Considering the significant morbidity and mortality associated withinvasive fungal infections in immunocompromised patients, it is particularlyimportant to make the diagnosis as early as possible and tomake best use of the available antifungal drugs for prophylaxis andtreatment. The newer antifungal drugs include the lipid products ofamphotericin B, such as amphotericin B lipid complex (ABLC) andliposomal amphotericin B; voriconazole (a triazole); and caspofungin(an echinocandin). ABLC and liposomal amphotericin B are as effectiveas amphotericin B deoxycholate but are less nephrotoxic; ABLC isprobably the drug of choice for zygomycosis. Voriconazole is approvedfor use in the treatment of invasive aspergillosis and may have a role inpreventing breakthrough fungal infections in patients with persistentfever and neutropenia. Caspofungin is effective against both invasiveaspergillosis and invasive candidiasis.
ABSTRACT: Considering the significant morbidity and mortality associated withinvasive fungal infections in immunocompromised patients, it is particularlyimportant to make the diagnosis as early as possible and tomake best use of the available antifungal drugs for prophylaxis andtreatment. The newer antifungal drugs include the lipid products ofamphotericin B, such as amphotericin B lipid complex (ABLC) andliposomal amphotericin B; voriconazole (a triazole); and caspofungin(an echinocandin). ABLC and liposomal amphotericin B are as effectiveas amphotericin B deoxycholate but are less nephrotoxic; ABLC isprobably the drug of choice for zygomycosis. Voriconazole is approvedfor use in the treatment of invasive aspergillosis and may have a role inpreventing breakthrough fungal infections in patients with persistentfever and neutropenia. Caspofungin is effective against both invasiveaspergillosis and invasive candidiasis.The prevention and managementof invasive fungal infections areof enormous importance in thecare of patients undergoing cancerchemotherapy or bone marrow transplantation.Fungal infections such asinvasive aspergillosis and candidiasiscontinue to be important causes ofmortality in these patients. Key managementstrategies include accurateand rapid diagnosis, optimal use of antifungaldrugs for prophylaxis and empirictherapy, and, in select patients,additional interventions such asimmunomodulation therapies and surgery.This article will evaluate the newerantifungal agents, along with someagents that are still being investigated,for use in specific patient populationsand for management of specific mycoses.Although not uniformly successfulin every patient, these newagents nevertheless will have a verypositive impact on the management ofdifficult invasive mycoses.OverviewSome of the major developmentsin the treatment of invasive mycosescan be highlighted by a brief reviewof three landmark, evidence-basedstudies:
Considering the significant morbidityand mortality associated with invasivefungal infections inimmunocompromised patients, it isparticularly important to diagnose afungal infection as early as possible.Unfortunately, the diagnosis is oftenchallenging. In invasive aspergillosis,for example, the signs and symptomsare nonspecific, and blood cultures arerarely positive.Although it is often difficult to obtainsamples for histopathology andculture, it is important to make everyattempt to identify the organism becausethe findings will influence treatment.The combination of histopathologyand culture is necessary becausethe results of one method might notbe definitive. For example, regardingthe technique of histopathology, thepresence of branching septae and hyphaecould indicate
species,and only a culture would identify thecorrect pathogen.In addition, with histopathology,some patients may have conidia intissue that produce adventitial formsof
The histopathology reportmay indicate that one of thoseorganisms is the likely pathogen. Incontrast, the finding of conidia andhyphae in tissue is not seen with
Thus, the histopathologyresults can help complementculture results.Although there is no absolute proofthat early diagnosis results in less burdenof organisms, there is some evidencethat early diagnosis affects outcome.One study of patients with pulmonaryaspergillosis indicated thatmore frequent use of bronchoscopyand high-resolution CT led to a morerapid diagnosis and, therefore, earliertreatment. The mortality rate was41% when the diagnosis was madewithin 10 days or less after the onsetof signs and symptoms, comparedwith 90% when the diagnosis wasmade after 10 days.CT scanning can be very useful inthe diagnosis of invasive pulmonaryaspergillosis. The most characteristicCT findings are the halo sign and aircrescentformation. The halo sign isvisualized as an area of low attenuationaround a nodule or pleural-basedlesion. Although these signs can occurin other diseases, they are highlysuggestive of invasive pulmonary aspergillosisin febrile neutropenic patients.The halo sign has a short duration;therefore, the use of early CT canbe quite valuable. A more nonspecificbut common finding is the presenceof nodular lesions on a CT scan; thishas less predictive value.
