Antifungal Prophylaxis during Neutropenia and Immunodeficiency

28 Pages·1997·0.45 MB·English

CLINICALMICROBIOLOGYREVIEWS,July1997,p.477–504 Vol.10,No.3
0893-8512/97/$04.00(cid:49)0
Copyright©1997,AmericanSocietyforMicrobiology
Antifungal Prophylaxis during Neutropenia and Immunodeficiency
OLIVIERLORTHOLARY1,2ANDBERTRANDDUPONT2*
ServicedeM´edecineInterne,CentredeRecherchesenPathologieInfectieuseetTropicale,HoˆpitalAvicenne,
Universit´eParis-Nord,93009BobignyCedex,1andUnit´edeMycologieandCentreNationaldeR´ef´erence
desMycosesetdesAntifongiques,InstitutPasteur,75724ParisCedex15,2France
INTRODUCTION.......................................................................................................................................................478
GeneralComments.................................................................................................................................................478
WhoIsSusceptibletoFungalInfections?...........................................................................................................479
Neutropenicpatients..........................................................................................................................................479
Bonemarrowtransplantrecipients..................................................................................................................479
Solid-organtransplantrecipients.....................................................................................................................479
(i)Generalities................................................................................................................................................479
(ii)Kidney........................................................................................................................................................480
(iii)Liver..........................................................................................................................................................480
(iv)Pancreas....................................................................................................................................................480
(v)Heart,lung,andheart-lung....................................................................................................................480
HIV-infectedindividuals....................................................................................................................................480
Otherhigh-riskgroups......................................................................................................................................481
(i)Qualitativedefectsofneutrophils...........................................................................................................481
(ii)Connectivetissuediseases......................................................................................................................481
(iii)Otherimmunedeficits............................................................................................................................481
WhichPathogensToConsider?............................................................................................................................481
Candidaspp.
(i)Mucosalinfection......................................................................................................................................481
(ii)Systemicinfection....................................................................................................................................481
Aspergillusspp.....................................................................................................................................................482
Cryptococcusneoformans.....................................................................................................................................482
Endemicmycoses................................................................................................................................................482
Emergingfungalpathogens...............................................................................................................................482
WhenToAdministerDrugs?.................................................................................................................................483
COMMONPROPHYLACTICMEASURESFORALLIMMUNOCOMPROMISEDINDIVIDUALS..........483
Candidaspp.............................................................................................................................................................483
Aspergillusspp.........................................................................................................................................................483
Zygomycosis(Mucormycosis)................................................................................................................................483
Cryptococcusneoformans.........................................................................................................................................483
EndemicMycoses....................................................................................................................................................483
OtherFungalPathogens........................................................................................................................................484
NEUTROPENICPATIENTSOTHERTHANTRANSPLANTRECIPIENTS...................................................484
NonabsorbedOralTherapy...................................................................................................................................484
Topicalazoles......................................................................................................................................................484
(i)Clotrimazole...............................................................................................................................................484
(ii)Oralmiconazole.......................................................................................................................................484
Oralpolyenes.......................................................................................................................................................484
(i)OralamphotericinBversusplaceboornotreatment.........................................................................484
(ii)Nystatinsuspensionversusnotreatment.............................................................................................484
(iii)Nystatinsuspensionversustopicalclotrimazole................................................................................484
SystemicTherapy....................................................................................................................................................485
IntravenousamphotericinB..............................................................................................................................485
Systemicazolesversusplaceboornotreatment............................................................................................485
(i)Intravenousmiconazole............................................................................................................................485
(ii)Ketoconazole.............................................................................................................................................485
(iii)Fluconazole..............................................................................................................................................485
(iv)Itraconazole..............................................................................................................................................486
Systemicazolesversusoralpolyenes...............................................................................................................486
(i)Azolesversusnystatin...............................................................................................................................486
*Correspondingauthor.Mailingaddress:ServicedesMaladiesIn-
fectieusesetTropicales,Hoˆpitaldel’InstitutPasteur,209-211,ruede
Vaugirard,75724ParisCedex15,France.Phone:[phone].
Fax:[phone].E-mail:[email protected].
477
478 LORTHOLARY AND DUPONT CLIN.MICROBIOL.REV.
(ii)AzolesversusoralamphotericinB........................................................................................................486
(iii)AzolesversusintravenousamphotericinB.........................................................................................487
AzolesinassociationwithoralorintravenousamphotericinB..................................................................487
Comparisonoforalazoles.................................................................................................................................487
SpecificPreventionofInvasiveAspergillosis......................................................................................................487
HematopoieticGrowthFactorsandOtherCytokines.......................................................................................488
ProphylaxisagainstRelapse..................................................................................................................................488
AUTOLOGOUSORALLOGENEICBONEMARROWRECIPIENTS.............................................................489
Low-DoseIntravenousAmphotericinB...............................................................................................................489
AmphotericinBdeoxycholate............................................................................................................................489
LipidformulationsofamphotericinB.............................................................................................................489
Azoles........................................................................................................................................................................489
Ketoconazole........................................................................................................................................................489
Fluconazole..........................................................................................................................................................489
Itraconazole.........................................................................................................................................................490
SOLID-ORGANTRANSPLANTRECIPIENTS.....................................................................................................490
Kidney.......................................................................................................................................................................490
Liver..........................................................................................................................................................................490
PancreasandKidney-Pancreas............................................................................................................................491
Heart,Lung,andHeart-Lung...............................................................................................................................491
HIV-INFECTEDINDIVIDUALS..............................................................................................................................491
MucosalCandidiasis..............................................................................................................................................491
Primaryprophylaxis...........................................................................................................................................491
Suppressivetherapy............................................................................................................................................491
Cryptococcosis.........................................................................................................................................................492
Primaryprophylaxis...........................................................................................................................................492
Suppressivetherapy............................................................................................................................................492
HistoplasmosisDuetoHistoplasmacapsulatum..................................................................................................492
Primaryprophylaxis...........................................................................................................................................492
Suppressivetherapy............................................................................................................................................492
(i)AmphotericinB..........................................................................................................................................492
(ii)Itraconazole...............................................................................................................................................493
(iii)Fluconazole..............................................................................................................................................493
Coccidioidomycosis.................................................................................................................................................493
Primaryprophylaxis...........................................................................................................................................493
Suppressivetherapy............................................................................................................................................493
Aspergillosis.............................................................................................................................................................493
Primaryprophylaxis...........................................................................................................................................493
Suppressivetherapy............................................................................................................................................493
InfectionDuetoPenicilliummarneffei..................................................................................................................493
OtherMycoses.........................................................................................................................................................493
QUALITATIVEDEFECTSOFNEUTROPHILS...................................................................................................493
CONCLUSION............................................................................................................................................................493
ACKNOWLEDGMENTS...........................................................................................................................................495
REFERENCES............................................................................................................................................................496
INTRODUCTION are also being observed more frequently (1) and pose major
challengesowingtothelackofeffectivetherapies(357).
