Candidemia

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Candidemia

• Pola de la Torre, M.D.
• Assistant Professor of Medicine
• Division of Infectious Diseases

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History

• Oral lesions that were probably thrush described
  in the era of Galen and Hippocrates.
• 1839 Langenback found fungi in oral lesions.
• 1841 Bergen established the fungal etiology of
  thrush.
• 1843 Robin gave the name Oidium albicans.

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History

• 1861 Zenker described the first case of
  deep-seated Candida.
• 1890 Zopt named Monilia albicans
• 1923 Berkhout named C. albicans
• 1940 first case of Candida endocarditis
• 1940s increasing antibiotic use

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The Organism

• Thin-walled ovoid cell of 4-6 µm that reproduces
  by budding.
• Yeast (fungi) exist mostly in unicellular form.
• Grows well in routine blood cultures and on agar
  plates.
• Under the microscope yeast forms, pseudohyphae,
  hyphae (10KOH, Gram stain).

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The Organism

• More than 150 species of Candida.
• Those that are most frequently associated with
  human disease C. albicans, C. glabrata, C.
  parapsilosis, C. tropicalis, C. krusei, C.
  lusitaniae, C. dubliniensis, C. rugosa, C.
  guilliermondii.

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The Organism

• Germ Tube Formation
• -Rapid presumptive identification
• -Organism placed in serum and observed
• for germ tube formation (appears within
  90 minutes)
• -Both false and can occur.
• -If , think C. albicans or C. dubliniensis
  (does not grow at 45).
• Also, chlamydospore formation.
• -If -, think others.

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Epidemiology

• Normal commensals of humans normally found
• -On skin
• -Throughout the GI tract
• -In expectorated sputum
• -In the female GU tract
• -In the urine of patients with chronic Foleys
• Majority of infections caused by Candida are
  endogenous although human-to-human transmission
  is possible.

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Epidemiology

• Invasive mycotic disease trends in the USA
  1980-1997
• -Cause of death 10th to 7th
• -Annual number of deaths where invasive
• mycoses listed on death certificate
• (multiple-cause mortality) 1557 to 6534.
• -Rates of MC mortality for different
• mycoses varied according to HIV status
• BUT consistently higher among men, blacks,
• age 65.

CID. 2001 33 641-7.
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Epidemiology

• The Surveillance and Control of Pathogens of
  Epidemiological Importance (SCOPE) prospective
  study analyzed 24,179 nosocomial bloodstream
  infections throughout the USA from 3/2005-9/2002.
• -Approximately 51 in ICU
• -9 of isolates Candida species
• -Most frequent predisposing factor
• -Intravascular device

CID. 200439 309-17.
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Epidemiology

• Risk factors for Candida BSI
• -Broad spectrum antibiotics
• -Corticosteroids
• -Chemotherapeutic agents
• -Malignancy
• -Neutropenia
• -Extensive intra-abdominal surgery

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Epidemiology

• -Burns
• -Mechanical ventilation
• -ICU admission
• -Central venous catheters
• -Parenteral nutrition
• -HD
• -Prior fungal colonization
• -Length of hospital stay

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Epidemiology

• From 1970-2000 C. albicans the dominant species
  in BSI throughout the world.
• Last decade has seen a shift to non-albicans
  Candida and resistant C. albicans.
• Previous antifungal therapy (?certain
  antibacterial agents?) and underlying hosts
  factors have contributed to non-albicans Candida
  spp.

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Epidemiology

• C. glabrata more likely where
• -high prevalence
• -current or recent azole exposure
• -any culture data where colonization of
• sputum, wound, urinary catheter
• The initiation of adequate and appropriate
  antifungal therapy has been associated with
  decreased mortality.

JAC. 2007 60 613-618. AAC. 2005
49 3640-3645.
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CUH Yeast Species 2009
C. albicans 264
C. glabrata 50
C. parapsilosis 47
C. tropicalis 26
C. dubliniensis 17
Cryptococcus neoformans 15
C. lusitaniae 4
C. famata 2
C. guilliermondii 1
C. krusei 1
Yeast isolated (not identified - from non-sterile site) 715
TOTAL 1,142
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CUH Yeast Species from BSI 2009
C. parapsilosis 31
C. albicans 28
C. glabrata 16
C. dubliniensis 8
C. tropicalis 5
Cryptococcus neoformans 3
C. lusitaniae 2
C. famata 1
C. guilliermondii 1
TOTAL 95
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Antifungal Agents
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Polyenes

• Most experience with amphotericin B deoxycholate
  (AmB-d) preparation.
• -Rapid cidal activity against most Candida sp.
• except C. lusitaniae.
• -0.5-0.7 mg/kg daily (to 1 mg/kg daily for
• less susceptible species such as C.
• glabrata and C. krusei).
• -Nephrotoxicity most common serious
• adverse effect where ARF up to 50.

