A Clinical Perspective for the Management of Invasive Fungal Infections: Focus on IDSA Guidelines

A Clinical Perspective for the Management of InvasiveFungal Infections: Focus on IDSA Guidelines

Dimitrios P. Kontoyiannis, M.D., Sc.D.

Invasive fungal infections, especially candidiasis and aspergillosis, are a majorcause of morbidity and mortality. Many controversies surround themanagement of these infections. A critical overview of the recent InfectiousDiseases Society of America practice guidelines is provided, as are commentson both the conundrums and future perspectives in medical mycology.(Pharmacotherapy 2001;21(8 Pt 2):175S–187S)

OUTLINE

CandidiasisKey Points of IDSA RecommendationsComment and Future Prospects

AspergillosisKey Points of IDSA RecommendationsComment and Future Prospects

Histoplasmosis, Coccidioidomycosis, Blastomycosis,Sporotrichosis, and CryptococcosisKey Points of IDSA RecommendationsComment

Conclusion

Invasive fungal infections are a significantcause of morbidity and mortality in numerouspatients with debilitation and immunosuppression.1

Medical progress, continued expansion of thepatient population with immune dysfunction,and the acquired immunodeficiency syndrome(AIDS) pandemic account for this surge.1 Fungalinfections will continue to be major health issueswell into the 21st century.1

For a long time, treatment of these infectionswas limited and consisted of amphotericin B, aparenteral, broad-spectrum but relatively toxicdrug (especially for the kidneys),2 or first-

generation imidazole antifungals plus flucytosine(5-fluorocytosine), which had relatively limitedtherapeutic spectra and potency.3 Since the1990s, potent, broad-spectrum oral andparenteral triazoles such as fluconazole anditraconazole, lipid formulations of amphotericinB that lack much of the parent compound’snephrotoxicity, and a new class of antifungals,echinocandins, have been welcome additions toavailable options.3–6 However, only a few well-conducted, prospective, randomized studies havecompared these therapeutic modalities. Thedifficulty in diagnosis, heterogeneity of patientswith different mycoses, changing epidemiology,and relative infrequency of these infectionsaccount for lack of controlled data.7

Expert panels attempted to address specificdiagnostic criteria and therapy for theseinfections,7, 8 but guidelines from the InfectiousDiseases Society of America (IDSA) are the mostthorough and systematic. After detailed reviewof the literature, the authors of these guidelines,all established mycologists with expertise invarious types of fungal infections, assigned eachrecommendation a level of endorsement based onthe extent of supporting information.9–16

Candidiasis

The spectrum of invasive candidiasis is broad,and any organ or combination of organs can beaffected acutely or chronically.17 Candidemia isthe fourth most common nosocomialbloodstream infection in the United States, andits frequency is rising rapidly.18, 19 Trends

From the Division of Internal Medicine, Department ofInfection Control, Infectious Diseases and Employee Health,University of Texas M.D. Anderson Cancer Center, Houston,Texas.

Address reprint requests to Dimitrios P. Kontoyiannis,M.D., Director of Clinical Mycology, Department ofInfection Control, Infectious Diseases, and EmployeeHealth, University of Texas M.D. Anderson Cancer Center,1515 Holcombe Boulevard, Box 402, Houston, TX 77030-4095.

Supplement to PHARMACOTHERAPY Volume 21, Number 8, 2001

accompanying this increase are a shift towardmore infections caused by Candida sp other thanCandida albicans and emergence of resistantisolates.19 The increased frequency of life-threatening bloodstream infections caused bythese organisms is related to the increasing sizeof the population at risk, namely, patients withvarious degrees of immunosuppression, thosewho are debilitated or who have undergonesurgery, those at the extremes of age, and thosehaving prolonged hospitalization in intensivecare units.17–21 The infections are associated withsubstantial attributable mortality and prolongedhospital stay.18, 20, 21 In addition, chronic, oftenrelapsing or refractory mucosal candidiasis is acommon opportunistic infection in patients withAIDS, even though its frequency is declining inthe era of highly active antiretroviral therapy(HAART).22 Introduction of several new drugsduring the last decade3–6 as well as availability, forthe first time, of a reproducible in vitro methodto measure the susceptibility or resistance ofCandida sp to azoles23 establish common groundregarding the management of various aspects ofcandidiasis.

