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Fungal infections for the community provider

April 25, 2014Peter V. Chin-Hong M.D.

Infectious Diseases UCSFpeter.chin-hong@ucsf.edu

UCSF

CaseA 38-year-old African-American female financial analyst is referred to you for asthma exacerbation. She reports shortness of breath with frequent expectoration of brownish plugs. Albuterol inhalers are only minimally helpful. She has had hemoptysis in the past.Temperature is 38.3°C. Chest with minimal wheezing. Her serum total IgE > 1000 ng/ml, she has a twofold elevation in specific anti-Aspergillus fumigatus IgE and IgG.

CaseWhich of the following should you recommend?

A. Albuterol nebulizers every six hoursB. Prednisone taper over 3-6 monthsC. Voriconazole D. Itraconazole

CaseWhich of the following should you recommend?

A. Albuterol nebulizers every six hoursB. Prednisone taper over 3-6 monthsC. Voriconazole D. Itraconazole

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Allergic bronchopulmonary Aspergillosis (ABPA)

Hypersensitivity reaction to noninvasive Aspergillus in the airwaysRepeated inflammation and mucoid impaction in airways can lead to bronchiectasisMay affect up to 5% of asthma patients

Mild bronchiectasis

Allergic Bronchopulmonary Aspergillosis (ABPA).

• Rx: Steroids ±itraconazole

Pulmonary Aspergilloma.• Rx: Surgery ±

itraconazole

Invasive Aspergillosis.• Rx: Voriconazole or

posaconazole or caspofungin or amphotericin

A

CaseYou see a 32 year

old woman with AML in your office with low grade fevers to 101, hemoptysis and increasing subcutaneous nodules

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CaseWhat would you do at this time?

A. AdmitB. Fine needle aspirationC. FNA and admitD. Voriconazole and return to clinic if worse

CXR HD#2

She becomes acutely short of breath after receiving some blood products

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SFGH mycology 10/00Aspergillus fumigatus

EpidemiologyAspergillus: Risk Factors

Diagnosis %Bone marrow transplant

Autologous 7Allogenic 25

Hematologic diseaseLeukemia/Lymphoma 29

Solid organ transplant 9AIDS 8Solid organ tumor 4Chronic granulomatous disease 2Other pulmonary disease 9

EpidemiologyAspergillus: Outcomes: Mortality

Risk group Fatality rate (%)Bone marrow transplant (BMT) 87Leukemia/Lymphoma 49AIDS 86Neutropenia (

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“Halo sign”

Medical Mycology:The Last 50 Years

5-FC MiconazoleKetoconazole

FluconazoleItraconazole

L-AmBABCDABLC Terbinafine

# of drugs

Dismukes WE, Clin Infect Dis 2006; 42:1289-96

Amphotericin B +/- OLATVoriconazole +/- OLAT

TreatmentVoriconazole: Global Comparative Aspergillosis Study

Number of Days of Treatment

Prob

abili

ty o

f Sur

viva

l

Hazard ratio = 0.59 ( 95% CI 0.42-0.88)

Survival at wk 12VORI OLAT 70.8%AmB OLAT 57.9%

Herbrecht et al. NEJM 2002: 347OLAT: Other Licenced Antifungal Therapy

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QuestionWhich of the following is voriconazole not

associated with?

A. Seeing white flashesB. Seeing Star Wars charactersC. Skin cancerD. Renal toxicity

VoriconazoleCancer

Arch Dermatol. 2010;146(3):300-304 J Am Acad Dermatol. 2010 Jan;62(1):31-7

Kontoyiannis et al, JID, 2005

Voriconazole available

AspergillusAllergic Bronchopulmonary Aspergillosis (ABPA).

• Rx: Steroids ±itraconazole

Pulmonary Aspergilloma.• Rx: Surgery ±

itraconazole

Invasive Aspergillosis.• Rx: Voriconazole or

posaconazole or caspofungin or amphotericin

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BMidwest, SE USA; Central and South America, AfricaLung (most common), dissemination to skin (like basal cell CA), bonesBlastomycosis

Itraconazole is drug of choice for blastomycosis

• Amphotericin B• Prior to 1980s, amphotericin B was drug of

choice. Cure rates up to 97% with 2g total dose. Significant toxicity.

