Choosing an Antifungal



Choosing an Antifungal


Paul Lewis

James W. Myers



Fungal infections are becoming increasingly common, mostly as a result of medical progression. Broad-spectrum antibiotics, aggressive surgeries, central lines, and immunosuppression are among the risk factors predisposing patients to fungal invasion. Risk factors are listed in Table 58-1. Susceptibility testing is available, usually as a send-out lab. Candida testing can be performed on some automated systems. This is usually not necessary, and treatment is generally guided by the knowledge of resistance patterns. For example, the majority of Candida species are susceptible to fluconazole; however, Candida krusei is inherently resistant and an alternative agent should be selected. This chapter focuses on selecting the most appropriate antifungal agent empirically and organism directed.


MORPHOLOGIES

Fungi come in a variety of shapes and sizes. Many fungi are noninvasive to humans and include organisms such as mushrooms, rusts, smuts, puffballs, truffles, and morels. Some fungi can cause infection in a normal host; however, most are opportunistic organisms taking advantage of a weakened immune system. Fungi that are invasive to humans usually come in three forms: yeasts, molds, and dimorphic fungi.



  • Yeasts



    • Unicellular spherical organisms


    • Reproduce via binary fission or budding


    • Common organisms



      • Candida



        • Most common cause of invasive fungal disease.


        • Candidemia is the fourth leading cause of nosocomial bloodstream infections.


        • Noted species



          • Candida albicans


          • Candida tropicalis


          • Candida parapsilosis


          • Candida glabrata


          • C. krusei


          • Candida lusitaniae


          • Candida guilliermondii


      • Cryptococcus



        • Encapsulated organism


        • Notable species



          • Cryptococcus neoformans


          • Cryptococcus gattii









            Table 58-1 Risk Factors for Fungal Infections































            Broad-spectrum antibiotics


            Central venous catheters


            Total parenteral nutrition


            Immunosuppression

            Transplants

            Antineoplastics and neutropenia

            HIV/AIDS

            Chronic steroid use


            Prosthetic valves and devices


            Aggressive surgeries


            Renal replacement therapy


            Diabetes mellitus



  • Molds



    • Complex in nature and exist as higher order structures


    • Filamentous fungi ubiquitously found in soil and decaying material


    • Contain filamentous branching structures known as hyphae


    • Notable species



      • Aspergillus



        • Aspergillus fumigatus


        • Aspergillus niger


        • Aspergillus terreus


      • Zygomycetes



        • Order of Mucorales



          • Rhizopus



            • Rhizopus arrhizus


            • Rhizopus microsporus


          • Absidia corymbifera


          • Rhizomucor pusillus


          • Mucor racemosus


          • Cunninghamella bertholletiae


      • Scedosporium



        • Scedosporium apiospermum



          • Pseudallescheria boydii (sexual form or teleomorph)


        • Scedosporium prolificans


      • Fusarium



        • Fusarium solani


        • Fusarium moniliforme


        • Fusarium oxysporum


      • Cladosporium


      • Penicillium marneffei


      • Paecilomyces lilacinus


  • Dimorphic fungi



    • Exist in both the yeast and mold form depending on the temperature


    • In the human body, these organisms present as yeasts.



    • These organisms also tend to be endemic to certain regions.


    • Common organisms



      • Histoplasma



        • Endemic to central and eastern United States covering the Ohio and Mississippi River valleys as well as Central and South America, the Caribbean islands, and temperate regions of Asia


        • Notable species



          • Histoplasma capsulatum


      • Blastomyces



        • Endemic to the southeastern and south central states adjacent to the Mississippi and Ohio Rivers, the midwestern states that border the Great Lakes, and parts of New York adjacent to the St. Lawrence Seaway, as well as parts of Canada adjacent to large waterways


        • Notable species



          • Blastomyces dermatitidis


      • Coccidioides



        • Endemic to southern Arizona, central or other areas of California, southern New Mexico, and West Texas


        • Most common clinical presentation is a self-limited subacute community-acquired pneumonia presenting 1 to 3 weeks after contact


        • May progress to an acute infection in select populations


        • Notable species



          • Coccidioides immitis


          • Coccidioides posadasii


      • Sporothrix



        • Found throughout the world in decaying vegetation, sphagnum moss, soil, and digging animals, such as armadillos


        • Notable species



          • Sporothrix schenckii



DIAGNOSIS

While diagnosis of superficial fungal infections can be accomplished easily by direct examination (thrush), invasive fungal infections can be difficult with limited available tests. Fungal cultures are available although sensitivity can be lacking. Blood cultures are only positive in about 50% of cases. Biopsies still play an important role if feasible, though many critical conditions prevent the attainment of reliable biopsies. In the absence of biopsy or culture-guided therapy, serologic markers, antigen testing, and nucleic acid testing have become increasingly common. Imaging and radiographic evidence also assist in diagnosis.