Key Points of IDSA Recommendations

In acute disseminated candidiasis, uncomplicatedfungemia, and chronic disseminated candidiasis intreatment-naïve, stable nonneutropenic patients,as well as those with single organ infections(esophagitis), fluconazole is favored.Amphotericin B deoxycholate 0.5–1.0 mg/kg/dayshould be given for unstable, profoundlyimmunosuppressed patients, especially whenidentification of Candida sp in blood cultures ispending. The drug was endorsed for treatment ofmost episodes of neonatal candidiasis. Heavilyinfluenced by rather predictable in vitrosusceptibility of various Candida sp to currentantifungals, the panel recommended thatidentification of the isolate at species level couldbe central for the decision. Measuring theminimum inhibitory concentration (MIC) ofisolates to azoles, flucytosine, and amphotericinB by the National Committee for ClinicalLaboratory Standards (NCCLS) method wasgenerally recommended since it providescomplementary information and could be a goodpredictor, particularly of lack of efficacy of aparticular drug against the particular isolate.

Empiric amphotericin B therapy appeared themost reasonable approach for presumed fungalsuperinfection in patients with refractory febrile

neutropenia, since the agent (in contrast tofluconazole) is active against most Candida sp,including the most common non-albicans sp.

Lipid formulations of amphotericin B were notrecommended as first-line therapy because oftheir expense. Instead, they are limited topatients with nephrotoxicity or severe infusion-related toxicity due to amphotericin Bdeoxycholate, or as salvage therapy for patientswith refractory candidiasis.

Most patients should not require treatment forasymptomatic funguria. Even though the subsetwho do require some type of treatment was notwell defined, fluconazole appears advantageouscompared with amphotericin B bladder washes.

For less common forms of organ-invasivecandidiasis (pneumonia), amphotericin B is thedrug of choice, with fluconazole as an option forless ill patients. Other recommendations inconjunction with effective systemic therapy areremoval of a foreign body (in patients withCandida peritonitis or shunt meningitis), earlyvalve replacement in combination withamphotericin B with or without flucytosine inthose with Candida endocarditis, and drainage orsurgical debridement for unusual cases ofCandida arthritis, osteomyelitis, pericarditis, orsuppurative thrombophlebitis.

Antifungal prophylaxis with fluconazole 400mg/day should be considered in selected highlyimmunosuppressed patients such as those withallogeneic or high-risk autologous bone marrowtransplantation, those with acute myelogenousleukemia undergoing remission-inductionchemotherapy, and patients who have undergoneliver or pancreatic transplantation. Primaryprophylaxis is not routinely recommended forpatients infected with the human immuno-deficiency virus (HIV) or after intraabdominalsurgery. Finally, several agents, includingnonabsorbable oral polyenes (nystatin) and oralor topical azoles are considered satisfactory fortreatment of mucocutaneous candidiasis.

Comment and Future Prospects

The limited number of comparative trialsmakes it difficult to offer definite recommen-dations for the treatment of various forms ofcandidiasis. It is accepted that fluconazole is asatisfactory, nontoxic alternative to amphotericinB in stable nonneutropenic patients withcandidemia, as evidenced by results of a pivotaldouble-blind trial24, 25 and of a meta-analysis thatincluded all published prospective studies

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IDSA GUIDELINES FOR MANAGEMENT OF FUNGAL INFECTIONS Kontoyiannis

comparing the two drugs in treatment ofcandidemia.26–28

Controversies remain however and arereflected in limitations of the literature,8, 29, 30

such as the relatively complex disease profile ofcandidemic patients and the fact that moststudies did not include enough episodes ofinfections due to non-albicans sp or infections inhighly immunosuppressed patients at high risk ofdeath due to Candida. These limitations do notallow a definite comparison between fluconazoleat different doses (400, 800 mg) and ampho-tericin B. Furthermore, the exact contribution ofMIC determination by NCCLS method, whichhas limitations as a reliable predictor of efficacyin bloodstream candidiasis of availableantifungals (especially amphotericin B), isunclear.31–33 Management of indwelling cathetersis even more controversial, since no studyaddressed in controlled fashion the contributionof exchange or removal of intravascular cathetersto clearance of bloodstream Candida infections.34

Uncertainty exists as to the agent of first choicefor less common single-organ candidiasis, sinceall the data regarding the management of theserather uncommon infections are uncontrolled.Finally, with regard to candiduria, a randomized,double-blind, placebo-controlled, multicentertrial dealing with funguria did not resolve theuncertainty regarding optimal management ofthis common infection.35 Specifically, it is oftenunclear whether asymptomatic funguriarepresents mere colonization, a semiinvasiveinfection of the bladder, a reflection of ascendinginfection in the kidneys, or even occultdisseminated candidiasis.36 This diagnosticdilemma is even more pronounced in patientswith indwelling Foley catheters.

