Carbapenem resistant Klebsiella pneumoniae in ICU-admitted COVID-19 Patients: Keep an eye on the ball

Carbapenem-resistant

Klebsiella

pneumoniae

in

ICU-admitted

COVID-19

patients:

Keep

an

eye

on

the

ball

G.

Montrucchio

*

,

S.

Corcione

,

G.

Sales

,

A.

Curtoni

,

F.G.

De

Rosa

,

L.

Brazzi

a

AnestesiaeRianimaizone1U,DepartmentofAnesthesia,IntensiveCareandEmergency,‘CittàdellaSaluteedellaScienza’Hospital,Turin,Italy

b

DepartmentofMedicalSciences,InfectiousDiseases,UniversityofTurin,Turin,Italy

c

TuftsSchoolofMedicine,Boston,MA,USA

d_{MicrobiologyandVirologyUnit,‘CittàDellaSaluteeDellaScienza’Hospital,Turin,Italy} e_{DepartmentofSurgicalSciences,UniversityofTurin,Turin,Italy}

ARTICLE INFO Articlehistory: Received25June2020

Receivedinrevisedform11September2020 Accepted6November2020

Availableonline23November2020 Keywords:

COVID-19 Superinfection Antimicrobialresistance Carbapenemase

Carbapenem-resistantKlebsiellapneumonia Infectioncontrol

ABSTRACT

Herewereportonsevenintensivecareunit(ICU)patientswithcoronavirusdisease2019

(COVID-19)-relatedacuterespiratorydistresssyndrome(ARDS)whodevelopedpositiverectalswabsandinvasive

infections due to carbapenemase-producing Klebsiella pneumoniae (CP-Kp). Notwithstanding the

infection prevention measures introduced during the COVID-19 pandemic and changes in the

hospitalisedpopulation,attentiontoCP-Kpinfectionsmustremainhigh,especiallyinthecriticallyill

setting.

©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforAntimicrobial

Chemotherapy.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.

org/licenses/by-nc-nd/4.0/).

1.Introduction

Bacterialand fungalinfectionsarecommoncomplicationsof viralpneumonia,especiallyincritically-illpatients,asevidenced duringthe2003severeacuterespiratorysyndromecoronavirus (SARS-CoV) epidemic, when Gram-negative bacteria (GNB) and Candidacausedthelargestnumberofsecondaryinfections[1].It follows that assessing the risk of difficult-to-treat bacterial superinfections such as those caused by GNB is crucial in all suspectedcasesofsevereacuterespiratorysyndromecoronavirus 2(SARS-CoV-2;2019novelcoronavirus)infection[2].

Patientswithcoronavirusdisease2019(COVID-19)are,infact, particularlyatriskofdevelopingsuperinfections,especiallythose caused by multidrug-resistant (MDR) pathogens, despite the improvementsininfectioncontrolproceduresworldwideadopted during theCOVID-19 outbreak, the changes in overall hospital admissionsforotherconditions[3],theconsiderablyyoungerage andtheabsenceofmultipleco-morbidities[4].

Duetothefactthat,priortotheCOVID-19outbreak,Italyhadan endemicsituationregardingthespreadofMDRinfections,mainly due tocarbapenemase-producingKlebsiellapneumoniae(CP-Kp) [5],weevaluatedtheincidenceandtimecourseofCP-Kpinfections during their intensive care unit (ICU) stay in a cohort of ICU patientsaffectedbyCOVID-19-relatedacuterespiratory distress syndrome(ARDS).