  • Fungal cultures



    • Single best method for detecting fungal pathogens


    • Generally require aeration and agitation


    • Can be taken from blood, skin, mucosa, tissues, CSF, and secretions


    • Yeasts grow easily on a variety of media.



      • Sometimes contain antibacterials to enhance fungal growth


      • Candida may be differentiated on plates such as the CHROMagar.



    • Molds can be determined by macroscopic and microscopic growth.


    • Advantages



      • Identifies species


      • Can be used to perform susceptibility testing


    • Disadvantages include



      • Cannot differentiate pathogen versus colonization



        • Candida in sputum or urine


        • Aspergillus in respiratory secretions


      • Long-time incubation period


  • Microscopic examination of tissue samples and fluids



    • Common stains on exudates and fluids



      • Gram stain


      • Potassium hydroxide (KOH)


      • Giemsa stain


      • Wright stain


    • Wet mounts with or without KOH



      • Budding yeast cells with hyphae indicate C. albicans.


      • Yeast with a “figure eight” or broad budding pattern is characteristic of B. dermatitidis.


      • Encapsulated cells indicate C. neoformans.


      • Large cells with endospores indicate C. immitis.


      • Septate hyphae with acute-angle branching indicate molds such as Aspergillus, Mucor, Fusarium, Penicillium, Pseudallescheria, and Scopulariopsis.


    • Special stains



      • India ink stain—used for C. neoformans


      • Mucicarmine stain—also used for C. neoformans


      • Gomori methenamine silver (GMS)—useful for H. capsulatum


      • Hematoxylin-eosin (H&E)—shows dematiaceous fungi


      • Periodic acid-Schiff—used to stain internal structures


    • Advantages



      • Practicality and sensitivity


      • Rapid detection


    • Disadvantages



      • Cannot differentiate pathogen from colonization


  • Biochemical markers



    • Serologies



      • Relies on immune system to form antibodies to pathogens


      • Not useful in clinical practice



        • Immunocompromised may not produce antibodies.


        • Positive results may only indicate exposure.


    • Antigen testing



      • Detects fungal component in blood, urine, or CSF


      • Advantages



        • Quick turnaround time


        • Specificity


      • Disadvantages



        • Potential for crossover between species


        • Not available for many organisms


    • Molecular testing



      • Uses nucleic acid amplification technology such as polymerase chain reaction (PCR) to detect individual genetic material



      • Advantages



        • Highly sensitive and specific


      • Disadvantages



        • Not universally available


        • Expensive


        • Cannot distinguish from contamination


    • See Table 58-2 for a list of biochemical markers


  • Imaging



    • Plays an important role, especially when more invasive diagnostic testing is not available


    • Some of the more common findings are listed below, though this list is far from all-inclusive.


    • Pulmonary aspergillosis



      • Plain radiographs are relatively insensitive


      • CT scan much more reliable



        • “Tree-in-bud” pattern or branching linear opacities


        • “Halo sign” macronodules surrounded by ground glass opacity


        • “Air-crescent” sign and cavitary nodules



          • Resulting from necrotic tissue separating from surrounding lung tissue


          • May develop into a thin wall cavity and become secondarily infected


    • Pulmonary mucormycosis



      • Chest radiograph shows rapidly progressive lobar or segmental consolidation.


      • Upper lung lobes most commonly affected.


      • Other findings include multilobar consolidation, nodules or masses, lymphadenopathy, and pleural effusions.


      • CT findings similar to aspergillosis.


    • Pulmonary cryptococcosis



      • Radiography may show diffuse interstitial opacities, especially in HIV+.


      • Immunocompromised may also show cavitation, miliary disease, pleural effusions, and lymphadenopathy.


    • Pulmonary coccidioidomycosis



      • Acute disease may present as airspace opacities and consolidation.