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Polyenes

• Three lipid formulations of amphotericin
• -L-AmB (liposomal)
• -AmB lipid complex (ABLC)
• -AmB colloidal dispersion (ABCD)
• More expensive
• Less nephrotoxicity
• Typical dosage 3-5 mg/kg daily

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Triazoles
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General Facts

• All azoles inhibit cytochrome P450
• WATCH FOR DRUG INTERACTIONS!
• Not all have equal susceptibilities
• -C. krusei has inherent resistance to
• fluconazole.
• -C. glabrata.

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Fluconazole

• Readily absorbed with oral bioavailability
  resulting in concentrations at 90 of those
  achieved via IV.
• Absorption not affected by food, gastric pH,
  disease state.
• Good penetration into CSF, vitreous body where
  concentration 50 of serum.

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Fluconazole

• Urine levels are 10-20 times the concentration of
  serum!
• For invasive candidiasis
• -Loading dose 800 mg (12 mg/kg)
• -Daily maintenance 400 mg (6 mg/kg)
• Adjust for creatinine clearance lt50 mL/min.

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Voriconazole

• Often used as step-down oral therapy for C.
  krusei and flu-resistant/vori-susceptible C.
  glabrata.
• Oral bioavailability gt90.
• -Not affected by gastric pH.
• -Decreases when given with food.
• No po dose adjustment for renal insufficiency but
  needs reduction for hepatic impairment.

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Voriconazole

• Oral loading dose 400 mg bid.
• Oral maintenance dose 200 mg bid.
• IV loading dose 6 mg/kg q 12 h.
• IV maintenance 3-4 mg/kg q 12 h.
• IV not recommended for creatinine clearance lt 50
  mL/min because of possible cyclodextrin toxicity.

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Echinocandins

• Fungicidal.
• Few drug interactions.
• Once daily dosing.
• No dose adjustment for renal disease.
• C. parapsilosis may be less responsive.
• Only caspofungin needs dose adjustment for
  moderate to severe hepatic dysfunction.

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Echinocandins

• Intravenous administration only.
• Caspofungin
• -Load 70 mg
• -Maintenance 35-50 mg daily
• Micafungin
• -100 mg daily
• Anidulafungin
• -Load 200 mg
• -Maintenance 100 mg daily

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Flucytosine

• Active against most Candida species except C.
  krusei.
• Oral preparation only.
• Usually administered with amphotericin.
• Rarely given as monotherapy as resistance
  develops quickly.

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Treatment of Candidemia
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All positive cultures must be treated. Yeast is
never to be considered a contaminant!!!

• A search for the source should always be done.

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Nonneutropenic Patients

• Fluconazole or echinocanidn.
• Echinocandin favored for those with recent azole
  exposure or moderately severe to severe disease.
• In those with a susceptible isolate who are
  clinically stable transition from an echinocandin
  to fluconazole.

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Nonneutropenic Patients

• Echinocandin preferred for C. glabrata where
  transition to fluconazole not recommended unless
  susceptibility known.
• Fluconazole recommended for C. parapsilosis. If
  patient started echinocandin and repeat blood
  cultures are negative and there is clinical
  improvement continuing echinocandin acceptable.

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Nonneutropenic Patients

• AmB-d (0.5-1.0 mg/kg/day) or LFAmB (3-5
  mg/kg/day) if other antifungal drugs are
  unavailable or if there is an intolerance.
• Voriconazole for oral step-down therapy for
  susceptible C. krusei or C. glabrata.

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Nonneutropenic Patients

• Duration of therapy, if no metastatic foci and if
  clinical improvement, is 2 weeks after documented
  clearance of blood cultures.
• IV catheter removal strongly recommended.
• Dilated funduscopic exam.
• Repeat blood cultures to document clearance.

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Neutropenic Patients

• Echinocandin recommended for most patients.
• If less critically ill and no recent azole
  exposure, fluconazole.
• If additional mold coverage, consider
  voriconazole.

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Neutropenic Patients

• Echinocandin preferred for C. glabrata.
• LFAmB an alternative for C. glabrata.
• If on fluconazole or voriconazole with clinical
  improvement and negative repeat blood cultures,
  and C. glabrata, continuing the azole reasonable.

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Neutropenic Patients

• Fluconazole or LFAmB preferred if C.
  parapsilosis.
• If patient with C. parapsilosis on echinocandin
  and clinically stable with negative blood
  cultures, continuing echinocandin acceptable.
• An echinocandin, LFAmB, or voriconazole
  recommended for C. krusei.

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Neutropenic Patients

• Duration of treatment if no metastatic foci, 2
  weeks after documented blood clearance,
  resolution of candida-associated symptoms, and
  resolution of neutropenia (retropsective cohort
  of 476 cancer patients demonstrated greater
  chance of treatment failure if persistent
  neutropenia).
• Am J Med. 1996 101 170-6.

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Neutropenic Patients

• Consider removal of venous catheters.
• Repeat blood cultures to document sterility.
• Dilated funduscopic exam should be done after
  neutrophil recovery.

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Thank you!!!