2.Materialsandmethods

From1Marchto20May2020,allCOVID-19patientswithARDS admittedtotheICUat‘CittàdellaSaluteedellaScienza’Hospitalin Turin (Italy) were studied. Bloodstream infection (BSI) and ventilator-associated pneumonia (VAP) were defined according totheEuropeanCentreforDiseasePreventionandControl(ECDC). Matrix-assistedlaserdesorption/ionisationtime-of-flight (MALDI-TOF),MicroscanWalkAwayplusSystem(BeckmanCoulter,Brea, CA,USA)andMASTDISCS1 CombiCarba plusdisksystem (Mast Group Ltd., Bootle, UK) were used for bacterial identification, antimicrobialsusceptibilitytestingand tocharacterise carbape-nemase-producingisolates,respectively.Detectionofcarbapenem resistancegenes was carried out usingan Xpert Carba-R assay (Cepheid, Sunnyvale,CA,USA). Antimicrobial susceptibilitywas

*Correspondingauthor.

E-mailaddress:g.montrucchio@gmail.com(G. Montrucchio).

1

Thesetwoauthorsequallycontributedtothiswork.

http://dx.doi.org/10.1016/j.jgar.2020.11.004

2213-7165/©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforAntimicrobialChemotherapy.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

JournalofGlobalAntimicrobialResistance23(2020)398–400

ContentslistsavailableatScienceDirect

Journal

of

Global

Antimicrobial

Resistance

interpretedaccordingtotheEuropeanCommitteeon Antimicro-bialSusceptibilityTesting(EUCAST)2019.

3.Results

Among35patients,7hadapositiverectalswabforCP-Kpand bilateral pulmonaryinfiltrates (Table1).Sixpatientsdeveloped invasiveinfectionsandonepatientwascolonisedbyCP-Kpduring their ICU stay (two patients were positive for CP-Kp at ICU admission).Sixofthesevenpatientsweretransferredfromother hospitals.Themedian[interquartilerange(IQR)]SequentialOrgan Failure Assessment (SOFA) score, Simpli_fied Acute Physiology Score(SAPS)andAcutePhysiologyandChronicHealthEvaluation (APACHE)IIscoreatICUadmissionwere,respectively,12(11–13), 54 (51–60) and 25 (24–26), whilstthe median (IQR) MuLBSTA score[6] was9(9–10).The median(IQR)duration ofCOVID-19 symptomsbeforehospitaladmissionwas7(4–7)days,whilstthe median(IQR)durationofICUstayandmechanicalventilationwas 34(24–40)daysand34(23–40)days,respectively.

Themedian(IQR)timebetweenCP-Kpinfectionandhospital and ICU admission was 13 (12–19) days and 12 (7–15) days, respectively.SixpatientsdevelopedVAPandfivehadcontextual BSI,inalloffiveofwhomtheinfectionresultedinsepticshockwith highvasopressorrequirement.

Allofthepatientsreceivedhydroxychloroquine,fiveofthem receivedantiviraltreatmentandfourweretreatedwith tocilizu-mab.Corticosteroidsweregiveninallbutonepatient (dexameth-asone 8 mg every 8 h, with variability according to different hospitals in transferred patients). At ICU admission, 71.4% of patientshad lymphocytopenia.Allpatientshadbeenpreviously treated with broad-spectrum antibiotics (all of them with β-lactams,fivewithazithromycin,twowithdoxycyclineandthree withvancomycin),infivecaseswithadocumentedpriorbacterial co-infectionbeforeCP-Kp,includingthreeVAPandtwoBSIcaused by Pseudomonas aeruginosa (n = 2), extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae (n = 1), coagulase-negativestaphylococcus(n=1)andEnterococcusfaecium(n=1), respectively. We observed two deaths within 28 days and five deaths intheICU in sevenpatients. Mortalityrelated toCP-Kp septicshockwas28.6%.

4.Discussion

Fewarticlesarereportingaboutsecondaryinfectionsin COVID-19,butsomedataconfirmthatsuperinfectionswereidentifiedin 13.5–44%of ICUpatientsowingtovariouspathogens, including MDR-GNB[2].

