OPPORTUNISTIC FUNGAL PATHOGENS II: Candida albicans, Aspergillus species, and Pneumocystis jiroveci

PJ: What is the infectious form? Is there an inanimate environmental reservoir? Is there an animal reservoir? Does exposure occur via direct or indirect transmission from infected individuals? Does latent infection occur? What is the extent of reactivation disease as compared to disease from primary exposure?

What is the infectious form? *Unknown.* Is there an inanimate environmental reservoir? *Unknown*. Is there an animal reservoir? *Unknown, but there is evidence against this possibility*: Pneumocystis "strains" display marked host specificity, i.e., samples isolated from one host species (e.g., human) do not infect other host species (e.g., rat). Thus, a non-human reservoir for human Pneumocystis is unlikely. Does exposure occur via direct or indirect transmission from infected individuals? *Unknown.* Does latent infection occur? *Unknown.* What is the extent of reactivation disease as compared to disease from primary exposure? *Unknown.*

Asp: mycotoxicosis - The main toxin, where it may be found (think of that famous duck) - Toxicities (2) (cow) - Infection? - Geography - Industrial use

*Aflatoxins* (originally described from A. flavus but also produced by other species) are one of several toxins produced by aspergilli, may be found in *raw or processed seeds, nuts, or corn* and are *hepatotoxic and carcinogenic*. Fungal toxins are involved, but *infection with viable fungi is not necessary*. Such disease is *not common in the US* and other countries in which *mycotoxin levels in foods are monitored and regulated*. Outbreaks and sporadic cases occur regularly in other parts of the world, e.g., *India and Africa*. Mycotoxins are also *potential bioterrorism/biowarfare agents*.

Asp: infection transmission (and other possibility) - Morphology of inhaled and invasive

*Inhalation of conidia* can lead to *hypersensitivity phenomena (infection not necessarily involved)* or to *colonization and infection*, with *germination* to form *hyphae* that *may invade tissue.*

C. albicans: geography and environmental niches - one word summary

*MOIST* C. albicans lives as a *commensal part of the normal microbiota on the surface of humans (particularly moist areas*), and *sites in direct communication with the surface*. Up to 80% of normal individuals may show colonization of the *oropharynx, GI tract, and vagina* in the absence of disease. The organism is *not generally found on normal dry skin* but may be isolated from moist sites, such as *intertriginous, perioral, and perianal areas*. Thus, the *geographic distribution is the same as for humankind*. Other Candida species may have other environmental niches.

Asp: morphology - They're kinky

*Mold, including hyphae and conidia (no yeast)*. However, these fungi can display complex morphologies as part of *asexual or sexual development.*

C. albicans: types of infections that happen in immunodeficient ppl (3 examples of these ppl)

*More severe mucosal infections* and *invasive and disseminated disease* occur in more seriously immunocompromised individuals, such as *AIDS and cancer patients and transplant recipients* receiving immunosuppressive therapy.

When candida infection merits Tx, what's important. Otherwise you can...

*culture of the isolate, species identification, and sometimes antibiotic susceptibility* testing are important Otherwise, *"statistical medicine" knowledge of isolates in particular patient populations, clinical settings, and communities* may provide useful guidance.

PJ: characteristics atypical for a fungus (6) - lipid, susceptibility, parasite morphology, fragility (think ground glass...), challenge for Dx

- *Absence of ergosterol, presence of cholesterol* as major sterol. - *Lack of susceptibility to amphotericin B*. - *Susceptibility to certain antiparasitic agents* to which other fungi are not susceptible (e.g., atovaquone, pentamidine, trimethoprim/sulfamethoxazole [TMP-SMX]). - *Morphology, "life cycle"* similar to some classes of parasites that convert between a *nonmotile, thick-walled, environmentally resistant form termed a "cyst"* and an active, *motile form termed a "trophozoite."* This misleading terminology has persisted. - *Relative fragility of trophozoite cell wall*, as opposed to rigid fungal cell walls. - *Lack of an in vitro cultivable form*, which presents *challenges for diagnosis* and for laboratory studies.

Asp: V factors (3)

- *Allergens* discussed above, although this category perhaps *reflects more the responsiveness of the host* rather than a particular virulence-associated function of the fungus. - *Toxins* discussed above. - *Several hydrolytic enzymes, e.g., proteases*, may play a role in destruction of host tissue components.