• Azoles have replaced amphotericin B as therapy of choice• Itraconazole cure rates 90-95%. Less toxic

than ketoconazole and amphotericin. Few relapses.Dismukes WE et al, Am J Med 1992; 93:489-97

Ohio and Mississippi River Valleys; Central and South America; Bird and bat droppingsLung (most common), dissemination, hepatosplenomegaly, oral ulcers…Histoplasmosis

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Itraconazole is drug of choice for most with histoplasmosis

• Amphotericin B• Prior to 1980s, amphotericin B was drug of

choice. Cure rates up to 57-100% depending on disease. Significant toxicity.

• Azoles have replaced amphotericin B as therapy of choice• Itraconazole cure rates 90-95%. Less toxic

than ketoconazole and amphotericin. Few relapses.Dismukes WE et al, Am J Med 1992; 93:489-97

Mexico, south to ArgentinaLungs, painful mouth ulcers, skin, can mimic TBMales >>> femalesParacoccidiodomycosis

Case49 year-old gardener comes to see you in clinic with a progressive rash1 week ago noticed a papule on the 4th finger which ulceratedNow more nodular lesions have developed proximally

CaseAfter no help with multiple courses of antibiotics, what is your next step?

A. More antibioticsB. Empiric antifungalsC. Referral for biopsyD. Reassurance

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WorldwideContact with soil or decaying wood; gardeningBegins as a hard nontender subcutaneous nodule then more nodules along lymphatics; can disseminateSporotrichosis

C

Case25 year-old Filipino-American runner comes to see you in clinic with fevers, cough, malaise for 4 weeksNo help with azithromycin for a 5 day course, followed by levofloxacinFamily lives in the Central Valley, California, and the patient visits often

Southwest USA, Mexico, Central and South AmericaFlu-like illness, lung, dissemination to CNS (meningitis), bone, skinErythema nodosum in someCoccidioidomycosis

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Dramatic increase in Valley Fever 1998-2011

CDC looked at incidence of coccidioidomycosis from 1998-2011Incidence increased from 5 cases per 100,000 in 1998 in endemic area to 43 cases per 100,00040% require hospitalization

MMWR 2013

Fresno dust storm

Coccidioidomycosis

Fiese MJ. Proc Symp Cocci, Phoenix, Feb 11-13, 1957 & Cal Med 1957; 86:119-20.

Pre-Rx post 3 mos RX

Cocci for 7 years with severe exacerbation in January 1956.

Rx: amphotericin B 2.4 g orally per day.

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Itraconazole and Fluconazole are both effective for cocci

• Amphotericin B was drug of choice for 50 years with cure rates up to 70%. • No clinical trials• Use as initial treatment for severely ill

• Itraconazole cure rates 63-75%. Preferred azole for skeletal disease.

• Fluconazole cure rates 50-67%. Preferred azole for meningitis. Treat for life.

Galgiani JN et al, Ann Intern Med 2000; 133:676-86

Galgiani JN et al, Ann Intern Med 2000; 133:676-86

C

WorldwideSoil and dried pigeon dungLung, dissemination in immunocompromised hosts (skin, CNS); most common cause of fungal meningitis…Can be first AIDS-defining illness Cryptococcosis

Use amphotericin plus flucytosine in AIDS patients with crypto

• Earlier studies showed lower dose of amphotericin (0.4mg/kg/day) plus 5-FC (150mg/kg/day) for 6 weeks cured 67% non-HIV

• First AIDS studies (RCT) showed amphotericin (same dose) vs fluconazole monotherapy for 10 weeks only successful in 40% vs 34% (P=NS)

Bennett JE et al, N Engl J Med 1979; 301:126-31

Saag MS et al, N Engl J Med 1992; 326:83-9

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Use amphotericin plus flucytosine in AIDS patients with crypto

• Amphotericin (0.7mg/kg/day) plus 5-FC (100mg/kg/day) vs amphotericin X 2 weeks. CSF neg in 60% vs 51% (P=0.06). No difference in mortality (overall 5.5%).

then• Fluconazole (400mg/day) vs. itraconazole

(400mg/day) X 8 weeks. Overall mortality 3.9%. No difference in CSF sterilization.

