Fungal and Yeast Flashcards
Candida Species
Yeast-like fungi that can form true hyphae & pseudohyphae
Typically confined to human and animal reservoirs
Frequently recovered from the hospital environment (e.g. foods, countertops, air-conditioning vents, floors, respirators & medical personnel
Normal commensals of diseased skin and mucosal membranes of the gastrointestinal, genitourinary, and respiratory tracts
Candidiasis – Systemic Risk Factors
Hematologic malignancies Foley catheters Solid neoplasms Recent chemotherapy or radiation therapy Corticosteroids Broad-spectrum antibiotics Burns Recent surgery Gastrointestinal tract surgery Central intravascular access devices Premature birth Hemodialysis
Epidemiology of Candidiasis
Oropharyngeal colonization - 30-55% of healthy young adults
Candidaspecies detected in 40-65% of normal fecal florae
75% of women have at least one bout ofvulvovaginal candidiasis (VVC) during their lifetime
> 90% of persons infected with HIV (not receiving HAART develop oropharyngeal candidiasis (OPC)
10% develop at least one episode of esophageal candidiasis
Candidiasis - Etiology
C albicans,the most common species identified (50-60%)
Candida glabrata(previously known asTorulopsis glabrata) (15-20%) - 20% resistance to fluconazole
C parapsilosis(10-20%) - associated with vascular catheters prosthetic devices
Candida tropicalis(6-12%) - candidemia in patients with leukemia & bone marrow transplantation
Candida krusei(1-3%) - intrinsic resistance to ketoconazole and fluconazole, less susceptible to amphotericen B
Candida kefyr(< 5%)
Candida guilliermondi(< 5%)
Candida lusitaniae(< 5%) - intrinsically resistant to amphotericin B
Candida dubliniensis,primarily recovered from patients infected with HIV
Generalized cutaneous candidiasis
Unusual, diffuse eruption over the trunk, thorax, and extremities with generalized pruritus, increasing vesicles genitocrural folds, anal region, axillae, hands, and feet becoming confluent
Intertrigo
vesciculopustules that enlarge and rupture in intertriginous areas, causing maceration and fissuring, scalloped border with a white rim consisting of necrotic epidermis that surrounds the erythematous macerated base; satellite lesions common with coalescence
Paronychiaand onychomycosis
associated with immersion of the hands in water and with diabetes mellitus; inflammation that becomes warm, glistening, tense, and erythematous and may extend extensively under the nail; 2nd nail thickening, ridging, discoloration, and occasional nail loss
5 types of oropharyngeal candidiasis (OPC)
Membranous candidiasis Erythematous candidiasis Chronic atrophic candidiasis (denture stomatitis) Angular cheilitis Mixed
Oropharyngeal candidiasis and symptoms
usually history of HIV infection, wears dentures, has diabetes mellitus, or has been exposed to broad-spectrum antibiotics or inhaled steroids; usually asymptomatic. Sore and painful mouth Burning mouth or tongue Dysphagia Whitish thick patches on the oral mucosa
Membranous candidiasis
most common; creamy-white curdlike patches on the mucosal surfaces
Erythematous candidiasis
erythematous patch on the hard & soft palates
Chronic atrophic candidiasis
common; chronic erythema and edema of palate portion coming in contact with dentures
Angular cheilitis
soreness, erythema & fissuring at the corners of the mouth
Esophageal candidiasis
typically with chemotherapy, broad-spectrum antibiotics or inhaled steroids, increased with HIV infection or hematologic/solid-organ malignancy Normal oral mucosa (>50% of patients) Dysphagia Odynophagia Retrosternal pain Epigastric pain Nausea and vomiting
Non-esophageal gastrointestinal candidiasis and symptoms
Esophagus most common site
2nd - stomach (chronic gastric ulcerations, gastric perforations, or malignant gastric ulcers with concomitant candidal infection)
3rd - small bowel (20%)
4th – colon (20%)
symptoms Epigastric pain Nausea and vomiting Abdominal pain Fever and chills Abdominal mass (in some cases)
Laryngeal candidiasis
Uncommon form of invasive candidiasis may result in disseminated infection
Primarily patients with underlying hematologic or oncologic malignancies
Present with a sore throat and hoarseness; unremarkable exam; requires direct or indirect laryngoscopy
Candidatracheobronchitis
Uncommon form of invasive candidiasis
Most patients are HIV-positive or are severely immunocompromised