Theincidenceofinvasivefungalinfectionsisdeterminedbythe
GeneralComments
interaction between epidemiological factors and the degree of
Systemic mycoses are defined as infections that invade be- immunosuppression. The advent of AIDS has dramatically in-
yond the superficial surfaces into tissues that are normally creasedtheproblemsofmucosalcandidiasis,cryptococcosis,his-
sterile. During the past three decades, dramatic alterations toplasmosis, and coccidioidomycosis, as well as, more recently,
haveoccurredinourclinicalenvironment(useofbroad-spec- penicilliosisinsoutheastAsiaandparticularlyNorthernThailand.
trumantibacterialagentsandvascularaccessdevices)andpa- To prevent antifungal colonization and mainly to counter
tient immune defenses (resulting from chemotherapy and theriseofseveresystemicmycoses,forwhichtheresponseto
radiation, neutropenia, and lymphopenia of human immuno- curative treatments remains suboptimal, antifungal prophy-
deficiencyvirus[HIV]infection).Thesechangeshaveprovided laxishasbeenexpanded.However,ithasalsobeenresponsible
opportunities for fungal pathogens to assume major roles in for rising costs and the emergence of (naturally or not) resis-
infectious diseases. Such pathogens in immunocompromised tant fungal strains. Simultaneously, indirect ways to prevent
hostsmaybeseparatedintothosethatarecommunityacquired invasive fungal infections in immunocompromised hosts have
(endemicmycosesandCryptococcusneoformansinfection)and beendevelopedtobettercontroltheimmunedeficiencyitself,
thosethatarenosocomiallyacquired(CandidaandAspergillus for example the use of hematopoietic growth factors in neu-
spp.).Therateofcandidalbloodstreaminfectionhasincreased tropenicpatients,theeffectivepreventionofgraftversushost
byasmuchas487%throughoutthe1980s(258).Otherfungi disease(GVHD)inallogeneicbonemarrowtransplant(BMT)
VOL.10,1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 479
patients(139,146,288),andtheuseofmoreefficientantiret- BMTrecipientstofungalinfectionsisthedurationofneutro-
roviral agents in double or triple combination, including pro- penia.Theincidenceoffungalinfectionshasbeenestimatedto
teaseinhibitors,duringAIDS. be21%inBMTrecipientswhoseneutropenialastedlessthan
When prescribing an antifungal agent for prophylaxis, phy- 3weekscomparedwith57%inthosewhoseneutropeniaper-
sicians should be aware of which immunosuppressed patients sistedfor6weeksormore(215).Of60deathsinBMTpatients
to treat; which types of pathogens they want to cover in the withsystemiccandidiasis,fungalinfectionwasdirectlyrespon-
therapeutic spectrum; the best time for the introduction of sible for 19 (32%) (344). Among 85 autopsies of BMT recip-
antifungalprophylaxis;thepotentialforemergenceofresistant ients (216), Milliken and Powles determined that 26% of the
strains;concomitantorgandysfunctions;thepotentialfordrug patients had fungal infections. Aspergillosis remains a partic-
interactions, especially in transplant recipients treated with ularlydifficultprobleminallogeneicBMTrecipients;over90%
cyclosporine or tacrolimus; the effects on survival and quality ofinfectedpatientsdie(11,124).
oflife;andthetotalcostofthetreatment. Marrow allograft recipients run the highest risk of invasive
This paper presents a general review based on articles and fungal infections, not only during the neutropenic phase but
recentabstractspublishedfromJanuary1976toJanuary1997. also during the months following transplantation, especially
It reports our current knowledge of antifungal prophylaxis in when GVHD occurs (118, 124, 223). Autologous BMT recip-
neutropenic and other immunocompromised patients with an ients who undergo total-body irradiation in association with
emphasisonclinicaltrialsthathavedemonstratedtheefficacy chemotherapy appear to have a duration of neutropenia sim-
and safety of such treatments. Although anecdotal reports ilartothatobservedinintensivelytreatedpatientswithacute
have documented the efficacy of topical chlorhexidine (96), myeloblasticleukemia.Forpatientswhoreceiveintensiveche-
this, like prophylaxis against Pneumocystis carinii, which has motherapy followed by stem cell transfusion and treatment
recently been reclassified by taxonomists as a fungus, will not with cellular growth factors, the overall risk of infections and
befurtherdetailedhere. thatofinvasivemycosesisdramaticallyreduced(243),asthese
patients have a median duration of neutropenia of 12 days
WhoIsSusceptibletoFungalInfections? (224). In that study, 2.3% of 219 patients developed invasive
fungal infections. It is therefore important to separate these
Neutropenicpatients.Neutropenicpatientsareathighrisk two subpopulations of patients undergoing autografts when
for developing deep mycoses. Autopsy data show that 5% of selectingcandidatesforantifungalprophylaxis(357).
patients with solid tumors, 12% of patients with lymphoma, In the allograft recipients, one study identified age, acute
and up to 25% of patients with leukemia have histological GVHD, and donor mismatch as risk factors for invasive can-
evidence of invasive fungal infections (27). One-third to one- didal infection (118). Another study (344) demonstrated that
half of the patients who die during prolonged episodes of neutropenia was an independent factor associated with the
neutropeniahavedeepmycosesatautopsy(158,212).Dissem- occurrence of systemic candidal infections, as well as increas-
inatedcandidiasisisassociatedwitha30to40%mortalityrate ingage,detectionofoneormorepositivesurveillancecultures
inpatientswithsolidtumors(378).Neutropenicpatientsrep- forCandidaspp.,andtotal-bodyirradiation.Positivecytomeg-
resentthemostappropriategroupinwhichtostudyantifungal alovirus (CMV) serologic test results and age of 18 years or
prophylaxis. Indeed, many of the data available on this topic older were significant risk factors for non-Candida fungal in-
havebeenobtainedinthispopulation. fectionsinallogeneicBMTrecipients(223).Pretransplantcon-
However, all neutropenic patients with solid or hematolog- ditioning regimens and T-cell depletion are also recognized
ical malignancies do not have the same risk for developing a riskfactors,asareunderlyingdisease,remissionstatus,muco-
fungal infection, which depends on the magnitude and the saldamage,andGVHDprophylaxis(244,359).
duration of the neutropenic phase (28, 124, 375). Indeed, be- Rossetti et al. recently analyzed fungal liver infection after
cause of the short duration of neutropenia (up to 7 days), no marrowtransplantationandfoundthefollowingpredictivefac-
antifungal prophylaxis should be given during cycles of adju- tors:anydeepfungalinfectionaftertransplantation;coloniza-
vantchemotherapy(78).Patientswithacutemyeloblasticleu- tion or superficial infection with fungi after transplantation;
kemiaorseveremyelodysplasiawhorequireintensivechemo- severeliverdysfunctioncausedbyvenoocclusivediseaseofthe
therapeutic regimens need particularly close surveillance for liver;and/orGVHD(285).Interestingly,inthatpaper,imaging
invasive fungal infections. Other patients who should be con- studies performed during the last 15 days of life had a sensi-
sideredforprophylaxisarethoseinwhomaprolongedcourse tivityofonly18%fordetectingfungalliverlesions.Otherrisk
ofneutropeniamayoccur(339).Thisisthepopulationthatwe factorsarethesameasthosedescribedinnongraftedneutro-
havetargetedforourdiscussionofantifungalprophylaxis.Be- penicpatients.
cause of the high incidence of invasive fungal infections in Sable and Donowitz separated several periods of risk for
cancerpatients,difficultiesinobtaininganearlydiagnosis(be- infections during BMT (293). During the pretransplantation
causeofdifficultiesinisolatingfungiinculturesandinterpret- period, the risk of fungal infection is low. The engraftment
ingtheresultsandbecauseofaninabilitytoperforminvasive period,fromdays0to30,isassociatedwithanincreasedrisk
procedures in patients with coagulation disorders), and their of invasive fungal infections. During the postengraftment pe-
adverse effect on patient outcome, the need for antifungal riod, from days 30 to 100, any mold infection may occur, but
prophylaxisisstrong.Thedataobtainedfromthesenumerous hepatospleniccandidiasismayalsooccur.Duringthelatepost-
studies are often difficult to interpret and there is still no transplantation period (day 100 or later), systemic fungal in-
definitiveconsensusonpreventivemodalitiesinthesepatients. fectionsareunusualandoropharyngealcandidiasisisthemost
The type of underlying disease and thus the type of antineo- frequentfungalinfection(293).
