Success stories about severe pneumonia caused by Panton-Valentine leucocidin-producing Staphylococcus aureus

The

Brazilian

Journal

of

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

Success

stories

about

severe

pneumonia

caused

by

Panton–Valentine

leucocidin-producing

Staphylococcus

aureus

夽

Paramythiotou

Elisabeth

_,

_Souli

_Maria

_,

_Galani

_Irene

_,

_Giamarellou

_Helen

_,

Armaganidis

Apostolos

a_{2ndUniversityDepartmentofCriticalCare,AttikonUniversityHospital,Athens,Greece} b_{4thUniversityDepartmentofInternalMedicine,AttikonUniversityHospital,Athens,Greece}

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Articlehistory:

Received7September2013 Accepted23November2013 Availableonline29March2014

Keywords: Community-acquiredpneumonia Clindamycin Staphylococcusaureus Panton–Valentineleukocidin

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Wedescribethreecasesofcommunity-acquirednecrotizingpneumoniawhichwerecaused by Panton–Valentine leucocidin-producingstrainsofStaphylococcus aureus (oneof them methicillin sensitive). Allcasesweresuccessfullytreated without anysequelaeforthe patientsduetothepromptinitiationofadequateantimicrobialtherapy.Highsuspicion towardthisfatalpathogenwasthekeytothesuccessfuloutcomeofthepatients.

©2014ElsevierEditoraLtda.Allrightsreserved.

Introduction

Community-acquiredpneumoniaduetoStaphylococcusaureus

isaninfrequentbutpotentiallylethalinfection.1,2_Itisoften

associatedwith the production ofPanton–Valentine leuco-cidin(PVL),whichisresponsibleforextensivetissuenecrosis andahighmortalityrate.3_{Hereinwepresentthreecasesof}

necrotizingpneumonia,oneofthemcausedbyamethicillin susceptiblestrain,allofwhichhadafavorableoutcome.

夽_{TheworkwasperformedatAttikonUniversityHospital.} ∗ _{Correspondingauthor.}

E-mailaddress:lparamyth61@hotmail.com(P.Elisabeth).

1 _{Presentaddress:6thdepartmentofInternalMedicine,HygeiaHospital,Athens,Greece.}

Case

histories

Case1

Apreviouslyhealthy18-year-oldboy,aPanamaresident trav-eling in Europe, was admitted to the ICU of our hospital sufferingfrompneumoniaandsevererespiratorydistress.He was transferredfrom anotherhospitalwherehepresented with high fever, weakness and productive cough. He had

http://dx.doi.org/10.1016/j.bjid.2013.11.011

been hospitalized forthree days and received oseltamivir, ceftriaxoneand moxifloxacin.Hereportedhavingaflu-like syndromesomedaysearlier.

AtICUadmissionhehadatemperatureof38◦C,a respi-ratoryrateof40permin,aheartrateof120beats/minand hewashemodynamicallystable.Thoraxauscultationrevealed cracklesover thelower andmiddle, rightlungfields,while chest X-ray (CXR) showed patchy alveolar opacities in the rightlung.Bloodgasesonadmissionshowed:pH7.31,pCO2:

50mmHg,pO2:65mmHginanon-rebreathingmask.

Labora-toryfindingsrevealedawhitebloodcount(WBC)of1220cells/L (59% neutrophils)and a CRP of306mg/L. TheAcute Phys-iology and Chronic Health Evaluation (APACHE) II severity score was 21. His respiratory distress gradually increased and24hlaterhewasintubatedand neededinotropic sup-port. The new CXR revealed that alveolar type infiltrates were spread in both lungs. Urine antigens for Legionella pneumophilatype1and Streptococcuspneumoniaewere nega-tive.

AbronchoscopywasperformedandtheGramstainofthe BALrevealedthepresenceofnumerousGram-positivecocci. Thetreatmentwasswitchedtolinezolidand moxifloxacin. CulturesfromBALspecimensyieldedaPVL,methicillin sensi-tiveS.aureus(MSSA)whilebloodcultureswerenegative.Test forHIVwasnegative.

Hydrocortisone was added to the therapeutic regimen becauseofthesepticshockandfilgrastimwasgivenforthe leukopenia.Clindamycinwasalsoaddedinordertodiminish thetoxinproductionbythePVLstrain.4

Onday8thefeversubsided buthiscoursewas compli-catedbyaspontaneouspneumothorax,whichnecessitated theinsertionofapleuralcatheter.Subsequentlyhesuffered anepisodeofbacteremicventilator-associatedpneumoniaby acarbapenem-resistantKlebsiellapneumoniae,whichwas suc-cessfullytreatedwithcolistinandtigecycline.Thepatientwas extubatedon day21 andhewas finallydischargedon day 27.