Presents usually with fever, productive cough, and shortness of breath; PE shows dyspnea and scattered rhonchi; diagnosed with bronchoscopy
Candidapneumonia
Rarely develops alone; may be associated with disseminated candidiasis
Most common form of infection is multiple lung abscesses due to the hematogenous dissemination
High degree ofCandidacolonization in the respiratory tract makes the diagnosis ofCandidapneumonia challenging
History shows risk factors similar to disseminated candidiasis: PE has shortness of breath, cough, respiratory distress, fever, dyspnea, and variable breath sounds, ranging from clear to rhonchi or scattered rales
Vulvovaginal candidiasis (VVC)
2nd most common cause of vaginitis
History of vulvar pruritus, vaginal discharge, dysuria, and dyspareunia; ~ 10% experience repeated attacks of VVC without precipitating risk factors
PE – erythema of vagina and labia, thick curdlike discharge; normal cervix
Candidabalanitis
Penile pruritus along with whitish patches on the penis
Acquired through direct sexual contact with a partner who has VVC
PE - vesicles on the penis that later develop into patches of whitish exudate; rash occasionally spreads to the thighs, gluteal folds, buttocks, and scrotum
Candidacystitis
Often asymptomatic; may have frequency, urgency, dysuria, hematuria, and suprapubic pain; increased risk with Foley catheter use
PE – may show suprapubic tenderness; limited findings otherwise
Asymptomatic candiduria
Catheterized patients with persistent candiduria usually asymptomatic, similar to noncatheterized patients
Invasive disease is difficult to differentiate from colonization based solely on culture; 5-10% of all urine cultures are positive for Candida
Ascending pyelonephritis
Stents and indwelling devices, along with the presence of diabetes, is the major predisposing risk factor in ascending infection
Most have flank pain, abdominal cramps, nausea, vomiting, fever, chills & hematuria
PE shows abdominal pain, CVAT & fever
Genitourinary tract candidiasis Fungal Balls
Accumulation of fungal material in the renal pelvis
May produce intermittent urinary tract obstruction with subsequent anuria and ensuing renal insufficiency
Hepatosplenic candidiasis history and PE
Form of systemic candidiasis with underlying hematologic malignancy and neutropenia
Occurs during the recovery phase of a neutropenic episode
History & PE:
Fever unresponsive to broad-spectrum antimicrobials
Right upper quadrant pain
Abdominal pain and distension
Jaundice (rare)
Right upper quadrant tenderness & hepatosplenomegaly (< 40%)
Candidemia History and PE
4th most commonly isolated organism in blood cultures
Generally considered a nosocomial infection
History
Several days of fever that is unresponsive to broad-spectrum antimicrobials; frequently the only marker of infection
Prolonged intravenous catheterization
A history of several key risk factors
Possibly associated with multiorgan infection
Physical examination
Fever
Macronodular skin lesions (approximately 10%)
Candidal endophthalmitis (approximately 10-28%)
Occasionally, septic shock (hypotension, tachycardia, tachypnea)
Disseminated candidiasis
Frequently associated with multiple deep organ infections or may involve single organ infection
Blood cultures are negative in up to 40-60% of patients with disseminated candidiasis
History
Fever unresponsive to broad-spectrum antimicrobials
Negative results from blood culture
Physical examination
Fever (may be the only symptom) with an unknown source
Sepsis and septic shock
Candida localized infections
Candida endophthalmitis
Exogenous (trauma/postoperative) and endogenous (hematogenous, 10-28% with candidemia)
Classic lesions are large and off-white, similar to a cotton-ball, with indistinct borders covered by an underlying haze form
Renal candidiasis
Consequence of candidemia or disseminated candidiasis
History includes fever that is unresponsive to broad-spectrum antimicrobials, otherwise asymptomatic lacking renal symptoms
CNS infections due toCandidaspecies
Rare and difficult to diagnose
Exogenous (trauma/postoperative) and endogenous (hematogenous with multiple small abcesses)
Mucocutaneous candidias- Workup
Wet mount for hyphae, pseudohyphae, or budding yeast cells
Potassium hydroxide smear, Gram stain, or methylene blue is useful for direct demonstration of fungal cells
Cultures from affected nails may help identify the etiologic agent responsible for onychomycosis versus other noninfectious causes
treatment.