The diagnosis of invasive aspergillosiscan be confirmed by serologictests to detect circulating antigens,such as cell wall galactomannanand measurement of β-1,3-D glucanconcentrations. For example, Kami etal evaluated the sensitivity andspecificity of real-time polymerasechain reaction (PCR), enzyme-linkedimmunosorbent assay (ELISA) forgalactomannan, and the β-D glucantest for the diagnosis of invasive aspergillosis(Table 2). The study included33 patients with invasive aspergillosisand 89 controls.The sensitivities and specificitiesranged from 58% to 79%, and 84% to97%, respectively. Real-time PCRwas more sensitive than the other twotests; it was also highly specific for
infection. This same studyalso evaluated the relationship betweentest results and CT findings.Positive findings on PCR precededthose of CT by -0.3 ± 6.6 days; thecorresponding figures were 2.8 ± 4.1days for ELISA and 6.5 ± 4.9 days forthe β-D glucan test.In high-risk patients, it is particularlyimportant to use every tool available-whether it is a serologic test orCT scan-to identify these invasivefungal infections as soon as possible.Often, CT scans show a small nodule,which the radiologist interprets as po-tentially being fungal-related. In thissituation, serologic findings could helpsupport the diagnosis of aspergillosis.Although these tests are not perfect,using a combination of them in highriskpatients may result in an earlierdiagnosis. The diagnosis of invasivecandidiasis could be improved by betterserologic tests, since at present,blood cultures are positive in only 50%to 60% of patients with invasive candidiasis.
Although immunomodulation hasbeen extensively studied at the basicscience level, clinically, its use has yetto be optimized. Some studies indicatethat immunomodulation therapiesdo not improve outcome inimmunocompromised patients. Forexample, a large, multicenter, EuropeanOrganization for Research onTreatment of Cancer (EORTC) studydemonstrated that the use of growthfactors-primarily granulocytecolony-stimulating factor (G-CSF)-had no impact on outcome in hematologypatients who had invasive aspergillosis. This study included130 cases, 20 hospitals, and 8 countries.Safdar et al, at the M. D. AndersonCancer Center, evaluated treatmentwith G-CSF-primed white bloodcells (WBCs), given every other day,in 29 patients with candidemia; 76%of the patients were neutropenic. Thecontrol group consisted of 441 cancerpatients with candidemia, 45% ofwhom were neutropenic. The associatedmortality was 48% in patientswho received WBC transfusions and45% in the control group. The authorssuggested that patients who receivedthe WBC transfusions may have hadworse prognostic factors than the controlpatients, and therefore, their comparablemortality may have actuallyrepresented a favorable response, butthis interpretation will require furthervalidation.
Another approach to immunomodulationinvolves immune reconstitution.In a study by Pappas and associates, two doses of adjuvant recombinantinterferon-gamma weregiven to patients with cryptococcalmeningitis. A trend toward faster declinein CSF yeast counts was seen inthose patients who received the interferon,compared with those who receivedplacebo. It is likely that the resultswere not statistically significantbecause there were not enough patientsin the study. However, interferonmay be difficult to use in organ transplantrecipients because of the rejectionrisk to the transplanted organ.A word of caution: the use ofgrowth factors to treat pulmonary aspergillosishas the potential complicationof acute respiratory distress syndrome.This may be related to themassive amount of degranulation ofWBCs in the area of the infection.There is some evidence that boostingthe WBC count too fast is detrimental.For example, in a small study, theimmediate mortality rate was 50% inpatients who received G-CSF for aspergillosiswho had a rapid increasein WBC count (0 to 4,500/μL in lessthan 5 days), compared with 17% inthose who had a more gradual increasein WBC count. It is clear that weneed further studies to optimize ouruse of immunomodulation as adjunctivetherapy for successful managementof fungal infections.
Antifungal Therapy: DrugRegimens or Prescriptions
A number of key questions remainabout antifungal drug regimens. Thefollowing is a representation of justsome of these questions:
The role of surgery for the managementof invasive fungal infectionsshould not be overlooked. Surgerydoes have a role in select patients withZygomycetes and black mold infectionsand in some patients with invasiveinfections with
andother hyalohyphomycetes. Caillot etal reported that combined medical-surgical therapy achieved a curerate of 84% in 25 neutropenic patientswho had surgically proven pulmonaryaspergillosis.Another study involved 87 patientswith hematologic malignancies inwhom invasive pulmonary aspergillosiswas suspected. Of the 39 patientswho underwent resection on thebasis of CT findings, 35 actually hadinvasive pulmonary aspergillosis. The2-year survival rate was 36% in theresected group and 20% in theunresected group.Thus, there is evidence that in somecircumstances, surgery can have apositive outcome, although it is importantto note that these are very selectpatient populations regarding the abilityto tolerate surgery.
Antifungal Therapy: A Focus on the Newer Drugs
Invasive fungal infections continue to be a significant cause of morbidityand mortality among patients undergoing cancer chemotherapy or bone marrowor stem cell transplantation. The toxicity associated with amphotericin Bdeoxycholate and the incidence of treatment failures have led to the developmentof new antifungal drugs, such as the lipid formulations of amphotericinB, the triazoles, and the echinocandins.
