Treatment of Fungal Infections in Adult Pulmonary Critical Care and Sleep Medicine

8/9/2019 Treatment of Fungal Infections in Adult Pulmonary Critical Care and Sleep Medicine

1/33

American Thoracic Society Documents

An Official American Thoracic Society Statement:Treatment of Fungal Infections in Adult Pulmonaryand Critical Care Patients

Andrew H. Limper, Kenneth S. Knox, George A. Sarosi, Neil M. Ampel, John E. Bennett, Antonino Catanzaro,Scott F. Davies, William E. Dismukes, Chadi A. Hage, Kieren A. Marr, Christopher H. Mody, John R. Perfect,and David A. Stevens, on behalf of the American Thoracic Society Fungal Working Group

THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS,MAY 2010

CONTENTS

IntroductionMethodsAntifungal Agents: General Considerations

Polyenes

TriazolesEchinocandinsTreatment of Fungal Infections

HistoplasmosisSporotrichosisBlastomycosisCoccidioidomycosisParacoccidioidomycosisCryptococcosisAspergillosisCandidiasisPneumocystis Pneumonia

Treatment of Other FungiGlossary of Terms

With increasing numbers of immune-compromised patients withmalignancy,hematologic disease, and HIV,as wellas thosereceiving

immunosupressive drug regimens for the management of organ

transplantation or autoimmune inflammatory conditions, the in-cidence of fungal infections has dramatically increased over recent

years. Definitive diagnosis of pulmonary fungal infections has also

been substantially assisted by the development of newer diagnostic

methods and techniques, including the use of antigen detection,

polymerase chain reaction, serologies, computed tomography and

positron emission tomography scans, bronchoscopy, mediastino-scopy, and video-assisted thorascopic biopsy. At the same time, the

introduction of new treatment modalities has significantly broad-

ened options available to physicians who treat these conditions.

While traditionally antifungal therapy was limited to the use of

amphotericin B, flucytosine, and a handful of clinically availableazole agents, current pharmacologic treatment options include

potent new azole compounds with extended antifungal activity,

lipid formsof amphotericin B, and newerantifungal drugs, including

the echinocandins. In view of the changing treatment of pulmonary

fungalinfections,theAmericanThoracicSocietyconvenedaworking

group of experts in fungal infections to develop a concise clinicalstatement of current therapeutic options for those fungalinfections

of particular relevance to pulmonary and critical care practice. This

document focuses on three primary areas of concern: the endemic

mycoses, including histoplasmosis, sporotrichosis, blastomycosis,and coccidioidomycosis; fungal infections of special concern for

immune-compromised and critically ill patients, including crypto-coccosis, aspergillosis, candidiasis, and Pneumocystis pneumonia;

and rare and emerging fungal infections.

Keywords: fungal pneumonia; amphotericin; triazole antifungal;echinocandin

The incidence, diagnosis, and clinical severity of pulmonaryfungal infections have dramatically increased in recent years inresponse to a number of factors. Growing numbers of immune-compromised patients with malignancy, hematologic disease,and HIV, as well as those receiving immunosupressive drugregimens for the management of organ transplantation orautoimmune inflammatory conditions, have significantly con-tributed to an increase in the incidence of these infections.Definitive diagnosis of pulmonary fungal infections has alsoincreased as a result of advances in diagnostic methods andtechniques, including the use of computed tomography (CT)and positron emission tomography (PET) scans, bronchoscopy,mediastinoscopy, and video-assisted thorascopic biopsy. At thesame time, the introduction of new treatment modalities hassignificantly broadened options available to physicians whotreat these conditions. Once largely limited to the use of amphotericin B, flucytosine, and a handful of clinically availableazole agents, today’s pharmacologic treatment options includepotent new azole compounds with extended antifungal activity,novel lipid forms of amphotericin B, and a new class of antifungaldrugs known as echinocandins. In light of all these developmentsin the incidence, diagnosis, and treatment of pulmonary fungalinfections, the American Thoracic Society convened a workinggroup on fungi to develop a concise clinical summary of thecurrent therapeutic approaches for those fungal infections of particular relevance to pulmonary and critical care practice. Thisdocument focuses on three primary areas of concern: the

endemic mycoses, including histoplasmosis, sporotrichosis, blas-tomycosis, and coccidioidomycosis; fungal infections of specialconcern for immune-compromised and critically ill patients,including cryptococcosis, aspergillosis, candidiasis, and Pneumo-cystis pneumonia; and rare and emerging fungal infections.

METHODS

For each fungal infection evaluated, the available literature hasbeen thoroughly reviewed and interpreted by the experts in-volved in this statement. In the search for published evidence,workgroup members reviewed journal articles and previouslypublished guidelines, and conducted an evaluation of electronicdatabases, including PubMed and MEDLINE. In general, only

articles written in English were used in the final recommenda-

Am J Respir Crit Care Med Vol 183. pp 96–128, 2011DOI: 10.1164/rccm.2008-740ST

Internet address: www.atsjournals.org


2/33

tions. The most relevant literature references are included in thispublication. Discussion and consensus among workgroup mem-bers formed the basis for the recommendations made in thisstatement. The authors reviewed the evidence base for eachmajor recommendation of this consensus statement and gradedaccording to an approach developed by the U.S. PreventiveServices Task Force (Tables 1 and 2). Although the AmericanThoracic Society (ATS) and Infectious Disease Society of America (IDSA) have recently adopted the GRADE approachto grading the quality of evidence and strength of recommenda-tions for clinical guidelines, the current project was initiated andmuch of the work was completed prior to the official adoption of

GRADE. The recommendations included were, therefore,graded according to the system used in prior guidelines (1–3).Each section also includes expert interpretations regarding thebest approach for challenging clinical situations that have notbeen well studied in the literature, but that are the basis forfrequent consultation of the members of the ATS working groupon fungal infections. For convenience, a glossary of definitions of uncommon terms is also included at the end of the document.

Each member of the writing committee has declared anyconflict of interest, and every effort was made by the Chair asadjudicator to ensurethat recommendations were free of anyrealor perceived conflict of interest; however, it should be noted thatthe process predates the official development and adoption of therevised ATS Conflict of Interest guidelines in 2008 (4).

ANTI-FUNGAL AGENTS: GENERAL CONSIDERATIONS

In most cases, treatment of fungal infections must be based onthe causative fungus, the severity of disease, and the clinicalfeatures of each patient. Specific guidelines for therapy, in-cluding dosing recommendations, are included in subsequentsections under specific organisms and infection site(s). Thissection will provide general comments about the major classesof available antifungal agents, including novel agents such asextended-spectrum triazoles and echinocandins.

Polyenes

The prototype of the polyenes is amphotericin B deoxycholate

(amphotericin B), which continues to be a fundamental treat-ment option for severe fungal infections, particularly life-threatening illnesses, including aspergillosis, cryptococcosis,systemic candidiasis, and severe cases of histoplasmosis, blasto-mycosis, coccidioidomycosis, and zygomycosis. Polyenes act bybinding to sterols in the fungal cell membrane, forming a trans-membrane channel that precipitates cell leakage and death.Amphotericin B is administered intravenously, and is associatedwith a broad range of side effects. Careful monitoring duringtherapy should focus on serum creatinine, blood urea nitrogen,serum electrolytes (particularly potassium and magnesium),complete blood counts, and liver function tests, and monitoringshould be conducted at least weekly during therapy, or evendaily in the presence of renal insufficiency. Because the renal

toxicity of amphotericin B can develop precipitously, we recom-

mend that patients with any degree of renal insufficiency be moreclosely monitored. Many experienced clinicians pre-medicatepatients with antipyretics, antihistamines, anti-emetics, or me-peridine to decrease the common febrile reaction and shak-ing chills associated with infusion (BIII). Meperidine ismost effective for ameliorating the severe rigors. Rapid in-travenous administration of amphotericin B has been observedto precipitate life-threatening hyperkalemia and arrhythmias(5); therefore, the daily dose of amphotericin B deoxycholateshould be infused over 2 to 6 hours. Hypotension and shockhave also occasionally been observed during amphotericin B

infusion. Amphotericin B should not be administered simulta-neously with leukocytes, as this may possibly precipitate pul-monary toxicity (6). There appears to be an additive, andpossibly synergistic, nephrotoxicity with other nephrotoxicagents such as aminoglycoside antibiotics (7). Adequate intra-venous fluid hydration has been shown to reduce the risk of nephrotoxicity (8). In complicated patients, consultation with anexperienced clinical pharmacist or use of tools such as softwareprograms that delineate drug interactions, particularly thosewith suspected synergistic nephrotoxicity or those requiringrenal clearance, is recommended. Additional side effects are com-mon, and may include hypokalemia, phlebitis/thrombophlebitis,anorexia and weight loss, fever and chills, headache and malaise,and cardiac dysrhythmias. Liver toxicity may also occur, but its

incidence is rare compared with renal toxicity. Nephrotoxicityand other untoward side effects of amphotericin B deoxycholateare largely dose-dependent. In clinical situations that requiredoses of amphotericin B deoxycholate greater than or equal to1.0 mg/kg/day, strong consideration should be given to usinglipid formulations of amphotericin to avoid the potentially highincidence of toxic side effects ( see below) (BIII).