Case2

A34-year-old woman wastransferredto ourICU from the DepartmentofObstetricsandGynecologyduetosevere respi-ratory failure six days after in vitro fertilization. She had no past medicalhistory. The embryo-transferwas compli-catedbyOvarianHyperstimulationSyndrome.Onadmission the APACHE II score was 26 and blood gases values were pH:7.33,pO2:80mmHg,pCO2: 38mmHgon facemask

pro-viding FiO2 of40%. Auscultation revealed diffuse crackles.

Duringthenext6hhertemperatureroseto39.5◦Candshe presented productive cough with dark sputum and short-nessofbreathatrest,soshewasadmittedtotheICU.CXR on ICU admission revealed an infiltrate ofthe left middle lung field and bilateral pleural effusions. Laboratory tests showedaWBCof3700/L,CRPof298mg/L,procalcitoninof 36ng/mL, fibrinogenof507mg/dL,and hypogammaglobuli-naemia, while human chorionic gonadotropin (hCG) levels werecompatiblewithpregnancy.SputumGramstainrevealed Gram-positivecocciand urinaryantigensforL.pneumophila

type1,andS.pneumoniaeandpharyngealaspiratefor Influen-zae A and B were negative. Treatment with intravenous

linezolidandclindamycinwasimmediatelystartedbecause the severity ofthe patient’s condition and the isolationof Gram-positive cocci in the sputum supported the clinical suspicionofcommunity-acquiredstaphylococcalpneumonia. Nevertheless, the patient worsened and became hemody-namically unstable requiring intubation and vasopressors. ShewasalsogivenhydrocortisoneandactivatedproteinC. The blood cultures and the tracheal aspirate grew MRSA. Thepatientshowedgradualhemodynamicimprovementand wasweanedfromvasopressorsafterthreedays,whilehCG values declined rapidly returning to nonpregnant range. A chestCTscanwasperformedandshowedbilateralinfiltrates withmultiplecavitatinglesions,leftlungabscessformation andbilateralpleuraleffusions.Cultureofpleuralfluid devel-opedalsoMRSA.Hercoursewascomplicatedbynosocomial bacteremia andshe wassubmitted toatracheostomy. Gas exchangeaswellaslungmechanicsgraduallystabilizedand shewasfinallyweanedfrommechanicalventilation.Shewas dischargedtothewardonday37andshehadalong rehabil-itationperiod.

Case3

A33-year-oldmalewithnosignificantpasthistorywas admit-ted totheICU ofourhospitalbecause ofacute respiratory failure due to a lower respiratory tract infection. He pre-sented to the Emergency Department several days earlier complaining for chest pain, high temperature (39◦C) and progressive dyspnea with blood-stained sputum. The CXR revealedthepresenceofbilateralpulmonaryinfiltrates.After hisadmissiontothe internalmedicinedepartment his sit-uationprogressivelydeterioratedandtwodayslaterhewas intubatedandtransferredtotheICU.Histreatmentinitially includedceftriaxone andclarithromycinbutbecauseofthe severityofhissituationastaphylococcalpneumoniawas sus-pectedandtheantibioticregimenwasempiricallymodified tolinezolidandmoxifloxacin.OnICUadmissionhepresented hemodynamic instability and had to be resuscitated with intravenousfluidsandnorepinephrine.Initiallaboratorydata obtainedintheICUshowedWBC:17.890/L(neutrophils:82%), CRP:250mg/L.Arterialbloodgasesanalysisshowed respira-toryacidosisandseverehypoxemia(pH:7.11,pCO2:91mmHg,

pO2:56mmHg–inassistcontrolventilation,FiO2:100%).Blood

culturesandsputumspecimenstakeninthewardgrewMRSA. Thebloodculturesremainedpositiveaftersevendaysof treat-mentwithlinezolidanddaptomycin.Clindamycinwereadded totheregimen.Twotransesophagealechosperformedin fif-teen daystime did notreveal the presenceofvegetations. Ofnote, HIVandtestsforotherrespiratorypathogenswere negative.