Candidemia and disseminated candidiasis- Workup
Blood cultures yield positive results in only 50-60% of cases of disseminated infection
Urinalysis may be helpful and may show either colonization or renal candidiasis
Cultures of nonsterile sites can be considered for initiating antifungal therapy in patients with fever unresponsive to broad-spectrum antimicrobials; interpretation is key
Positive blood cultures and cultures from other sterile sites always imply the presence of invasive disease; should always be considered significant and treated
Gastrointestinal, respiratory, and urinary tract cultures may not always represent invasive disease, but demonstrate colonization
Azole Antifungals (1 treatment of candidasis)
Synthetic compounds in 2 groups, imidazoles and triazoles
Triazoles (fluconazole, itraconazole, econazole, terconazole, butoconazole, and tioconazole) have 3 atoms of nitrogen in the azole ring
Imidazoles (miconazole, ketoconazole, and clotrimazole) have 2 nitrogen atoms
MOA - inhibition of lanosterol 14-alpha-demethylase, an enzyme required for the synthesis of ergosterol, the main component of fungal cell membranes
Glucan synthesis inhibitors (echinocandins)
Candidiasis - Treatment
Newer - excellent clinical efficacy, low incidence of adverse events, good safety profile & ease of use
MOA - inhibit the formation of fungal cell wall
Caspofungin, micafungin, and anidulafungin
Polyenes
Candidiasis Treatment
Broad-spectrum fungicidal agents; MOA - insertion into fungal cytoplasmic membrane, causing increases in permeability; membrane channel activity is increased at lower doses, and pores are formed at higher concentrations
Amphotericin B, Amphotericin B, lipid formulations, Nystatin (Mycostatin)
Allylamines
Candidiasis Treatment
Cause deficiency of ergosterol within the fungal cell wall, causing fungal cell death
Terbinafine (Daskil, Lamisil)
Cryptococus
Cryptococcus neoformansis an encapsulated yeast
> 50 species of Cryptococcus, only primarily pathogenic to humans
C neoformans (mostly immunocompromised hosts) found in U.S and temperate regions in pidgin poop
C gattii* (mostly immunocompetent hosts) found in the tropics not associated in birds
Cryptococcus - Pathophysiology
Inhalation with yeast spores deposited in pulmonary alveoli,
Spores must survive the neutral-to-alkaline pH and physiologic concentrations of carbon dioxide before they are phagocytized by alveolar macrophages (glucosylceramide synthase (GCS) is an essential factor in the survival outside alveolar macrophage)
Host response to cryptococcal infection includes both cellular and humoral components
Cryptococcus - Epidemiology
7%-15% of patients with AIDS develop cryptococcal infections
1993 CDC 6% of 274,150 patients with AIDS developed cryptococcal disease
Patients with AIDS-associated cryptococcal infections now account for 80%-90% of all cases of cryptococcosis
4% mortality rate in patients with cryptococcal disease treated with amphotericin B plus flucytosine; 28% mortality rate in patients treated with other regimens
Pulmonary cryptococcosis Presentation
Variable presentation from asymptomatic saprophytic airway colonization toacute respiratory distress syndrome (e.g. AIDS, organ transplant recipients
May present as a slowly progressive mass that may compress thoracic structures such as the vena cava
Pulmonary cryptococcosis may present with mild-to-moderate symptoms, including fever, malaise, cough with scant sputum, pleuritic pain, and hemoptysis (rare)
Unusual findings include rales or pleural rub
Pleural effusions may be present but are uncommon.
CNS Cryptococcosis Presentation
Meningitis/meningoencephalitis are the most common manifestations of CNS cryptococcosis
Typically subacute or chronic
Invariably fatal without appropriate therapy; death may occur from 2 weeks to several years after symptom onset.