In addition to amphotericin B deoxycholate, two differentlipid-associated formulations have been developed and are incurrent use: liposomal amphotericin B and amphotericin B lipidcomplex. These agents have variable dosing schedules andtoxicities, but, in general are significantly less nephrotoxic thanamphotericin B deoxycholate. Data concerning the improvedefficacy of any amphotericin lipid formulation over amphotericin

B deoxycholate are limited. So far, the clearest indication for useof a lipid formulation is to reduce renal toxicity (AII), which is anespecially important consideration in patients who have under-lying nephrotoxicity or in those who are receiving multipleconcomitant nephrotoxic drugs. For diseases where dosing of amphotericin B at 1.0 mg/kg/day or higher is standard, theintrinsic nephrotoxicity of amphotericin B itself dictates pre-ferred useof lipid formulations. As with standard amphotericin Bformulations, monitoring for side effects during therapy shouldinclude measurement of serum creatinine, blood urea nitrogen,and serum electrolytes (particularly potassium and magnesium),complete blood counts, and liver function tests which should beperformed at least weekly during therapy, or even daily in thepresence of renal insufficiency. Theoretically, lipid formulations

of amphotericin might have some benefit of higher central

TABLE 1. CATEGORIES INDICATING THE STRENGTH OF EACHRECOMMENDATION FOR OR AGAINST ITS USE IN THETREATMENT OF FUNGAL INFECTIONS

Category Definition

A Good evidence to support a recommendation for use

B Moderate evidence to support a recommendation for use

C Poor evidence to support a recommendation for or against use

D Moderate evidence to support a recommendation against use

E Good evidence to support a recommendation against use

TABLE 2. GRADES OF EVIDENCE QUALITY ON WHICHRECOMMENDATIONS ARE BASED

Grade Definition

I Evidence from at least 1 properly randomized, controlled trial

II

Evidence from at least 1 well-designed clinical trial without

randomization, from cohort or case-controlled analytic studies

(preferably from . 1 center), from multiple patient series studies,

or from dramatic results of uncontrolled experiments

III

Evidence from opinions of respected authorities, that is based on clinical

experience, descriptive studies, or reports of expert committees.

American Thoracic Society Documents 97


3/33

nervous system (CNS) penetration, especially when given inhigher doses, although conclusive clinical data to support thisapproach in treatment of fungal meningitis are lacking.

Recommendation. Among patients with renal insufficiencyor among those individuals who are receiving multiple concom-itant nephrotoxic drugs, we suggest a lipid formulation of amphotericin B to reduce renal toxicity (DII).

Remark. In certain clinical situations that require doses of am-photericin B deoxycholate greater than or equal to 1.0 mg/kg/day,

the incidence of such toxicities is high, and lipid formulationsof amphotericin are associated with fewer adverse effects, andtherefore may be preferred.

Triazoles

The azole antifungal agents contain three nitrogen atoms withinthe basic ring. Triazoles in clinical use include ketoconazole,itraconazole, fluconazole, voriconazole, and posaconazole. Tri-azoles target the 14-a-demethylase enzyme, which mediates theconversion of lanosterol to ergosterol in the fungus. Interactionsof azole drugs with human P450 cytochromes have been welldocumented (9). Therefore, azole-related drug interactions areespecially problematic in immunocompromised hosts, particularlytransplant patients and those infected with HIV. In these popula-

tions, decreased plasma concentration of the azole may occur asa result of increased metabolism, or of increases or decreases inconcentrations of co-administered drugs. With most of the azolecompounds, interactions occur with many such drugs, particularlycyclosporine,benzodiazepines, statins, and certain anti-HIV drugs,as a result of altered rates of drug metabolism and induction of therelative P450 enzymes (10). The use of azoles is contraindicatedduring pregnancy; in these patients, amphotericin is preferred,as amphotericin B and its lipid derivatives are rated class B forpregnancy. By contrast, fluconazole, itraconazole, and posacona-zole are class C drugs, while voriconazole is a class D drug. Earliergeneration azoles such as ketoconazole also have adverse effectson steroid hormone levels and adrenal function (11).

Itraconazole. Modifications to the azole structure have led to

additional extended spectrum antifungals. For instance, itraco-nazole contains a four-ring lipophilic tail that enhances itsinteractions with the CYP51 cytochrome, rendering it activeagainst molds. Itraconazole is effective for some Aspergillusinfections, mucosal candidal infections, histoplasmosis, blasto-mycosis, coccidioidomycosis, and other fungal infections (12).Unfortunately, due to itraconazole’s high protein binding andpoor CNS penetration, it is not an optimal choice for CNSinfections. Itraconazole is available as either oral capsules or anoral solution. The oral capsules require gastric acid for absorp-tion, and so are usually taken with food or acidic beverages. Inaddition, concurrent use of proton pump inhibitors and antacidsshould be avoided. To overcome problems with variable drugabsorption, particularly in settings in which proton pump in-

hibitors must be administered concurrently, itraconazole hasbeen solubilized in a cyclodextrin solution, resulting in sub-stantial improvement in absorption (13). In contrast to thecapsule form, the oral solution requires an empty stomach.Because of the widespread use of antacids, H2 blockers, andproton pump inhibitors, the committee recommends thoughtfulconsideration of the optimal form to use. When using oralitraconazole, it is important to routinely assure that adequatelevels of itraconazole are present in serum (AII). The bioassaysused to measure the antifungal activity of serum reflect allactive antifungal substances that are present in the serum at thetime of testing, and therefore may not specify the level of theunique agent of interest. In contrast, the high-performanceliquid chromatography (HPLC) method measures the actual

concentration of the specific compound in question in the serum

or other body fluids. The report usually provides the concen-tration of the parent compound and its active metabolites, butdoes not take into account binding of active drug, because of theextraction process, used before the assay. Thus, the target rangeprovided by the lab for each particular assay should be followedwhen making dose adjustments. Dosage adjustments of orallyadministered itraconazole are not required in patients withrenal impairment, and do not appear to be required duringhemodialysis. Itraconazole is extensively metabolized in the

liver, and caution should be employed in patients with signif-icant liver insufficiency (12).Contraindications to itraconazole use include previous hy-

persensitivity to itraconazole or co-administration of cisapride,dofetilide, midazolam, pimozide, levacetylmethadol, quinidine,statin medications, triazolam, and other agents. Precautionshould be used in patients with severe congestive heart failure(CHF), achlorhydria, hepatic dysfunction, or hypersensitivity toother azoles. Side effects of itraconazole are rare and mayinclude rash, diarrhea, and nausea. Serious, though uncommon,side effects include worsening of CHF, Stevens-Johnson syn-drome, and hepatotoxicity. As with other azole compounds,interactions occur with many such drugs, particularly cyclospor-ine, benzodiazepines, statins, certain anti-HIV drugs, and many

other agents related to its metabolism by the P450 cytochromesystem (10). Pharmacy and medication cross-reference re-sources should be consulted whenever instituting treatment.

Fluconazole. In the 1990s, fluconazole joined this class of antifungals, offering a reduced lipophilicity that allows for easieradministration. This agent has been shown to have good activityagainst Candida albicans, and is used for prevention and treat-ment of both mucosal and invasive diseases. Fluconazole also hassignificant activity in cryptococcosis and coccidioidomycosis.Dose adjustments are recommended in renal impairment, anddosages are reduced by 50% when the creatinine is less than 50ml/minute. Patients on hemodialysis require replacement of theentire dosage aftereach dialysissession(14).Contraindications tofluconazole therapy include known hypersensitivity to the agent.

Side effects are generally uncommon, but can include skin rashand pruritus, nausea and vomiting, increased liver enzymes, andheadache. Anaphylactic reactions are generally rare for all azoles.Compared with other azole antifungal agents, such as itracona-zole, voriconazole, and posaconazole, drug–drug interactions arerelatively less common with fluconazole, as the drug is a relativelyless active inhibitor of P450. Prescribing physicians shouldgenerally consult pharmacy and medication cross-reference re-sources when initiating treatment.

Voriconazole. Voriconazole is a newer azole antifungal thatis increasingly being used for invasive aspergillosis and othermold infections. As with most other azoles, the drug is contra-indicated in patients receiving co-administration of P450–CYP3A4substrates, including fexofenadine, astemizole, pimozide, or

quinidine, as these interactions may lead to increased plasmaconcentrations of these drugs, electrocardiographic Q to T waveinterval (QT) prolongation and, rarely, torsades de pointes. Inaddition, coadministration of rifampin, carbemazapine, barbi-turates, ritonavir, and efavirenz should be avoided. Voriconazoleshould be used with caution in patients with hypersensitivity toother azole antifungal agents, or with hepatic cirrhosis. Due tothe cyclodextrin component, intravenous preparations of vor-iconazole should be used with caution in patients with renalinsufficiency (creatinine clearance ,50 ml/min), as the cyclo-dextrin vehicle may accumulate. Although there are no directdata that indicate that the cyclodextrin in intravenous vorico-nazole is in fact nephrotoxic, the oral form can be used instead.Dose adjustments are not necessary for oral voriconazole in

patients with mild to moderate renal impairment. If intravenous

98 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 183 2011


4/33

voriconazole is absolutely necessary in patients with moderateor severe renal insufficiency (creatinine clearance , 50 ml/min),serum creatinine should be monitored closely. For patientsreceiving hemodialysis, the removal of the drug by hemodialysisis not sufficient to warrant dosage adjustment. Voriconazoleshould not be used in patients with severe hepatic insufficiency,unless the benefits outweigh the risk of liver problems. Patientsalso need to avoid direct sunlight, since photosensitivity re-actions can occur. Side effects include peripheral edema, rash,

nausea, vomiting, and liver dysfunction. Severe liver dysfunc-tion and failure have rarely occurred (15). Visual disturbance(scotomata) occurs in approximately one-third of patients, butthe condition is rapidly reversible, and will abate within minutesto hours following discontinuation of the agent (16). Somereports suggest that cutaneous malignancies have been asso-ciated with voriconazole use. Metabolism of the drug can bevariable, and recent experience indicates a potential need formonitoring of serum levels. Again, drug interactions are com-mon, and medication cross-reference resources should be con-sulted when instituting therapy.