Asp: epidemiology - Allergy (describe) - _____ abnorms are assoc. w/colonization - What cells are the front-line defense for hyphae, for conidia - Eg of immunocompromise combination that works against activity of both of these cells, increases risk for what

- *Allergy* to Aspergillus antigens is *common*, but can display a *wide range of severity.* - *Anatomic abnormalities* (e.g., pulmonary cavities secondary to emphysema secondary to tobacco smoking) are *associated with colonization.* - *Neutrophils* are a front-line defense against Aspergillus *hyphae* via extracellular killing mechanisms, whereas *macrophages* can ingest and kill Aspergillus *conidia*. *Compromise of CMI* by various mechanisms can increase susceptibility to different manifestations of Aspergillus infection. For instance, *severely neutropenic patients (e.g., those receiving cytotoxic chemotherapy*), especially if combined with *corticosteroid immunosuppressive therapy compromising macrophage function* (e.g., to ameliorate graft-vs-host disease *following bone marrow transplants)* are at *high risk for localized invasive aspergillosis (IPA) and disseminated aspergillosis.*

C. albicans non-culture diagnostic methods - BDG detection in fluids, a marker of ... - 4 other methods (4 things you can detect)

- *Beta-D-glucan detection* in blood or other body fluids. This *cell wall component* is a marker of *invasive fungal processes but not specific for Candida*. A commercially available, US FDA-approved kit uses a Limulus (horseshoe crab) amebocyte lysate assay similar to that used to detect bacterial endotoxin (LPS). - Other investigational approaches: o Detection of *Candida antigen, a cell wall mannan*, or *antibodies* specific for this Candida antigen. o Detection of *Candida metabolites*, e.g., mannose, arabinitol. o Detection of *Candida enzymes*, e.g., enolase, secreted aspartyl proteinase. o *PCR* detection of *Candida rDNA.*

C. albicans: V factors (4, describe) - morphology, adhesins, catheters, tissue destruction

- *Morphogenesis,* or the ability to switch between yeast and hyphal forms, is considered *essential for pathogenesis*, but the mechanism and regulation of this process are incompletely understood. - C. albicans produces a number of cell-surface *adhesins* that have protein or carbohydrate constituents or both. These molecules are important for *adherence at the surface during commensal and pathologic growth, tissue invasion, dissemination, and interaction with various host cells*. Some of these fungal determinants *mimic mammalian cell surface components*, such as the integrin complement receptors *CR3 and CR4* found on host phagocytes. - *Biofilm* formation allows colonization of intravenous catheters and other *medical devices* ( e.g., artificial heart valves, urinary catheters, dentures), which may lead to bloodstream infection or be a result of bloodstream infection via hematogenous seeding. - C. albicans secretes a number of *hydrolytic enzymes*, including several *proteases and phospholipases*, which may play a role in *destruction of host tissue components*.

PJ: Tx (3) - The main drug: uses, admin, problem (it's not resistance...) - List of other possible drugs (paddle) (leprosy) - Also add ___ to mitigate ___

- *TMP-SMX: Tx and Px in high-risk patients*. *Oral or IV* administration. There is a relatively *high incidence of adverse drug reactions and toxicity, especially in AIDS patients.* - Other drugs used for treatment and/or prophylaxis: *pentamidine*, dapsone, pyrimethamine, atovaquone, clindamycin + primaquine. - *Steroids in acutely ill patient* to mitigate deleterious consequences of host inflammatory responses, especially *fluid accumulation in the lungs*. This immunosuppressive regimen is given in concert with antimicrobial therapy.

Candida Tx: in general what you use for: - Less serious infections - Moderate infections - Serious infections, dangerous pt settings - Nothing --> pinecone --> hat --> frog - Topical/oral --> IV

- *topical antifungals and/or oral azoles (or no Tx)* are used for less serious infections and less dangerous patient settings, - *intravenous azoles or echinocandins* are used for moderately severe situations, - *intravenous echinocandins or amphotericin B* are used for more serious infections or more dangerous patient settings.