Clinical presentation and course variable depending of host immune status (e.g. glucocorticoid use, DM, sarcoidosis)
Most common symptoms are headache and altered mental status, including personality changes, confusion, lethargy, obtundation, and coma
Nausea and vomiting common (associated with increased intracranial pressure)
Fever and stiff neck (symptoms of more aggressive inflammatory response) are less common
Cryptococcus - Presentation
Cutaneous lesions occur in 10%-15% of cases; papules, pustules, nodules, ulcers, or draining sinuses
Umbilicated papules in patients with AIDS may resemble molluscum contagiosum
Cellulitiswith necrotizing vasculitis occurs in patients who undergo organ transplantation
Bone lesions develop in 5%-10% of patients and are usually osteolytic or resemble cold abscesses (may resemble tuberculosis or neoplasm)Chorioretinitis
Hepatitis
Peritonitis
Renal abscess
Cryptococcus – Workup
Cutaneous lesions – biopsy with fungal stains and cultures
Blood and CSF should be cultured for fungi; cryptococcal antigen testing
CSF (obtain after CT/MRI to exclude masses) - opening pressures should be measured at each spinal tap; elevated pressures (≥250 mm H2O) portend a poor prognosis, CSF glucose depresses, protein elevated, lymphocytic cell count @ 20 or higher, positive for India ink or antigen
Serologic testing of blood and CSF recommended if cryptococcal CNS infection considered
Antigen tests unobtainable in impoverished countries; cryptococcosis often goes undiagnosed (2009, lateral flow assay (LFA) for diagnosing cryptococcosis was developed, may provide a point-of-care assay in resource-poor areas
Culturing forCryptococcusmay be appropriate, even when the CSF profile is unremarkable
Cryptococcus Treatment
Cryptococcal meningitis with AIDS (mortality 25-30%; sequelae 40%)
Account for more than 80% of the patients with cryptococcosis
Initially, administer amphotericin B at 0.7-1 mg/kg/d for 2 weeks, with or without 2 weeks of flucytosine at 100 mg/kg/d in 4 divided doses, followed by fluconazole at 400 mg/d for a minimum of 8-10 weeks
Cryptococcal meningitis without AIDS (effective 70-75%)
Initial therapy should be amphotericin B (0.7-1 mg/kg/day) alone or in combination with flucytosine (100 mg/kg/day in 4 divided doses). Amphotericin B can be administered alone for 6-10 weeks or in conjunction with flucytosine for 2 weeks, followed by fluconazole for a minimum of 10 weeks
Pulmonary cryptococcosis
Without concomitant immunosuppression/deficiency; observation possible as the infection may resolve without antifungal therapy
Observing allowed if CSF chemistry parameters are normal; the CSF culture, India ink preparation, and serology results are negative; urine culture results are negative; the pulmonary lesion is small and stable or shrinking; and the patient has no predisposing conditions for disseminated disease.
Mild-to-moderate cryptococcal pulmonary disease*: fluconazole for 6-12 months, itraconazole for 6-12 months, or amphotericin B
Severe pulmonary disease: amphotericin B (0.7-1 mg/kg/d) plus flucytosine (100 mg/kg/d) for 6-10 weeks or same for 2 weeks followed by fluconazole at 400 mg/kg/d for at least 10 weeks (some recommend consolidation therapy for 6-12 months)
Treatment of extraneural nonpulmonary disease
Without AIDS, cryptococcal lesions of the skin, bones, or other organs treated with amphotericin B plus flucytosine or with amphotericin B alone
Patients with cryptococcal infection require lumbar puncture ensure absence of CNS infection
Histoplasmosis - Epidemiology
Histoplasmosis is the most common endemic fungal infection seen in humans
Central river valleys in the midwestern and south central United States are endemic for histoplasmosis
~ 250,000 individuals are infected annually
Clinical manifestations of histoplasmosis occur < 5% of the population
Most infections are sporadic, although large outbreaks of histoplasmosis may occur
Histoplasmosis - Pathophysiology
Most individuals with histoplasmosis are asymptomatic
Clinical disease is usually in immunocompromised or are exposed to a high quantity of inoculum
Histoplasmaspecies may remain latent in healed granulomas and recur, resulting in cell-mediated immunity impairment
Conversion from the mycelial to the pathogenic yeast form occurs intracellularly.