plastic chemotherapy, mucosal damage, and duration of neu- Solid-organtransplantrecipients.(i)Generalities.Thesuc-
tropenia have to be clearly defined before the efficacy of any cessrateofsolid-organtransplantationhasgreatlyimprovedas
kindofantifungalprophylacticstrategycanbeevaluated. aresultofadvancesinsurgicaltechniques,immunosuppressive
Bone marrow transplant recipients. During clinical trials, therapy, and medical management. However, infections and
BMTrecipientsshouldbeseparatedfrompatientswithother allograftrejectionremainmajorcausesofmorbidityandmor-
causesofneutropenia.Themostimportantfactorpredisposing tality during solid-organ transplantation. Occasionally, the
480 LORTHOLARY AND DUPONT CLIN.MICROBIOL.REV.
transplantedorganitselfisthesourceoftransmissionofinfec- vasive fungal infections. Requirement for intensive care, me-
tion(138).Fungalinfectionsarereportedinalltypesofsolid- chanical ventilation before transplantation, operative time,
organ transplantation and are associated with high mortality type of anastomosis, and operative transfusion requirements
(27to77%)(250),withAspergillusinfectionsbeingresponsible were also defined as risk factors for fungal infections in liver
forthehighestdeathrate.Theincidenceoffungalinfectionsin transplant recipients (51, 251, 352, 384). Enhanced immuno-
solid-organtransplantrecipientsvariesaccordingtotheimmu- suppression with steroids, OKT3 monoclonal antibody treat-
nosuppressivetreatment,transplantedorgan,andtransplanta- mentofrejection,andpriorCMVinfectionmayfacilitatethe
tionteam:itislowestinrenaltransplantrecipientsandhighest development of invasive fungal infections. In a multivariate
in liver and pancreas transplantees, in whom underlying dis- analysis of factors associated with invasive lung aspergillosis
easeandcomplicatedabdominalsurgeryplayimportantroles after liver transplantation (167), high creatinine levels at the
(138). This incidence has been estimated to be 2 to 14% of time of Aspergillus isolation and use of OKT3 monoclonal
kidney,18to38%ofpancreasorpancreas-kidney,2to42%of antibodyweresignificantriskfactors.Inthatstudy,respiratory
liver, 0 to 32% of heart, and 15 to 35% of lung/heart-lung secretions and wound drainage positive for Aspergillus organ-
transplantations(126,250,251,253,351). ismswereassociatedwithinvasivedisease.
Immunosuppressive therapy and the use of corticosteroids, (iv) Pancreas. In pancreas transplant recipients, the most
particularlywhenadministeredasanintravenousbolusforthe commonsitesoffungalinfectionsaresurgicalwoundsandthe
treatment of acute rejection, are important predisposing fac- urinary tract. Infectious complications following pancreatic
tors(88,127),inassociationwiththetypeofunderlyingdisease transplantationwererecentlyanalyzedin34consecutiverecip-
and other factors during the posttransplantation period, in- ients. In 27 recipients who developed severe infectious epi-
cluding the presence of immunomodulating viral infections, sodes, 26% of the infections were caused by fungi (87% by
suchasEpstein-Barrvirus,CMV,andHIV(126).Thereisstill Candida spp.) (192). In a recent retrospective study, intra-
a debate concerning the increased incidence of fungal infec- abdominal fungal infections occurred after pancreatic trans-
tionsinlungtransplantrecipientsreceivingtacrolimus(250). plantationin41(9.2%)of445patients(20).Inthatstudy,the
(ii) Kidney. There is a significant relationship between the rate of infections was higher for enteric-drained (21%) than
total dose of steroids given to renal transplant recipients and forbladder-drained(10%)transplants,fororgansdonatedby
thesubsequentdevelopmentofinvasiveaspergillosis(125).In livingrelatives(16%)thanforthosefromcadavers(9%),and
thispopulation,somepreciseriskfactorsforfungalinfections for pancreas-after-kidney (12%) and simultaneous pancreas-
have been identified: diabetes, cadaveric allograft, increased kidney(11%)thanforpancreas-only(5%)recipients.Therate
corticosteroid use (to prevent or control rejection), retrans- of fungal infections was 6% in patients receiving prophylaxis
plantation, and recent CMV infection (126). Recipients of (fluconazole, 400 mg/day for 7 days) compared with 10% in
kidney transplants are at high risk for the development of those without prophylaxis. It should be noted that the 1-year
candiduria, including asymptomatic colonization of the blad- graft survival rate was significantly decreased for recipients
der,andrenalparenchymaldiseasesmayshortengraftsurvival. withinfection.
In a recent series of 50 transplant recipients (197), 228 epi- (v)Heart,lung,andheart-lung.Fungalinfectionsfrequently
sodesofinfectionweredocumented(4.5perpatient),11%of occurduringthefirstmonthposttransplantation.Mostfungal
whichwerefungal;47%oftheseepisodesoccurredwithinthe infectionsinthesepatientsarecausedbyCandidaandAspergil-
first2monthsaftertransplantation.Candidaspp.weretheonly lus spp. (155). Some risk factors are more specifically associ-
etiologicalagentsisolated.Inthatprospectivestudy,pyelone- atedwiththesurgicalproceduresusedinheartorlungtrans-
phritis due to Candida spp. was the only infection associated plantees:colonizationofthedonortracheabyCandidaspp.is
withahighriskofallograftloss. a notable risk factor for pneumonia, anastomotic dehiscence,
(iii) Liver. Liver transplant recipients are at high risk for andmediastinitisintherecipient(69,84).
developinginvasivefungalinfections(51),especiallywhenor- In a series of 100 consecutive heart transplant recipients,
thotopic liver transplantation is performed. The reasons are Waser et al. (360) reported only one lethal case of Candida
thelongerdurationoftheprocedure,thefrequencyofcoloni- sepsis(originatingfromaperitonealdialysiscatheter)andone
zation with Candida spp. (166), and surgical complications lethal case of invasive aspergillosis occurring 27 months post-
such as bile duct obstruction and vascular anastomotic prob- operatively.
lems,whicharemorecommonthaninothertransplantoper- Krameretal.(162)publishedaretrospectiveanalysisof200
ations(359).Inonestudy,themedianposttransplantationtime episodesofseriousinfectionsin73heart-lungrecipients.Four-
tothefirstepisodeoffungalinfectionhasbeenreportedtobe teen percent were fungal, with Aspergillus spp. (14 episodes)
60days(251).Theincidenceofinvasivefungalinfectionswas and C. albicans (12 episodes) being the most common patho-
reportedtobeashighas42%(352).Infectionsoftheabdom- gens. C. albicans infected mainly the upper tracheobronchial
inalcavityarefrequentlyobserved,buturinarytractandchest tree and was the second most common pathogen in patients
infectionsalsooccur(351),withCandidaspp.beingresponsi- with obliterative bronchiolitis. Aspergillus spp. tended to dis-
blefor87%ofalldeepmycoses(62,127). seminateandwereresponsibleforthedeathofthreepatients.
The risk factors for systemic fungal infections were retro- However,intheserecipients,itissometimesdifficulttodistin-
spectively analyzed in 186 orthotopic liver transplant proce- guish between Aspergillus infection and colonization (162).
dures performed in 152 patients (37). The total incidence of PreoperativecolonizationwithAspergillusspp.inpatientswith
invasivefungalinfectionswas16.5%(25of152).Theincidence cystic fibrosis, intercurrent infection with CMV, neutropenia,
of disseminated candidiasis, aspergillosis, and combined can- and steroid therapy has been reported to increase the inci-
didiasis plus aspergillosis was 6.5, 7.2, and 2.6%, respectively. denceofthedisease(155).