Posaconazole. Posaconazole has received FDA approval foruse as prophylaxis against invasive fungal infections in severelyimmunocompromised patients and for treatment of oropharyn-

geal candidiasis that is refractory to fluconazole and itracona-zole. In addition, this agent has proven effective when used assalvage therapy in severely immunocompromised patients withrefractory infection with Aspergillus species (17), and as a treat-ment for coccidioidomycosis (18). The agent also displaysactivity against zygomycetes (19) and a variety of other fungi.Posaconazole is contraindicated in patients receiving ergotalkaloids, and in those receiving terfenadine, astemizole, pimo-zide, or quinidine, as these interactions may lead to increasedplasma concentrations of these drugs with QT prolongation(20). Common adverse effects include diarrhea and abdominaldiscomfort, and serious side effects include occasional hepaticdysfunction, in addition to long QT syndrome. Posaconazole hassaturable absorption, requiring adequate dietary fat that limits

oral dosing to approximately 800 mg per day. The optimal wayto provide the drug is 200 mg four times per day, and with fattymeals when possible. Dose adjustments for posaconazole are notnecessary in patients with mild to severe hepatic insufficiency orrenal impairment. Dose adjustments are also not necessary afterdialysis. Appropriate clinical monitoring is indicated, includingliver function tests at the start and during the course of therapy,and assessment of serum potassium, magnesium, and calciumlevels, with rigorous correction of levels as needed beforeinitiating therapy. As additional drug interactions may emerge,medication cross-reference resources should be consulted wheninstituting treatment.

Recommendations. In patients receiving itraconazole, vori-conazole, or posaconazole, we recommend measurements of

drug levels in serum to be certain that the drug is beingabsorbed and to guide treatment (AII).

In patients with renal insufficiency (creatinine clearance,50 ml/min), we suggest reducing the dose of fluconazole by 50%(BIII).

Remark. Patients undergoing hemodialysis require redosingafter each dialysis session.

Echinocandins

The echinocandins are an entirely novel class of antifungalagents that disrupt fungal cell walls through inhibition of the1,3-b-glucan synthase complex. Thus, they have been referredto as the ‘‘penicillins of the antifungal armamentarium.’’Currently, three agents are available: caspofungin, micafungin,

and anidulafungin.

Caspofungin. Caspofungin exhibits fungicidal activity againstCandida species and fungistatic activity against Aspergillusspecies. Caspofungin has been used primarily for candidiasis,treatment of febrile neutropenia, and for salvage therapy of invasive aspergillosis. Laboratory studies support activity againstPneumocystis species and some other fungal infections, althoughclinical data are lacking (21, 22). Caspofungin is only adminis-tered via intravenous infusion, with dosage adjustment beingrequired in the case of hepatic impairment. The medication is

contraindicated in patients with hypersensitivity, and precautionshould be exercised in patients with liver impairment, those whoare pregnant, and those concomitantly receiving cyclosporine.Common side effects include increased liver enzymes, nausea,facial swelling, headache, and pruritus. Notably, caspofungin andthe other echinocandins are not inhibitors or inducers of thecytochrome metabolism enzymes. However, drug–drug interac-tions may still be observed, especially with cyclosporine andtacrolimus, rifampin, and certain anti-HIV drugs.

Micafungin. Like caspofungin, micafungin also has activityagainst Candida and Aspergillus species. This agent has beenapproved for treatment of invasive candidiasis, for prophylaxis of stem cell transplantation patients against Candida, and forCandida esophagitis (23). Precaution should be used in patients

with prior hypersensitivity to other echinocandins. Serious hyper-sensitivity reactions, including anaphylaxis and shock, have rarelyoccurred. Side effects include phlebitis; rash; abdominal discom-fort with nausea, vomiting, or diarrhea; and hyperbilirubinemia.

Anidulafungin. Anidulafungin is the most recently approvedechinocandin, and has received approval for use in candidemia,candidiasis, and candidal esophagitis, with additional activityexhibited against Aspergillus species (22). Studies of its relativeactivity in comparison to other agents are underway. This agentis generally well tolerated, but should be infused slowly.Common side effects include diarrhea and hypokalemia. Seri-ous adverse reactions include deep vein thrombosis and, rarely,liver toxicity. The drug should be used cautiously in patientswith liver dysfunction, and appropriate clinical monitoring

should be implemented in these patients. At present, all threeof the currently licensed echinocandins should be viewed asequally effective for candidemia.

TREATMENT OF HISTOPLASMOSIS

Histoplasma capsulatum is a dimorphic fungus that is endemicto the Ohio, Missouri, and Mississippi River valleys in theUnited States, as well as some river valleys in Central America.Severity of illness after inhalational exposure to Histoplasmacapsulatum depends on the intensity of exposure, as well as theimmune status and underlying lung architecture of the host, andplays a major role in treatment decisions (Table 3). The chronicmanifestations of healed histoplasmosis will be briefly men-

tioned and, as a rule, do not require specific antifungal therapy.In all instances, severe progressive disseminated disease, as wellas CNS involvement, require initial treatment with amphoter-icin B, while mild to moderate disease can usually be treatedwith itraconazole (AII).

Pulmonary Nodules

Although not treated with antifungal agents, asymptomaticpulmonary nodules due to recent or remote Histoplasmaexposure are common and diagnostically challenging, as theymimic malignancy. Often these nodules are biopsied or excised,and may on occasion stain positively for Histoplasma. Univer-sally, when Histoplasma cannot be cultured, antifungal treat-ment is not recommended (EIII). The time to calcification is

variable and cannot generally be used alone to absolutely



5/33

distinguish from malignancy, though some reveal typical centraland concentric calcification on CT imaging, which is suggestiveof being benign. Moreover, many nodules never calcify. PETscans can also show increased uptake in these histoplasma-induced lesions (24). The decision to pursue diagnosis in thispatient population depends on many factors, including smokingstatus, chronicity, and patient preference. In patients who are

symptomatic with pulmonary nodule(s) and associated chestadenopathy, recent infection is presumed and treatment withantifungal agents may be warranted depending on diseaseseverity, as discussed below for the immunocompetent host.

Broncholithiasis

Broncholithiasis occurs when calcified lymph nodes erode intothe airway, causing symptoms of dyspnea, wheezing, or hemop-tysis. Many times these are managed conservatively and thepatient may spontaneously cough the broncholith out of theairway. In instances in which the patient requires intervention,bronchoscopic evaluation is first recommended (BIII). Remov-ing a partially or completely eroded broncholith can usually be

safely performed at the time of bronchoscopic evaluation (25),but surgical intervention may be required if broncholithiasis iscomplicated by obstructive pneumonia, fistula formation, ormassive hemoptysis (BIII) (26). Antifungal treatment is notgenerally recommended (BIII).

Fibrosing Mediastinitis

Fibrosing mediastinitis is uncommon, but is often progressivewith distortion and compression of major vessels and centralairways. It must be differentiated from granulomatous media-stinitis related to recent infections, malignancy, and chronicpulmonary thromboembolism. Patients may experience symp-toms for years prior to diagnosis. Fibrosing mediastinitis can befatal and, despite lack of proven therapy, some clinicians

recommend a 12-week course of itraconazole at 200 mg twicedaily (CIII) (27, 28). If radiographic or physiologic improve-ment is obvious, therapy should be considered for 12 months.The use of corticosteroids is not routinely recommended (DIII),and the role of antifibrotics (for example, tamoxifen) areunclear (CIII) (29). Intravascular stents may be useful inappropriately selected patients—typically those with advanceddisease, open airways, and severe manifestations of vascularcompromise (BIII) (30). The algorithm for compressive diseaseof the airway is complicated. The committee suggests consider-ing balloon bronchoplasty, followed by consultation with a sur-geon specializing in mediastinal disease, and endobronchialstenting (CIII). Stenting of the airway in benign disease isreserved for those with no other options, and a removable

silicone stent is initially preferred (CIII). Endobronchial laser

therapy has been used for hemoptysis related to fibrosingmediastinitis and hyperemic airways (31).

Immunocompetent Hosts with Symptomatic Histoplasma

Pneumonia, or with Progressive or Severe Disease

Because healthy individuals with progressive disease are un-common, recommendations for treatment of immunocompetentpatients are based primarily on expert opinion. In healthyindividuals, asymptomatic infection follows low-intensity expo-sures and typically requires no therapy (32). Because effectiveand minimally toxic oral therapy is now available, 200 mgitraconazole twice daily for up to 12 weeks is appropriatetherapy for patients who remain symptomatic after 3 weeks of observation (BIII). In contrast, inhalation exposure to a largeinoculum may cause severe pulmonary infection with massivemediastinal lymphadenopathy, hypoxemia, respiratory failure,and acute respiratory distress syndrome (ARDS), even inhealthy individuals. In patients with life-threatening pulmonaryinfections, including patients with severe gas-exchange abnor-mality, severe toxicity, and rapid progression, amphotericin Bdeoxycholate (0.7 mg/kg/d) or a lipid formulation of amphoter-icin (5 mg/kg/d) should be used initially in these severely illpatients (AIII), followed by itraconazole 200 mg twice daily tocomplete at least a 12-week course once the patient clinicallyimproves (BIII). Initiating therapy with itraconazole 200 mgtwice daily for 12 weeks is recommended for patients with mildor moderate disease (BIII). The role of corticosteroids in acuteinfection is controversial. Patients with hypoxemia associatedwith diffuse infiltrates and patients with massive granulomatousmediastinitis may benefit as long as steroid therapy is used incombination with antifungal therapy (CIII). The panel felt thatprednisone 40–60 mg/day for 1 to 2 weeks was an appropriatelyconservative regimen (CIII).