Positive Candida culture (as described above for VVC) from blood or other normally sterile fluid (e.g., CSF, peritoneal fluid) is: (4) - High ___. low ___

- A *definitive diagnostic procedure.* - Always considered significant, i.e., *not a contaminant.* - Associated with *high mortality rate.* - Plagued by *limited sensitivity*. Frequently a patient may have multiple negative cultures only to have candidiasis diagnosed on autopsy

9 risk factors for candidiasis - 3 aren't the regular immunodepression ones (one is same as M. furfur)

- Antibiotic use, especially broad-spectrum antibacterial antibiotics - Extremes of age - Chemotherapy - Neutropenia - *Gastric acid suppression* - *Abdominal surgery* - Central venous catheters (CVCs) - *Total parenteral nutrition (TPN)* via intravenous hyperalimentation - Variety of genetic defects or variants (recently recognized and expanding)

Asp: RFs for invasive and dissimeinated infections (6) - 3 bolded that are different from candida RFs

- Neutropenia - *Solid organ transplantation (cytotoxic + steroid Tx)* - Advanced AIDS - *Chronic granulomatous disease (CGD)* - Chemotherapy (cytotoxic) (decr PMN fcn) - *Steroid therapy (decr mac fcn)*

C. albicans: epidemiology - What affects majority of AIDs pts - Invasion frequency and prog - In hospitalized pts...

- Oropharyngeal candadiasis aka *thrush* in most AIDs pts - Frequently extends to esophagitis in them (can be debilitating) - Candida infection is in all AIDs pts, often before detectable immune def - Invasion (including skin infection) not common (10-30% in AIDs), poor prognosis - Nosocomial candida fungemia (from central venous catheters) is 4th leading cause of nosocomial bloodstream infections

PJ: fungal attributes (5) - glucans, susceptibility, spores, genes, taxonomy

- Presence of *cell wall chitin and glucans, including β-glucans.* - Sensitivity to *β-glucan synthase inhibitors (echinocandins)*, which are antifungal agents. - Resemblance of cysts to ascomycetous fungal spore cases (asci), and formation of intracystic bodies resembling ascospores. - Presence of specific *genes* and gene arrangements characteristic of fungi. - *rDNA* and other nucleic acid sequences establish *fungal taxonomy*, probably on a phylogenic branch between Ascomycetes and Basidiomycetes. This feature represents the *"gold standard" for classification.*

PJ: diagnosis - The gold standard - The nonspecific test - Serology?

- The *gold standard* is *histopathologic demonstration* of organism in *biopsy, BAL, or sputum* using *stains or specific antibodies.* - *Beta-D-glucan detection* in blood or other body fluids. This cell wall component is a *marker of invasive fungal processes* but *not specific* for Pneumocystis. - *No culture* method is available. - *Serology is of little benefit* for identifying acute infection because *nearly everyone is seropositive*. - There are ongoing attempts to identify new sensitive and specific assays for clinically significant infection.

C. albicans: 4 clinical syndromes - 3 cutaneous ones I forgot - What causes chronic ___ ___ - List the invasive infection tissues (7 tissues)

1. *Cutaneous* Dermatitis, *onychomycosis (nails), paronychomycosis (nail beds), otitis externa*. 2. *Mucosal* Vulvovaginal, oropharyngeal (thrush), esophageal, perianal infections. 3. *Chronic mucocutaneous candidiasis* - rare This is a heterogeneous collection of clinical syndromes characterized by *extensive, chronic, generally treatment-resistant superficial infections of skin, nails, and oropharynx*, virtually always *without deeper invasion or dissemination*. Frequently, there are global or specific *T-lymphocyte or macrophage defects in CMI,* but *normal or even exaggerated humoral responses*. However, in up to *25-30% of patients, no immunological defect is identified*. In some cases, the CMI defect appears specific for Candida antigens and organisms. In rare cases in which antifungal therapy is successful, the immunologic defect may disappear. Alternately, if the immune defect can be corrected, the fungal infection may resolve. 4. *Invasive/disseminated* Fungemia / bloodstream infection / sepsis, endocarditis, urinary tract infection, meningitis, hematogenous seeding of skin, endophthalmitis, pneumonia.

PJ: clinical syndromes (2) Pneumonia: - location of fungal cells - Pathophys - Exudate and lung appearance - CLinical implications - Lung regions involved, damage is where

1. *Diffuse interstitial pneumonia*. Fungal cells are generally found *extracellularly* (outside host cells). *Trophozoites associate with and damage pneumocytes and cause loss of cells lining alveoli*. The combination of *trophozoite proliferation, cyst formation, and host response* results in *"foamy" eosinophilic exudate filling alveoli, leading to "honeycomb" appearance that may also include host cell debris*. *Gas exchange is seriously compromised. pO2 may descend dramatically*. The *entire lung may be involved*. There may be *significant damage in areas in which the presence of the fungus cannot be demonstrated.* 2. *Dissemination.* Multiple sites.