After phagocytosis by macrophages, the yeast replicates in approximately 15-18 hours
Despite fusion with lysosomes, multiplication continues within the phagosomes (possible inhibition of lysosomal proteases)
As the host immunity response develops, yeast growth ceases within 1-2 weeks after exposure
Acute pulmonary histoplasmosis
Approximately 90% of patients are asymptomatic
If symptoms develop, onset occurs 3-14 days after exposure
Fever, headache, malaise, myalgia, abdominal pain, and chills are common symptoms; usually, histoplasmosis is self-limited
With exposure to a large inoculum patient may develop severe dyspnea resulting from diffuse pulmonary involvement
Joint pain and skin lesions occur in 5-6% of patients, mostly in females
Enlarged hilar and mediastinal lymph nodes are present in 5-10% of patients
Cough, hemoptysis, dyspnea, and/or chest pain may be present and are related to the degree of compression on the pulmonary airway and circulation
Paratracheal involvement may cause cough or dyspnea because of compression on the trachea or bronchi
Rarely, compression of the esophagus occurs, which causes dysphagia
Chronic pulmonary histoplasmosis
This form occurs mostly in older patients with underlying pulmonary disease and is associated with cough, weight loss, fevers, and malaise
Generally, infection involves the apical segments and occurs near emphysematous bullae
Pleural thickening is often seen
If cavitations are present, hemoptysis, sputum production, and increasing dyspnea are common symptoms
Histoplasmosis - Presentation
Acute form - fever, worsening cough, weight loss, malaise, and dyspnea; 5-20% of patients have CNS involvement
Subacute form - wide spectrum of symptoms
Constitutional symptoms
GI involvement may produce diarrhea and abdominal pain
Cardiac involvement resulting in valvular disease, cardiac insufficiency, or vegetations may produce dyspnea, peripheral edema, angina, and fever
CNS involvement may produce headache, visual and gait disturbances, confusion, seizures, altered consciousness, and neck stiffness or pain
Mucous membrane lesions are common in disseminated histoplasmosis
Histoplasmosis Workup
CBC – anemia in chronic histoplasmosis & pancytopenia and thrombocytopenia in disseminated
Alkaline phosphatase - elevated in acute disseminated and chronic pulmonary histoplasmosis
Lactate dehydrogenase increases in AIDS patients with disseminated histoplasmosis
Sputum culture - positive in ~ 15% from patients with acute and 60-85% from patients with chronic pulmonary histoplasmosis
Blood cultures – positive in 50-70% of patients with progressive disseminated histoplasmosis, usually negative otherwise
Complement-fixing antibodies
Immunoprecipitating antibodies – detects anti-M and anti-H glycoproteins, vary in duration and presence with acute infection
Serum and urine antigen detection - useful in immunocompromised when antibody production may be impaired
Angiotensin-converting enzyme – may be elevated with acute infection
Third-generation antigen assays – 100% disseminated histoplasmosis antigenemia; antigenuria has variable senstivities for acute and subacute infections
CXR – may detect healed lesions, hilar LN reactivity and disseminated disease
CT/MRI – considered for CNS or abdominal presentations
Pulmonary function tests – determine extent of disease
Acute pulmonary histoplasmosis Treatment
No treatment is required for individuals who are asymptomatic, monitor symptoms
Prolonged symptoms (>4 wk) or those with overwhelming pulmonary involvement, initiate medical therapy with itraconazole for 6-12 weeks; CXR to monitor response to therapy; then followed for several years after treatment for possible relapse
Patients with severe infection should be treated with amphotericin B for 1-2 weeks; once stable, amphotericin B may be changed to itraconazole and should be continued for 1 year
Patients with acute respiratory distress symptoms may require methylprednisone for 1-2 weeks
Chronic pulmonary histoplasmosis Treatment
Often fatal if not treated (mortality rate ~ 50% without treatment; 28% with treatment)
May have progressive loss of pulmonary function
Cavitary lesions must be treated; itraconazole given for one year; relapse in 15%
Persistent cavitations despite medication warrant surgical consideration
Progressive disseminated histoplasmosis and meningitis
Treatment
Initiate medical therapy with amphotericin B with progressive disseminated histoplasmosis and meningitis
Thoracentesis or pericardiocentesis in patients with severe pleural effusions and pericardial tamponade
Pneumocystis
Pneumocystisorganisms are commonly found in the lungs of healthy individuals