Several gaps exist in our knowledge that wouldbe fertile areas for investigation. The duration ofantifungal therapy and timing of the switch frommore potent parenteral agents (amphotericin B)to less intense therapy (oral azoles) requireclarification. Greater delineation of the riskstratification of candidemic patients18, 21, 37–41

would allow better use of available antifungals.The effect of underlying disease and itsassociated immunosuppression, severity ofinfection, effect of neutrophil recovery, causativespecies, and attempt to eradicate the source allare important.18, 21, 37–41 For example, theduration of antifungal treatment could be muchshorter in patients without significantimmunosuppression who develop transientcandidemia.41 Experience with routine computed

tomography (CT) to assess the evolution oflesions in chronic disseminated candidiasis afterantifungal therapy is an example of the fact thattherapy tends to be individualized.42

After treatment is completed, adequate follow-up of at least 3 months is necessary to detectearly signs of late complications of candidemia.8

Follow-up should be much longer in patientswho are at risk for Candida endocarditis (thosewith prosthetic valves).43 It is unclear the extentof work-up needed for a patient with recentuncomplicated fungemia, if any (retinalexamination, CT of abdomen) to rule out anoccult organ involvement that would necessitatelonger treatment.

The optimal dosage of available antifungals isnot clear. Very few published studies admin-istered fluconazole in dosages higher than theconventional 400 mg/day. The issue is moreapplicable for C. glabrata since 95%44 of isolateshave dose-dependent susceptibility tofluconazole in vitro and therefore high dosages of6 mg/kg twice/day could overcome that relativeresistance.10 Not all candidemias respondsimilarly to the recommended conventionaldosage of amphotericin B 0.5–1 mg/kg/day. Forexample, C. krusei and C. glabrata, two speciesthat either are (C. krusei) or could be (C.glabrata) resistant to fluconazole in vitro tend torequire higher (> 1 mg/kg/day) than the usualdosages of amphotericin B.45, 46–49

What is the best empiric choice in the stablefebrile neutropenic patient with documented orpresumed candidiasis who had no azoleexposure? Available data, somewhat outdatedand limited in number, support the equivalenceof fluconazole and amphotericin B in thispopulation.28,50–55 Fluconazole could be anoption in patients whose neutropenia is expectedto be short lived. However, we believe that ifneutropenia is expected to last longer than 10–14days (in most patients with hematologicmalignancies), in which molds and resistant non-albicans sp emerge as common causes of fungalsuperinfection,45, 46, 49 one should move away ofazoles in general as an early empiric choice andgive preference to amphotericin B. Availability ofbroad-spectrum parenteral triazoles such asitraconazole or voriconazole,4 as well asintroduction of echinocandins that have activityagainst both Candida and Aspergillus sp, willprobably offer additional options for empirictreatment in persistently febrile neutropenicpatients. These studies are urgently needed.

What is the best empiric choice in the stable

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febrile neutropenic patient with candidemia whohad azole exposure? Exposure to azoles isbecoming rather common in patients at highrisk.56 This is another controversial issue thathas not been addressed adequately by publishedstudies to date. Our experience seems to indicatethat it would be prudent to choose amphotericinB in these patients when a screening in thelaboratory identifies the Candida isolate as germtube-negative.30 Breakthrough fungemia,especially in neutropenic patients receivingazoles either prophylactically or empirically,could have a poorer prognosis, although this isstill controversial.49, 57, 58

How about the stable patient with or withoutneutropenia with candidemia who is doing wellwith fluconazole but in whom the isolate inblood culture is C. glabrata? No evidenceindicates, in our view, that C. glabrata respondsless well or differently to either fluconazole oramphotericin B in this situation.59 According to ameta-analysis, although amphotericin B wasmarginally better than fluconazole with regard tomycologic eradication, this difference did notclearly translate into a better clinical outcome.28

Related to this controversy, should Candidabloodstream isolates routinely undergosusceptibility testing by the clinical laboratory?If the susceptibility profile of each species ispredictable, does knowing the local antibiogramfor antifungals help decision making? Suchroutine testing is not recommended33, 60, 61

because no clear-cut correlation between in vitrosusceptibility provided by the NCCLS methodand bloodstream candidiasis was found in thefirst randomized study,32 even though a smallerstudy suggested that such correlation exists.62

Continuing and future studies should determinethe correlation between NCCLS MIC andoutcome in bloodstream candidiasis. It would beinteresting to see whether other susceptibilityassays (E-test) have better discriminatory value,especially for the efficacy of amphotericin B.63