Immunocompromised Hosts

In immunosuppressed patients, progressive disseminated histo-plasmosis occurs and amphotericin B (0.7–1.0 mg/kg/d to clin-ical improvement or up to a total of 2 g), or a lipid formulationof amphotericin (3–5 mg/kg/d), is the initial recommendationfor patients who are sufficiently ill to require hospitalization.This should be followed by itraconazole, 200 mg twice daily for12 months once clinical improvement is noted (AII). In one study,initial treatment of patients with AIDS with liposomal ampho-tericin B (AmBisome) showed a survival benefit (33) (BI).However, patients treated with amphotericin B deoxycholate inthis study inadvertently had more severe disease activity, whichmay have influenced the results in favor of liposomal ampho-tericin B. Patients with mild to moderate disease can be treated

with itraconazole monotherapy. A loading dose of 200 mg three

TABLE 3. TREATMENT RECOMMENDATIONS FOR HISTOPLASMOSIS

Disease Manifestation Treatment Recommendations Comments

Mild pulmonary histoplasmosis;

therapy deemed necessary

Itraconazole (200 mg twice daily for 12 wk) Liposomal amphotericin is preferred in patients

with renal insufficiency.

Consider itraconazole serum level at 2 wk of therapy.

Monitor renal and hepatic function.

Moderately to severely ill

pulmonary histoplasmosis

Amphotericin B (0.7 mg/kg/day) 6 corticosteroids

for 1–2 wk, then itraconazole

(200 mg twice daily for 12 wk)

Chronic pulmonary histoplasmosis Itraconazole (200 mg twice daily for 12–24 mo) Continue treatment until no further radiographic improvement.

Monitor for relapse after treatment is stopped.

Itraconazole serum level at 2 wk, then every 3–6 mo recommended.Progressive disseminated

histoplasmosis

Lipid formulation amphotericin B (3–5 mg/kg/d) or

amphotericin B (0.7–1.0 mg/kg/d for 1–2 wk),

then itraconazole (200 mg twice daily for 12 mo)*

Chronic maintenance therapy may be necessary

if immunosuppression cannot be reduced.

Monitoring antigen levels may be useful.

Monitor renal and hepatic function.

* For mild to moderate disease in progressive disseminated histoplasmosis, itraconazole 200 g twice daily for 12 mo may be an option.



6/33

times daily is recommended for the first 3 days of therapy,followed by 200 mg twice daily for 12 months (AII) (34).Monitoring of itraconazole levels is useful and should beperformed using either the bioassay or HPLC methods. Ther-apeutic reference ranges should be obtained from the locallaboratory and testing method, since the effective range willvary with the method employed. In general, the bioassaytherapeutic range is believed to be between 1 and 10 mg/ml.The reference ranges for various HPLC assays vary by the

methods used, though they are generally in ranges three to fivetimes lower than those obtained through bioassay methods.Patients with HIV and AIDS may require prolonged itraco-

nazole maintenance therapy (e.g., itraconazole 200 mg twicedaily) after appropriate initial therapy (35). However, wheneffective immune reconstitution occurs, maintenance therapygenerally can be safely discontinued when CD4 counts greaterthan 200/ml are achieved (36) (BII). In those patients whoremain immunosuppressed and require lifelong maintenancetherapy, Histoplasma polysaccharide antigen levels, checkedseveral times a year, should be monitored in urine and serum, asa rise in antigen levels may predict relapse (BIII). The use of glucocorticoids in immunocompromised patients with severehypoxemia and diffuse infiltrates, such as in the setting of

immune reconstitution inflammatory syndrome which can occurwith histoplamosis, remains poorly studied and controversial (37).However, the writing group felt that prednisone 40–60 mg/dayfor 1 to 2 weeks was an appropriately conservative regimen if deemed useful on a patient-by-patient basis (CIII). Patientswith AIDS who live in endemic areas, particularly those who donot exhibit significant immune reconstitution through HAARTreflected by CD4 cells greater than 200/ml, or those with a highlikelihood of occupational or recreational exposure, may be con-sidered for prophylaxis with itraconazole 200 mg/day (38);however, whether the benefits outweigh the cost and risk is notwell established (BII). In addition, recent treatment with anti–tumor necrosis factor-a (TNF-a) agents has also been associatedwith histoplasmosis, as well as other endemic and opportunistic

fungal infections (39). Clinicians should be aware of this associ-ation and have a high index of suspicion for this diagnosis in suchpatients. In addition, adrenal insufficiency has been estimated tocomplicate disseminated histoplasmosis in 7% of cases, and thispossibility should be considered, particularly in patients who donot respond well to therapy (40).

Patients with underlying structural lung disease (particularlyemphysema) may develop ‘‘chronic pulmonary histoplasmosis.’’This condition has beenobserved during histoplasmosis outbreakswhen acute infection occurs in patients with centrilobular emphy-sema or other forms of upper lobe structural disease. The clinicaland radiographic findings may resemble those classically seen inreactivation tuberculosis, and infection is likely to progress if nottreated (41). However, it needs to be emphasized that current

concepts indicate that chronic pulmonary histoplasmosis does not represent reactivation of a prior infection (42). Treatment failurescommonly occur and provide a rationale for prolonged treatment(43). Itraconazole given at 200 mg twice daily for12 to 24 months isthe current treatment of choice for chronic pulmonary histoplas-mosis (AIII). Itraconazole levels should be monitored to verifythat the patient is absorbing the agent. Amphotericin B canalternatively be used if clinical severity warrants (41). Histoplasmaantigen testing, complement fixation titers, and gel diffusion testshave no rolein following treatment efficacyin patientswith chronicpulmonary histoplasmosis.

Although older studies suggest that fluconazole and ketoco-nazole can be used to treat both acute and chronic pulmonaryhistoplasmosis, they are inferior to itraconazole and should be

used only in special circumstances or when itraconazole is not

tolerated (DII). Voriconazole and posaconazole are activeagainst H. capsulatum and have been successfully used insalvage therapy (44–48). The echinocandins do not appear tobe an effective treatment for Histoplasma infection (49).

Recommendations. IMMUNOCOMPETENT HOSTS WITH H ISTOPLASMA-RELATED PULMONARY NODULES, BRONCHOLITHIASIS, OR FIBROSINGMEDIASTINITIS. Among asymptomatic patients with pulmonarynodules in whom Histoplasma cannot be cultured, we recom-mend that antifungal treatment not be used (DI).

In most patients with broncholithiasis, we recommend thatantifungals not be used (BIII).In selected patients with broncholithiasis who require in-

tervention, such as those with significant hemoptysis, we suggestbronchoscopic evaluation and removal of the broncholith eitherbronchoscopically or surgically (BII).

Among selected patients with broncholithiasis complicatedby obstructive pneumonia, fistula, or massive hemoptysis, wesuggest surgical intervention (BII).

In patients with fibrosing mediastinitis, some clinicians rec-ommend itraconazole 200 mg twice daily for 12 weeks (CIII). Inpatients with radiographic or physiologic improvement after aninitial 12 weeks of therapy, we suggest longer treatment, up to12 months (CIII). In these patients, we also suggest that antifibrotic

agents and systemic glucocorticosteroids not be used (DII).In selected patients with fibrosing mediastinitis and severevascular or airway compromise, we suggest placing intravascu-lar stents (BII), bronchoplasty, and/or placing endobronchialstents, if appropriate expertise is available (BIII). If a decisionis made to place a stent, we suggest initially using removablestents (BIII).

IMMUNOCOMPETENT HOSTS WITH SYMPTOMATIC, PROGRESSIVE, ORSEVERE PULMONARY HISTOPLASMOSIS. In asymptomatic patients,we recommend that no antifungal treatment be used (BII).

In symptomatic patients with mild pulmonary histoplasmosis,whoremain symptomatic after 3 weeks of observation, we suggestitraconazole 200 mg twice daily for up to 12 weeks (BIII).

In selected patients with mild to moderate pulmonary

histoplasmosis, we suggest initiating treatment with itraconazole200 mg twice daily rather than with amphotericin B (BIII).

In patients with severe pulmonary histoplasmosis, such asthose with life-threatening pulmonary infections including pa-tients with severe gas-exchange abnormality, severe toxicity, andrapid progression, we recommend amphotericin B 0.7 mg/kg/dayuntil clinical improvement is observed or until a cumulativedose of 2 g of amphotericin B is reached (BI). In patients whoimprove clinically after initial treatment with amphotericin B,we suggest maintenance itraconazole 200 mg twice daily for atleast 12 weeks (BII).

In patients with severe pulmonary histoplasmosis withdiffuse pulmonary infiltrates or massive granulomatous media-stinitis, we suggest adjunctive systemic glucocorticosteroid

therapy be used (CII).Remark. Prednisone 40–60 mg/day (or equivalent) for 1 to 2

weeks seems appropriate in these patients.In patients with pulmonary histoplasmosis, we suggest

itraconazole rather than fluconazole or ketoconazole (CII).Remark. In selected patients who do not tolerate itracona-

zole, fluconazole or ketoconazole may still be used.IMMUNCOCOMPROMISED HOSTS WITH PULMONARY HISTOPLASMO-

SIS OR WITH PROGRESSIVE OR DISSEMINATED DISEASE, OR WITHCHRONIC PULMONARY HISTOSPLAMOSIS. In patients with mild tomoderate histoplasmosis, we recommend itraconazole 200 mgthree times daily for 3 days followed by 200 mg twice daily for12 months (CI).

In patients with severe progressive disseminated histoplas-

mosis requiring hospitalization, we recommend amphotericin



7/33

B 0.7–1.0 mg/kg/day (or a lipid formulation of amphotericin3–5 mg/kg/d) until clinical improvement is observed or until a cu-mulative dose of 2 g of amphotericin B is reached (BII). In patientswho improve clinically after initial treatment with amphotericin B,we suggest itraconazole 200 mg twice daily for 12 months (CI).