Most children have been exposed to the organism by age 3 or 4 years
Occurrence is worldwide
Pneumocystis cariniipneumonia (PCP) is the most common opportunistic infection in persons withHIV infection (renamedPneumocystis jiroveci [pronounced “yee-row-vet-zee”])
Classified as afungal pneumonia, but PCP does not respond to anti fungal treatment
Antibiotics (e.g. trimethoprim-sulfamethoxazole TMP-SMX) are primarily recommended for treatment of mild, moderate, or severe PCP
Corticosteroids are used as adjunctive initial therapy only in patients with HIV infection who have severe PCP
Pneumocystis – Risk Factors
HIV infection whose CD4+cells fall below 200/µL and who are not receiving PCP prophylaxis
HIV with opportunistic infections (e.g. oral thrush) increases the risk of PCP, regardless of CD4+count
Primary immune deficiencies, including hypogammaglobulinemiaandsevere combined immunodeficiency(SCID)
Long-term immunosuppressive regimens for connective-tissue disorders, vasculitides, or solid-organ transplantation (e.g. heart, lung, liver, kidney)
Hematologic and nonhematologic malignancies, including solid tumors and lymphomas
Severe malnutrition
Pneumocystis - Epidemiology
Pneumocystisinfection in lung transplant patients was 88% without prophylaxis
With routine prophylaxis, PCP is very rare in solid-organ transplant patients and has significantly decreased in patients infected with HIV
Prior to the widespread use of highly active antiretroviral therapy (HAART), PCP occurred in 70-80% of patients with HIV infection
Mortality rate with HIV and PCP previously 20-40%, presently 10-20%
Pneumocystis - Presentation
Symptoms ofP cariniipneumonia (PCP) are nonspecific
PCP in patients with HIV infection tends to run a more subacute indolent course and tends to present much later, often after several weeks of symptoms, compared with PCP associated with other immunocompromising conditions
Symptoms infection can be found in any organ system Fever nonproductive cough chills wt loss
Pneumocystis - Workup
Sputum - Pneumocystisorganisms are frequently found in sputum induced by inhalation of a hypertonic saline solution; sensitivity varies with technique (< 50% to >90%); specificity is high (99-100%)
Lactic dehydrogenase (LDH) - usually elevated (>220 U/L) in patients withP cariniipneumonia (PCP); elevated in 90% of patients with PCP and HIV; high sensitivity (78-100%); but limited specificity
LDH levels appear to reflect the degree of lung injury; improving with successful treatment; consistently elevated LDH levels during treatment may indicate therapy failure & poor prognosis
Quantitative PCR - useful in distinguishing between colonization and active infection (not yet available for routine clinical use)
β-D-Glucan (BDG) - cell-wall component of many fungi, including candida, aspergillus, and pneumocystis
Sensitive test to detect PCP, not specific
CXR
Response for Pneumocystis Treatment
Treatment of PCP may be initiated before the workup is complete in severely ill high-risk patients
Pneumocystis organisms persist in the host for days to weeks after therapy is started, allowing time for completion of the appropriate workup
Treatment of PCP depends on the degree of illness at diagnosis, based on alveolar-arterial gradient:
Mild (< 35 mm Hg)
Moderate/severe (35-45 mm Hg)
Severe (>45 mm Hg); also O2 < 70 mm Hg
In patients without HIV infection, response to treatment should begin in 4-5 days; patients infected with HIV, the treatment response typically takes longer; within the first 8 days
Treatment for Pneumocystis
Antibiotics are primarily recommended for treatment of mild, moderate, or severeP cariniipneumonia (PCP)
Trimethoprim-sulfamethoxazole (TMP-SMX) has been shown to be as effective as intravenous pentamidine and more effective than other alternative treatment regimens
Recommended duration of treatment for PCP is 21 days in patients with HIV infection and 14 days for all other patients; patients infected with HIV tend to have a higher organism burden and respond to treatment slower than patients without HIV infection requiring a longer duration of therapy
Corticosteroids are used as adjunctive initial therapy only in patients with HIV infection who have severeP cariniipneumonia (PCP): RA pO2 < 70 mm Hg or an arterial-alveolar O2gradient > 35 mm Hg
Pneumocystis - Prevention
Smoking cessation
Smokers are at an increased risk ofP cariniipneumonia (PCP) and have a more complicated treatment course
Chemoprophylaxis in patients with HIV Infection
Two types of outpatient chemoprophylactic therapies exist: primary prophylaxis in immunocompromised patients without a history of PCP; secondary prophylaxis is used in patients with a prior bout of PCP