The mortality rate associated with invasive fungal infections HIV-infected individuals. Opportunistic fungal infections
was80%.Of10patientswithdisseminatedcandidiasis,4sur- are common in patients with HIV infection and represent
vived;of11patientswithinvasiveaspergillosis,only1survived. majorcausesofmorbidity(10,373).Theirincidenceincreases
Acuterenalfailurerequiringhemofiltrationandtheamountof withtheprogressionoftheHIVinfectionandreductionofthe
freshplasmatransfusedbecauseofpoorinitialfunctionofthe CD4 lymphocyte counts. Specific risk factors for each oppor-
liverallograftwereindependentsignificantriskfactorsforin- tunistic fungus are detailed below. Decisions to administer
VOL.10,1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 481
primaryprophylaxismustconsidertheprevalenceandseverity those observed during lymphomas. Interestingly, recovery of
of these infections, the efficacy and safety of antifungal treat- Candidaspp.fromthemouthsofneutropenicpatientsispre-
ment, the risk of emergence of resistant fungal species, the dictive of the subsequent occurrence of oropharyngeal candi-
quality of life and the survival time in control groups of pa- diasis(389).
tients without prophylaxis, and the cost of antifungal treat- Mucosal candidiasis contributes markedly to the morbidity
ment.Indeed,itwasestimatedin1994thatantifungalprophy- of HIV-infected patients in both developed and developing
laxisfor100,000AIDSpatientsintheUnitedStateswouldcost nations, as it is the most common fungal infection in this
over half a billion dollars yearly (368). The impact on overall population (373). The increasing resistance of C. albicans,
survival is minimal, since the incidence of systemic fungal in- whichoccursin7to15%(89,234)(butupto41%inarecent
fectionsislow. report [195]) of HIV-infected patients undergoing long-term
Other high-risk groups. (i) Qualitative defects of neutro- fluconazole therapy to control mucosal candidiasis, has be-
phils. Chronic granulomatous disease is a hereditary abnor- comeamajorproblem(16,47,99,260,278,290,298,299).In
malityofphagocyticcellsandcausesmicrobicidaldefectsdue this population, fluconazole MICs correlated with the clinical
toalackofproductionofreactiveoxygenspeciesnecessaryfor outcome(105,278).Inthreerecentstudies,prioruseofazole
microbicidal activity. Aspergillus and Candida spp. were iso- therapywasidentifiedasariskfactorassociatedwiththeemer-
lated in 20.4% of a large series of 245 patients and were gence of resistant candidiasis (194, 195, 337). The recent ex-
frequentlyresponsibleforinfection(60).InaFrenchseries,14 tensionofCandidaresistancetootherantifungaldrugsiswor-
of37affectedchildrenwhopresentedwithinvasiveaspergillo- risome (159, 174). Chronic administration of low doses of
siswerecharacterizedbyapaucityofsymptoms(225).Myelo- fluconazole may also facilitate the emergence of C. glabrata
peroxidase deficiency, a hereditary defect of the lysosomal andC.krusei,butthepreciseimpactofazolesonthesespecies
enzyme myeloperoxidase, may also favor Candida infections remainscontroversial(259).Thesespecieshavebeenisolated
(294). from the oral cavity of AIDS patients (55, 75, 290), but their
(ii)Connectivetissuediseases.Despitetheintensiveimmu- pathogenicityinHIV-infectedindividualsremainstobeeluci-
nosuppressiveregimensadministeredandtheuseofprolonged dated. Indeed, in a recent study, none of 10 patients from
steroidtherapyduringsystemicinflammatorydiseases,patients whomonlynon-albicansspeciesofCandidawereisolatedhad
with connective tissue diseases are not specifically prone to active thrush (195). For patients harboring resistant or less-
developingdeepfungalinfections.Invasivefungalinfectionsin susceptible strains of C. albicans, C. krusei, and C. glabrata,
thesepopulationshavebeenreportedintheliteraturebutnot stricthygienicproceduresmustbeusedtoavoidtransmission
to a degree that requires general recommendations for their within the hospital (347). Such transmission has also been
prophylaxis (183). However, monitoring for fungal coloniza- clearly documented between sexual partners and may explain
tion to ensure rapid diagnosis of such infections should be the discovery of azole-resistant Candida spp. isolated from
performedinpatientswithprolongedneutropeniaorprofound previouslyuntreatedpatients(85).
CD4 lymphocyte depletion, in particularly patients with We- (ii) Systemic infection. Systemic infections are of both en-
gener’sgranulomatosisorsystemiclupuserythematosus(183). dogenous (61) and exogenous (259) origins. The insertion of
(iii) Other immune deficits. Other defects can be classified central venous catheters predisposes neutropenic patients to
as chronic quantitative neutrophil deficiencies, in which sys- fungemia,especiallythosereceivingparenteralnutrition(100).
temiccandidiasisandinvasiveaspergillosisaremostcommon, Hematogenous candidiasis also follows colonization of the
or as cellular immune deficits, such as idiopathic low-CD4 mouth or gastrointestinal tract (42, 72, 297), as reported for
syndrome, in which Cryptococcus neoformans, candidal muco- patientshospitalizedinsurgicalintensivecareunits(263).Col-
sal infection, and dimorphic fungal infections are more likely onization of multiple noncontiguous sites in contrast to colo-
to develop. Infants with severe combined immunodeficiency nization of a single site, is highly predictive of invasive candi-
may also develop fungal infections, particularly candidiasis diasis in neutropenic patients (198). Because the duration of
(320,361).Thus,thesepatientsshouldbemanagedwithanti- prophylactictreatmentisshort,theappearanceoffluconazole-
fungal prophylaxis according to the nature of their immuno- resistantC.albicansislesslikelytobeproblematicforpatients
deficiency, which indicates the probable type of fungal infec- with cancer (379). Whether these patients need more protec-
tionstoprevent. tionwhentheyarehousednexttoHIVunitsrequiresfurther
No specific study has addressed the use of antifungal pro- investigation. The major problem in this neutropenic popula-
phylaxis in these last two populations. Thus, they will not be tion is the emergence of fluconazole-resistant C. krusei (204,
furtherdiscussedhere. 208, 256, 380) and C. glabrata (92, 236, 381). C. parapsilosis
(187,362)mayalsoemergeasasignificantpathogen,particu-
WhichPathogensToConsider? larlyinpatientsreceivingparenteralnutrition.
Systemic candidal infections have been reported in 11.4 to
Aspergillus and Candida spp. are the most common fungal 12.5%ofBMTrecipients(118,344)withinamediantimeof15
pathogens isolated from neutropenic patients and represent daysaftertransplantation(118).Inonestudy,theincidenceof
90% of all fungal infections (343). They are thus the most candidal infections was similar in allogeneic and autologous
commonfungaltargetsofprophylaxisinalltypesofimmuno- marrowrecipients(344).Themortalityis39%forcandidemia
deficiencies. alone and 90% when tissues are involved with or without
Candidaspp.(i)Mucosalinfection.Inneutropenicpatients, fungemia (118). Candida infection of multiple organs was di-
predisposition to mucosal Candida infections is facilitated by agnosed postmortem in 26 of 132 patients (344). In BMT
antineoplastic chemotherapeutic regimens and radiation, patients,C.albicansremainsbyfarthemostfrequentpathogen
which cause mucosal ulcerations. The use of broad-spectrum responsible for fungal infections (313), but C. tropicalis has
antibioticswithanaerobicactivity(295)orglycopeptides(280) emerged as another frequent pathogen (359). In liver trans-
alsopromotesthegrowthofCandidaspp.Thus,trialsofpro- plant recipients, more than 85% of invasive fungal infections
phylaxisagainstCandidaspp.shouldincludegroupsofpatients are candidal (138) and occur early after transplantation (62).
with similar exposure to antibiotics (386). Mucosal infections Theincidenceofcandidalinfectioninpancreastransplantre-
arealsomorecommoninpatientswithT-celldeficiencies,like cipientsapproaches100%(137).
