In addition, drug susceptibility studies

also may not correlate with clinical efficacy because in vitro results for individually

tested drugs may show resistance, but combination therapy may be additive or

synergistic. Finally, some antimycobacterial agents exhibit large differences between

the minimum inhibitory concentration and maximum bactericidal concentration. This

finding may reflect the difficulty in eradicating this organism, particularly in a

severely immunocompromised host. Despite these limitations, in vitro drug

susceptibility testing is only recommended for macrolide antibiotics because of the

correlation with clinical outcomes.

115

p. 1618

p. 1619

DRUG THERAPY

CASE 77-8, QUESTION 4: What drug regimens could be selected to treat M.E.?

The guidelines recommend a two-drug or more MAC regimen, because

monotherapy can lead to breakthrough bacteremia and resistance; at least one of these

drugs must be a macrolide. Clarithromycin (500 mg PO BID) is the preferred agent

because there are more clinical data; however, if intolerable or significant drug

interactions need to be avoided, azithromycin 500 to 600 mg PO QD is an

alternative. Doses of clarithromycin greater than 1 g/day in the treatment of MAC

have been associated with increased mortality.

12 Ethambutol (15 mg/kg/day PO) is

recommended as the second agent. Several drugs can be used as the third agent,

including rifabutin (300 mg/day), amikacin (10–15 mg/kg/day), and fluoroquinolones.

The choice of the third agent depends on the severity of the illness including high

mycobacterial loads, CD4 count less than 50, drug interactions, hepatic and renal

function, patient tolerability, patient compliance, and cost. Long-term therapy may be

discontinued in patients who have completed a course of more than 12 months of

treatment for MAC, remain asymptomatic, and have a sustained increase (e.g., >6

months) in their CD4 count to greater than 100 after HAART.

12

Although four-drug regimens have been used, one study observed that a three-drug

macrolide regimen (clarithromycin, ethambutol, and rifabutin) was more effective

than a four-drug regimen (ciprofloxacin, clofazimine, ethambutol, and rifampin).

116

Benefits of the macrolide regimen included more rapid clearing of MAC bacteremia

and a longer duration of survival. Rifabutin, at 600 mg/day, induced uveitis in

approximately one-third of patients. Subsequently, the rifabutin dosage was lowered

to 300 mg/day, and the incidence of uveitis decreased to 5.6%. Although clearance of

bacteremia was superior at the higher rifabutin dose, no differences in survival were

observed.

IRIS can also occur with MAC disease. IRIS-associated fever and lymphadenitis

are difficult to differentiate from active MAC disease. IRIS most commonly occurs in

patients with MAC and very low CD4 counts with the initiation of antiretroviral

therapy. The disease is often self-limiting and requires no therapy; however, steroid

therapy may be warranted in severe disease. For this reason, for patients not taking

antiretroviral therapy, it may be warranted to administer MAC therapy for 2 weeks

before the initiation of antiretroviral therapy to minimize the risk of IRIS.

12

M.E. is placed on a regimen of clarithromycin 500 mg twice daily and ethambutol

15 mg/kg/day. The choice to use two drugs, rather than three, is based on M.E.’s poor

adherence profile. Other considerations for the addition of a third-line agent include

the severity of the illness, potential drug interactions, tolerability, hepatic and renal

function, and cost. M.E. must be counseled regarding the slow response to treatment.

If she improves, therapy should be continued and HAART should be reinstituted.

Monitoring Therapy

CASE 77-8, QUESTION 5: How should M.E. be monitored?

The primary goals of MAC therapy are to eradicate or reduce the number of M.

avium organisms, decrease symptoms, enhance quality of life, and prolong survival.

M.E. should be monitored for symptomatic relief (temperature spikes and frequency

of night sweats), as well as a microbiologic response (colony-forming units/mL).

Clinical response, as well as a decline in the quantity of mycobacteria, is expected in

2 to 4 weeks but may be delayed in patients with extensive disease. If no clinical

response is seen in 4 to 8 weeks, repeat blood cultures for MAC should be obtained

along with repeat susceptibility testing for clarithromycin and azithromycin. If

resistance is observed or suspected, two new drugs should be added based on

susceptibility testing with or without the macrolide. If the organism is found to be

susceptible to macrolides, therapy should be continued and adherence, absorption,

tolerance, and drug interactions should be considered.

