Long-term treatment of persistent disseminated Nocardia cyriacigeorgica infection

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Case

report

Long-term

treatment

of

persistent

disseminated

Nocardia

cyriacigeorgica

infection

Onur

Özgenc¸

_,

_Meltem

_Avcı

_,

_Alpay

_Arı

_{, ˙Ismail}

_Yunus

_C¸

_elebi

_,

_Seher

_Ayten

_Cos¸kuner

a_{DokuzEylulUniversityHospital,ClinicsofInfectiousDiseases,Karsiyaka,Izmir,Turkey}

b_{IzmirBozyakaTeachingandResearchHospital,ClinicsofInfectiousDiseasesandClinicalMicrobiology,Izmir,Turkey} c_{BursaInegolPublicHospital,ClinicsofInfectiousDiseases,Bursa,Turkey}

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Articlehistory:

Received29January2014 Accepted11March2014 Availableonline13May2014

Keywords:

Nocardiacyriacigeorgica Chronicinfection Treatment

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InthispaperadisseminatedpersistentNocardiacyriacigeorgicainfectioninan immunocom-petentpatientisdescribed.Thepatient’slong-termtreatment,aswellasitsimplicationsfor managingsimilarcasesinthefuture,isemphasized.Presentingwithhighfever,multiple nodules,andulcerativecutaneouslesionsofbodysites,thepatientwastreatedwithvarious antimicrobials.Undercombinedtherapy,empyemaandarthritis,leadingtodisseminated nocardiosis,wereseen.Theoveralltreatmentcoursewas28months.Itcanbeconcluded thatthechoiceoftheantibioticsandoptimaldurationoftreatmentareuncertain;therefore thetreatmentofnocardiosisrequiresexpertise.

©2014ElsevierEditoraLtda.Allrightsreserved.

Introduction

Herein we describe a case of disseminated Nocardia cyr-iacigeorgica infection, a recently identified species, in an immunocompetent patient. The infection was most likely acquiredfromdirectinoculationofbodysurfacesasaresultof occupationalexposure.Differentfactorsthatmayhave con-tributedtothe long-termtreatmentofthe disease andthe subsequentrelapseinthispatientinspiteofinvitro suscepti-bilityoftheisolatetoalldrugsadministeredarediscussed.

∗ _{Correspondingauthor.}

E-mailaddresses:ozgenc.onur@gmail.com,onur.ozgenc@deu.edu.tr(O.Özgenc¸).

Case

report

Patientclinicalstatus

A 45-year-old woman, who has been working as a farmer washospitalizedwithsymptomsofhighfever,multiple nod-ules,andulcerativelesionsofvariousbodysites.Shehadno underlyingdiseasesandonlyhadscratchesonherhandas aprobableindicatorofoccupationaltrauma. Previouslyshe hadbeentreatedforcellulitisandlymphedemaintheward

http://dx.doi.org/10.1016/j.bjid.2014.03.007

Fig.1–Theulcerativelesiononthepatient’schin.

ofinternalmedicine fortwoweeksandthen movedtothe infectiousdiseasesclinic.Shepresentedwithfever(38.5◦C), multiplecutaneous,erythematous,edematousnodules,and abscessesovertheleftbreastandontheleftupperandlower extremities.Similaredematousorulcerativelesionswerelater seen under the chin (Fig. 1), on dorso-thorocal, and lom-barregions. Thelower extremitieswere edematous. Under therapy somepartial resolutionof cutaneous lesions were observed.Also,painfulnewnodulesappearedinthefollowing twoweeksandsomeexistingnodulescontinuedtoexpandin size.Thenodulesandulcerativelesionsvariedinsizefrom2 to12cmandweretenderanderythematous.Remarkable res-olutionofsomecutaneousandsubcutaneouslesions(Fig.2) wasseen.Someofthe pre-existing noduleshaveulcerated and that underwent surgical debridement. Despite in vitro susceptibility ofthe isolateto all drugsadministered, new pyogenicabscesses,empyemaofthethorax,andrespiratory distresshaveensued.Thechestradiographshowedleft-sided pleuralcollection.Thoracocentesisandsurgicaldrainagewere

Fig.2–Thescarsofthehealedlesionsonthe dorso-thorocalregionofthebody.