PJ: 2 morphologic forms, refractivity - Host predominant form (kind of a yeast) - Formation of the second one

1. *Trophozoites* - 2-5 μm, often in groups, *relatively nonrefractive,* individually may resemble cell debris. *Predominant morphological form in host*, generally outnumbering cysts 10:1. May represent *vegetative form similar to yeasts.* 2. *Cysts* - larger than trophozoites, *highly refractive*. May be generated by *fusion of two haploid trophozoites followed by meiotic division* within cyst wall.

Asp: clinical syndromes (list) - 2 not infectious - 1 in bad lung - 2 bad

1. Allergy/hypersensitivity pneumonitis/allergic bronchopulmonary aspergillosis (ABPA) 2. *Mycotoxicosis* 3. *Cavitary colonization* 4. Invasion 5. Dissemination

Asp: Allergy/hypersensitivity (plane) - Name of syndrome (tissue affected) - Progression - Mech

1. Allergy/hypersensitivity pneumonitis/allergic bronchopulmonary aspergillosis *(ABPA)* Over time, *episodes of respiratory distress may become increasingly severe and debilitating. Fungal allergenic components* are involved, but *infection with viable fungi is not necessary.*

LOOBS

1. Identify the *ecological niches, environmental and pathogenic tissue forms, and discuss epidemiology, diagnosis, and treatment for Candida albicans, Aspergillus species, and Pneumocystis jiroveci*. 2. Describe the common clinical situations in which *Candida albicans* can cause disease due to a *localized decrease in host defenses* in an otherwise immunocompetent individual. 3. Identify *oropharyngeal candidiasis (thrush)* as a common and relatively early clinical manifestation in *immunocompromised individuals*, and discuss the *significance of candidiasis in these groups*. 4. Discuss the *clinical syndromes of Aspergillus*. 5. Describe the *most common clinical manifestation of Pneumocystis jiroveci infection* and the *significance of Pneumocystis in an immunocompromised individual.*

Aspergillus: three types (?) the names

A. fumigatus, A. flavus, A. niger

Candida Tx: - AIDs thrush (topical + oral) - Serious (disseminated/blood) infection: the three examples of echinocandins

AIDS patients with oropharyngeal candidiasis typically receive *topical antifungal and oral azole therapy.* Bloodstream infections or other disseminated infections typically merit intravenous treatment with an echinocandin (3 currently available: *caspofungin, anidulafungin, mycafungin)*, or amphotericin B.

Asp: diagnosis - Culture: media, importance - Types of specimens for microscopic analysis (2) - Non-culture: (2) assays: (one is that nonspecific one) - For invasive pulm asp: X-ray findings (2 signs, temporally separated...), utility

Aspergillus *grows well on standard media* and *culture confirmation is important for differentiating Aspergillus spp. from other filamentous fungi*. *Tissue* (e.g., biopsy materials) and *fluid* (e.g., fluid from a bronchoalveolar lavage *[BAL]*) specimens are stained and examined for evidence of the *branching septate hyphae* formed by Aspergillus spp. *Non-culture* based methods include galactomannan and beta-D-glucan assays. *Galactomannan is a component of the cell wall* of Aspergillus, and can be detected in blood and other body fluids. *Beta-D-glucan is a marker of invasive fungal processes* but is *not specific for Aspergillus.* For *invasive pulmonary aspergillosis* there are 2 chest imaging (Xray or CT) findings worth knowing - *the halo sign (earlier in disease progression)* and the *air-crescent sign (later)*. These radiographic signs relate to the *angioinvasiveness* of Aspergillus and are highly suggestive (but not diagnostic) of Aspergillus infection. When either of these is seen in an individual with risk factors for aspergillosis, a prompt evaluation should take place.