12

If the problem is determined

to be drug absorption, IV agents can be considered. M.E. should also be followed for

the development of toxicities related to drug therapy. Furthermore, because many

drugs used to treat MAC infections are associated with drug interactions, this issue

must be considered each time a new drug is prescribed. In some cases, drug doses

need to be modified or alternative drugs should be selected to prevent adverse events

or therapeutic failures.

12

,

115

CASE 77-8, QUESTION 6: What drug(s) should be used to provide primary prophylaxis against MAC

infection?

Prophylaxis

The most recent official guidelines recommend oral therapy with clarithromycin (500

mg BID) or azithromycin 1,200 mg every week or 600 mg twice weekly for persons

with a CD4 count less than 50. Although the combination of azithromycin and

rifabutin is more effective than azithromycin alone, the increased cost, adverse

events, potential for drug interactions with rifabutin, and the absence of a survival

benefit preclude this regimen from being routinely recommended. If neither

clarithromycin nor azithromycin is tolerated, rifabutin 300 mg/day may be used

(Table 77-1).

12

Six hundred eighty-two patients with AIDS, CD4 counts less than 100, and

negative MAC blood cultures were randomly assigned to receive clarithromycin

(500 mg PO BID) or placebo.

33 The clarithromycin arm had a 69% reduction in MAC

bacteremia and fewer (16% vs. 6%) cases of MAC infection. Significantly more

patients in the clarithromycin arm survived during the 10-month follow-up (68% vs.

59%), with an accompanying longer median duration of survival. This trial was the

first prospective MAC prophylaxis study demonstrating a survival benefit and a

reduced risk of disseminated MAC infection.

33

Azithromycin 1,200 mg every week, rifabutin 300 mg/day, and a combination of

both drugs in the same doses were compared in patients with AIDS and CD4 counts

less than 100. The incidence of MAC bacteremia was 13.9% in the azithromycin

monotherapy arm, 23.3% in the rifabutin monotherapy arm, and 8.3% in the

azithromycin plus rifabutin combination arm. Time to death was not significantly

different among the treatments; however, the combination arm had an increased

incidence of adverse drug effects. Although combination therapy was superior to

azithromycin alone, its use is considered second-line therapy because of the

increased cost, toxicity, and lack of survival benefit.

117

The decision to use clarithromycin or azithromycin (both first-line

recommendations for primary prophylaxis) is based on patient compliance and the

potential for drug interactions. Azithromycin (1,200 mg once weekly or 600 mg twice

weekly) may be preferable for a patient who has difficulty with compliance. In

contrast to clarithromycin, azithromycin does not affect the cytochrome P-450 enzyme

system and is therefore less likely to interact with other drugs. M.E. would have

benefited from MAC prophylaxis when her CD4 count decreased to less than 50.

Patients whose CD4 count increases from 100 for more than 3 months may

discontinue primary prophylaxis (Table 77-2). However, prophylaxis should be

reintroduced if the CD4 count decreases to less than 100.

12

p. 1619

p. 1620

MUCOCUTANEOUS CANDIDIASIS

CASE 77-9

QUESTION 1: P.J. is a 45-year-old, HIV-positive man who was started on abacavir, lamivudine, and

darunavir/cobicistat when he was diagnosed 1 year ago. P.J. is a heroin user and has not been seen in the clinic

since his initial presentation. He appears today complaining of difficult, painful swallowing and diffuse pain. On

examination, localized white plaques are observed in the oral cavity. His CD4 count is 280 cells/μL. What is the

most likely cause of this patient’s dysphagia and odynophagia?

Candida can cause both oropharyngitis and esophagitis in HIV-infected patients

typically when CD4 counts are <200 cells/μL. Additionally, patients can present

with CMV, HSV, or aphthous ulcers in the oropharynx. Symptoms include dysphagia,

odynophagia, and thrush (with Candida infections). Oral ulcers are common with

HSV, rare with Candida, and uncommon with CMV or aphthous ulcers. Pain is

usually diffuse in Candida infections and more focused with HSV, CMV, and

aphthous ulcers. Fever is primarily associated with CMV.