Thepatient’scoursewascomplicatedbythedevelopment ofspontaneouspneumothoraxandempyemaoftherightlung (Fig.1).Hehadtobesubmittedtolungdecortication.MRSA wasalsoisolatedfromthecultureofthepleuralfluid.Onday 23hewassubmittedtoatracheostomy.Hissituation amelio-rated,thetracheostomy wasclosedandhewastransferred tothewardonday40.Hewasdischargedfromthehospital onemonthlater.Itshouldbenotedthatoneoftheherein describedcaseshasbeenpreviouslypublished.5

Fig.1–C/Tscanofthechestshowingrightpneumothorax aswellasbilateralconsolidationsandcharacteristicbullae.

In

vitro

evaluation

of

S.

aureus

clinical

isolates

Sevenisolateswereavailableforfurthertesting. Susceptibil-itiesto various antimicrobial agents were evaluated by an automatedsystem(BDPhoenixautomatedmicrobiology sys-tem;BDDiagnosticSystems,Sparks,MD)(Table1).Allisolates were foundtocarrythe lukF-PVand lukS genescoding for Panton–Valentineleukocidin(PVL),6_{whileallisolatesofcases}

2and3werefoundtoalsocarrythemecAgeneintypeIVc/e staphylococcalcassettechromosomemecelement(SCCmec).7

ThePFGEpatternsofSmaI-digestedDNAofallisolatesof cases2and 3 were identical. MLSTtyping performed only tobloodisolateslinkedPFGEpatternwiththewell-described ST80clonethatseemstobespreadingthroughEurope.Isolate m4442Bofcase1waslosttosubcultureandwasnotsubmitted toMLSTtyping.

Discussion

S.aureus is a commonlyrecognized cause ofinfections in humans.Theseinfectionscanbecomelife-threateningdueto theabilityofthemicroorganismtoproducevirulencefactors

includingadhesionfactorsandtoxins.PVLisatoxinproduced byS.aureusstrains(carryingthelukS-PVandlukF-PVgenes) oftenassociatedtosevereskinandsofttissueinfectionsbut alsocausingnecrotizingpneumoniawithahighmortality.The presenceofthistoxinhasbeendetectedamongMRSAaswell asMSSAstrains.

TheusualpatientwithPVL-associatedS.aureuspneumonia isachildorayoungotherwisehealthyadult.Aviralillnesscan precedepneumoniawhileleucopeniaattributedtothetoxin is notanuncommon finding.A specificdisease entityhas alsobeenascribedtoPVL-positiveS.aureus-associated respi-ratoryinfectionincludingarapidlyprogressinghemorrhagic andnecroticpneumoniawhichcancauseAcuteRespiratory DistressSyndrome(ARDS)possiblyleadingtosepticshockand multi-organfailure.

Wedescribethreepatientswithseverepneumoniacaused byPanton–Valentine-producing S.aureus.In twocases bac-teremia was also present. Diagnosis of influenza was not confirmedinanycasewhileprodromeflu-likesymptomswere present in only onepatient. Both MRSAisolates belonged to ST80, which is the most common clone causing infec-tioninthecommunityaswellasinthehospitalinGreece.8

AmongbloodstreaminfectionscausedbyMRSA,the hospital-associatedcloneST239andsporadiccasesofST30,ST97and ST3989_{followST80.OneofthestudyisolateswasMSSA}

pro-ducing PVL. Althoughrare, the productionofPVL toxin by MSSAstrainshasbeenreportedpreviously.6

Three similar cases due to MRSA strains have also been described in Greece, two of them with an unfavor-able outcome.10,11 _{The mortality of PVL-positive CAP lies}

between45%and56%.7,8_{Theseverityofthediseaseis}

sim-ilarwhethertheisolateisamethicillin-resistantstrainornot becauseitisassociatedtootherfactorssuchasmulti-organ failure, ICU admission, mechanical ventilation,leukopenia, necrotizing pneumonia, shock, disseminated intravascular coagulation,rash,ARDS,airwaybleedinganddevelopmentof complications.12,13

OurpatientspresentedsomeofthesefactorssuchasICU treatment,mechanicalventilationduetopneumonia-induced ARDSandneedforinotropicsupportwhileallofthem devel-oped several complications. Two cases had leucopenia on admission,whichisconsideredtobeinverselyassociatedwith survival.Onthecontrary,anotherunfavorableprognostic fac-tor,airwaybleeding,wasabsentpossiblycontributingtothe favorableoutcome.

Theoptimaltreatmentofthisoftenlethaldiseasehasnot beenestablished.Sincethedetrimentaleffectsofthe infec-tionaremainlycausedbytheproductionofPVLratherthan

Table1–Minimuminhibitoryconcentrations(MICs)of15antimicrobialsagainstS.aureusstudyisolates.