In patients with AIDS and progressive disseminated histo-plasmosis who completed 12 months of initial itraconazoletherapy, we suggest itraconazole 200 mg twice daily untileffective immune reconstitution occurs (i.e., CD41 T cell

counts . 200/ml) (CII).In patients with AIDS who remain immunosuppressed andrequire lifelong maintenance therapy, we suggest monitoringHistoplasma polysaccharide antigen levels in urine and serumseveral times per year (BIII).

In patients with chronic pulmonary histoplasmosis, werecommend itraconazole 200 mg twice daily for 12 to 24 monthsrather than no antifungal treatment (BI), and suggest thatHistoplasma antigen is not monitored (BIII).

In patients with severe chronic pulmonary histoplasmosis, werecommend initial treatment with amphotericin B over itraco-nazole (BII).

In selected immunocompromised patients with severe pul-monary histoplasmosis and diffuse pulmonary infiltrates, we

suggest adjunctive systemic glucocorticosteroid therapy (BII).Remark. Prednisone 40–60 mg/day (or equivalent) for one to

two weeks seems appropriate in these patients.

TREATMENT OF SPOROTRICHOSIS

Introduction

Sporotrichosis is an illness caused by the dimorphic fungusSporothrix schenkii. The organism is found throughout the world,and is associated with various forms of vegetation. The mostcommon form of the infection is caused by inoculation of theorganism into skin and subcutaneous tissues. The usual pre-sentation of the disease is the characteristic lymphocutaneous orulcerative skin form of sporotrichosis. Occasionally patients will

inhale the organism, leading to the development of pulmonarysporotrichosis, which may occasionally disseminate to variousparts of the body, predominantly to large joints. The treatmentrecommendations for sporotrichosis are derived predominantlyfrom nonrandomized trials, case series, and case reports (50–52).There have been no randomized controlled therapeutic trials.Itraconazole remains the drug of choice for most forms of sporotrichosis (53). Doses range from 200 mg/day for thelymphocutaneous form to 200 mg twice daily for pulmonaryand osteoarticular disease (BIII). Conventional amphotericin Bdeoxycholate or a lipid formulation of amphotericin is used formeningeal disease and may be used for severe pulmonary andosteoarticular disease in a course of 1 to 2 g total dose (BIII).Relapse following therapy is unfortunately common.

Recommendations. In patients with mild to moderately severepulmonary sporotrichosis, based on the extent of radiographicinvolvement and oxygenation status, we suggest itraco-nazole 200 mg twice daily, with a total duration of therapygenerally of 3 to 6 months based upon overall clinical response(BIII).

In patients with severe pulmonary sporotrichosis, such asthose with life-threatening pulmonary infections including pa-tients with severe gas-exchange abnormality, severe toxicity,and rapid progression, we suggest amphotericin B 0.7 mg/kg/dayuntil clinical improvement is observed or until a cumulativedose of 1 to 2 g of amphotericin B is reached, followed byitraconazole 200 mg twice daily, with total duration of therapygenerally of 3 to 6 months based upon overall clinical response

(BIII).

TREATMENT OF BLASTOMYCOSIS

Introduction

Blastomyces dermatidis is a dimorphic fungus endemic in thecentral and southeastern United States. Blastomycosis is ac-quired by inhalation and can present as an acute, subacute, oreven chronic infection. A small number of cases present as aninfectious ARDS with fulminant diffuse pneumonia (54). Thewide range of less severe pulmonary presentations includes

lobar pneumonia, mass lesions, single or multiple nodules, andchronic fibronodular or fibrocavitary infiltrates. Disseminationfrom the lung is generally believed to occur in a minority of cases, either concurrent with the pulmonary infection or afterresolution of a clinical or subclinical primary infection (usuallywithin 1 or 2 yr) (55). It is unknown whether these delayed casesrepresent a manifestation of reactivation of the primary in-fection. The usual pattern of spread is to skin and bone. Lessthan 5% of disseminated cases involve the central nervoussystem, the meninges, or, less commonly, the brain itself. Inimmunosuppressed patients, especially those with AIDS, thedisease is more severe and the pace of illness is accelerated (56,57). Considerations for treatment of blastomycosis have to beviewed in the context of this wide spectrum of clinical illness

(Table 4).Immunocompetent Hosts

The vast majority of clinically recognized cases are mild tomoderate in severity, involving the lung and/or the skin andbones. For these infections, the usual treatment is itraconazole200 mg orally twice daily for 6 months (AII) (43, 58, 59). Thistreatment is highly effective and is the same for pulmonaryinfections and for nonmeningeal dissemination (accompanyingpulmonary disease or in isolation), except that treatmentduration is extended to 12 months when bones are involved(BII) (59–63). Thus, a 6- to 12-month course of oral itraconazoleis appropriate treatment for most patients who present withblastomycosis. The challenge is to define the range of treatment

options for the small minority of patients with the most difficultand life-threatening infections. Because patients with verysevere infection, including all patients with CNS disease, wereexcluded by protocol from the large clinical trials that showeditraconazole equal to amphotericin B deoxycholate, the latteragent remains the gold standard for such patients. It should benoted, however, that subsequent case reports do suggest efficacyof itraconazole for patients who are quite ill (63, 64).

Life-threatening pulmonary infections include patients withsevere gas-exchange abnormality, severe toxicity, and rapidprogression. The recommended treatment is intravenousamphotericin B deoxycholate (0.7–1.0 mg/kg/d) to a totalcumulative dose of 1.5–2.5 g (AII) (58, 65). Treatment can begiven daily until clinical improvement has been established, and

then three times weekly to completion (AIII) (65). Lipidformulations of amphotericin should be used for patients withpre-existing renal failure or with renal complications from am-photericin B deoxycholate. The usual daily dosage is 5 mg/kg/day,but even higher dosing has been used (BIII). Although thereis a large positive experience in clinical practice, there are nodisease-specific clinical trial data proving equivalency of lipidformulations of amphotericin versus amphotericin B deoxycho-late in blastomycosis, and the total cumulative dose andduration of required treatment have not been studied. Incurrent clinical practice, sequential therapy is often used afterinitial therapy with either agent. Amphotericin B deoxycholate(or lipid formulation amphotericin) is used until clinical im-provement is achieved (500–1,000 mg of amphotericin B

deoxycholate or 1–3 wk of lipid formulation amphotericin),



8/33

followed by itraconazole 200 mg orally twice daily for 6 months(BIII) (58). Thus, it is difficult to gauge the optimal duration of lipid formulation amphotericin B treatment, since it is seldomused for the entire treatment course. Six to eight weeks of

amphotericin administration has been suggested depending ontreatment response, only by comparison to the treatment of other fungal infections.

Meningeal infections are also treated differently due to highprotein binding and poor CNS penetration of itraconazole. Therecommended treatment is amphotericin B deoxycholate ata dose of 0.7 mg/kg/day, to a total dose of at least 2 g (BIII) (58,65). Lipid formulations of amphotericin B may be used inpatients who cannot tolerate the standard deoxycholate formu-lation. Lipid formulations of amphotericin B have the theoret-ical benefit of higher brain tissue levels (versus amphotericin Bdeoxycholate) in animal models. There are case reports of suc-cessful retreatment of CNS blastomycosis with lipid formulationamphotericin B after failure of amphotericin B deoxycholate

(66, 67). Triazoles alone should not be used in blastomycoticmeningitis (CIII). However, combination therapy may be use-ful. High-dose fluconazole (400–800 mg daily, either intrave-nous or oral) can be used together with amphotericin Bdeoxycholate (or lipid formulation amphotericin B) from onset,or used in sequence after initial improvement. The time courseof fluconazole treatment should be extended to at least 6 months.Although fluconazole is less effective than itraconazole forpulmonary and nonmeningeal disseminated blastomycosis (68,69), it has been used for meningitis because of better CNSpenetration (CIII). Voriconazole, a newer triazole, is interme-diate between itraconazole and fluconazole in terms of CNSpenetration, and in animal models has efficacy against blasto-mycosis (70, 71). It is attractive conceptually as the triazole

component of a combination or sequential strategy for menin-gitis (CIII), but supporting clinical data is limited to individualcase reports and small series of patients (72, 73).

Treatment of Immunosuppressed Hosts

Blastomycosis in immunosuppressed patients is another settingin which the standard 6- to 12-month course of oral itraconazoleis often altered, again based on very limited specific data. Thebasic principle is that immunosuppressed patients have highermortality and likely require more aggressive and prolongedtherapy (56, 57). Recommended treatment for pulmonary andnonmeningeal blastomycosis in moderately immunosuppressedpatients, such as solid organ recipients, includes sequentialtherapy with amphotericin B deoxycholate (or liposomal

amphotericin B in cases of renal insufficiency or intolerance

of amphotericin B deoxycholate) until clinical improvement,followed by oral itraconazole 200 mg twice daily for a minimumof 12 months. In mild to moderate clinical infections, itracona-zole from the onset of therapy may be adequate. For patients

with AIDS, lifetime maintenance, such as with itraconazole, isnecessary unless immunity is fully restored, with CD4 lympho-cytes greater than 200/ml for 3 months (BII).

CNS involvement may also occur in immunosuppressedpatients, either isolated or more likely as part of widespreaddissemination. Mortality is high and treatment should be aggres-sive. Combination therapy is often used, again without specificsupporting data. One option is amphotericin B deoxycholate (orliposomal amphotericin B) together with high dose fluconazole(400–800 mg daily) from onset. The amphotericin B deoxycholate(or liposomal amphotericin B) component is continued to clinicalimprovement and then fluconazole is continued for at least anadditional 12 months. Lifetime maintenance therapy, such as withfluconazole, is recommended when AIDS without immune re-

constitution is the underlying immunosuppressive illness (AII).As discussed previously, liposomal amphotericin B has thetheoretical benefit of achieving higher brain tissue levels inanimal models and voriconazole has some attraction as a potentialtriazole component, but there are no disease-specific datacomparing one regimen to another (CII).