      • May also show as multifocal, ill-defined pulmonary nodules


    • Acute pulmonary histoplasmosis



      • Radiographs may be normal or minimal parenchymal opacities.


      • In severe cases, may show bilateral diffuse reticulonodular opacities.


ANTIFUNGAL AGENTS

Unlike bacteria, fungi are eukaryotic organisms. Many of the cellular structures are similar to mammalian cells. Due to the overlap, many of the fungal targets create significant toxicities limiting their use. Ergosterol, the fungal cell membrane equivalent of cholesterol, is the target of the polyene antifungals and azole antifungals. The first in class agent, ketoconazole, also inhibited several enzymes in mammalian steroid metabolism leading to many of the adverse events. Newer azoles have greater specificity for fungal targets and have less toxicity than older agents. Flucytosine gets deaminated to 5-fluorouracil inside the fungal cell resulting in similar toxicity. Fungi also contain a cell wall, unlike mammalian cells. This is the target of the newest class of antifungals known as the echinocandins with minimal adverse effects. For a comparison of toxicity, see Table 58-3.









Table 58-2 Non-Culture-Based Laboratory Tests for Invasive Fungal Diseases
































































































Assay

Organisms

Source

Accuracy (%)

Advantages

Disadvantages


1,3-β-D-glucan (Fungitec)

Multiple

Serum, BAL

Sen 85-90 Spec 95-100

Rapid turnaround

Does not detect Cryptococcus or Zygomycetes


PCR

Multiple

Many

Sen 64-100 Spec 64-95

Able to detect species

False positives (contamination)


Mannan Ag/Ab α/β-Ag

Candida, except C. krusei and C. parapsilosis

Serum

Sen 80-85 Spec 93-95

Good for surveillance

Does not differentiate species


D-arabinitol assay

Candida except C. krusei

Serum, urine

Sen 58-100 Spec 86-91

Good for surveillance

Poor sensitivity for C. glabrata


FISH

C. albicans C. glabrata

Gram stain

Sen 95-100 Spec 100

Differentiates organisms

Limited detection threshold


Antibodies

Multiple

Serum

Poor

None

Poor performance


Galactomannan

Aspergillus

Serum

Sen 22-90 Spec 84-93

Surveillance in high-risk groups

False positives with piperacillin-tazobactam or ampicillin/sulbactam


D-mannitol

Aspergillus

BAL, serum

No data


Animal studies only


Cryptococcal Ag

Cryptococcus

Many

Sen 71-100 Spec 97-100

Very good for CSF, serum, BAL

Does not differentiate species, false positives


Coccidioidomycosis IgM

C. immitis C. posadasii

Many

Sen 56-83 Spec 75-10

IgG can track treatment

Delayed antibody response


Histoplasma Ag

H. capsulatum

Many

Sen 70-95 Spec 99

Antigen levels follow treatment response

Poor sensitivity for subacute disease


Blastomyces Ag

B. dermatitidis

Many

Sen 80-93 Spec 79

Good performance

Cross reactivity with other fungi


BAL, bronchoalveolar lavage; Sen, sensitivity; Spec, specificity; PCR, polymerase chain reaction; FISH, fluorescent in situ hybridization; Ag, antigen; CSF, cerebrospinal fluid; Ab, antibody










Table 58-3 Adverse Reactions of Antifungal Agents













Amphotericin

Azoles

Echinocandins

Flucytosine


Infusion-related reactions: fever, chills, rigors, myalgias, arthralgias, nausea, vomiting, headaches, sweating and bronchospasm Nephrotoxicity: potassium- and magnesiumwasting azotemia, renal tubular acidosis, and impaired urinary concentration


Hepatotoxicity


Bone marrow suppression


Hypocalcemia


Anemia


Phlebitis


Rash


Hypotension


Hypertension


Tachycardia


Metallic taste

Hepatotoxicity


Skin rash


Hypokalemia


QTc prolongation


Voriconazole: transient visual disturbance (photopsia), CNS disturbances


Itraconazole: CHF exacerbation

Histamine-mediated symptoms: rash, pruritus, facial swelling


Increased LFTs, bilirubin


Phlebitis


Anaphylaxis (rare)

(Similar to 5-fluorouracil)


Gastrointestinal intolerance (diarrhea)


Bone marrow suppression


Pruritus


Peripheral neuropathy


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Jun 22, 2016 | Posted by in INFECTIOUS DISEASE | Comments Off on Choosing an Antifungal

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