What is the optimal treatment of chronicdisseminated (hepatosplenic) candidiasis? Therarity and the chronicity of this infection makefirm recommendations difficult. In contrast tothe IDSA panel’s recommendations, we believethat amphotericin B is not the drug of choice.Triazoles (for less ill patients) or lipidformulations of amphotericin B (for more illpatients) 5 mg/kg/day or more seem moreefficacious.42

Clearly, experience with systemic infectionscaused by other, more rare Candida sp such as C.

guillermondii, C. lusitaniae, and C. dubliniensis28,

64, 65 is too limited to allow firm recommendations.For example, C. lusitaniae could either haveprimary resistance to amphotericin B or acquiresuch resistance with high frequency duringtherapy.65

What is the optimal management of centralvenous catheters in subsets of candidemicpatients? Future randomized studies mustaddress the role and the timing of catheterexchange or removal.34 This is particularlyimportant in patients with pancytopenia,especially those with surgically implanted centralvenous catheters (Hickman catheters). Theavailable literature, consisting solely ofretrospective or uncontrolled studies,34, 66–68 tendsto support catheter removal in patients withprimary catheter-related candidemia. However,in neutropenic patients with candidemia aftercytotoxic chemotherapy who have extensivegastrointestinal mucosal damage as the cause ofinfection,69 secondary catheter seeding appears tobe uncommon.70 Studies examining the role oftime to positive blood culture71 as a noninvasivemeans to diagnose catheter-related infectionsshow promise.

Development of sensitive and reliablenonculture-based methods for earlier diagnosis ofinvasive candidiasis could change the timing ofadministration of antifungals and shift to earlier,preemptive therapy.72, 73 However, these methods,although promising, are far from clinicalimplementation.

Future studies should address carefully and ina prospective fashion the predictive value ofcolonization of one or more sites by Candida spin different populations at risk for invasivecandidiasis (surgical patients, immuno-suppressed patients, patients in intensive careunits).74–77 Such information, which is currentlylacking, would allow a shift from targetedtherapy for documented candidiasis to earlierpreemptive or prophylactic strategies and couldaffect patient outcomes.

Availability of lipid formulations ofamphotericin B, which allow relatively nontoxicdelivery of large dosages, raises the question ofwhether these agents should be given early asempiric treatment in febrile neutropenic patientsat high risk for severe candidiasis.78, 79 In onestudy, compared with amphotericin B 0.5–0.7mg/kg/day, liposomal amphotericin B 3mg/kg/day had equivalent efficacy, was bettertolerated, and decreased the frequency ofdocumented breakthrough fungal infections in

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such patients, particularly bone transplantrecipients.78 Controversy surrounds whetherlipid formulations are more cost-effective thanconventional amphotericin B and their optimaldosage.79, 80 Preclinical pharmacodynamicevidence suggests a dose response for theseagents81; however, the drugs’ high acquisitioncost makes their routine use problematic, eventhough a pharmacoeconomic analysis of theirtrue benefit in treatment of severe complexcandidiasis would be of interest.

Would the recent introduction of itraconazolein formulations (intravenous, liquid solutionwith dextran vector) that achieve reliablytherapeutic blood and tissue levels3, 4 have a rolein overcoming resistance to fluconazole inselected cases of non-albicans candidiasis?Experience with fluconazole-resistant muco-cutaneous candidiasis in patients with AIDSsuggests that cross-resistance to itraconazole isnot commonly seen4, 60, 82; however, there isvirtually no experience with bloodstreamcandidiasis.

Similarly, what is the role of newer potenttriazoles such as voriconazole, posaconazole(SCH 56592), and ravuconazole?4, 83 These drugsare expected to be increasingly administered asprophylactic, empiric, and targeted therapy inpatients at high risk, but whether cross-resistancewith older azoles will become an issue remains tobe seen.

Introduction in the near future of a new classof fungal cell wall-active agents will be welcome.The glucan-1,3-b-synthetase inhibitors(caspofungin, micafungin, anidulafungin) arebroad-spectrum fungicidal drugs that are alsoactive against azole-resistant Candida sp.3, 5 It ispossible that these relatively nontoxic agentscould replace azoles or lipid formulations ofamphotericin B in many cases for prophylactic,empiric, preemptive, or targeted treatment ofinvasive candidiasis, especially if their cost iscompetitive.

The role of combination therapy such asamphotericin B plus azoles,84, 85 azoles plusechinocandins, azoles plus flucytosine, andechinocandins plus amphotericin B for refractoryforms of candidiasis in selected patients,although still theoretical, remains an attractiveconcept. More preclinical and clinical data areneeded for better understanding of the subset ofpatients who would benefit most.