KnownriskfactorsforthedevelopmentofCP-Kpinfectionsdo notappearfullyapplicableinthiscohortofpatients[4].Infact,our population was relatively young and free of significant co-morbidities, except obesity (57.1%). The reduction in hospital accessforallcauses[3],apartfromthoseduetoCOVID-19,should, at least theoretically, have contributed to a reduction in the disseminationofMDRpathogens.Furthermore,infectioncontrol proceduresarehighlyimplementedinthecontextoftheCOVID-19 pandemic toensure safety for healthcare workers, maximising contactprecautions.

Conversely,factorspotentiallyimplicatedin therisk ofMDR infectionsareincreasedpatienttransfercausedbythepandemic affectingthe wholeof Northern Italy,previousbroad-spectrum antibiotictreatment beforehospital admission, the presenceof otherpreviousinvasivebacterialco-infection,andtheseverityof the patient cohort requiring venovenous extracorporeal mem-brane oxygenation (VV-ECMO) support in 71.4% of cases and continuousrenalreplacementtherapyin28.6%. Inparticular,in patientsundergoingECMO,colonisationbyMDR-GNBisfrequent

T able 1 Charact eristics of ICU-admitt ed patients with C O VID-1 9-re lat ed acute re spir at ory distr ess syndr ome (n = 7). Pa tient Ag e (y ears) Se x BMI Co-morbidities SOF A scor e PCT (m g/ L) Day s fr o m sympt oms to HA Day s fr o m HA to ICU Da y s of MV Day s o f VV- ECMO Day s of ICU C O VID-1 9 thera p y Day s fr o m ICU to CP -Kp+ CP -Kp infection/ colonisation Septic shock T arg et antibio tic therap y 28-day mortality 1 5 0 M 26 N one 1 3 3.84 5 3 2 4 1 4 24 DR V/r + HCQ + st eroids 7 BSI/VAP Y e s CAZ/A VI + FOS + T MP/SMX Death 2 4 1 M 40 Obesity 1 6 6.4 7 7 0 4 6 2 3 5 5 LPV/r + HCQ + st e roids + re m desiv ir 1 2 VAP/BSI Y e s CAZ/A VI + TMP/SMX Ali v e 3 5 4 F 45 Obesity , h ypert ension, C OPD 8 2.7 4 3 0 3 4 2 7 3 4 D R V/C OBI + HCQ + st eroids + tocilizumab 22 BSI/VAP Y e s CAZ/A VI + C O L Ali v e 4 6 2 F 38 Obesity , h ypert ension, h ypoth yr oidism 1 3 0.9 1 7 1 3 3 7 35 3 7 HCQ + ste ro ids + tocilizumab + remdesivir 6 BSI/VAP Y e s CAZ/A VI Ali v e 5 7 1 M 30 Ex-smoker 1 2 0. 1 3 7 1 20 N o ECMO 24 HCQ 1 7 R ectal sw ab N o N one Ali v e 6 5 2 M 2 7 Ex-smoker 1 2 0.4 3 0 42 3 7 42 HCQ + ste ro ids + tocilizumab 1 3 VAP N o MEM + ETP + TGC Ali v e 7 6 7 F 32 Obesity , asthma 1 0 0.2 7 4 2 1 N o ECMO 2 1 HCQ + ste ro ids + tocilizumab + remdesivir 7 VAP/BSI Y e s CAZ/A VI + FOS Death Median 54 – 31 .3 – 1 2 7 1 34 2 7 34 – 12 –– ICU , int ensi ve car e unit ; C O VID-1 9, cor ona virus disease 20 1 9 ; BMI, body mass inde x; SOF A, Seq uential Organ Failure Assessment; PCT ,pro calcit onin (normal ra ng e, < 0.5 m g/L); HA, hospital admission; MV, m echanical ventila tion; VV-ECMO, v eno v enous e xtr acorpor eal membr ane o x y g enation; CP -Kp, carbapenemase-pr oducing Klebsiella pneumoniae ; D R V/r ,daruna vir/rit ona vir ; HCQ, h ydr o x y chlor oq uine; BSI, bloodstr eam infection; VAP ,v entilat or associat ed pneumoniae; CAZ/A VI, ceftazidime/a vibactam; FOS, fosfom y cin; TMP/SMX, trimethoprim/sulfametho xazole; LPV/r ,lopina vir/rit ona vir; C OPD, ch ronic obstructi ve pulmonary disease; DR V/C OBI, daruna vir/cobicistat; C OL, colistin; MEM, m ero penem; ETP , ertapenem; TGC, tig ecy cline.