Asp: geography and niches - Frequent pain in the neck for whom (not sick ppl)

Aspergillus species are essentially *ubiquitous* in the environment worldwide. *Exposure to airborne fungal cells* is exceedingly common. Aspergillus species are a *frequent contaminant of laboratory media.*

Candida: importance of species ID - Also, importance of resistance (2 types) - Implication for Dx/Tx

C. albicans is the most common for human disease. However, *other species show substantial and increasing incidence*, particularly in certain patient populations, ages, clinical settings, and communities (e.g., neonatal intensive care unit at a major urban medical center). In some studies, other species such as C. glabrata may surpass C. albicans in incidence. Additionally, *both innate (or natural) and acquired (or developed) antifungal drug resistance are increasingly important*. As discussed more below, some Candida species show substantial natural resistance to some antifungals, and any Candida species can potentially develop antifungal drug resistance. *Thus, in some cases, it may be an important goal to culture Candida organisms from disease sites, to determine species, and sometimes to perform antibiotic susceptibility testing.*

C. albicans: diagnosis: oropharyngeal candadiasis (OPC)(thrush); dermatitis, onychomyosis - Presentation - Presumptive and confirmatory methods

Classic clinical presentation includes *adherent white plaques on tongue, buccal mucosa, or corner of the mouth (angular cheilitis).* The syndrome may be *asymptomatic* or *painful in severe cases or when infection proceeds down the esophagus* (esophagitis), which may result in *poor feeding and nutritional compromise*. Similar syndromes can be seen with dermatitis such as *diaper rash and onychomycosis (nail infection).* Presumptive diagnosis is typically based on *clinical presentation and patient history.* Confirmation may be performed by microscopic examination of a *KOH prep* on a scraping from the lesion.

C. albicans: diagnosis: vulvovaginal (yeast infection) - Presentation - PE: Canada slide - Fluid testing: pH, KOH appearance - Next most common species, morphological difference - Culture an further typing (3: differentiate albicans from others, colored colonies, wells)

Classic clinical presentation includes *vulvar erythema (redness) and pruritis (itching), and/or thick cheesy vaginal discharge*, but these signs / symptoms are not specific and may not be present. Diagnosis is accomplished by *pelvic speculum examination* (classically showing *white plaques adherent to the vaginal wall)* and *testing of vaginal fluid* with following results: - *pH 4-4.5 (same as normal vaginal fluid pH;* higher pH is observed in bacterial vaginosis or Trichomonas vaginitis). - *Microscopic examination* of wet mount or KOH prep (fluid mixed with 10-20% potassium hydroxide solution and incubated at room temperature or heated to 50C). Most (80-90%) isolates are Candida albicans, which will show *filamentous fungal elements (hyphae, pseudohyphae, germ tubes)*. The next most common species, and the most common in some communities or patient populations, is *Candida glabrata*, which has *no filamentous form and shows only budding yeasts.* - *Culture* on selective media, followed by *further typing*: 1) *Germ-tube test*: culture sample is mixed with serum and incubated at 37C for 1-2 hr. Appearance of germ tubes on microscopic exam indicates C. albicans. This rapid assay *differentiates C. albicans from most other Candida species*. 2) Use of *solid medium* containing components causing *different Candida species* to grow as colonies with distinct colors and appearances. 3) *Colorimetric metabolic profiling* using microwell plates or strips, similar to tests used with bacteria.

Relevance of candida species for azole Tx

Currently, most C. albicans isolates are highly susceptible to many antifungal agents, including fluconazole. However, *C. glabrata and C. krusei show natural resistance to fluconazole*, which therefore would not be appropriate therapy for infections with these species

Asp: dissemination

Dissemination to a variety of sites and systemic disease has a very *poor prognosis*

PJ: - Epidemiology: risk group - V factors

E. Epidemiology *70-80% of AIDS patients have PCP at least once*. PCP is the *cause of death in 15-20%* of AIDS patients. F. *Virulence Determinants - difficult to identify* in very technically challenging organism with *lack of in vitro culture system.*

Asp: Tx - Standard until recently - The DOC now - In transplant pts (vori + ____) - Recently approved drug (think of posing scarecrow)

High-dose amphotericin B has been the standard of care for invasive infections until recently. *Voriconazole is now considered the drug of choice*. In *transplant recipients* (therapeutically immunosuppressed), combination therapy with *voriconazole and an echinocandin* appears to yield the best results. *Posaconazole* has recently been approved for preventing Aspergillus infections *in immunocompromised individuals.*

Asp: cavitary colonization (fungal balls aka) - Progression/presentation - RFs (think types of cavities) - Complications (think hemoptysis) - Tx

Infection due to colonization of pre-existing cavities may occur and *remain chronic for years with minimal symptoms*. Risk factors for cavitary colonization include *tuberculosis, emphysema, smoking, and hereditary alpha-1-antitrypsin deficiency.* Fungus balls *(aspergillomas)* may lead to problems from *mass effects* such as *bronchial obstruction*, or rarely *erosion into blood vessels*, which may result in *life-threatening hemoptysis*. Resolution typically requires *surgical excision* if indicated and allowed by the patient's condition, since access by host white blood cells or antibiotics to the fungal mass is very limited.

