesses. However, needle aspiration may be preferred on the face, as it provides the best cosmetic results. Systemic antibiotic therapy is indicated as adjuvant, and is mandatory when there is an erythematous halo of ≥2cm around the furuncle and in cases of carbuncle. As previously mentioned, CA-MRSA is resistant to -lactam antibiotics, such as penicillins,
first- to fourth-generation cephalosporins, carbapenems, and monobactams. Cephalosporins resistance is relevant to clinical practice, as they are among the most used antimicrobials for the treatment of SSTI and community-acquired pneumonia. Therefore, CA-MRSA infections may not be treatable by most treatment regimens empirically used for such infections.79 The antibiotics indicated are thosewithaction againstMRSA,suchassulfamethoxazole plus trimethoprim or clindamycin for at least seven days inuncomplicatedcases,andvancomycinordaptomycin in complicated cases(i.e.,thosewithextensive involvement andtoxicityorinimmunocompromisedpatients).78,80,81
Final
remarks
Consideringthesedata,itshouldbenotedthatthe semio-logicaltrainingandpracticalandtheoreticalknowledgeof thediseasesdescribedhereandothersthatcanbe consid-ered in the differential diagnosis make thedermatologist akeyelementinthesuspicion,earlydiagnosis,and treat-ment/referralofpotentiallysevere/fatalSSTI.
Financial
support
Nonedeclared.
Authors’
contributions
Silvio Alencar Marques: Conception and planning of the study;elaboration anddraftingofthemanuscript,critical reviewoftheliterature;criticalreviewofthemanuscript; approvalofthefinalversionofthemanuscript.
Luciana PF Abbade: Elaboration and drafting of the manuscript;criticalreviewoftheliterature;criticalreview of the manuscript; approval of the final version of the manuscript.
Conflicts
of
interest
Nonedeclared.
Acknowledgements
ToElieteCorreiaSoares,photographeroftheDermatology DepartmentatFMB-Unesp,fordocumentingseveralofthe casesshowninthisarticle.ToDr.HamiltonOmettoStolffor thesharedmedicalattentiontothecasesmentionedinthis article andfor hisenthusiasm inthe studyof clinical and surgicalemergenciesindermatology.
CME
Questions
1.Regardingnecrotizingfasciitis(NF),checkthecorrect alternative:
a)Itisaninfectionthataffectsthesuperficialandeven deepmuscularfasciaofthesubcutaneoustissue,ofthe dermis,andoftheepidermis,withevolutiontolocal necrosis,toxemia,andpossiblesepsis.
b)NFthatisassociatedwithinfectionbymultiplebacterial species(polymicrobial),calledtypeI,isconsideredmore frequent.
2.WhichofthefollowingarecorrectregardingNF? a)NFcanoccurevenintheabsenceoflossofcontinuityof theskin.
b)ThemostcommoninfectiousagentisEscherichiacoli. c)HumanoranimalbitesdonottriggerNF.
d)Painisnotanimportantphenomenoninthenatural historyofNF.
3.Whichoftheconditionslistedbelowconstitutesa predisposingfactortoNF?
a)Alcoholismandmalnutrition. b)Illicitdrugsuse.
c)Obesityanddiabetesmellitus. d)Alloftheabove.
4.IntheLaboratoryRiskIndicatorforNecrotizingFasciitis (LRINEC)NFscoringsystem,thefactorthatmost
contributestothediagnosisis:
a)Polymerasechainreaction(PCR)value. b)Bloodglucosevalueatadmission. c)Serumcreatininevalue.
d)Leukogramdataonadmission.
5.ConsideringthatFournier’sgangreneisalocal
presentationofnecrotizingfasciitis,whichoftheconducts listedbelowarecorrectforbothdiseases:
a)Broad-spectrumintravenousantibiotictherapyassoon asthediagnosticissuspected.
b)Considerthedebridementofthenecrotictissuethat maybepresentasasurgicalemergency.
c)Proceedtotheetiologicalinvestigationfromthe suspecteddiagnosisthroughbloodculturesandcultureof tissuefragmentsfromtheskinlesion.
d)Alloftheabovearecorrect.
6.Ecthymagangrenosumwasinitiallydescribedasa manifestationofbacteremiacausedby:
a)Streptococcuspyogenes b)Staphylococcusaureus c)Escherichiacoli
d)Pseudomonasaeruginosa
7.Regardingecthymagangrenosum,itiscorrecttostate: a)Ifcarbapenemsarechosen,evenifthereisrenalfailure, itisnotnecessarytocorrectthedosebycreatinine clearance.
b)Treatmentmustbeinitiateduponsuspicion,aimed towardsinfectionbyS.pyogenesorotherGram-positive bacteria.
c)Skinbiopsyisnotanadequatemethodtoreachthe etiologicaldiagnosis.
d)Primaryimmunodeficiencyorneutropeniaarefrequent predisposingfactors.
8.Checkthecorrectalternativeforskininfectionscaused bymethicillin-resistantStaphylococcusaureus(MRSA):
c)TherearetwodifferenttypesofMRSAstrains,CA-MRSA andHA-MRSA,whichoccurinpopulationswithdifferent epidemiologicalprofiles.
d)MRSAinfectionsoccurpredominantlyin immunosuppressedpatients.
9.CharacteristicsofCA-MRSAinfectionsare: a)Youngandhealthypatients,suchasathletes,and bacterialcloneswithproductionofPanton-Valentine leukocidin.
b)Patientswithahistoryofhospitalizationandresistance to-lactamantibiotics.
c)Userofillicitdrugswithahistoryofhospitalization. d)Immunosuppressedpatientswhoconstantlyreferto healthservices.
10.Checkthecorrectstatement:
a)Thefirstapproachtoanabscessisantibiotictherapy, whilesurgicaldrainageshouldbereservedforcaseswhere thereisnoimprovement.
b)Thefirstchoiceofantibioticsforfurunclesandanthrax arefirst-generationcephalosporins.
c)Surgicalfuruncledrainageiscontraindicated. d)Theantibioticsofchoicefortreatingfurunclesare sulfamethoxazoleplustrimethoprimorclindamycin.
ANSWERS
Post-finasteridesyndrome.AnBrasDermatol. 2020;95(3):271-277.
1.d 3.b 5.d 7.a 9.c
2.d 4.d 6.c 8.d 10.a
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