12

Most infections are due to Candida albicans; however, because of the exposure of

fluconazole, emergence of non-albicans species such as Candida glabrata has

appeared and in some cases led to refractory candidiasis.

12 Patients with localized

white plaques in the oral cavity likely have oral candidiasis (thrush) and should be

started on antifungal therapy. Oral fluconazole (100 mg once daily) is considered the

drug of choice for the treatment of oropharyngeal candidiasis because it is more

convenient and better tolerated than topical therapies. Patients may also be treated

with local antifungal therapy (e.g., “swish and swallow” nystatin suspension, 1

teaspoon 4 or 5 times daily, or clotrimazole troches 4 or 5 times daily). The

preferred therapy for esophageal candidiasis is 14 to 21 days of fluconazole at higher

doses (up to 400 mg PO or IV daily). Alternate therapies include itraconazole and

posaconazole (for oropharyngeal disease) and voriconazole, anidulafungin,

caspofungin, micafungin, and amphotericin B (for esophageal disease).

13 Primary

prophylaxis is not recommended for candidiasis.

12

A presumptive diagnosis of Candida esophagitis can be made for P.J. because he

presents with oral pharyngeal candidiasis, dysphagia, and odynophagia. P.J. should

be empirically treated with fluconazole 200 mg/day for 14 to 21 days. If he is

unresponsive to fluconazole, endoscopy with biopsy and culture should be performed

to confirm the diagnosis as well as Candida speciation. If candidiasis is confirmed,

P.J. should be checked for medication adherence and potential drug interactions. If

the patient is adherent and does not have malabsorption, posaconazole suspension or

itraconazole solution should be considered. In addition, higher doses of fluconazole

could be considered before the initiation of alternative IV therapy. Relapse is

common in patients who do not receive secondary prophylaxis. Chronic suppressive

therapy (fluconazole, 100–200 mg/day) could be considered in patients responsive to

fluconazole therapy who have frequent or severe recurrent esophagitis; however, the

risks of fluconazole resistance should be considered.

12

ACKNOWLEDGMENTS

The authors acknowledge Angela D.M. Kashuba, Gene D. Morse, Alice M.

O’Donnell, Marjorie Robinson, and Mark J. Shelton, for their contributions to this

chapter in the previous editions.

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cryptoccal meningitis. N EnglJ Med. 1979;301:126.

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Larsen RA et al. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in

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for the treatment of cryptococcal meningitis: a randomized trial in Malawi. Clin Infect Dis. 2010;50:338.

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p. 1620

Owing to increased numbers of immunocompromised patients, the use of

invasive devices, and an aging patient population, invasive fungal

infections are the fourth most common nosocomial infection.

Yeast infections are generally easier to treat than mold infections.

However, mortality is stillsignificant for both types of infection, even

when treated appropriately.

Table 78-2

Most common risk factors for acquiring mycotic infections include

immunocompromised host, the use of broad-spectrum antibacterials, and

breakdown of physical barriers including invasive catheterization.

Case 78-3 (Questions 1,3)

Diagnostic tools (i.e., serum galactomannan or β-glucan) can be useful

as monitoring parameters for therapeutic outcome assessment.

Case 78-3 (Question 2)

The Infectious Disease Society of America (IDSA) and the Mycoses

Study Group are important sources for guidelines and evidence-based

approaches to therapy.

Case 78-5 (Question 1)

Dermatophyte infection is most commonly associated with Tinea

ringworm, and the most effective antifungal agents include itraconazole

and terbinafine.

Case 78-1 (Questions 1–3)

Sporothrix is one of the most common fungal pathogens associated with

subcutaneous infections. Amphotericin, terbinafine and itraconazole are

useful treatments.

Case 78-2 (Questions 1–3),

Figure 78-1

Candida represents the most common cause of systemic fungal infection

in hospitalized patients. Candidemia must be treated promptly and

appropriately. Delay in treatment or failure to adhere to IDSA

guidelines results in a significant increase in mortality. Fluconazole and

echinocandins are the most recommended prephylaxis and therapies for

disseminated candidiasis.

