Eggimann, P.

Lamoth, F.

Marchetti, O.

Serveur académique lausannois

Philippe EggimannFre´de´ric LamothOscar MarchettiOn track to limit antifungal overuse!Received: 20 January 2009Accepted: 25 January 2009 Springer-Verlag 2009This editorial refers to the article available at:doi:10.1007/s00134-009-1431-6.P. Eggimann ())Department of Adult Intensive Care and Burn Center,Centre Hospitalier Universitaire Vaudois (CHUV)and University of Lausanne (UNIL), Lausanne, Switzerlande-mail: philippe.eggimann@chuv.chF. Lamoth  O. MarchettiInfectious Diseases Service, Department of Medicine,Centre Hospitalier Universitaire Vaudois (CHUV)and University of Lausanne (UNIL),Lausanne, Switzerlande-mail: frederic.lamoth@chuv.chO. Marchettie-mail: oscar.marchetti@chuv.chInvasive candidiasis (IC) has emerged as a main cause ofmorbidity and mortality among critically ill patients.Candida colonization at multiple sites promoted by pro-longed exposure to antibiotics, intravascular devices forparenteral nutrition or renal replacement therapy, andcomplicated abdominal surgery are associated with thedevelopment of IC [1]. The gastrointestinal tract and en-dovascular catheters are thus the most common sources ofIC [2].Early recognition and appropriate management of ICare crucial for outcome [3, 4]. However, the sensitivity ofconventional blood cultures remains limited. The utilityof fungal blood markers such as beta-(1,3)-D-glucan ormannan/antimannan and PCR testing for the early diagnosisof IC needs to be confirmed in the ICU setting [5, 6].Pending the conclusion on ongoing investigations and onthe role of composite clinical scores which may improve theprediction of IC, therapeutic decisions remain essentiallybased on the clinical risk profile [7]. This approach resultsin a low threshold for starting antifungals (prophylactic,pre-emptive or empirical treatment) and in a high numberneeded to treat to target a single IC episode [8, 9].It has been suggested that the epidemiological shiftfrom Candida albicans to species intrinsically resistant(Candida krusei) or with decreased susceptibility toazoles (Candida glabrata) observed in some institutionsis a consequence of an overuse of antifungals [10, 11].While the efficacy of fluconazole as first-line therapy ofIC is being challenged, well tolerated but expensivealternative broad-spectrum antifungal agents are nowavailable and will be recommended in the updated IDSAguidelines for the management of IC [11–14]. These newdrugs are expected to impact positively on the outcome ofIC; however, the economical and ecological conse-quences of their increasing use are difficult to predict[15, 16]. Despite an improved therapeutic armamenta-rium, there is thus an urgent need for new managementstrategies for better targeting the use of antifungal agents.This is the aim of the paper published by Pe´rez-Para et al.[17] in the current issue of the Journal, in which a frequentnot evidence-based trigger for starting antifungal therapy ischallenging. In a retrospective analysis the authors suggest,in contrast to the common opinion, that a central venouscatheters (CVC) tip culture positive for Candida spp. is notsynonymous of IC or of increased risk for developing IC.Among 215 non-neutropenic critically ill patients with apositive CVC culture at a single academic institution, asubgroup of 58 patients (27%) with negative blood culturesdrawn within 7 days before and 7 days after catheterremoval was analyzed. Twenty patients received antifun-gals and only one developed IC (i.e., 2% of the cases),Intensive Care MedDOI 10.1007/s00134-009-1432-5 EDITORIALsuggesting that the number needed to treat a single ICepisode would be substantial. Independent predictors ofpoor outcome were a McCabe score corresponding toultimately fatal underlying disease and the presence ofsevere sepsis, septic shock or multiorgan failure. Theauthors concluded that antifungal treatment did not impacton the clinical outcome in these patients [17].In patients with bloodstream infection removal of theCVC has been suggested in previous investigations toaccelerate the clearance of bacteremia or fungemia. Incritically ill patients with sepsis and no documentedinfectious focus it is common practice to promptly removeand/or exchange the indwelling intravascular devices. Inthe absence of concomitant positive blood cultures, theclinical signification of a catheter tip culture positive forCandida spp. remains to be determined [18]. Nevertheless,in order to avoid acute and late complications of IC, manyclinicians start antifungal therapy in this setting. The studyby Pe´rez-Para et al. suggests that this subgroup of patientsshould not receive antifungal therapy.However, many questions remain unanswered. Thereason for CVC removal and culture are not specified. Didthese patients present a sepsis of unknown origin or wasthe device removed for end of use and routinely sent forculture despite absence of any symptoms and signs ofinfection? [18]. The cut-off value of one colony formingunit used for defining catheter colonization may haveselected a subgroup of patients with an extremely lowlevel of CVC colonization: whether a higher colony countis associated with an increased risk of IC remainsunknown. The significance of a positive catheter culturefor Candida spp. in the absence of candidemia and ofclinical signs of infection may differ according to thepresence or absence of a colonization at other sites.Although the dynamics of colonization