Fig.3–Thecutaneousnoduleonthelowerextremity.

performed; pleural fluid was obtained for culture. Pleural empyemaalsooccurredontherightsideofthelungwithin two weeks; again surgical drainage was performed. Three months after admission, empyema and skin nodules had fullyresolvedwithscarring.Undersuppressionmaintenance therapy,relapsingfeverandcutaneousnodules(Fig.3)have ensuedwhichwerelaterclearedbyanadditionaltwomonths oftreatment.Sixmonthslaterwithcombinedantimicrobial therapy,thepatientwasdischargedfromthehospitalon doxy-cyclinemaintenancemonotherapy.Arthritisoftherightknee andankle,highfever,andnewcutaneouslesionsdeveloped withina monthof hospitaldischarge and the patient was againhospitalized.Thepatientpresentedwithhighfeverand newnodules.Anewdrug (linezolid)whichwasnoton the marketatthattimewasinitiated.Afterclinicalandlaboratory responsetotherapyattheendofoneyear,somefluctuating cutaneoussymptomshadappearedforaperiodoftenmore months.Thepatientthenremainedhealthyinthefollowing threeyearsoffollow-up(Table1).

Laboratorymethodsfordiagnosis

Erythrocyte sedimentation rate (EST) was 10mm/h, blood count was as follows: leukocyte 7070mm–3_{, Hb 9.1g/L, Ht} 32.5, platelet 419,000mm–3_{. CRP was 9.7mg/dL. All} bio-chemical tests exceptmoderate hypoproteinemia (albumin 3mg/dL, globulin 1.9mg/dL) were within normal ranges. Chest radiograph and urinalysis were also normal. Gram-stained preparationsofpusfrom ulcerativelesionsshowed mostly Gram-positive small rods and coccoid fragments withinleukocytes. Ziehl–Nielsenstained preparationswere negative. Bacteriological culture showed no growth. Later, abscessesmaterialandpleuralfluidculturedonMyco/F-Lytic BACTEC liquid medium(brain–heartand 7H9 Middlebrook) andLoewenstein–Jenseen mediumgrewpresumptive Nocar-diaspeciesinapureculturewithinoneweek.Branchingrods were seen inZiehl–Nielsenwith1%sulfuricacid (modified Kinyoun technique) stained preparations, a typical feature of nocardiae.1–4 _{The microorganism was confirmed as N.}

cyriacigeorgica at the reference laboratory in France. The strain was reported as sensitive to amikacin, gentamicin,

b r a z j i n f e c t d i s . 2 0 1 4; 1 8(5) :556–560

Table1–FeaturesofdisseminatedNocardiacyriacigeorgicainfection.

Symptoms Laboratoryfindings Treatment Durationoftherapy Clinicaloutcome

Highfever,newnodules ESR10mm/h,WBC7070mm–3_,Hb

13.8g/L,CRP9.7mg/dL

Ceftizoxime6g/d+clindamycin 1800mg/d

1st⇒14thdays Partialresolution,newlesion(chin) Ulcerativelesionunderchin Gramstain:smallrodsandcoccus TMP/SXT10mg/kg/day+Imipenem

2g/day

14th⇒45thdays Newlesions(dorso-thorocalregion)bone marrowsuppression(WBC7240mm–3_,Hb

6.7g/dL,Ht22.1,PLT118,000mm–3₎

“Breakthrough” Disseminatedskin

lesions+respiratorydistress

Chestradiogram:Pleuralempyema Pleuralfluid:“Aerobicnocardiform actinomycetes

ESR63mm/h,CRP21.6mg/dL

Imipenem2g/day+amikacin 1g/day+doxycycline200mg/day Surgical:drainageanddebridement

45th⇒90thdays Resolutionofcutaneouslesionsand empyema

Scarredcutaneouslesions ESR38mm/h,CRP0.65mg/dL Amikacin1g/day+doxycycline 200mg/day

3rd⇒4thmonths Relapse Highfever,newnodules ESR85mm/h,CRP5.2mg/dL Imipenem2g/day+amikacin

1g/day+vancomycine2g/day

4th⇒6thmonths Suppressionorcure Dischargefromhospital None ESR45mm/h,CRP0.66mg/dL Doxycycline200mg/day 6th⇒7thmonths Re-activation