Liposomal Amphotericin B
The lipid formulations of amphotericin B are approved for use in the treatmentof invasive fungal infections when amphotericin B deoxycholate fails orwhen it is associated with unacceptable toxicity. Liposomal amphotericin Bhas been reported to have an overall response rate of about 60% in this setting[46,47] and is associated with less nephrotoxicity than amphotericin Bdeoxycholate.[48,49]
Voriconazole is a broad-spectrum triazole with efficacy against invasive aspergillosis,[2,50] fluconazole-resistant candidiasis, and a variety of othermycoses. It is also effective in preventing breakthrough fungal infectionsin patients with fever and neutropenia. Voriconazole has been approved by theFDA for primary treatment of acute invasive aspergillosis and for salvage therapyfor serious infections caused by
Scedosporium apiospermum and Fusarium
species.Data from 85 patients who received voriconazole have been reviewed.Approximately 50% of the patients were bone marrow transplant recipients,approximately 27% had aspergillosis, and 24% had neutropenia; 13% receivedcombination therapy. Within 72 hours of initiating voriconazole therapy, themost common drug interactions were with cyclosporin A (52%) and tacrolimus(29%); for both, the levels fell outside the therapeutic range. Liver function testresults were elevated in 10% of patients. Therefore, when using voriconazole,it is important to be aware of these drug interactions and to carefully considerthe cost-benefit ratio.
The echinocandins include caspofungin, micafungin, and anidulafungin.These drugs are glucan synthesis inhibitors. Caspofungin is active against
species, but it does not have significant activity against
It has good in vitro activity against
species,including those resistant to fluconazole and itraconazole.[54,55]Caspofungin has been demonstrated to be effective in the treatment of oropharyngealand esophageal candidiasis,[56-58] fluconazole-resistant esophagealcandidiasis, and invasive candidiasis.Caspofungin is approved by the FDA for salvage therapy in patients withinvasive aspergillosis who have been refractory to or intolerant of amphotericinB, amphotericin B lipid complex, and/or itraconazole. It is also approvedfor the treatment of oropharyngeal and esophageal candidiasis and invasivecandidiasis. The standard dosage is 50 mg/d IV after a 70-mg loading dose;higher dosages (70 mg/d) have been safely used. The duration of treatmentdepends on the severity of the patient's underlying disease, recovery from immunosuppression,and clinical response. Caspofungin has an excellent safetyprofile and does not appear to be antagonistic when combined with other antifungaltherapies.Micafungin is an investigational agent that has a broad spectrum of activityagainst
species. Anidulafungin is also aninvestigational agent that is active against
Managing Specific Infections
There are several evidence-basedtreatment strategies for candidemia.The early studies demonstrated that theeffectiveness of fluconazole is probablyequivalent to that of amphotericinB in most patients withcandidemia. Rex et al reported asuccess rate of 79% with amphotericinB (0.5 to 0.6 mg/kg/d) and 70%with fluconazole (400 mg/d) in nonneutropenicpatients with candidemia;this difference was not statistically significant.Phillips et al reportedsuccess rates of 62% with amphotericinB and 57% with fluconazole innon-neutropenic patients withcandidemia. These studies are limitedin their evaluation of
It is important to note, however, thatfluconazole has limited activity against
and some strains of
has been the predominant
species, an increased incidenceof non-
-hasbeen observed in many US hospitals.[25,26] Infections caused by non-
species are associated withincreased morbidity and mortality.
Herbrecht et al compared intravenousvoriconazole (two doses of 6mg/kg on day 1, followed by 4 mg/kgtwice daily for at least 7 days) withamphotericin B deoxycholate (1 to 1.5mg/kg/d) in patients with invasive aspergillosis,most of whom were allogeneichematopoietic cell transplantrecipients. According to several differentcriteria, voriconazole was moreeffective than amphotericin B; successfuloutcomes were achieved in52.8% of the voriconazole group,compared with 31.6% of the amphotericinB group.A subsequent analysis focused onoutcomes of those patients who firstreceived voriconazole or amphotericinB and then received some otherantifungal therapy. For those whofirst received voriconazole and thenreceived amphotericin B, there did notappear to be significant antagonism(Table 6). Patients who were switchedfrom amphotericin B to ABLC did nothave dramatically better outcomes, butsuccess occurred in 14 of 47 patients(30%).The authors concluded that thestrategy of following amphotericin Bdeoxycholate with another therapy,including ABLC, was less successfulthan initial therapy with voriconazole.The important message to be gainedfrom this study is that the best chancefor treatment success is most likelywith the initial treatment regimen.