G.Montrucchio,S.Corcione,G.Salesetal. JournalofGlobalAntimicrobialResistance23(2020)398–400

andisassociatedwithamorethanten-foldoddsforsubsequent infectionsthatareassociatedwithanincreasedriskofdeath[7]. Ourresultsappeartosuggesttheneedtokeepamajorfocuson CP-Kpinfectionseven,andespecially,amongCOVID-19patients owingtotheirextremefragility,probablylinkedtoimmunological mechanismsstillnotfullyclarified,andtheirneedforprolonged ICUstay.

Funding None.

Conflictofinterest Nonedeclared. Ethicalapproval

ThisstudywasapprovedbytheLocalEthicalCommittee[Prot. no.0039964;22/04/2020].

Acknowledgments

Theauthorsthankallofthedoctors,nurses,thecollaborators andtheresidentsworkingintheICUin‘CittàdellaSaluteedella

Scienza’Hospital(Turin,Italy)fortheirpreciousandcontinuous collaborationandsupport.

References

[1]ZhengZ,ChenR,LiY,etal.Theclinicalcharacteristicsofsecondaryinfectionof

lowerrespiratoryinsevereacuterespiratorysyndrome.ChinJRespirCritCare

Med2003;2:270–4.

[2]ClancyCJ,NguyenMH.COVID-19,superinfectionsandantimicrobial

develop-ment:whatcanweexpect?ClinInfectDis2020,doi:http://dx.doi.org/10.1093/

cid/ciaa524[Epubaheadofprint]PMID:32361747;PMCID:PMC7197597.

[3]DeFilippoO,D’AscenzoF,AngeliniF,BocchinoPP,ConrottoF,SagliettoA,etal.

Reducedrateofhospital admissionsfor ACSduring Covid-19outbreak in

NorthernItaly.NEnglJ Med2020;383:88–9,doi:http://dx.doi.org/10.1056/

NEJMc2009166.

[4]ZhouF,YuT,DuR,FanG,LiuY,XiangJ,etal.Clinicalcourseandriskfactorsfor

mortalityofadultinpatientswithCOVID-19inWuhan,China:aretrospective

cohortstudy.Lancet2020;395:1054–62,

doi:http://dx.doi.org/10.1016/S0140-6736(20)30566-3.

[5]EuropeanCentreforDiseasePreventionandControl(ECDC).Surveillanceof Antimicrobial Resistance in Europe 2018. ECDC; 2019. https://www.ecdc.

europa.eu/en/publications-data/surveillance-antimicrobial-resistance-europe-2018.

[6]GuoL,WeiD,ZhangX,WuY,LiQ,ZhouM,etal.Clinicalfeaturespredicting

mortalityriskinpatientswithviralpneumoniae:theMuLBSTAscore.Front

Microbiol2019;10:2752,doi:http://dx.doi.org/10.3389/fmicb.2019.02752.

[7]GrasselliG,ScaravilliV,AlagnaL,BombinoM,DeFalcoS,BanderaA,etal.

Gastrointestinalcolonizationwithmultidrug-resistantGram-negativebacteria

duringextracorporealmembraneoxygenation:effectontheriskofsubsequent

infectionsandimpactonpatientoutcome.AnnIntensiveCare2019;9:141,doi:

http://dx.doi.org/10.1186/s13613-019-0615-7.

G.Montrucchio,S.Corcione,G.Salesetal. JournalofGlobalAntimicrobialResistance23(2020)398–400