482 LORTHOLARY AND DUPONT CLIN.MICROBIOL.REV.
The occurrence of candidemia in HIV-infected children (129).TheriskofcryptococcosisamongHIV-infectedindivid-
(356) and adults (173) cannot be ignored, especially in AIDS ualsishighestatCD4(cid:49)lymphocytecountsbelow100/mm3.
patients with central venous catheters for prolonged periods Endemicmycoses.Endemicsystemicmycosesaregeograph-
(115).Fungemiaduetofluconazole-resistantalbicansandnon- ically restricted and include histoplasmosis, blastomycosis,
albicans Candida species are now being reported in this pop- paracoccidioidomycosis, coccidioidomycosis, and penicilliosis.
ulation(168,173,336). However,thetransformationofendemicmycosesintooppor-
Aspergillus spp. Aspergillus fumigatus and A. flavus are the tunistic diseases is now being noted. In immunocompromised
most common pathogenic species, but other species are also patients, they may be observed as primary infections, reinfec-
responsibleforhumaninfections.Aspergillusspp.areobserved tion, or reactivation which may occur much later, sometimes
mainly in patients with prolonged neutropenia, those with several years after the person has left the area of endemic
qualitative disturbances of their neutrophil function, or those infection (138). Such mycoses are particularly problematic in
receiving steroids (100). Invasive aspergillosis has recently patientswithAIDSbecauseoftheirhighincidenceinareasof
been described in patients with lymphoid hematological ma- endemicinfectionandtheirmajorcomorbidity.
lignancieswhoarereceivingpurineanalogs(56).Theriskwas HistoplasmosisduetotheH.capsulatumhasbeenreported
calculatedbyGersonetal.,whoestimatedittobefrom1%per in2to5%ofpatientswithAIDSinareasofendemicinfection
dayafterthefirst3weeksofneutropeniato4.5%perdayafter intheUnitedStatesandupto25%inselectedcities(367).In
5 weeks (104). The risk of developing invasive aspergillosis is a recent survey in France, we found 56 AIDS patients who
alsodependentontheenvironment;therefore,historicalcon- developedthediseasesometimesupto21yearsaftertheyhad
trols cannot be used for studies on Aspergillus chemoprophy- lefttheareaofendemicinfection(182).Mostcaseshavebeen
laxis(386). observedduringthelast5years,whichshouldserveasanalert
Invasive aspergillosis was most often reported in patients tophysicians.Bycontrast,Histoplasmaduboisiihistoplasmosis
with acute leukemia or in allogeneic BMT recipients, espe- is rare in the immunocompromised host. Indeed, in a recent
ciallythosewithGVHD(205);itisaleadingcauseofdeathin nationalsurveyinFranceinvolving25patients,wefoundthis
the latter group (79). The incidence of invasive aspergillosis organisminonly2HIV-infectedindividuals(90).
may be as high as 25% in some allogeneic BMT populations Duringtheearly1990s,theincidenceofCoccidioidesimmitis
(287). More recent data were summarized by Denning (77) infection increased dramatically (161). Disseminated coccid-
andshowedthattheincidencevariedbetween3.8and8.7%in ioidomycosis has been reported in 602 AIDS patients in the
allogeneic BMT recipients and between 0.6 and 4.5% in au- UnitedStates(151).
tologousBMTrecipients.Aspergillusspp.werethemostprev- Penicilliosis is increasing sharply in Thailand (325), South
alent fungi responsible for brain abscesses following marrow China (76), and Hong Kong (57) and has become the third
transplantationinonerecentreport(128). most common infection associated with AIDS after extrapul-
The incidence of invasive aspergillosis among renal trans- monary tuberculosis and cryptococcal meningitis in Northern
plant recipients was estimated to be around 3% in the early Thailand(325).Paracoccidioidomycosisisstillrareinthispop-
1980s(125,363);itwas5.5%and14to19%inliverandheart ulation, with 27 cases reported in the literature (111), as is
transplant recipients, respectively (77, 155). A recent study blastomycosis (249). Antifungal prophylaxis might have the
reported an incidence of 16.5% in orthotopic liver transplant greatest impact on HIV-infected patients with less than 100
recipients (145), and the eyes were the second most common CD4(cid:49)Tcellslivinginareaswherethesepathogensarehyper-
site of infection. The outcome of infection in the solid-organ endemic.
transplant recipient population depends on the extent of the Intransplantrecipients,histoplasmosisisthemostfrequent
fungaldisease(79,359). endemic fungal infection, causing primarily disseminated but
In HIV-infected patients, aspergillosis is becoming more also chronic forms of disease (138). Coccidioidomycosis has
prevalent as a consequence of longer survival and complica- beenreportedmostlyinrenal,heart,andheart-lungtransplant
tions of other therapies (160, 188). A higher risk for invasive recipients (138, 162), but blastomycosis is rarely reported
aspergillosisisobservedwhenpatientshaveaCD4(cid:49)cellcount (307).
below 50/mm3 and when they have recently taken corticoste- Emergingfungalpathogens.ThemembersoftheMucorales
roids or recently been neutropenic. However, the last two are ubiquitous molds that cause invasive fungal infections in
factorsarenotalwayspresent,andaspergillosismayalsocom- neutropenic patients whether or not the patients have under-
plicatepreexistinglungdamage(188). goneBMT(100).Themostfrequentorganismsresponsiblefor
Cryptococcusneoformans.Cryptococcosisisobservedmainly zygomycosis are Rhizopus arrhizus, Absidia corymbifera, and
in patients with impaired T-lymphocyte–monocyte/macro- Rhizomucor pusillus (359). Zygomycoses also arise in pro-
phage interactions, such as HIV-infected individuals (58), foundlyimmunocompromisedHIV-infectedindividuals(341).
those with Hodgkin’s disease, and those receiving high-dose Theymayalsobeobservedintransplantrecipientstreatedwith
corticosteroids. C. neoformans infection rarely occurs during steroids (250), usually several months after transplantation.
the first 4 to 6 months after organ transplantation (138). A However, a case occurring 5 days after heart transplantation
recentpaperreported10cryptococcalinfectionsoccurringaf- hasalsobeenreported(227).
ter liver transplantation within a median of 3.5 months after Several other species are becoming increasingly recognized
transplantation (148). In that study, the incidence of crypto- asthesourceofdeepfungalinfectionsincancerpatients(13,
coccal infection was 0.25%. In France, 14% of cryptococcal 254);theyincludeFusariumspp.(102,207),Trichosporonasa-
diseases occur in non-HIV-infected immunodeficient individ- hii (beigelii), Blastoschizomyces capitatus (254, 358), and Sce-
uals(86). dosporium spp. (11). Disseminated fusariosis frequently man-
Inmostareasoftheworld,thisfungalinfectionoccursin5 ifestsitselfascutaneouslesions,andthefungushasfrequently
to 10% of HIV-infected patients (86, 262), but in Africa it been isolated from blood cultures (207). Potentially severe
affects up to 30% (217), and it may become an even larger infections caused by Acremonium spp., Malassezia furfur, and
problem in Thailand (147). By contrast, recent results of a dematiaceous fungi have also been reported (254). They are
multistatepopulation-basedsurveillanceshowedadecreasein often resistant to one or several antifungal agents (357), and
the incidence of cryptococcal infection in North America effectiveantifungalprophylaxisremainstobefound.Interest-
VOL.10,1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 483
ingly,twelvedifferentunusualfungalpathogenswereisolated Modern equipment such as high-efficiency particulate air fil-
from cancer patients at M. D. Anderson Hospital between ters, laminar air flow, positive room air pressure to the corri-
1974and1986(13). dor,well-sealedrooms,andhighratesofroomairchangescan
In HIV-infected patients, invasive fungal infections due to reduce the incidence of aspergillosis (100, 279, 310, 363), but
unusualpathogenshavealsobeenfound(65,185). theseprecautionsarenotavailableeverywhere.