Case Isolateno Source P OX FOX VA TEC GM E CIP LVX CC SXT RA SYN LZD FA

1 m4442B BAL >1 0.5 ≤2 ≤1 ≤1 ≤2 0.5 ≤0.5 ≤1 ≤0.5 ≤0.5 ≤0.5 ≤0.5 2 ≤2 2 SP8728 Sputum >1 >2 >8 ≤1 ≤1 ≤2 >4 ≤0.5 ≤1 >2 ≤0.5 ≤0.5 ≤0.5 2 4 SP8753 Trachealaspirate >1 >2 >8 ≤1 ≤1 ≤2 >4 ≤0.5 ≤1 >2 ≤0.5 ≤0.5 1 2 8 P6538 Pleural-fluid >1 >2 >8 ≤1 ≤1 ≤2 >4 ≤0.5 ≤1 >2 ≤0.5 ≤0.5 1 2 8 b8503 Blood >1 >2 >8 ≤1 ≤1 ≤2 >4 ≤0.5 ≤1 >2 ≤0.5 ≤0.5 1 2 >8 3 b3286 Blood 1 2 8 ≤1 ≤1 ≤2 ≤0.25 ≤0.5 ≤1 ≤0.5 ≤0.5 ≤0.5 ≤0.5 2 4 m2332 Pleural-fluid 1 1 4 ≤1 ≤1 ≤2 ≤0.25 ≤0.5 ≤1 ≤0.5 ≤0.5 ≤0.5 ≤0.5 2 4

themicroorganismitself,aneffectivetreatmentshouldtarget firstattheeradicationofS.aureusbutadditionallyat dimin-ishingtheeffects ofthe toxin.Drainageofthe suppurative collection,ifpossible,issuggestedinordertoremovePVL con-tainingtissues.Furthermorecertainantimicrobialagentsare abletoreducetheproductionofPVL.Suchmoleculesinclude clindamycin,linezolidandrifampicin.14_{Theseantimicrobial}

agentsareeffectiveinreducingPVLproductionevenat sub-optimalconcentrationsinnecrotictissues.Dumitreskuetal. haveshownthatifotheragentssuchasbeta-lactamsareused andlevelsabovetheMIC(minimuminhibitoryconcentrations) arenotachievedintheinfectedtissues,PVLsecretionmay beenhanced.14_{MoreoverupregulationofPVLtoxinobserved}

withnafcillin15_{couldalsoresultwithflucloxacillinwhenused}

for treating MSSA.16 _{As for clindamycin additional}

advan-tagesofthedrugincludeitsability(a)todecreaseToxicShock Syndrome Toxin-1 production17 _{and (b)to stop production}

ofalpha-toxinbytranslationalinhibition.18_{Combineduseof}

clindamycinandlinezolidhasbeendescribedashaving suc-cessfulresultsonPVLtoxinandpatients’survivalintwoof threecasesofnecrotizingpneumonia.19 _{Ontheotherhand}

vancomycin,atraditional drugforthe treatmentofMRSA, hasno impact onexotoxin formation.20 Polyvalenthuman intravenousimmunoglobulin(IVIg)isanadjunctivetherapy forseriousPVL-associatedinfections.Itactsbyneutralizing thePVLporeformationandbyinhibitingthecytotoxiceffects ofPVLonpolymorphonuclearcellsasshownbyGauduchon etal.21_{Althoughtheresultappearstobedose-dependent,the}

usuallyreporteddosedoesnotexceed2g/kg.16_TheuseofIVIg

hasbeen reportedtohaveabenefitonpatients’survivalin sporadiccases.19,22,23

Allourpatients receivedacombinationoflinezolidand clindamycin agents that provide both antimicrobial action and anti-toxin effect. In the second case we used IVIg as adjunctivetherapy,afactorprobablycontributingtopatients recovery.Ofnote,althoughtheuseoflinezolidisonly recom-mendedforhospital-acquiredMRSApneumonia,ithasthe advantageofachievinghighconcentrationsintheepithelial liningfluidofthelung24anditisareasonablefirstchoicefor community-acquiredMRSApneumoniaaswell,particularly inthesuspicionofPVLfortheaforementionedreasons.

Panton–Valentineassociatedpneumoniaremainsadisease entitywithahighfatalityrate.Ahighdegreeofawarenessis necessaryinordertoinitiateaproperand aggressive treat-mentevenintheabsenceofaprecedingflu-likesyndrome.As theidentificationofthetoxinisnotalwaysfeasibleorquickly performed,empiricalchoiceofantimicrobialsisofparamount importance.

Funding

Nograntorfinancialsupportwasreceivedforthestudy.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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