Infections caused by Zygomycetesare being seen with increasingfrequency. Zygomycosis usuallyinvolves the rhino-facial-cranial areas,lungs, skin, or GI tract, but widelydisseminated infection can occur.Rhinocerebral disease is the mostcommon form. Pulmonary zygomycosisis less common and usuallypresents as rapidly progressingpneumonia. The risk factors forzygomycosis are diabetes, cancer, andtransplantation.Zygomycosis is one of the mostdifficult invasive fungal infections totreat. There is a three-part strategy formanagement: control of the underlyingdisease, surgical debridement, andmedical therapy. ABLC (5 mg/kg/d)is probably the drug of choice, becauseit is as effective as-or more effectivethan-amphotericin B deoxycholateand is associated with less nephrotoxicity.Larkin and Montero studiedthe efficacy and safety of ABLC in 64patients with zygomycosis. The overallsuccess rate was 72%, and the successrate was 64% in patients with disseminateddisease (Table 7).Posaconazole may be an alternativetherapy, and there is some support forit from in vitro and animal model data.In a small study of 23 patients withzygomycosis, Greenberg et alfound a 71% success rate for treatmentwith posaconazole, and the drug waswell tolerated (Table 8). These resultsdo not prove that posaconazole is moreeffective than amphotericin B butrather suggest that it has potential useas an alternative therapy.
The combination of surgicaldebridement and therapy with anextended-spectrum triazole appears tobe effective in the treatment ofphaeohyphomycosis. In one study,voriconazole successfully managed12 of 12 black mold infections.In a different study, 9 of 13 mycetomas-difficult chronic skin infections-were successfully managedwith posaconazole. Finally, threeof five cases of
meningitis,which were associated with contaminatedcorticosteroids, were successfullytreated with voriconazole.
Refractory Fungal Infections
The efficacy and safety ofvoriconazole as salvage therapy forpatients with refractory fungal infections,and as primary therapy forpatients with infections for whichthere is no approved therapy, havebeen evaluated. Successful outcomeswere observed in 47% ofpatients with refractory infections andin 68% of those who had infectionswith no approved therapy. The efficacyrates were 43.7% for aspergillosis,57.5% for candidiasis, 38.9% forcryptococcosis, 45.5% for fusariosis,and 30% for scedosporiosis. Voriconazolewas well tolerated in thesepatients.Table 9 shows the success rates withvoriconazole, ABLC, and caspofunginin patients with refractory fungal disease.[37,40-42] In patients with aspergillosiswho have not responded totreatment (usually with amphotericinB), a 40% to 45% success rate can beachieved with another drug. Thesuccess rates are somewhat higher inpatients with candidiasis, withcaspofungin being the most effective(87%). To a certain extent, these findingsmay reflect the fact that thesepatients have been treated extensivelywith triazole compounds, and theremay be some cross-resistance betweenvoriconazole and fluconazole in certainpatient populations.Walsh et al reviewed the efficacyand safety of ABLC in 556 casesof refractory invasive fungal infections.There was a complete or partialresponse in 42% of cases of aspergillosis,67% of cases of disseminated candidiasis,71% of cases of zygomycosis,and 82% of cases of fusariosis.
The emergence of resistance to antifungaldrugs is a significant concern.The mechanisms for fluconazole resistanceare understood, and in vitrosusceptibility testing has been standardized.At Duke University MedicalCenter, approximately 10% of selected
isolates were foundto be resistant to fluconazole. Resistanceto flucytosine has also been observed,and this agent is rarely used asmonotherapy. Resistance to other antifungalagents has also been reported.For example:
The new antifungal drugs are outstandingand can have a significantimpact on the management of invasivefungal infections. We are still in theprocess of establishing determiningtheir optimal use; further studies areneeded to establish the best dosing,combinations, and timing of therapy.There are still questions about preciselywhen the glucan synthesis inhibitorsshould be used in aspergillosis.Should they be used after patientshave been treated extensively withanother drug or in the initial treatmentregimen?Amphotericin B deoxycholate isnow relegated to a minor use. Consideringits toxicity and the availabilityof effective and less toxic drugs, thereare few circumstances in which its usecan be justified. For instance, in treatmentof cryptococcal meningitis, amphotericinB deoxycholate is still appropriate.It is very important to try to preventfungal infections wheneverpossible and to make best use of thenew antifungal therapies. However, thepatient's underlying disease remainsthe major factor in determining clinicaloutcomes. Many treatment failuresare actually the result of the patient'sunderlying disease rather than thespecific fungal infection.
Dr. Perfect has receivedresearch support from, acted as a consultant for,and served on speakers' bureaus for Merck,Pfizer, Enzon, PLIVA, Schering-Plough, andFujisawa.
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