Simplification of the procedures used for the care of neu-
WhenToAdministerDrugs? tropenic patients, including outpatient management, should
specifically address the risk of fungal infection. It has been
Whenantifungalprophylaxisisusedinneutropenicpatients, proposedthatallhigh-riskneutropenicpatientsshouldbeex-
itshouldbestartedatthetimechemotherapyisinitiatedsoas aminedforpossiblecolonizationbyAspergillusspp.inthenasal
to be active when the neutrophil count drops. Once the neu- cavityandtheupperrespiratorytractbeforehigh-dosechemo-
trophilcountrecovers,theprophylaxisshouldbediscontinued therapy is given or prior to BMT (364). This practice is not
(339). standard and is costly but may provide data with which to
In BMT recipients, prophylaxis must be continued, regard- initiate preemptive therapy. Particularly rigorous precautions
less of the neutrophil count, because of the risk of systemic should be taken when renovation, repair, and/or construction
fungalinfectionsshouldthepatientdevelopGVHD.Particular work is under way in medical units for care of HIV-infected
attentionmustbepaidtopatientswhoneedhigh-dosesteroids individuals.
to counter transplant rejection and those with active CMV Althoughinhaledsporeshavebeenthoughttobethemajor
infection.Althoughnooptimaldurationofantifungalprophy- source of invasive aspergillosis, reactivation of endogenous
laxishasbeendefinedforthispopulation,arecentrecommen- Aspergillus spp. can also be responsible for the disease (283).
dation proposed a duration of 3 months posttransplantation Recentstudiesthatinvestigatedtheepidemiologyofaspergil-
(386). losis by molecular techniques provided limited evidence for a
For solid-organ transplant recipients, this question remains readilyidentifiableenvironmentalsourceofAspergillusstrains
unanswered,butantifungalprophylaxismightbeindicatedfor thatcanbeshowntoberesponsibleforeithersporadiccasesor
atleastthefirstmonthposttransplantation. outbreaks of aspergillosis (106, 189). Ideally, prevention of
In HIV-infected patients, the risk of systemic fungal infec- invasive aspergillosis involves action at two different levels:
tions dramatically increases below a level of 100 CD4(cid:49) lym- environmentalcontroltoavoidacquisition,andchemoprophy-
phocytes/mm3. Thus, studies on primary prophylaxis should laxisofalreadycolonizedpatients(283).
target these patients. Lifelong suppressive therapy should be
giventopatientswhopreviouslyexperiencedasystemicfungal
Zygomycosis(Mucormycosis)
infection.
There is no recognized method to prevent systemic infec-
tions with members of the Mucorales. Housing patients with
COMMONPROPHYLACTICMEASURESFORALL
severe neutropenia in rooms supplied with laminar-flow-puri-
IMMUNOCOMPROMISEDINDIVIDUALS
fiedairhasbeenshowntoreducetherisksofaspergillosisand
Careful barrier nursing is essential for all immunosup- mucormycosis (324). Replacing deferoxamine by hydroxypyr-
pressedpatients(269).Inaddition,specificmeasuresaretaken idinonechelatorsmaybeoneapproachtodecreasingtherisk
forcertainfungalagents. ofdevelopingmucormycosisinpatientsrequiringsuchtherapy
(31).DeferoxamineallowsasignificantuptakeofironbyRhi-
Candidaspp. zopus spp. and promotes the in vitro growth of these patho-
gens.
The most important prophylaxis against candidiasis is to
minimizethefactorspredisposingtoCandidainfections.Indi-
Cryptococcusneoformans
vidualmajorriskfactorsforsystemiccandidiasisintheimmu-
nocompromisedhostweredefinedinatleastfourcase-control The lungs are the major portal of entry of Cryptococcus
studies(40,156,280,365).Riskfactorsforcandidemiamainly neoformans through inhalation of yeasts or basidiospores of
include the use of invasive procedures, neutropenia, and ad- the fungus. The fungus is ubiquitous in the soil; therefore,
ministration of at least two broad-spectrum antibiotics (364). there is no way to avoid inhalation. Bird (pigeon and canary)
Severalclustersoroutbreaksofcandidiasishavebeenreported droppings are a source of contamination of dust and soil,
(100, 259, 283). Therefore, it is absolutely essential that phy- although there is no proof that droppings are the primary
sicians,nurses,andpeoplevisitingthepatientsbemadeaware environmental source of cryptococcosis (262). In any case,
ofthepotentialtransmissionofCandidaspeciesbytheirhands patients with cellular immunodeficiency, AIDS, or on high-
(323) and be taught strict hygienic (handwashing) practices. dose corticosteroids should probably avoid close contact with
Thesestepswillpermitprophylacticdrugstoplaytheirrole. birds(262).Thereisnodocumentedinterhumantransmission
ofcryptococcosis,andnospecialrecommendationcanbegiven
Aspergillusspp. forhospitalpractice.
Aspergillus spp. are ubiquitous in nature. The incidence of
EndemicMycoses
invasive aspergillosis is increased during hospital renovation
and/orconstructionandwhenairfiltrationisinadequate(100, Educational efforts should be made to better acquaint the
286, 359). However, a recent study failed to demonstrate any public with histoplasmosis in areas of endemic infection and
temporalassociationbetweenperiodsofhighAspergillusspore thetypesofleisureorworkactivitiesthatcanincreasetherisk
countsandcasesofaspergillosis(116). of contracting infections. For severely immunocompromised
Exposure to plants is strongly contraindicated (78), as is patientsnotlivinginregionsofhighlyendemicinfection,travel
consumptionofrawvegetablesandpepper(70),andfoodmust intheseareasshouldbediscouraged.ForEuropeantravelers,
be properly cooked. Regular cleaning and maintenance of a theFrenchAntillesandFrenchGuianashouldbeconsidered
dust-freeenvironment,especiallywallsurfaces,areimportant. high-risk areas. Visiting caves should also be proscribed for
484 LORTHOLARY AND DUPONT CLIN.MICROBIOL.REV.
TABLE 1. Studiesonnystatinprophylaxisversusnotreatmentinneutropenicpatients
Population No.ofpatients Method Mainresultsb Reference
Acuteleukemiainchildren 67 Randomizeda NoreductionofFUO;reductioninhospitalization 172
Cancer 164 Comparative Reductionofmultiple-sitecolonization;nochange 42
inIFIrate
Acuteleukemia 70 Retrospective NoreductionofOPC;noreductionof 72
disseminatedcandidiasis
Leukemiainchildren 94 Historicalcomparative Reductionofclinicalcandidiasis 49
Acuteleukemia 56 Randomized Nodifference 376
aInassociationwithtrimethoprim-sulfamethoxazole.
bFUO,feverofunknownorigin;IFI,invasivefungalinfection;OPC,oropharyngealcandidiasis.
these patients because of possible contamination by animal didiasis (1% became infected versus 27% in the untreated
droppings(130).Immunocompromisedpatientsshouldremain group)(389).
indoors during dust storms in areas where of Coccidiodes im- These three studies suggest that topical clotrimazole is an
mitisisendemic(203). effective alternative for the prevention of oral candidiasis in
It is important to look for serological evidence of previous cancerpatients,buttherearenodatatosupportitsuseforthe
exposuretoHistoplasmacapsulatumorC.immitiswhenimmu- preventionofsystemicinfections(211).
nodeficiency is diagnosed or before transplantation in people (ii)Oralmiconazole.Oralmiconazoleascapsulesorbuccal
who have lived or traveled in areas of endemic infection. No gel is marketed in some countries. As capsules, the drug is
general recommendation can be made for the prevention of poorly absorbed, and gastrointestinal intolerance and side ef-
blastomycosis in immunocompromised individuals, and sero- fects are frequent. Very few data concerning its use in the
logical tests to determine possible exposure to Blastomyces prophylaxis of fungal diseases are available (38). The buccal
dermatitidisarenotreliable.Immunocompromisedindividuals, gel, a formulation available in France, represents an effective
especially those infected with HIV, should be aware of Peni- topicaltreatmentagainstoropharyngealcandidiasisinourclin-
cillium marneffei endemicity in Southeast Asia, South China, ical practice; however, no comparative randomized study has
and Hong Kong. Finally, immunocompromised individuals beenundertakentoassessitsuseasaprophylacticagent.
shouldnotworkinmycologylaboratories. Oralpolyenes.(i)OralamphotericinBversusplaceboorno
treatment.AmphotericinBisinactivatedinfeces(142),sothat
highdosesarenecessarytoobtainantifungalactivity(81).One
OtherFungalPathogens
old study demonstrated that oral amphotericin B (200 mg/d)
Theremainingpathogensmaybeassignedtotwocategories: was significantly superior to placebo in preventing dissemi-
endogenousfungalflora,includingyeastssuchasTrichosporon, nated candidiasis (this formulation is not available in the
Malassezia, Rhodotorula, and Saccharomyces spp.; and exoge- UnitedStates(95).AmphotericinB(tabletsorinsuspension)
nous, mainly filamentous fungi, such as Fusarium, Scedospo- has sometimes been shown to be effective in preventing can-
rium, Penicillium, Curvularia, Bipolaris, and Alternaria spp. didiasis,buttheseformulationsarepoorlytoleratedbypatients
(254).Theportalofentryofendogenousfungiisthedigestive (206), which may greatly affect the outcome. Yamada et al.