The beneficial role of immunomodulation withcytokines or infusion of immune effector cells invarious combinations—granulocyte-macrophage

(GM) colony-stimulating factor (CSF),granulocyte CSF, g-interferon, and GM-CSF-primed white cell transfusions—in patients withrefractory or recurring candidiasis has beensuggested only in preliminary anecdotalreports.86–88 Nevertheless, the effect that (partial)immunorestoration in patients with AIDS has onoverall frequency of mucosal candidiasis,22, 89

once a very common chronic and refractoryinfection in that population, attests to theimportance of the immune system in controllingthese opportunistic fungi. Further work isnecessary in this important area.

For less common forms of organ candidiasis,specific issues for each infection, such asduration of suppressive therapy with fluconazoleafter native or prosthetic valve replacement forCandida endocarditis, and therapeutic benefit ofintravitreal amphotericin B, vitrectomy, orintraocular steroids, have not been addressedadequately.

It is unclear which patients require antifungaltreatment for asymptomatic funguria, in view ofthe fact that removal of Foley catheter alonecleared the disorder in up to 40% of patients. Nolong-term benefit was shown from such therapyin one trial.35 Better definition of theheterogeneous syndrome complex would helpdelineate subsets of patients who would benefit.

For prophylaxis in patients at high risk forinvasive candidiasis, fluconazole might not be thedrug of choice in the near future. Emergence ofsome non-albicans sp and molds against whichfluconazole has limited activity3, 90–92 necessitatesfuture trials with agents having a broaderspectrum of activity such as the newer triazoles,including new formulations of itraconazole,echinocandins, and better-tolerated lipidformulations of amphotericin B.

Aspergillosis

Since the first description of invasiveaspergillosis in the 1950s, the frequency andseverity of this opportunistic infection haveincreased continually.93–97 It has emerged as theleading cause of death due to fungal infection,and its prevalence, even in unselected autopsies,was reported to be as high as 4–5%.93–95

Increased intensity of chemotherapy in patientswith hematologic malignancies, increases inallogeneic bone marrow and solid organrecipients, the AIDS pandemic, and expansion ofthe population treated with steroids for variousconditions account for that relentless rise.93–95

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Management of the disease is particularlyproblematic because the diagnosis is difficult andcomes late and because the efficacy of antifungaltherapy in heavily immunosuppressed patientswith invasive aspergillosis is poor,96–99 with afailure rate approaching 85% (I. Raad, D. P.Kontoyiannis, unpublished data). Suboptimaldelivery of antifungals at sites of infection due toaspergilli invading blood vessels and causingthrombosis and tissue infarction frequentlyunderlies therapeutic failure.100

Introduction of several drugs for treatment ofinvasive aspergillosis (lipid formulations ofamphotericin B and caspofungin) and testing inphase II–III trials of antifungals with promisinganti-Aspergillus activity (newer-generationtriazoles, echinocandins), as well as developmentof sensitive and specific surrogate markers forearly diagnosis (antigenemia assays, polymerasechain reaction [PCR}), renew optimism for betterstrategies to control this devastating infection.


For acute invasive aspergillosis in heavilyimmunosuppressed patients, regardless of site ofinvolvement, most accumulated evidencesupports the use of amphotericin B 1–1.5mg/kg/day. Oral itraconazole is reserved formaintenance therapy once the patient improves,or as initial therapy for less immunosuppressedand ill patients.

For aspergilloma, surgery is the best strategy inaverting severe recurring hemoptysis. Itraconazolemay provide some benefit; amphotericin B has norole in this disorder. Allergic bronchopulmonaryaspergillosis is best treated with steroids.

Comment and Future Prospects

Aspergillosis is a complex, heterogeneous,opportunistic, and frequently multifocalinfection.96, 97, 101 The degrees and types ofdeficits of the host immune system influenceclinical features.96–99, 101 Hence, the clinicalspectrum extends from colonization of theairways at one extreme, to hypersensitivity illness(allergic bronchopulmonary aspergillosis) inpredisposed atopic patients, to semiinvasiveinfections such as otitis externa or chronicallergic sinusitis, to locally invasive disease(pseudomembranous tracheobronchitis) tochronic necrotizing pneumonia, and finally, toacute sinopulmonary or disseminated forms inpatients with leukemia or allogeneic bonemarrow transplantation.96–99, 101 There is a

paucity of well-conducted clinical studies in thetreatment of aspergillosis. Lack of uniformdefinitions (until recently) for diagnosis andresponse, small patient numbers, differences inpatient populations, and institutional orpublication biases created uncertainty about theoptimal management of this frequently lethalinfection. 98, 99, 102, 103 Many factors other thanantifungal therapy per se, such as failure torecover from neutropenia, leukemic relapse,delayed therapy, and site of involvement, affectoutcome and are not clearly controlled in manystudies.96–99, 101–103 Therefore, we have morecontroversies than answers in the treatment ofinvasive aspergillosis.