Case 78-3 (Questions 1–4,

11),

Table 78-4–78-6

Fluconazole, although reliable against Candida albicans, is less reliable

against certain non-albicans Candida species, including Candida glabrata

and Candida krusei.

Case 78-3 (Question 5)

Conventional amphotericin is associated with significant infusion-related

adverse events, nephrotoxicity, and electrolyte abnormalities.

Case 78-3 (Questions 6–10),

Table 78-3

Consequently, other agents, including lipid-based amphotericin B,

triazoles, and echinocandins, are drugs of choice for most deep-seated

fungal infections.

In patients with yeast identified in urine, the selection of drug therapy for

a simple candiduria versus organ infection as a result of disseminated

candidiasis is complicated by difficulties with diagnostics.

Case 78-4 (Question 1)

Blastomycosis, histoplasmosis, and coccidioides are associated with

endemic infection from specific geographic areas. Long-term treatment

with polyenes and/or azole antifungals is useful in the management of

these diseases.

Case 78-5 (Questions 1–3),

Case 78-6 (Questions 1–3),

Case 78-7 (Questions 1–3),

Figures 78-2–78-4, Table 78-

7

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Aspergillus is the most significant fungal pathogen associated with

severely immunocompromised patients. Aggressive, immediate

treatment with voriconazole alone or in combination with other

antifungals is the most effective therapy for disseminated disease.

Case 78-8 (Questions 1–3),

Figure 78-5, Table 78-8

Cryptococcus neoformans is associated with opportunistic infection,

particularly in acquired immunodeficiency syndrome (AIDS), and the

central nervous system (CNS) is a common site of infection. Initial

treatment of meningitis in AIDS should include amphotericin B plus

flucytosine, followed by long-term fluconazole.

Case 78-9 (Questions 1–3)

Mycotic (fungal) infections are now the fourth most commonly encountered

nosocomial infection. Attributable mortality associated with invasive yeast infections

can approximate ~40%, whereas molds typically double that observed rate (i.e.,

invasive aspergillosis). This increase can be attributed, in part, to the growing

numbers of immunocompromised hosts as a result of organ transplants, cancerchemotherapy–associated neutropenia, and AIDS. This chapter reviews the

mycology, diagnosis, and pharmacotherapeutics for common mycotic infections. For

a more in-depth presentation of the basic biology of fungi, as well as the

epidemiology, pathogenesis, immunology, diagnosis, and monitoring of mycotic

infections, see Clinical Mycology.

1 You are referred to other chapters including

Chapter 65, Central Nervous System Infections; Chapter 66, Endocarditis; Chapter

70, Intra-Abdominal Infections; Chapter 73, Osteomyelitis and Septic Arthritis;

Chapter 75, Prevention and Treatment of Infections in Neutropenic Patients; Chapter

76, Pharmacotherapy of Human Immunodeficiency Virus Infection; and Chapter 77,

Opportunistic Infections in HIV-Infected Patients for detailed pharmacotherapy in

these human pathologies.

MYCOLOGY

Morphology

The pathogenic fungi that infect humans are nonmotile eukaryotes that are reproduced

by sporulation, and they exist in two forms: filamentous molds and unicellular yeasts.

These forms are not mutually exclusive, and depending on the growth conditions, a

fungus may exist in one or even both of these forms (Table 78-1).

The dimorphic fungi (e.g., Histoplasma capsulatum and Blastomyces dermatitidis)

grow as a mold in nature (27°C) but quickly convert to the pathogenic yeast form

after infecting the host (37°C). This mycelium-to-yeast conversion is an important

factor in the pathogenesis of disease caused by these organisms. Other pathogenic

fungi, such as Aspergillus species, grow only in a mold form, whereas C. neoformans

usually grows in a yeast form. Candida species grow with a modified form of

budding whereby newly budded cells remain attached to the parent cells and form

pseudohyphae. Fungi are aerobic and are easily grown on routine culture media

similar to that used to grow bacteria. Most fungi grow best at 25°C to 35°C. Fungi

that cause only cutaneous and subcutaneous disease grow poorly at temperatures

greater than 37°C. This temperature-selective growth explains, at least in part, why

these organisms rarely disseminate from a primary focus in the skin or subcutaneous

tissues.