mucosa or skin; exogenous fungi are generally contracted by reported that oral amphotericin B in combination with nor-
inhalation of spores. As a rule, to prevent these yeast infec- floxacin was able to lower the rate of fungal infections com-
tions, the integrity of the skin and mucosal barriers must be pared with amphotericin B alone (388). Resistant fungal
preservedandtheuseofantibioticsandintravenouslinesmust strainshavebeenfoundinpatientsreceivingtopicalpolyenes
be limited. For the filamentous fungi, the main prophylactic (267).Becauseofthelackofconvincingdatashowingthatoral
measureisefficientairfiltrationandlaminarairflow. amphotericin B is effective as antifungal prophylaxis, the
Working Party of the British Society for Antimicrobial Ther-
NEUTROPENICPATIENTSOTHERTHAN apy did not recommend its use alone (386), as had been pre-
TRANSPLANTRECIPIENTS viouslysuggested(73,314).
(ii) Nystatin suspension versus no treatment. It has been
demonstratedinhealthyvolunteersthatthereisnoinhibitory
NonabsorbedOralTherapy
concentration of nystatin against C. albicans in the feces, de-
Nonabsorbedoraltreatmentshavebeendesignedtoreduce spite treatment with as much as 12 (cid:51) 106 U/day (141). In an
fungalcolonizationandinfectionofthedigestivetractandare uncontrolled study, nystatin could not eradicate existing Can-
notusedforprimaryprophylaxisofinvasiveaspergillosis. dida colonization or prevent colonization in patients with ini-
Topical azoles. (i) Clotrimazole. Clotrimazole troches (10 tiallynegativecultures(17).Theresultsofstudiesonnystatin
mgthreetimesaday[t.i.d.])werestudiedversusplaceboin84 suspensionvsnotreatmentaresummarizedinTable1.
patients (this study also included 47 patients who had under- Anoldstudyreportedthatnystatinusedinassociationwith
gonerenaltransplantation).Clotrimazolewassuperiortopla- antibioticshadapoorefficacyagainstdisseminatedcandidiasis,
cebo in preventing oral candidiasis in patients with solid tu- which was not attenuated, regardless of the dose (350). In
mors but not in those with leukemia; however, both groups another study reported by the same group, filamentous fungi
were small (246). A prospective, randomized, double-blind wereacquiredsignificantlymorefrequentlybypatientsreceiv-
studyinvolvingthesamedosageofclotrimazoleversusplacebo ingacombinationoftrimethoprim-sulfamethoxazoleplusnys-
in patients with acute leukemia showed fewer oral candidal tatinthanthosereceivingnalidixicacidplusnystatin(349).
infectionsintheclotrimazolegroup(67).Athirdstudyevalu- (iii) Nystatin suspension versus topical clotrimazole. Clo-
ated clotrimazole (10 mg t.i.d.) versus no treatment and trimazole(25mgt.i.d.)wasmoreeffectiveandbettertolerated
showedthesuperiorityofclotrimazoleinpreventingoralcan- than oral nystatin for the prevention of oropharyngeal candi-
VOL.10,1997 ANTIFUNGAL PROPHYLAXIS DURING IMMUNODEFICIENCY 485
TABLE 2. Studiesonfluconazoleprophylaxisversusplaceboornotreatmentinneutropenicpatients
Population No.ofpatients Method Regimena Mainresultsa Reference
Solid-organmalignancies 112 Double-blind Flu(50mg/day)versus LessOPC(2versus28%);noother 296
placebo fungalinfectionintwogroups
Acuteleukemia 257 Double-blind Flu(400mg/day)versus Lessfungalcolonization(29versus 383
placebo 68%);lesssuperficialfungal
infection(6versus15%);no
changeofIFIrate,AmBuse,or
deaths
AcuteleukemiaandBMT 47 Double-blind Flu(400mg/day)versus Lesssuperficialfungalinfection 52
placebo (34versus79%);fewerfebrile
daysbeforeAmBuse;reduction
ofAmBuse(22versus58%)
Hematologicalorsolid- 70 Randomized Flu(400mg/day)versus LessIFIb 387
organmalignancies notreatment
Hematological 96 Double-blind Flu(400mg/day)versus DelayedAmBuse;fewerfebrile 303
malignancies placebo days;preventionofOPC;no
effectsonIFI,outcome,andcosts
aFlu,fluconazole;OPC,oropharyngealcandidiasis;IFI,invasivefungalinfections;AmBuse,intravenousamphotericinBgivenempirically.
bMycologicalevaluationquestionable.
diasis in 63 patients (54). Patient compliance with nystatin brile days, the number of days during which antibiotics were
therapyismoderate,asithasanunpleasanttasteanddigestive administered, or the need for amphotericin B (132). A pla-
disordersaredoserelated(339).Inaddition,oralnystatinhas cebo-controlled study suggested a reduction in fungal coloni-
apoorbioavailability. zation in patients receiving ketoconazole, but no significant
Thus, use of nystatin for fungal chemoprophylaxis in neu- effect on the incidence of documented fungal infections or
tropenic patients has not given consistently favorable results mortality was found (247). One study of patients with solid
andhasnoeffectonthepreventionofhematogenouslyspread tumors reported that 400 mg was more effective than 200
candidiasis;itsroleinthisindicationisminor. mg/dayinpreventingcolonization(306).
Different published trials with ketoconazole demonstrate
SystemicTherapy thatitmaybeusefulinpreventingoropharyngealdiseaseand
reducing yeast colonization. Ketoconazole has no activity
IntravenousamphotericinB.AmphotericinBhasbeenpro- againstAspergillusspp.andmembersoftheMucorales;itmay
posedasaprophylacticantifungalagentbecauseithasabroad select for some resistant fungal strains; its absorption may be
spectrumofantifungalactivities,butitspotentialforimmedi- impairedincasesofachlorhydria,whetherinducedbydrugsor
atetoxicity(nausea,fever,andchills)andrenaldamage,which not; it may interact with other drugs such as cyclosporine in
is further enhanced in combination with other nephrotoxic transplant recipients (222); and its potential liver toxicity is a
drugs, may limit its use in clinical practice. A recent study matterofconcern.Thus,itcannolongerberecommendedas
demonstrated that patients without myocardial or renal dys- afirst-lineprophylacticregimenforpatientswithneutropenia.
function receiving hydrocortisone and diphenhydramine can (iii) Fluconazole. Fluconazole is water soluble and has fa-
tolerate central line infusions of prophylactic amphotericin B vorable pharmacokinetic properties, including a large volume
for 2 h (237). At present, its parenteral use is not associated ofdistributionandhigh-levelpenetrationintomosttissues.It
withtheemergenceofresistantstrains. hasalonghalf-lifeandfewinteractionswithotherdrugsdur-
Systemicazolesversusplaceboornotreatment.Mostofthe ingitsabsorptionphaseandmetabolism(36,109).Fluconazole
regimens described here were used for anti-Candida prophy- bioavailability is not affected by changes of gastric acidity.
laxis. Fluconazole is also available in an intravenous form and can
(i)Intravenousmiconazole.Onlyonedouble-blindstudyhas therefore be administered to patients who have difficulty in
evaluated intravenous miconazole (5 mg/kg t.i.d.) versus pla- swallowing.Itssafetyhasbeendemonstrated.
cebo(180patientswerestudied):theoverallincidenceoffun- Fluconazole is effective in the treatment of oropharyngeal
galsepsiswassignificantlylowerinthemiconazolegroup,but candidiasis(109),chronicdisseminatedcandidiasisinleukemic
deathsresultingfromfungalsepsiswerenotstatisticallydiffer- patients (12, 98, 158), and candidemia (277). A recent paper
entbetweenthegroups(382).Miconazolewaswelltoleratedin suggestedthatitcouldminimizeorpreventacutemucositisin
thisstudy,butseveresideeffects,mainlynauseaandvomiting, association with sucralfate in patients undergoing radiation
pruritus, phlebitis, and cardiac arrhythmias, have been re- therapyabovethediaphragm(8).However,therespectiverole
ported by others. Wiley et al. (375) demonstrated in a multi- ofeachdrugremainsunknown,andnomycologicaldatawere
variateanalysisthatadministrationofintravenousmiconazole reportedinthepaper.Walshetal.demonstratedthatflucon-
(5 mg/kg t.i.d.) to children with acute leukemia, beginning at azole was most effective against disseminated candidiasis in
theonsetofthefirstfeverduringneutropenia,wasanegative persistentlygranulocytopenicrabbitswhenusedforprevention
riskfactorforthedevelopmentofinvasivefungalinfections. orearlytreatmentofinfection(354).