Is amphotericin B deoxycholate still the drugof choice, or should lipid formulations ofamphotericin B replace it? This is a difficultquestion since no study has compared the agentshead-to-head, and it is highly unlikely that suchstudy will be conducted in the future. Inuncontrolled studies lipid formulations hadefficacy rates of 40–60% in patients who wererefractory or intolerant to amphotericin B.104, 105

It is agreed that the lipid products, whose dailyacquisition prices are much higher than those ofamphotericin B deoxycholate, result in lessnephrotoxicity and less infusion-relatedtoxicity.79, 80 This nephrotoxicity appearsfrequently to be clinically significant, especiallyin the most heavily immunosuppressedpatients.106 A pharmacoeconomic analysis ofrandomized, double-blind, comparative trials ofamphotericin B with liposomal amphotericin Bfor empiric therapy in febrile neutropenicpatients showed that nephrotoxicity (mostlycaused by amphotericin B) increased hospitalcosts. When modeled in a sensitivity analysis,the higher acquisition cost of liposomalamphotericin B neutralized the increased hospitalcosts associated with nephrotoxicity once thecost of liposomal amphotericin B was $85/50-mgvial or less.107

What is the best lipid formulation ofamphotericin B? This is even more controversialsince the first question cannot be answeredconvincingly.80 Most available data are derivedfrom indirect comparisons and suggest that alllipid formulations when administered in thestandard dosage of 5 mg/kg/day have comparableefficacy.104 This therapeutic equivalence wassuggested in the only large comparative studybetween amphotericin B lipid complex andliposomal amphotericin B.108 However, this studymight have been underpowered to compare these

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two agents specifically in terms of efficacy.Liposomal amphotericin B, the most expensiveagent, appeared to be less toxic,108 even thoughsome toxicities might have been insignificant orpreventable.80 Hence, the overall cost-effective-ness of these formulations remains undefined.

What is the optimal dosage of lipidamphotericin B for treatment of invasiveaspergillosis? Preclinical and clinical evidenceindicate a dose response with both amphotericinB deoxycholate and the lipid formulation ininvasive aspergillosis.109, 110 This was challengedin the only randomized, published trial ininvasive aspergillosis111 that compared twodosages of liposomal amphotericin B, 1 and 4mg/kg/day. No difference in overall response ratewas found between arms in 87 eligible patients,most of whom had probable invasiveaspergillosis. Among the subset of patients withdocumented invasive aspergillosis, however,response rates were 58% and 37% for 4 and 1mg/kg/day, respectively. It would be interestingto study in a controlled fashion the strategy ofvery high dosages of lipid amphotericin B10–12.5 mg/kg/day early in the disease asinduction therapy for the first 7–14 days,followed by consolidation therapy with lipidamphotericin B at 5 mg/kg/day, followed bymaintenance therapy, possibly with an oraltriazole.

Is dose intensity more important thancumulative dose of amphotericin B? We believe,as do others,103 that reports emphasizing the totalcumulative dose are erroneous since a strongsurvival bias correlates with high total doses ofamphotericin B. The duration of therapy ininvasive aspergillosis should be highlyindividualized with respect of resolution of allsymptoms and signs of infection, radiologic proofof near return to normal, negative cultures, and,ideally, restoration of impaired immune defenses.

Does itraconazole have a role as beginningtherapy? The efficacy of oral itraconazole inheavily immunosuppressed patients with invasiveaspergillosis was studied in a large multi-institutional trial.101 In the cohort of 180patients, itraconazole (capsules) was primarytherapy in only 10, with an efficacy rate of 40%(4 patients). On the other hand, the drug had ahigh efficacy rate (61%) in less immuno-suppressed patients, which agrees with previousuncontrolled data in a comparable patientpopulation.101, 112 Itraconazole should be primarytherapy only in less immunosuppressed patientswith a stable clinical picture and in whom

gastrointestinal absorption is predictable(absence of diarrhea or gastrointestinal graft-versus-host disease). Since cyclodextrin sus-pension has superior absorption to itraconazoletablets,3 it should be used. If there is concernabout the bioavailability of itraconazole throughinteractions with other concomitant drugs,3

itraconazole should be replaced by amphotericinB, even in stable patients, unless itraconazolelevels can be routinely monitored.