Van der Horst et al, N Engl J Med 1997; 337:15-21

Other key crypto studies• Maintain AIDS patients on fluconazole

200mg PO daily• Relapse 4% (FLU) vs 23% (ITRA)

• Mortality associated with opening pressure >250mmHg• 21% 350mmHg

• Stop maintenance if CD4>100 on HAART (6 mo)

Saag MS et al, Clin Infect Dis 1999; 28:291-6

Graybill JR et al, Clin Infect Dis 2000; 30:47-54

Vibhagool A et al, Clin Infect Dis 2003; 36:1329-31

Case31 year old with AIDS CD4 157, VL

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Cryptococcus immune reconstitution inflammatory syndrome (IRIS)

• Can occur in up to 30% of patients with a history of cryptococcus after starting HAART

• Usually within 30 days after initiating HAART• Can have higher CSF cryptococcal antigen

titers and opening pressures• Usually treated with amphotericin followed by

fluconazole• Treatment outcomes better in IRISShelburne SA et al, Clin Infect Dis 2005; 40:1049

Haddow LJ et al, Lancet ID 2010; 10:791

Cryptococcus gattiiCompared to C. neoformans, C. gattii occurs in immunocompetent and has more brain lesions

Clinical Infectious Diseases 2009;49:591–595

C

Case

A 43 year-old previously healthy woman sees you in clinic s/p discharge from the hospital for bowel perforation repairShe was treated with broad-spectrum antibiotics for two weeks then dischargedYou note that the patient is febrile with T39, HR 130, BP 120/80

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QuestionWhich of the following organisms would you most

be worried about as you prepare the ED accepting physician with the sign out?

A. Candida albicansB. Candida non-albicans sppC. CitrobacterD. Coagulase negative Staphylococcus

EpidemiologyCandidemia

• Candida now the 4th most common isolate recovered from blood cultures in the US

• Half of all Candida infections occur in surgical ICUs

• Transmission can occur from patient to patient and from health care worker to patient

• Significant shift in infection caused by non-albicans spp of Candida

Nosocomial Bloodstream Infections in 49 US Hospitals

* Surveillance and Control of Pathogens of Epidemiologic Importance.Adapted with permission from Edmond et al. Clin Infect Dis. 1999;29:239-244.

The SCOPE* Program (1995-1998)

1 Coagulase-negative staphylococci 3908 31.9 21

2 Staphylococcus aureus 1928 15.7 25

3 Enterococci 1354 11.1 32

4 Candida species 934 7.6 40

No. of CrudeRank Pathogen Isolates % Mortality (%)

UCSF

Azarbal F et al, 2011

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EpidemiologyCandidemia: Risk Factors

Use of antibioticsIndwelling cathetersHyperalimentationCancer chemotherapyImmunosuppressive rx post-transplantICU hospitalizationCandiduriaColonization with Candidal spp

Candida spectrum

• Oral

• Esophageal

• Vaginal, Balanitis

• Candidemia

• Other: Eye, Spleen, Liver, Endocarditis

• Not usually: Lungs, Urine

Macular abscess with “string of pearls” inferiorly.

Vose M et al. Postgrad Med J 2001;77:119-120

Copyright © The Fellowship of Postgraduate Medicine. All rights reserved.

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Candida Infection (non bloodstream)Treatment pearls

• Don’t routinely prophylax (resistance may develop)

• For treatment, fluconazole 100mg po qd• If no response, can use up to 800mg/day• Alternatives: itraconazole po 200mg/day,

voriconazole po 200mg/day, amphotericin IV 0.3 mg/kg/day, caspofungin 70mg IV X 1 then 50mg IV qd.

Bartlett J and Gallant JE. Medical Management of HIV Infection, 2006 ed.

D

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Dermatophyte pearls• Scrape your patient’s skin and add KOH to

the slide• Most dematophytes can be treated by topical

antifungals or oral agents (terbinafine, fluconazole, itraconazole)

• except oral medication will be needed for tinea capitis and tinea versicolor

• Treatment is generally for 2-4 weeks (1 dose usually enough for tinea versicolor)

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Bonus case

Patient with meningitis 19 days following epidural steroid injection at an ambulatory surgery center

Lab calls you about this weird fungus

What is this?