There are two other specific clinical circumstances that meritcomment. First, if CNS disease progresses on amphotericin Bdeoxycholate therapy or develops while a patient is being treatedwith itraconazole for pulmonary or non–CNS-disseminated dis-ease, then a change in strategy is warranted (64, 67, 69, 74). Areasonable but unproven regimen might be combination ther-apy with liposomal amphotericin B plus fluconazole 800 mgdaily to clinical improvement, followed by fluconazole for 6

months (immunocompetent), 12 months (immunocompromised/non-AIDS), or indefinitely (AIDS without satisfactory immunereconstitution) (BIII). Voriconazole 200 mg twice daily mightbe an alternative for fluconazole in the above regimen, based onpharmacokinetic properties and in vitro sensitivities (CIII).Surgical resection may play a role in some patients with fo-cal CNS disease, in combination with aggressive antifungalchemotherapy.

Second, patients with highly unstable pulmonary or dis-seminated blastomycosis who require advanced physiologicsupport (including mechanical ventilation, advanced oxygen-ation techniques, and vasopressors) have a guarded prognosis.Many have severe ARDS. A reasonable but unproven reg-imen might be amphotericin B deoxycholate or liposomal

amphotericin B plus itraconazole 200 mg twice daily until clinical

TABLE 4. TREATMENT RECOMMENDATIONS FOR BLASTOMYCOSIS

Disease Manifestation Treatment Recommendations Comments

Mild to moderately ill patients with pulmonary

and nonmeningeal disseminated blastomycosis

Itraconazole (200 mg twice daily for 24 wk) Monitor levels to insure absorption.

Consider liquid preparations.

Skin disease Itraconazole (200 mg twice daily for 24 wk) Monitor levels to insure absorption.


Bone disease Itraconazole (200 mg twice daily for 12 mo) Monitor levels to insure absorption.


Life-threatening severe blastomycosis,

including ARDS

Liposomal amphotericin B (5 mg/kg/d) or

amphotericin B (0.7–1.0 mg/kg/d) untilclinical improvement, then itraconazole

(200 mg twice daily for 6–12 mo)

Consider concurrent corticosteroids for

severe gas-exchange abnormalities.For immune-suppressed patients, treat for a

minimum of 12 mo and indefinitely for

AIDS without immune reconstitution.

Meningeal infection Liposomal amphotericin B (5 mg/kg/d) or

amphotericin B (0.7–1.0 mg/kg/d) until

clinical improvement, and concurrent or

sequential itraconazole (400 mg/d) or

fluconazole (400-800 mg/d) for 6–12 mo

For immune-suppressed patients, treat for

a minimum of 12 mo and indefinitely for

AIDS without immune reconstitution.



9/33

improvement, followed by oral itraconazole for 6 months (im-munocompetent), 12 months (immunocompromised/non-AIDS),or indefinitely (AIDS) (CIII). Voriconazole 200 mg twice dailymight be substituted for itraconazole in the above regimen,based on pharmacokinetic properties and in vitro activity (CIII).A role for corticosteroids for severe diffuse pulmonary diseaseis not proven, but they are sometimes used to try to improvesevere hypoxemia during the initial and most unstable period,together with mandatory appropriate antifungal therapy (75). In

addition, the use of glucocorticoids in immunocompromisedpatients with severe hypoxemia and diffuse infiltrates related toblastomycosis, such as in the setting of immune reconstitutioninflammatory syndrome, also remains poorly studied and con-troversial. As discussed above for histoplasmosis, the writinggroup felt that adjunctive corticosteroid doses in the range of 40–60 mg prednisone daily for 1 to 2 weeks was an appropriatelyconservative regimen if deemed useful on a patient-by-patientbasis (CIII).

Additional Treatment Considerations

1. Special consideration should be given for treating patientswith blastomycosis who are pregnant. In these patients,

amphotericin B is preferred over the azole agents. Ampho-tericin B and its lipid derivatives are rated class B forpregnancy, while fluconazole, itraconazole, and posacona-zole are classC drugs, and voriconazole isa class D drug (76).

2. The high efficacy of itraconazole for the great majority of blastomycosis cases has been proven in large clinical trialsthat will not likely be repeated with voriconazole or withnewer triazoles such as posaconazole, despite some the-oretical advantages for those newer agents in absorptionand tissue penetration. Since there likely will be noprospective studies comparing these agents to itracona-zole for either standard cases or in special situations suchas CNS disease, there also will likely be no strong

evidence-based guidelines forthcoming that will advancecurrent preferences beyond those outlined above.

3. Echinocandins likely have no role (either alone, incombination, or sequentially) in treatment of blastomy-cosis, even in situations warranting a nontraditional ap-proach (DIII). Although the echinocandins have someactivity in vitro, clinical efficacy of these agents againstBlastomyces has not been demonstrated (77).

4. The prostate, like the CNS, can serve as a sanctuary sitewith respect to itraconazole with its high protein binding.Lipid formulations of amphotericin B and newer triazoleswith less protein binding, sometimes in concert withsurgery, have been used successfully in some cases (CII).

Recommendations. IMMUNOCOMPETENT HOSTS. In patientswith mild to moderate pulmonary blastomycosis, we recom-mend oral itraconazole 200 mg twice daily for 6 months (AII).

In patients with severe pulmonary blastomycosis, we recom-mend amphotericin B 0.7–1.0 mg/kg/day daily until clinicalimprovement is observed (BII), followed by continuation of amphotericin B 0.7–1.0 mg/kg three times weekly, until a cumu-lative dose of 1.5–2.5 g is reached (BII). Once clinical improve-ment is observed, we suggest oral itraconazole 200 mg twicedaily for 6 months (BII).

Remarks. In patients with renal failure, lipid formulations of amphotericin are preferred.

Because patients with very severe blastomycosis have been

excluded from clinical studies that compared itraconazole to

amphotericin B, there is serious uncertainty about the relativeefficacy of itraconazole compared with amphotericin.

In patients with pulmonary blastomycosis and bone involve-ment, we suggest prolonging treatment with itraconazole to12 months (CII).

In patients with pulmonary blastomycosis and concomitantCNS involvement, we suggest:

d liposomal amphotericin B 0.7 mg/kg/day until a cumulative

dose of 2 g is reached (BII);d triazoles should not used as monotherapy for meningeal

blastomycosis (DII);

d high dose intravenous or oral fluconazole 400–800 mgdaily may be provided as an add-on therapy to intravenousamphotericin B in patients with severe or refractorydisease, with the total duration of fluconazole therapyextended for at least 6 months (BIII).

IMMUNOCOMPROMISED HOSTS. In patients with severe pulmo-nary blastomycosis without CNS involvement, we recommend am-photericin B 0.7 mg/kg/day until clinical improvement is observed(BII). Once clinical improvement is observed, we recommend oral

itraconazole 200 mg twice daily for at least 12 months (BII).In patients with mild to moderate pulmonary blastomycosiswithout CNS involvement, we suggest oral itraconazole 200 mg

twice daily for at least 12 months (BIII).When AIDS is involved, we suggest oral itraconazole

200 mg/day indefinitely or until immunity is fully restored (BII).In patients with pulmonary blastomycosis and concomitant

CNS involvement, we recommend:

d combined therapy with amphotericin B 0.7 mg/kg/day to-gether with intravenous or oral fluconazole 400–800 mg dailyfrom the onset until clinical improvement is observed (BIII).

d use of fluconazole for at least 12 months total afterdiscontinuation of combined intravenous treatment with

amphotericin B and high-dose fluconazole (BIII);d use of liposomal amphotericin B rather than amphotericin

B deoxycholate should be considered due to theoreticbetter CNS penetration (CIII);

d triazoles are not used as monotherapy (DII);

d patients with AIDS should continue to receive oralfluconazole 400 mg per day indefinitely or until immunityis restored (AII).

In patients with pulmonary blastomycosis with new orprogressing CNS involvement despite amphotericin B mono-therapy, we suggest:

d combined therapy with liposomal amphotericin B 5 mg/kg/dayuntil clinical improvement is observed, together with intra-venous or oral fluconazole 800 mg/day (CIII);

d fluconazole is used for at least 6 months in immunocom-petent patients, and at least 12 months in immunocom-promised patients, after discontinuation of combinedtreatment with amphotericin B and fluconazole (CIII);

d patients with AIDS receive oral fluconazole 400 mg dailyindefinitely or until immunity is restored (AII).

In some carefully selected patients with blastomycosis andfocal CNS lesions, consideration of surgical resection of the fo-

cal CNS lesions may occasionally be considered, if appropriate

expertise is available (CIII).



10/33

In critically ill patients with pulmonary blastomycosis, wesuggest:

d combined therapy with amphotericin B (0.7–1.0 mg/kgamphotericin B deoxycholate or 5 mg/kg daily liposomal

amphotericin B) until clinical improvement is observed,

together with oral itraconazole 200 mg/day (CII);

d following the initial intravenous therapy, oral itraconazoleis used for at least 6 months in immunocompetent patients,

and at least 12 months in immunocompromised patients,after discontinuation of combined treatment with ampho-

tericin B and itraconazole (CII);

d after initial therapy is complete, patients with AIDSshould receive oral itraconazole 200 mg/day indefinitely,

or until immunity is restored (CII). Voriconazole 200 mg

twice daily may be used as an alternative to itraconazole

(CIII).