Intravenous itraconazole is approved, althoughdata about its efficacy in invasive aspergillosis areincomplete. The intravenous preparation offersthe possibility of achieving rapid and reliabletherapeutic serum levels and should be analternative to amphotericin B for less ill patients.It is unclear whether increased and prolongeditraconazole therapy, either prophylactic ortherapeutic, in invasive aspergillosis would resultin increased itraconazole-resistant aspergilli.This scenario appears to be uncommon.113

What is the role of surrogate markers indecision making? Encouraging early results withserologic markers with very good sensitivity andpredictive value (Aspergillus galactomannanassay)114, 115 as well as the amplification ofAspergillus DNA with PCR116,117 couldrevolutionize treatment of invasive aspergillosisand shift it from targeted to preemptive therapy.The key question would be whether routineimplementation of those diagnostic methodscould be translated to improvement of clinicaloutcome.115 Incorporating these valuable newdiagnostic tests to decision making (determiningthe cut-of-point distinguishing colonization,semiinvasive disease or full invasion, interpretingchanges in value of the galactomannan assay inpatients who are already receiving antifungaltreatment, integrating these tests to decisionsabout the timing of CT scan or bronchoscopy)would be critical. Such preemptive strategiescould result in improved outcomes of thisdevastating infection.118

What is the role of adjunctive surgery in themanagement of invasive aspergillosis? Aspergillusendocarditis, endophthalmitis, osteomyelitis, andarthritis are clear indications even though theoptimal timing of surgery is not clearlydefined.119 In addition, preemptive removal ofwell-circumscribed central (next to pulmonaryarteries) lesions to prevent bleeding andemergency surgery for early bleeding from acavitary mycotic lung sequestrum appearconvincing indications in uncontrolled studies.119

What is unclear is the role of surgery in

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refractory cases, debulking of a pulmonary massif the patient already has several fungal lesions,removal of a single residual mass after it hasdiminished with treatment, and extent of sinussurgery in documented Aspergillus sinusitis.Uncontrolled data suggest that resection of thelobe most affected by invasive aspergillosis couldbe beneficial for pulmonary lesions that worsendespite intense antifungal therapy, and for stableor improving lesions if the patient is a candidatefor high-risk bone marrow transplantation.120

New antifungal drugs are encouraging in thetreatment of invasive aspergillosis. Intravenoustriazoles with activity against Aspergillus sp(itraconazole), investigational triazoles(voriconazole, ravuconazole, SCH 59884, andprodrug SCH 56592) and the echinocandins offerpotential therapeutic alternatives. Figuring outwhich subset of patients would benefit most withthese drugs could be a challenge. Investigationaltriazoles show impressive activity in vitro and inanimal models of aspergillosis,4, 83 and earlyclinical experience suggests that they are alsoactive in humans.121, 122 Their availability in oralform allows long-term therapy. Whether cross-resistance would devitalize these drugs (inpatients who develop breakthrough invasiveaspergillosis after prophylaxis with anotherazole) is a theoretical concern.

Echinocandins are static in vitro againstAspergillus sp, but their activity in animal modelsand in selected groups of patients with invasiveaspergillosis appears promising.123, 124 Whetherthey could be an option as monotherapy or aspart of combination therapy with amphotericinB125 or triazoles in invasive aspergillosis remainsto be seen.

Terbinafine, a squalene epoxidase inhibitor, hasefficacy against Aspergillus sp, and whencombined with azoles resulted in synergy invitro.126 More studies are necessary.

What is the future of combination therapy ininvasive aspergillosis? Lack of effective treatmentmakes the concept of combination therapytheoretically appealing.84, 85, 127 Combinations ofamphotericin B with either flucytosine orrifampicin were evaluated despite conflicting invitro and animal data.127 To date, no clinicalstudy has answered convincingly whether thesecombinations are more beneficial than therapywith amphotericin B alone. The sequence ofadministration of itraconazole in combinationwith amphotericin B produced a spectrum ofresponses from synergy to antagonism.84, 85, 127

Evidence from preclinical studies suggests that

prior or concomitant administration ofitraconazole produces antagonism.84, 85, 127, 128 Onthe other hand, administration of amphotericin Bfollowed by itraconazole resulted in responses inas high as 42% in heavily immunosuppressedpatients, compared with only 24% in patientsreceiving amphotericin B in that population.101

With introduction of echinocandins that have adifferent mechanism of action (inhibition of cellwall synthesis),5 it would be important to seewhether new combinations (azoles-echinocandins,amphotericin B-echinocandins, terbinafine-azoles, amphotericin B-azoles-echinocandins),given either concomitantly or sequentially, wouldresult in additive or synergistic effects. Forexample, preclinical evidence suggests thatechinocandins could augment the efficacy ofamphotericin B.124 The sequence and timing ofthese combinations are important areas ofinvestigation.