assessed semi-quantitatively by the colonization index has been shownto predict the risk of IC, this information is lacking in thepresent study [8, 9, 12]. Simultaneous sampling of bloodcultures from a catheter line and by peripheral veni-puncture is recommended. Results of blood culturesobtained through the colonized device have, however, notbeen reported. Whether a positive result or other clinicalcharacteristics did influence the decision to start an anti-fungal therapy remains unknown. Further, blood cultureswere drawn within 7 days before or after CVC removal: issuch a large time window reasonable to exclude candi-demia in a patient with a positive CVC culture? Finally,one may challenge the decision to a priori exclude fromthe analysis the 64 patients with a concomitant candide-mia, the 44 patients in whom no blood cultures have beendrawn and the 26 children. These selection criteria mighthave biased the retrospective assessment of the targetpopulation [17].Beyond these major limitations, these data suggest thata catheter tip culture positive for Candida spp. in theabsence of candidemia should not be automatically con-sidered as an IC or a condition at high risk for developingIC. This observation suggests a reduction of the undis-criminated use of antifungal agents in this setting.However, this conclusion needs to be confirmed in pro-spective investigations assessing in which subset ofpatients with a positive CVC tip culture withholding or de-escalating antifungals is safe. These should be designed bydefining the underlying conditions (risk factors, coloni-zation, clinical signs of infection), by standardizing thediagnostic procedures (CVC cultures, blood cultures) andby distinguishing the type of intervention (i.e., prophy-lactic or pre-emptive/empirical antifungal therapy).References1. Eggimann P, Garbino J, Pittet D (2003)Epidemiology of Candida speciesinfections in critically ill non-immunosuppressed patient. LancetInfect Dis 3:685–7022. Nucci M, Anaissie E (2001) Revisitingthe source of candidemia: skin or gut?Clin Infect Dis 33:1959–19673. Raad I, Hanna H, Boktour M, GirgawyE, Danawi H, Mardani M, KontoyiannisD, Darouiche R, Hachem R, Bodey GP(2004) Management of central venouscatheters in patients with cancer andcandidemia. Clin Infect Dis38:1119–11274. Garey KW, Rege M, Pai MP, MingoDE, Suda KJ, Turpin RS, Bearden DT(2006) Time to initiation of fluconazoletherapy impacts mortality in patientswith candidemia: a multi-institutionalstudy. Clin Infect Dis 43:25–315. Prella M, Bille J, Pugnale M, DuvoisinB, Cavassini M, Calandra T, MarchettiO (2005) Early diagnosis of invasivecandidiasis with mannan antigenemiaand antimannan antibodies. DiagnMicrobiol Infect Dis 51:95–1016. Senn L, Robinson JO, Schmidt S,Knaup M, Asahi N, Satomura S,Matsuura S, Duvoisin B, Bille J,Calandra T, Marchetti O (2008) 1, 3-Beta-D-glucan antigenemia for earlydiagnosis of invasive fungal infectionsin neutropenic patients with acuteleukemia. Clin Infect Dis 46:878–8857. Leon C, Ruiz-Santana S, Saavedra P,Almirante B, Nolla-Salas J, Alvarez-Lerma F, Garnacho-Montero J, Leo´nMA, EPCAN Study Group (2006) Abedside scoring system (‘‘Candidascore’’) for early antifungal treatment innonneutropenic critically ill patientswith Candida colonization. Crit CareMed 34:730–7378. Eggimann P, Garbino J, Pittet D (2003)Management of Candida speciesinfections in critically ill patient. LancetInfect Dis 3:772–7859. Mean M, Marchetti O, Calandra T(2008) Bench-to-bedside review:Candida infections in the intensive careunit. Crit Care 12:20410. Pfaller MA, Diekema DJ, Gibbs DL(2007) Results from the ARTEMISDISK Global Antifungal Surveillancestudy, 1997 to 2005: an 8.5-yearanalysis of susceptibilities of Candidaspecies and other yeast species tofluconazole and voriconazoledetermined by CLSI standardized diskdiffusion testing. J Clin Microbiol45:1735–174511. Brion LP, Uko SE, Goldman DL (2007)Risk of resistance associated withfluconazole prophylaxis: systematicreview. J Infect 54:521–52912. Guery BP, Arendrup MC, Auzinger G,Azoulay E, Borges Sa´ M, Johnson EM,Mu¨ller E, Putensen C, Rotstein C,Sganga G, Venditti M, Zaragoza CrespoR, Kullberg BJ (2009) Management ofinvasive candidiasis and candidemia inadult non-neutropenic intensive careunit patients: Part II. Treatment.Intensive Care Med. doi:10.1007/s00134-008-1339-613. Playford EG, Eggimann P, Calandra T(2008) Antifungals in the ICU. CurrOpin Infect Dis 21:610–61914. Rex JH. http://www.uncedu/*churt/id_cc_ppts/IDSA_Candidiasis_Rex ppt.Accessed 9th Jan 200915. Forrest GN, Weekes E, Johnson JK(2008) Increasing incidence of Candidaparapsilosis candidemia withcaspofungin usage. J Infect 56:126–12916. Johnson E, Espinel-Ingroff A, SzekelyA, Hockey H, Troke P (2008) Activityof voriconazole, itraconazole,fluconazole and amphotericin B in vitroagainst 1763 yeasts from 472 patients inthe voriconazole phase III clinicalstudies. Int J Antimicrob Agents32:511–51417. Pe´rez-Parraz A, Munoz P, Guinea J,Martin-Rabadan P, Guembe M, BouzaE (2009) Is Candida colonization ofcentral vascular catheter in non-candidemic, non-neutropenic patientsan indicator for antifungals? IntensiveCare Med. doi:10.1007/s00134-009-1431-618. Eggimann P (2007) Diagnosis ofintravascular catheter infection. CurrOpin Infect Dis 20:353–359

On track to limit antifungal overuse!

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On track to limit antifungal overuse!

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