Asp: invasion - 2 tissues, leading to... (name of one complication, and another)

Invasion of *lung tissue* or *erosion into blood vessels* may occur, leading to *localized inflammatory, granulomatous, and necrotizing disease of lung (invasive pulmonary aspergillosis, or IPA)* or *other tissues*. Erosion into blood vessels may lead to *life-threatening bleeding*, as exemplified by *massive hemoptysis* when the lung is involved.

PJ: environmental niche

It is *unknown* if there is an environmental reservoir. Pneumocystis *DNA sequences have been amplified* using PCR from environmental sources, e.g., room air, an apple orchard.

Candida and C. albicans: morphology - Yeasts, hyphae, everything else, where they exist as each (20 and 37) (pH) - Which forms are invasive - Could get a variety all at once - Which species is monomorphic, which is the only species that gets germ tubes

Most Candida species are *dimorphic*, with yeast and hyphal morphotypes, also often showing *pseudohyphae* (chains of elongated yeasts) and *yeasts with germ tubes (extensions) during conversion to hyphae*. Environmental regulation of morphology is complex. C. albicans exists as a *yeast while living as a commensal organism on the body surface*, causing disease confined to the outer surface of the skin or mucosal surfaces, and in the *laboratory at room temperature* and under some other conditions (e.g., acid pH). The *hyphal form invades tissue* and can be grown in the *laboratory under certain conditions (e.g., 37 °C, neutral pH, presence of serum)*. In any particular clinical specimen, a variety of forms may be observed. In general, *all filamentous forms including hyphae, PSEUDOHYPHAE, and germ tubes are considered invasive elements*. Yeast cells are generally observed when the fungus is present as a benign commensal organism, but may also be observed in disease states. One species, *C. glabrata, shows only a yeast form, i.e., it is not dimorphic*. Small group: *germ tubes are only on ALBICANS*

C. albicans: infections in immunocompetent ppl (2 examples)

Pathologic *skin, nail, and mucosal infection* occurs in apparently immunocompetent hosts due to a *localized diminishment in host defenses*. - *Dermatitis* when *moist skin is abraded* or environmental conditions particularly favor fungal growth. - *Vaginitis (vulvovaginal candidiasis)* when *antibiotic therapy* changes the *composition of the normal flora* or *physiologic changes in the microenvironment* occur.

PJ: infection - Ways to ID organism - What serologic studies indicate - Most common disease manifestation - What this all says about exposure and route of infection - ______ IS COMMON, ROUTE IS ______

The organism can be identified (*visualized microscopically, specific DNA sequences and proteins detected, infection transferred to another animal*, *NOT CULTURED IN VITRO*) from the lungs (and other tissues in cases of dissemination) of infected people and animals. *Serologic studies* (looking for anti-Pneumocystis antibodies) *indicate common exposure* to the organism in the *normal human population*. The incidence of infection in immunocompromised animal colonies and in AIDS patients indicates common exposure. The most common disease manifestation is *pneumonia (PCP).* *Thus, it is presumed that environmental exposure is common, and that the route of infection is respiratory.*

RFs for C. albicans fungemia/dissemination (3) - CMI (2 groups) - GI tract ____ - cath

This syndrome may occur in patients with particular risk factors, often multiple risk factors: - Severe compromise of cell-mediated immunity (CMI), e.g., premature neonates, late-stage AIDS. - *GI tract leakage* due to significant abdominal pathology resulting from malignancy, perforation, or surgery. - Iatrogenic introduction of a foreign body, e.g., intravenous catheter, surgical drain, breaking the skin barrier and providing a nidus for biofilm formation. *Candida is one of the top 4 causes of nosocomial BSI, and shows particularly high mortality (40-100%).*

Pneumocystis jiroveci (Formerly Pneumocystis carinii f.sp. hominis) and Pneumonia (PCP)

Yeah that's just a lot of words.