Are all Aspergillus sp created equal? Preclinicaland clinical evidence from retrospective studiessuggests that some non-fumigatus sp such as A.terreus, and possibly A. flavus, are less susceptibleto amphotericin B.96 In the same vein, what willbe the role of in vitro susceptibility testing ofAspergillus sp to antifungals in the future?Difficulties establishing standard in vitromicrodilution-based susceptibility methods infilamentous fungi are well known.129 This field isin its infancy, and correlation between in vitrosusceptibility testing and outcome in invasiveaspergillosis is controversial.130, 131 Other lesscumbersome in vitro susceptibility methods(compared with the proposed NCCLS microdilutionmethod) such as the E-test show promise.132

What is the role of immunomodulators? As isthe case with other refractory opportunisticmycoses, the beneficial adjunctive role ofimmunomodulation with cytokines or infusion ofimmune effector cells in various combinations(GM-CSF, G-CSF, g-interferon, GM-CSF-primedwhite cell transfusions) in refractory or recurringinvasive aspergillosis is only suggested bypreliminary anecdotal clinical reports.88, 133

However, substantial preclinical evidencesupports the role of immunomodulation tocontrol Aspergillus sp.88, 133 Further studies arenecessary.

Histoplasmosis, Coccidioidomycosis,Blastomycosis, Sporotrichosis, andCryptococcosis

Endemic mycoses and cryptococcosis continue

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to cause morbidity and mortality in populationsat risk, namely, patients with T cell dysfunction.The AIDS pandemic converted geographicallyrestricted fungi and cryptococcosis to trueopportunists, even though their frequencyappears to be decreasing with HAART.22 Theseinfections have a significant spectrum ofmanifestations, severity, and course.134–137

Availability of oral effective azoles revolutionalizedtreatment of many, especially less acute forms, ofthese mycoses.


Pulmonary infections caused by these fungi,with the possible exception of blastomycosis,may be followed carefully without treatment.Progressive pneumonia, dissemination, and rapidclinical deterioration should be treated withamphotericin B, whereas more subacute orchronic illness could be treated with itraconazolefor histoplasmosis, fluconazole for cryptococcosis,and either agent for nonmeningeal coccidioido-mycosis. For cryptococcal meningitis, ampho-tericin B is the drug of choice for initial therapy,with addition of flucytosine or even fluconazoleconsidered for severe disease. Fluconazole couldbe given to patients intolerant to amphotericin B,those with milder forms of meningitis, andpatients requiring chronic suppressive therapy.Fluconazole is preferred for central nervoussystem coccidioidomycosis. Patients with AIDSrequire lifelong maintenance therapy. Forlymphocutaneous and osteoarticular sporotri-chosis, itraconazole is preferred; amphotericin Bis reserved for disseminated and meningeal formsof disease.

Comment

With few exceptions,138 most studies oftreatment of these infections are eitherretrospective or uncontrolled. For nonimmuno-suppressed patients it is unclear what factorsaffect the severity of the disease and need fortherapy. It would be helpful to have more dataregarding duration of antifungal therapy for eachform of infection, need of lifelong secondaryprophylaxis in patients with AIDS who have asustained recovery of CD4+ cells after HAART,management of increased intracranial pressure,especially in HIV-infected patients withcryptococcal meningitis (role of steroids,frequency of lumbar drainage, need for lumbardrain), and correlation between in vitrosusceptibility and outcome. With widespread

azole therapy in populations at risk for theseinfections, it is unclear whether we will witnessan increasing problem with azole resistance bythese fungi. Fluconazole-resistant cryptococcosishas been reported.139 Finally, the need forprimary or secondary prophylaxis in heavilyimmunosuppressed patients without HIV (thosewith positive serology for Coccidioides immitis orhistory of histoplasmosis who are undergoingintense immunosuppression) have not beendefined.

Conclusion

Major diseases are caused by fungi. Since mostof these mycoses are opportunistic, they remaindifficult to control. Early diagnosis andpreemptive treatment appear important inreducing mortality. Development of newfungicidal compounds that could be given aspotent primary or combination therapy, andimmune based-strategies directed at immuno-restoration, are important areas for investigation.

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