Arthritis(rightkneeandankle) ESR95mm/h, CRP21mg/dL

Ceftriaxone2g/day+amikacin 1g/day+doxycycline200mg/day

7th⇒9thmonths Hospitalization

Noresponse,newsymptoms Newnodulesformation

(subclaviancatheterregion)

ESR104mm/h,WBC8800mm–3_,Hb

12.7g/L,CRP14.7mg/dL

Linezolid1200mg/day+doxycycline 200mg/day

9th⇒12thmonths Suppressionorcure+adverseeffectsdue tolinezolid

Periphericneuropathy,severe malaise

ESR42mm/h, CRP1.06mg/dL

TMP/SXT5mg/kg/day+doxycycline 200mg/day+B6vitamin

12th⇒15thmonths Resolutiondischargefromhospital(13th month)

Fluctuatingmildcutaneous symptoms

ESR26mm/h,Hbg/L,Ht39.8,CRP 0.73mg/dL

TMP/SXT5mg/kg/day+doxycycline 200mg/day

15th⇒22ndmonths Resolutionandcure

None ESR10mm/h, WBC8080mm–3_{,Hb14.2g/L,Ht43.1} CRP0.3mg/dL TMP/SXT5mg/kg/day+doxycycline 200mg/day 22nd⇒28thmonths Well-being

cefotaxime, ceftriaxone, cefepime, imipenem, vancomycin, trimethoprim/sulphamethoxazole (TMP/SXT), minocycline, doxycycline,andlinezolid. Disksusceptibilitytest was per-formedaccording toBoiron and Provost.5 _{Empyema ofthe}

thoraxwas diagnosedbychest radiographand chest com-puted tomography (CT). Further tests did not reveal any evidenceofanunderlyingimmunocompromisedstate.

Treatmentandclinicaloutcome

Ceftizoximeandclindamycincombination(twoweeks)were switchedtoTMP/SXTplusimipenem(onemonth)fortreating oneofthosefastidiousmicroorganismsincludingRhodococcus, Nocardia,Actinomyces,Peptococcus,etc.,whichwassuspectedas acausativeagentbasedontheGramsmear.Surgical debride-mentofthedorso-thorocallesionsandsurgicaldrainageofthe left-sidedandthentheright-sidedempyemafluidwerealso implementedinaddition tomedicaltherapy. Bonemarrow suppressionduetoTMP/SXTwitha10mg/kg/day trimetho-primdosehaddeveloped.Thetargetedantibiotictherapyto theisolatedNocardiawasthenacombinationofimipenem, amikacin,anddoxycyclinefor45days.Theresponsetothis regimenwasgood. Asmaintenancetherapyamikacin plus doxycycline(onemonth)wasgivenbutthisregimenhadfailed andthe diseasesymptoms reactivatedwithhigh feverand newnodules’formation.Therapywasdiscontinuedaftersix monthsandthepatientdischargedfromthehospital. Mainte-nancetherapywithdoxycyclinemonotherapywasprescribed. Approximatelyamonthlaterthediseaserecurredwith symp-tomsofarthritisandfollowedbyhighfeverandcutaneous nodules.Neitherresolutionnorprogressionofsymptomswas observedbycombining ceftriaxone,amikacin,and doxycy-cline for two additional months. After nine months from initiationofdiseasesymptomslinezolid,adrugnotonthe market at that time, in combination with doxycycine was started.Clinicalcureofthediseasewasobtainedafter line-zolidtherapyforthreemonthsbuteradicationoftheorganism couldnotbeachievedduetocessationoflinezolid,becauseof significantadverseeffects(ESRandCRPlevelsdecreasedto 26mm/hfrom104mm/handto0.73mg/dLfrom14.7mg/dL, respectively). Mild relapsing episodes ofcutaneous lesions weretreatedwithTMP/SXT(5mg/kg/day)anddoxycyclinefor tenmoremonthstillnoremissionandthesame antimicro-bialcombinationwasfurtherlengthenedforsixmoremonths afterresolutionofalldiseasesymptomswithnosideeffects. Theoveralltreatmentcoursewas28-monthlong.Thepatient remained healthy and had no signs ofrelapse afterbeing followed-upforadditionalthreeyearswithouttherapy.