QuestionWhich of the following has been in the news as the

main organism associated with injection of epidural steroids?

A. AspergillusB. ExserohilumC. RhizopusD. Candida

Exserohilummeningitis, United States

Multistate outbreak of fungal meningitis associated with three lots of preservative‐free methylprednisolone acetate (80mg/ml) from the New England Compounding Center (NECC) that were recalled on September 26, 2012. The potentially contaminated injections were given starting May 21, 2012. CDC 10/23/13.

Exserohilum what?• Dermatiaceous (pigmented) 

mould• Lives on grass and in soil• Can cause disease in 

immunocompetent• In vitro susceptibility to 

Amphotericin B, voriconazole, itraconazole, caspofungin

• CDC recommends voriconazole +/‐ lipsosomalAmphotericin B

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Z

Case•Patient with DKA, renal failure, immunosuppressed•Black necrotic lesions of nose with invasion•Broad, branching, non-septate hyphae•Almost 100% mortality in immunosuppressed•Rx: Surgery and Ampho•Zygomycosis

Zygomycosis

Fungus MortalityRisk group Fatality rate (%)Aspergillosis 45-54Non-Aspergillus hyalohyphomycetes 80

(Scedosporium spp, Fusarium spp)

Zygomycosis 100(Rhizopus, Mucor)

Phaeohyphomycosis 20

Candida 29

Hussain et al, CID 2003:37 Pappas, ICAAC 2003

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Kontoyiannis et al, JID, 2005

Voriconazole available

ABCD and Z

Take home points -Aspergillus

•Aspergillus can cause a spectrum of disease

•Think of ABPA in patient with wheezing and refractory disease

•Treatment of choice for ABPA is steroids

•Invasive Aspergillosis is a rare disease but is important to recognize patients at risk

•Voriconazole is the most effective agent for invasive disease

•Important complications seen with voriconazole

•Amphotericin will also work but limited by toxicity

•Key challenge in the future remains better diagnostic strategies

Take home points – Blasto and others

Think of geography and epidemiology in your patients with strange pulmonary and skin findings:

Blastomycosis: Histoplasmosis:Penicillium marneffei:

Sporotrichosis:

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Take home points - Cocci•Increasing in incidence –so coming soon to a clinic near you

•Think of coccidioidomycosis in a person from an endemic area with a pneumonia that is not improving with antibiotics

•Disseminated disease to bones and CNS can occur

•Latinos, Asians particularly at risk for disseminated disease

•Low threshold to call your favorite ID consultant for help

Take home points - Crypto•May be the most common AIDS defining illness in some parts of the world

•Use Amphotericin and 5-FC as first line therapy in patients with AIDS

•Watch out for cryptococcal IRIS, especially in patients with a history of cryptococcal meningitis put on ART

•Most cases of cryptococcal IRIS occur within 4 weeks after starting ART

Take home points - Candida•Infections due to Candida species are the most common fungal infections

•There is a broad range of infections possible from oral thrush to invasive candidiasis that may involve any organ

•Candidal spp are the 4thmost frequent cause of nosocomial bloodstream infections but comprise a disproportionate mortality (40%)

•Early recognition is key –think of the risk factors of candidiasis

•There has been a recent trend of non-albicans spp

Take home points –Dermatophytes

• Scrape your patient’s skin and add KOH to the slide

• Most dematophytes can be treated by topical antifungals or oral agents (terbinafine, fluconazole, itraconazole)

• except oral medication will be needed for tinea capitis and tinea versicolor

• Treatment is generally for 2-4 weeks (1 dose usually enough for tinea versicolor)

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Take home points -Zygomycosis

•Invasive Zygomycosis is a rare but fatal disease and is increasing

•Traditional risk group: DKA, now BMT and other transplant patients

•Diagnosis is tough like all the invasive mycoses. Get a biopsy

•Voriconazole is not effective. Only amphotericin as backbone

•Key challenge in the future remains better diagnostic strategies