In selected critically ill patients with severe pulmonaryblastomycosis, such as blastomycosis-associated ARDS, wesuggest consideration of adjunctive systemic glucocorticoste-roids (CIII). Prednisone 40–60 mg daily (or equivalent) for 1 to

2 weeks seems appropriate in these patients.In patients with pulmonary blastomycosis with new or

progressing CNS involvement despite amphotericin B mono-therapy, we suggest:

d combined therapy with liposomal amphotericin B 5 mg/kg/day until clinical improvement is observed, together with

intravenous or oral fluconazole 800 mg/day (CIII);

d fluconazole is used for at least 6 months in immunocom-petent patients, and at least 12 months in immunocom-

promised patients, after discontinuation of combined

treatment with amphotericin B and fluconazole (CIII);

d patients with AIDS receive oral fluconazole 400 mg daily

indefinitely or until immunity is restored (AII).d Voriconazole 200 mg twice daily may be considered as an

alternative to fluconazole, though extensive disease-spe-

cific data are currently lacking (CIII).

In some carefully selected patients with blastomycosisand focal CNS lesions, consideration of surgical resection of thefocal CNS lesions may occasionally be considered, if appropri-ate expertise is available (CIII).

In critically ill patients with pulmonary blastomycosis, wesuggest:

d combined therapy with amphotericin B (0.7–1.0 mg/kgamphotericin B deoxycholate or 5 mg/kg daily liposomal

amphotericin B) until clinical improvement is observed,together with oral itraconazole 200 mg/day (CII);

d following the initial intravenous therapy, oral itraconazoleis used for at least 6 months in immunocompetent patients,

and at least 12 months in immunocompromised patients,

after discontinuation of combined treatment with ampho-

tericin B and itraconazole (CII);

d after initial therapy is complete, patients with AIDSshould receive oral itraconazole 200 mg/day indefinitely,

or until immunity is restored (CII).

d Voriconazole 200 mg twice daily may be considered as analternative to itraconazole, though this is based largely on

in vitro sensitivities and limited case based data (CIII).

TREATMENT OF COCCIDIOIDOMYCOSIS

Coccidioidomycosis is caused by the soil-dwelling fungi Cocci-dioides immitis and Coccidioides posadasii that are localized torelatively arid regions of the Western hemisphere. The areas of highest endemicity in North America are the San JoaquinValley of California, the south-central region of Arizona, andnorthwestern Mexico. The vast majority of cases of coccidioi-domycosis are acquired by inhalation. Approximately 60%of infections are asymptomatic (78). Many of the remainderare associated with a pulmonary syndrome resembling othercommunity-acquired pneumonia (CAP) syndromes or an upperrespiratory tract infection. Acute pulmonary coccidioidomyco-sis may be distinguished from CAP by its lack of responseto antibacterial therapy, and sometimes by hilar adenopathy,peripheral blood eosinophilia, severe fatigue, night sweats, andthe presence of erythema multiforme or erythema nodosum.The diagnosis can be established by the presence of anticocci-dioidal antibody in the serum, measurable by ELISA, immu-nodiffusion, or by tube precipitin and complement fixationassays. The diagnosis can also be established by the identifica-tion of coccidioidal spherules in tissue or by isolating the fungusby culture from a clinical specimen. Because acute primarypulmonary coccidioidomycosis is frequently self-limited, manycases appear to respond to antibacterial antibiotics and areconsequently misdiagnosed as CAP. In endemic regions, coc-cioidomycosis may be responsible for nearly one-third of patients presenting with lower respiratory tract symptoms (79).

Immunocompetent Patients

Most cases of primary pulmonary coccidioidomycosis in individ-uals without identified risk factors are self-limited and do notrequire treatment (BIII) (Table 5) (78). Therapy of primarypulmonary coccidioidomycosis should be considered when symp-toms persist for more than 6 weeks or for especially severe acutedisease (80). The principles of therapy in this group are identicalto those discussed next for treatment of immunosuppressed

patients and other patients at risk for disseminated disease.Immunosuppressed Patients and Others at Risk

for Disseminated Disease

Therapy for primary pulmonary coccidioidomycosis should beconsidered for patients with impaired cellular immunity, such asthose with solid-organ transplants, those with HIV infectionwith peripheral blood CD4 cell counts less than 200/ml, and inthose with co-morbidities likely to be adversely affected byongoing primary infection, such as chronic lung disease, chronicrenal failure, or congestive heart failure (BIII) (Table 5).Patients receiving TNF-a inhibitor therapy are also at increasedrisk for developing symptomatic coccidioidomycosis (81). Pa-tients with diabetes mellitus are likely to develop chronic

pulmonary coccidioidomycosis, particularly cavitary disease,and require close monitoring, with clinical assessment andradiography every 1 to 2 months until the cavity resolves orstabilizes (82). Cavitary disease can be complicated by hemop-tysis, which independently represents an indication for therapy.All patients with primary pulmonary coccidioidomycosis shouldbe followed for at least 1 year to assure complete resolution andabsence of complications (BIII). A small fraction of patientsdevelop persistent pulmonary disease or dissemination. Patientswith solid-organ transplants and those with HIV infection anddepressed CD4 cell counts are at particularly high risk fordissemination. African-American and Filipino-American menare also at increased risk for developing disseminated coccidi-oidomycosis, as are pregnant women who experience coccidioi-

dal infection during the second or third trimester (83). The most



11/33

common sites of disseminated coccidioidomycosis are the skin,soft tissues, bones and joints, and the meninges. A lumbarpuncture with analysis of cerebrospinal fluid should be done inany patient with primary coccidioidomycosis presenting withheadache, blurry vision, photophobia, meningismus, or anyother CNS symptom, and should be considered in any patientwho is severely ill or not likely to be subsequently followed.

Persistent pulmonary disease comprises nodules, cavities,

and chronic infiltrates. Coccidioidal nodules are usually asymp-tomatic, presenting a problem only in distinguishing them frommalignancies, and generally require no treatment. Cavities mayoccasionally be associated with pleuritic chest pain, productivecough, or hemoptysis. Patients with cavities should be consid-ered for therapy, especially when hemoptysis is present, or withprogressive enlargement of the cavity (BIII). Chronic pulmo-nary coccidioidomycosis, defined as symptoms ongoing for morethan 3 months, frequently occurs in patients with underlyinglung disease and should be treated (BIII).

All forms of disseminated coccidioidomycosis require anti-fungal therapy (AIII). Meningitis represents a special situationbecause currently available azole antifungal therapy should becontinued throughout a patient’s lifetime (AII) (84), given the

extremely high relapse rate. Intravenous amphotericin B deox-ycholate is considered ineffective for coccidioidal meningitis,but intrathecal amphotericin B has a role in its management incases of azole therapy failure, or when a more rapid response isdesired (AII) (85). Because of the risk of hydrocephalus andother complications even in the face of appropriate antifungaltherapy, an expert should be consulted in the management of coccidioidal meningitis (BIII) (82).

Antifungal therapy for chronic coccidioidomycosis is gener-ally prolonged, with a minimum course of 12 to 18 months (AII)(86–88). Courses beyond 18 months should be considered inpatients with underlying immunocompromising conditions. De-clining titers of serum anticoccidioidal antibody indicate treat-ment effectiveness. Available agents for the treatment of

coccidioidomycosis include azole antifungals and amphotericin

B. The echinocandin class of antifungals has not been adequatelyassessed in coccidioidomycosis, but does not appear to possessefficacy. Azole antifungals that are well studied in coccidioido-mycosis include ketoconazole, fluconazole, and itraconazole.There are small series and case reports suggesting efficacy of voriconazole and posaconazole in recalcitrant cases of coccidi-oidomycosis (18, 89–91). Ketoconazole has been largely sup-planted by fluconazole and itraconazole, and the latter has

greater efficacy than fluconazole for bone and joint coccidioido-mycosis (AI) (87). When fluconazole and itraconazole areemployed, the minimum dose is 400 mg/day (BII) (86–88).

Amphotericin B is currently reserved for the most severecases of coccidioidomycosis or those that do not respond toazoles (AIII). Although there is no evidence that the newer lipidformulations of amphotericin B possess any greater efficacy thanthe conventional amphotericin B deoxycholate preparation, thelipid formulations are better tolerated and allow treatment witha reduction in renal and other toxicities (BIII).

Recommendations. IMMUNOCOMPETENT HOSTS. In most immu-nocompetent patients with primary pulmonary coccidioidomy-cosis and no additional risk factors for dissemination, wesuggest no antifungal treatment (BII).

Remark. Additional risk factors for dissemination includeCOPD or other chronic structural lung disease, chronic renalfailure, congestive heart failure, diabetes mellitus, pregnancy,African-American or Filipino-American heritage, HIV, andthose patients receiving TNF-a antagonists.

In immunocompetent patients with primary pulmonary coccid-ioidomycosis and moderate to severe symptoms, or those in whomsymptoms persist for more than 6 weeks, we suggest treatmentwith triazole antifungal drugs for at least 3 to 6 months or longer if symptoms and radiographic abnormalities persist (BII).

IMMUNOCOMPROMISED HOSTS AND OTHERS AT RISK FOR DISSEM-INATED DISEASE. Therapy for primary pulmonary coccidioido-mycosis should be considered for patients with impaired cellularimmunity, such as those with solid organ transplants, those with

HIV infection with peripheral blood CD4 cell counts less than

TABLE 5. RECOMMENDED INITIAL THERAPY FOR COCCIDIOIDOMYCOSIS

Disease Manifestation Nonimmunocompromised Host Immunocompromised Host

Primary pulmonary No therapy in most; fluconazole (400 mg/d)

or itraconazole (400 mg/d) for 3–6 mo

in selected cases.*

Fluconazole (400 mg/d) or itraconazole (400 mg/d)

for 3–6 mo or longer depending on clinical response.

Pulmonary nodule No therapy. Consider fluconazole (400 mg/d) or itraconazole (400 mg/d)

during periods of significant immune suppression.