Definitions

Disseminatednocardiosiswasdefinedasnocardiainfectionin twoormorenon-contiguoussites.Breakthroughnocardiosis wasdeemedwhenarecurrentnocardialinfection occurred in a patient receiving systemic antibacterials with known invitroactivityagainstNocardiaspp.Relapseorreactivationof thediseasewasnotedwhenaninitialimprovementwas fol-lowedbyreappearanceofclinicalsymptomsandlaboratory findings.6

Discussion

Theliteraturesurveyofpost-treatmentfollow-upofNocardia infectionsisoftentoobrieforunknown,makingtheultimate successoftherapyuncertain.7 _{MembersoftheN.asteroides}

complex are morefrequentlyinvolved inpulmonary infec-tions.Recently,severalnewspecieshavebeen describedin this complex.Thepresent reportisacaseofdisseminated persistentinfectioninanimmunocompetentpatientwith pri-marycutaneousinvolvement,empyema,andarthritisdueto N.cyriacigeorgica,whichwasformerlypartoftheN.asteroides complex.PreviouscasesofN.cyriacigeorgica infectionshave beenreportedinimmunocompromisedpatients.8,9

Theexperiencewithnocardiosissuggeststhatwhenthe infection is disseminated, the clinical response is slow.10

Thereforesuccessfultherapyrequirescombinationof antimi-crobialdrugsandappropriatesurgicaldrainage.Theoptimal antimicrobialtherapydependsontheseverityandlocalization oftheinfection,thespeciesofNocardia,hostimmunestatus, potentialdruginteractions,toxicityassociatedwithantibiotic usage,anddurationofillnesspriortodiagnosis.1,2,11

Imipenemandamikacinseemedtobethemosteffective agents,andinvitrosynergismhasbeendemonstratedbetween imipenemandTMP/SXT,imipenemandcefotaxime,amikacin andTMP/SXT.1,2,12,13_{Althoughsynergyhasbeenreportedin}

theliterature,Kanemitsuetal.14_{describedthatsynergywas}

presentin83%of23N.asteroidesstrainstreatedwithamikacin andTMP/SXT,in26%of15strainstreatedwithamikacinplus ceftriaxone,andin5%of26testsconductedwithamikacin andimipenem,thusshowingthatsynergiceffectof antimi-crobialcombinationswere notobservedinall cases.Inthe presentcase,combinationtherapywithimipenem,amikacin, anddoxycyclinedidnotimprovediseaseoutcomeunless van-comycinwasadded.

Newantimicrobialagentsareneeded.Therelativelyhigh incidenceofadverseevents,suchasdiffuserashand myelo-suppressionoccurrenceduringsulfonamidetherapy,hasbeen reported. Besides, there islack ofalternative highlyactive oral agents.1,2,14 _{Linezolid is the first antimicrobial to be}

active againstall clinicallysignificant speciesofthe genus Nocardia.14,15_{Ithasbeenreportedtobeeffectiveintreatment,}

especially in disseminated disease. Because of its activity andavailabilityasanoralagentandthecurrentlimitations of the sulfonamides, linezolid has the potential to be the primarydrugofchoicefortreatingNocardiadisease.16

Treat-ment relatedanemiaandperipheralneuropathyhavebeen reported,16_{whichresolvedwhenlinezolidtherapyis}

discon-tinued,asobservedinthepresentcase.

Remissionsand exacerbations lastingfordaysorweeks are characteristic of the disease.11,17,18 _{The disease may}

spread hematogenously leading to long-term persistent nocardiosis.18_{Intheabsenceofconsensusonthelengthof}

therapy,investigatorsmostlyrecommendtoprolong medica-tionbetween6and24monthsbecauseoftherelapsingnature oftheinfection.6,19_{Furtherprogressionofcutaneousdisease}

toempyemaandarthritis,“breakthroughnocardiosis”under combined therapywasseeninthepresent case.Therefore, treatment duration of28monthswas the longestreported periodintheliterature.

itymaybebeneficialinlong-termtreatmentofthedisease.As therearenounanimousguidelinesonthetherapyofnocardia infections,atthemomenttheoptimaldurationoftreatment isuncertainandrequiresexpertise.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

TheauthorsareindebtedtoProf.PatrickBoironfrom Mycol-ogyLaboratoryofClaudeBernardUniversity,France,andProf. RamazanIncifromtheMycologyLaboratoryofEgeUniversity SchoolofMedicine,Izmir,Turkey,fortheir contributionsin identifyingN.cyriacigeorgicainspecieslevel.

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