(ii) Ketoconazole. Ketoconazole was the first systemic imi- Therefore,theavailabilityoffluconazoleledtolargemulti-
dazole investigated for antifungal prophylaxis (39, 94, 209). center protocols to evaluate the drug for prophylaxis in neu-
Ketoconazole(400mg/day)versusplacebowasinvestigatedin tropenicpatients.Themainstudiesoffluconazoleversuspla-
a prospective, randomized, double-blind study: no fungal in- ceboornotreatmentinneutropenicpatientsaresummarized
fection occurred in the ketoconazole group, but there was no inTable2.
difference between the groups in terms of the number of fe- Fluconazoleispresentlythemosteffectiveagenttoprevent
486 LORTHOLARY AND DUPONT CLIN.MICROBIOL.REV.
TABLE 3. Studiesonketoconazoleprophylaxisversusoralpolyenesinneutropenicpatients
No.of
Population Method Regimena Mainresultsforazolesa Reference
patients
Hematologicalorsolid-organ 72 Randomized Keto(400mg/day) LessOPCandgenitalcandidiasisb 131
malignancies versusNy(cid:49)AmB
Hematologicalmalignancies 36 Randomized Keto(200mg/day) Lessfungalesophagitisand 152
versusNy vaginitis;nodisseminated
candidiasisineithergroup;no
betterpreventionagainstOPC
Leukemia 51 Randomized Keto(400mg/day) NoreductionofOPC;no 346
versusNy significantreductionofIFI
(23versus33%)
Lymphoma 32 Randomized Keto(200mg/day) Lessmucosalfungalinfection 338
versusNy (8versus16%)
Acuteleukemia 48 Randomized Keto(400mg/day) Noreductionoffungal 83
versusAmBc colonization
aKeto,ketoconazole;Ny,nystatin;AmB,oralamphotericinB;OPC,oropharyngealcandidiasis;IFI,invasivefungalinfections.
bExceptinallogeneicBMTrecipients(duetodecreasedbioavailabilityinthispopulation).
cKetoconazolewasadministeredincomparisonorinassociationwithoralamphotericinB.
oropharyngealcandidiasisinneutropenicpatients,butseveral tion of gastric acidity, which may lead to reduced levels in
studiesdidnotdemonstrateaprotectionagainstdeepmycoses serumandtissueand,consequently,totherapeuticfailuresin
(303,383).Interpretationoftheseresults,includingempirical some cases. Because intestinal absorption can be impaired,
amphotericinBuseinfluconazoleprophylacticstudies,isdif- itraconazole levels should be measured after 1 week of treat-
ficult to assess, because no consensus exists between the ment in all patients and regularly thereafter in patients with
United States and Europe regarding the optimal time of am- dysphagia,gastrointestinaldamage,orGVHDorthosetaking
photericin B initiation for persistent fever. In the American antacids, H -receptor antagonists, or drugs that enhance he-
2
study reported by Winston et al. (383), 64% of patients re- patic drug metabolism (355, 386). It is the only commonly
ceived empirical amphotericin B (383) compared with 24.2% available azole active in vitro against Aspergillus spp., and its
in the European study by Philpott-Howard et al. (261). The activityagainstvariousformsofaspergillosishasbeendemon-
optimal daily dose of fluconazole for prophylaxis in neutro- strated(177).
penic patients has not yet been clearly defined; it varies be- When itraconazole (200 mg/day) was first compared versus
tween50and400mgforadultsandbetween1and4mg/kgin no treatment in a study involving a small number of neutro-
children(48,175).IntheUnitedStates,higherdosesareused penic patients, there was no difference in terms of the total
forprophylaxisthaninEurope,butnocost-effectivenessstudy numbers of episodes of invasive fungal infections (270). Itra-
isyetavailable.Thereisnoconclusiveevidencetofavorhigh conazole(100mgtwiceaday[b.i.d.])wasalsoinvestigatedin
dosesoffluconazole(400versus50to100mg/day).TheWork- anoncomparativestudy:18%ofthesubjectsdevelopedmicro-
ingPartyrecommendedadoseof50mg/dayin1993(386).As biologicallyprovenfungalinfections,12.5%ofwhichwerefatal
recommended for the HIV-infected population, a careful fol- (32). In that study, itraconazole was not effective when the
low-upofthesusceptibilityofC.albicansstrainsisrequiredin levelsinplasmawerebelow250ng/ml.
this population (379). It has recently been reported that pa- A prospective, randomized, double-blind, placebo-con-
tients with an indwelling central venous catheter and under trolled study reported a lower incidence of C. albicans infec-
fluconazole prophylaxis can develop fluconazole-susceptible tionsinpatientstreatedwithitraconazole(200mgb.i.d.)than
candidemia, thereby suggesting that this regimen fails to pre- inthosegivenaplacebo,butthetreatmenthadnosignificant
ventcathetercolonizationandsubsequentdissemination(107). effect on the overall incidence of fungal infections, the dura-
AlthoughtheactivityoffluconazoleagainstC.albicanswas tionoffever,ortheuseofintravenousamphotericinB(348).
demonstrated in the reported studies, its use also potentially The bioavailability of itraconazole was not monitored in that
led to the selection of resistant strains, such as C. krusei, re- trial. Superinfections with C. krusei and C. glabrata have also
sponsibleforcolonizationandinfection(5,50,187,256,380), beenreportedinpatientstreatedwithitraconazole(32).
andlesssusceptiblestrains,suchasC.glabrata(143,381).The Systemicazolesversusoralpolyenes.(i)Azolesversusnys-
epidemiologyofsuchnon-albicansCandidastrainsisvariable, tatin. Studies with ketoconazole are described and their find-
since some centers using fluconazole have not reported an ingsaresummarizedinTable3.Table4givesthemajorfind-
increaseinthenumberofsuchstrains(165)andothercenters ings from several studies comparing fluconazole with oral
had observed these infections before fluconazole was intro- polyenes. For itraconazole, one study demonstrated that the
duced. It is also possible that elimination of other fungal in- prophylacticuseof400mgofdrug/dayinneutropenicpatients
fections by prophylactic fluconazole (53, 383) leaves these reducedtheincidenceofinvasivefungalinfectionswhencom-
fungi as persistent pathogens without necessarily increasing paredwitharecenthistoricalcontrolgroupreceivingnystatin
their absolute incidence. Finally, intravenous amphotericin B (327).
should be promptly administered to persistently febrile neu- (ii) Azoles versus oral amphotericin B. The results derived
tropenic patients who are colonized at multiple sites by any from one study of ketoconazole are reported in Table 3. The
Candida spp., whether or not they had recently received any resultsoftheketoconazolestudydidnotdemonstratesufficient
antifungalprophylaxis. efficacy against mucosal Candida infections and indicated no
(iv)Itraconazole.Itraconazoleishighlylipophilicandbinds roleforthepreventionofdeepmycoses.Theavailabledatafor
stronglytoproteins.Itsdegreeofabsorptionvariesasafunc- fluconazolearesummarizedinTable4.Inmostofthesestud-