Pulmonary cavity No therapy. Consider therapy in some cases†;

in those consider fluconazole (400 mg/d) or

itraconazole (400 mg/d) for 3–6 mo or longer until cavity and symptoms stabilize.

Fluconazole (400 mg/d) or itraconazole (400 mg/d)

for 12–18 mo or longer until cavity and symptoms stabilize.

Diffuse pulmonary Liposomal amphotericin B (5 mg/kg/d) or

amphotericin B (0.7–1.0 mg/kg/d) until clinical

improvement, followed by fluconazole (400 mg/d)

or itraconazole (400 mg/d) for at least another year.

Liposomal amphotericin B (5 mg/kg/d) or amphotericin

B (0.7–1.0 mg/kg/d) until clinical improvement, followed

by fluconazole (400 mg/d) or itraconazole (400 mg/d)

for at least a year. ‡For ongoing immune suppression

consider long-term maintenance with azole.

Disseminated, nonmeningeal

(including bone disease)

Fluconazole (400 mg/d) or itraconazole‡ (400 mg/d)

for at least a year and until clinical improvement

and stabilization; in severe cases, liposomal

amphotericin B (5 mg/kg/d) or amphotericin

B (0.7–1.0 mg/kg/d) until clinical improvement

followed by fluconazole (400 mg/d) or itraconazole

(400 mg/d) for at least another year.

Fluconazole (400 mg/d) or itraconazole‡ (400 mg/d)

for at least a year and until clinical improvement and stabilization.

In severe cases, liposomal amphotericin B (5 mg/kg/d)

or amphotericin B (0.7–1.0 mg/kg/d) until clinical

improvement followed by fluconazole (400 mg/d)

or itraconazole (400 mg/d) for at least another year.

Meningitis Fluconazol e (400–1,000 mg/d) or itraco nazole

(400–600 mg/d) for life; intrathecal amphotericin

B in some cases.

Fluconazole (400–1000 mg/d) or itraconazole (400–600 mg/d)

for life; intrathecal amphotericin B in some cases.

* Moderate, severe, or prolonged infection (. 6 wk), or for patient factors including chronic obstructive pulmonary disease, chronic renal failure, congestive heart

failure, diabetes mellitus, and certain ethnicities and demographic factors as discussed in the text.† In cases in which persistent productive cough or hemoptysis, continued pleuritic chest pain, or increasing size of cavity occurs or rising serologic titer.‡ Itraconazole preferred for bone disease.



12/33

200/ml, and in those with comorbidities likely to be adverselyaffected by ongoing primary infection, such as chronic lungdisease, chronic renal failure, or congestive heart failure, orthose receiving TNF-a antagonists (BII).

In patients with primary coccidioidomycosis presenting withneurologic symptoms, we recommend lumbar puncture with anal-ysis of cerebrospinal fluid for presence of Coccidioides spp. (BII).

Remark. Symptoms that may prompt performing analysis of cerebrospinal fluid for presence of Coccidioides spp. include

headache, blurry vision, photophobia, meningismus, and otherneurologic symptoms.In many patients with pulmonary coccidioidomycosis and

pulmonary nodules only, we suggest consideration of observa-tion for at least 1 year without antifungal treatment. However,fluconazole (400 mg/d) or itraconazole (400 mg/d) may beconsidered during periods of significant immune suppression(i.e., chemotherapy, systemic corticosteroid therapy, or CD4counts , 250/ml) (CII).

In patients with pulmonary coccidioidomycosis and pulmo-nary nodules who have additional risk factors for disseminateddisease, patients with cavities, and those presenting withhemoptysis, we suggest treatment with triazole antifungal drugs,either fluconazole (400 mg/d) or itraconazole (400 mg/d) (BII).

Remark. Additional risk factors for more severe disease in-clude COPD or other chronic structural lung disease, chronicrenal failure, congestive heart failure, diabetes mellitus, preg-nancy, African-American or Filipino-American heritage, HIV,and those patients receiving TNF-a antagonists.

Azole therapy for chronic pulmonary coccidioidomycosis (nod-ules or cavities with symptoms . 3 mo) is generally prolonged,with a minimum course of 12 to 18 months or longer until thecavities and symptoms stabilize (BIII).

For diffuse pulmonary coccidioidomycosis with significantimpairment of gas exchange, we recommend initial liposomalamphotericin B (5 mg/kg/d) or amphotericin B (0.7–1.0 mg/kg/d)until clinical improvement, followed by fluconazole (400 mg/d)or itraconazole (400 mg/d) for at least another year (BIII). In

patients with ongoing immune suppression, azole therapy maybe continued indefinitely.

All patients, whether immunocompetent or immunocom-promised, with any form of disseminated coccidioidomycosisrequire treatment. For nonmeningeal disseminated disease, werecommend treatment with fluconazole (400 mg/d) or itracona-zole (400 mg/d) for at least a year and until clinical improve-ment and stabilization (BII). Itraconazole is preferred in bonedisease. In severe or refractory cases, liposomal amphotericin B(5 mg/kg/d) or amphotericin B (0.7–1.0 mg/kg/d) may be initiateduntil clinical improvement, followed by fluconazole (400 mg/d) oritraconazole (400 mg/d) for at least another year (BIII).

In patients with meningitis, we recommend fluconazole(400–1,000 mg/d) or itraconazole (400–600 mg/d) for life (BII).

In patients with meningitis in whom treatment with triazoleantifungal drugs failed, we suggest consideration of intrathecalamphotericin B in selected cases (BIII).

Remark. We suggest that patients with disseminated coccid-ioidomycosis and meningitis be managed in conjunction withclinicians with appropriate expertise in the treatment of cocci-dioidal meningitis (BIII).

TREATMENT OF PARACOCCIDIOIDOMYCOSIS

Paracoccidioidomycosis is caused by the dimorphic fungus Para-coccidioides brasiliensis. The organism is endemic in certainparts of South and Central America, including Mexico, but doesnot involve the Caribbean or any part of the United States. The

presumed pathogenesis is via inhalation of airborne spores,

leading to pulmonary and disseminated disease. This disease ismore common among male patients, and many infected in-dividuals are manual laborers, suggesting that exposure isoccupation-dependent.

The majority of diagnosed patients present with dissemi-nated disease, involving lymph nodes producing painful muco-cutaneous ulcers. The infection may also present as a chronic,tuberculosis-like infection with low-grade fever, weight loss, andupper zone infiltrates on chest radiogram. The less common

juvenile form produces a rapidly progressive pulmonary diseasewith multiple areas of infiltrates, hepatosplenomegaly, andadenopathy. The infection may occur as an opportunistic in-fection in patients with HIV and/or AIDS, in which case it is isusually widely disseminated.

Information regarding treatment of paracoccidioidomycosisis limited to case series and one randomized study. Critically illpatients are usually treated with amphotericin B, either as thedeoxycholate or a lipid formulation (BIII). The more slowlyprogressive form of the infection may be treated with ketoco-nazole 200–400 mg daily, itraconazole 100–400 mg daily, orsulfadiazine 4–6 g daily. The last three agents were shown to besimilarly effective (BII) (92, 93).

Recommendations. In critically ill patients with disseminated

paracoccidioidomycosis, we recommend initial amphotericin B(0.7–1 mg/kg/d) therapy until clinical stabilization or until 2 gtotal dose administered (BI). This may be followed by azoletherapy as listed below.

In patients with disseminated paracoccidioidomycosis andmild to moderate or slowly progressive symptoms, we recom-mend one of the following options until clinical stabilization andresolution of symptoms (BII). The total duration of therapymust be individualized to clinical response, but generallytherapy for 6 to 12 months or longer is employed. Potentialregimens include:

d ketoconazole 200–400 mg daily

d itraconazole 100–400 mg daily

d sulfadiazine 4–6 g daily

TREATMENT OF CRYPTOCOCCOSIS

The most common cause of cryptococcosis is Cryptococcusneoformans. The closely related organism Cryptococcus gattii(previously C. neoformans var. gattii) is emerging as an impor-tant pathogen in the Pacific Northwest of the United States andVancouver Island in Canada, as well as tropical or subtropicalclimates such as Africa, India, Papua New Guinea, SouthAmerica, and Australia (94). Cryptococcus is a basidiomycetousyeast that occurs in a minimally encapsulated form in natureand rapidly synthesizes a polysaccharide capsule upon entering

the pulmonary environment (95). C. neoformans commonlyproduces disease in immunocompromised hosts, and patientswith AIDS are particularly susceptible. By contrast, C. gattiimore commonly infects immunocompetent hosts in uniquegeoclimatic regions (96–98).

Immunocompetent Hosts

While meningitis is the most serious and common manifestationof cryptococcosis, pulmonary disease occurs in both immuno-competent and immunocompromised individuals. Skin, pros-tate, eye, and bone infections are the most common secondarysites of infection (97). In immunocompetent patients, thepulmonary manifestations include asymptomatic colonization,often in patients with underlying structural lung disease (99,

100). In symptomatic patients, the most common abnormalities



13/33

are pulmonary nodules, masses, or interstitial pneumonitis(100–102). However, pleural effusions, adenopathy, and evensevere ARDS can occur with large fungal burdens (100, 103).

In immunocompetent patients that are asymptomatic andsimply colonized with C. neoformans (asymptomatic with noevidence of disease), specific therapy may not be necessary(Table 6) (104) (AII). Although pulmonary cryptococcosis mayresolve spontaneously, it may be difficult to define whichpatients are truly immunocompetent, or who may becomeimmunosuppressed in the future. Since pulmonary cryptococ-

cosis occasionally disseminates, it is prudent to treat infectedpatients with fluconazole (oral and nontoxic), and close follow-up is recomm