Classification

Fungal infections are best classified by the area of the body infected (Table 78-2).

Superficial mycoses involve only the outermost keratinized layers of the skin (stratum

corneum) and hair. The cutaneous mycoses extend deeper into the epidermis and may

also infect the nails. The subcutaneous mycoses infect the dermis and subcutaneous

tissues; entry into these sites is by the inoculation or implantation of dirt or vegetative

matter. The systemic mycoses cause disease of the internal organs of the body.

Standard definitions that are useful in daily patient care for invasive fungal infections

have been developed for epidemiologic and clinical trials. The guidelines are

referenced under each infection. The respiratory tract is the most common primary

portal of entry, and lung infection may be symptomatic or asymptomatic. Systemic

infection with Candida usually results from a primary focus on the gastrointestinal

(GI) tract or skin. In each case, the organism may spread hematogenously from the

primary focus throughout the body, resulting in disseminated disease. The

opportunistic mycoses occur primarily in the immunocompromised host and require

immediate and aggressive treatment. The list of fungi that cause opportunistic

infection has expanded, especially with the AIDS epidemic; however, the now

commonplace use of highly active antiretroviral therapy has resulted in some

decrease in this incidence.

2 The nonopportunistic fungi (primary pathogens) usually

cause disease in the immunologically normal host. Some primary pathogens,

however, result in unique clinical syndromes when infection occurs in the

immunocompromised host, such as histoplasmosis in AIDS.

1

Table 78-1

Organism Classification

Hyphae (Molds)

Hyalohyphomycoses

Aspergillus species, Pseudallescheria boydii

Dermatophytes: Epidermophyton floccosum, Trichophyton species, Microsporum species

Phaeohyphomycoses

Alternaria species, Anthopsis deltoidea, Bipolaris hawaiiensis, Cladosporium species, Curvularia geniculata,

Exophiala species, Fonsecaea pedrosoi, Phialophora species, Fusarium species

Zygomycetes

Rhizopus spp., Mucor spp., Rhizomucor spp. Absidia corymbifera

Dimorphic Fungi

Blastomyces species, Coccidioides species, Paracoccidioides species, Histoplasma species, Sporothrix species

Yeasts

Candida species, Cryptococcus neoformans

Pathogenesis of Infection

ENDOGENOUS

Fungal infection can be acquired from both exogenous and endogenous sources. The

only pathogenic fungi identified as commensals within the human microbiome are

Pityrosporum orbiculare, which causes the noninflammatory superficial condition of

tinea versicolor, and Candida species. Infections with these yeasts primarily develop

from the patient’s own normal flora (endogenous infection). These endogenous fungal

infections of the skin or mucous membranes generally occur when host resistance is

lowered and the organism proliferates in high numbers. Excess heat and humidity,

oral contraceptive use, pregnancy, diabetes, malnutrition, and immunosuppression

facilitate endogenous local infection by both Pityrosporum and Candida. Systemic

candidal infections occur in the immunocompromised or genetic deficient host (Table

78-2)

3,4 when the organism colonizing the patient’s skin or GI tract disseminates

hematogenously throughout the body.

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Table 78-2

Clinical Classification of Mycoses

Classification Site Infected Example Potential Gene Deficiency

Superficial Outermost skin and hair Malasseziasis (tinea

versicolor)

Cutaneous Deep epidermis and nails Dermatophytosis

Subcutaneous Dermis and subcutaneous

tissue

Sporotrichosis

Systemic Disease of more than one

internal organ

Opportunistic Candidiasis Mannose-binding Lectin-1

Toll-like Receptor 4

Cryptococcosis Dectin-1

Aspergillosis

Mucormycosis

Nonopportunistic Histoplasmosis

Blastomycosis

Coccidioidomycosis Interferon-γ receptor 1

Dectin-1

Mannose Binding Lectin-1

EXOGENOUS

Exogenous infections occur when the fungus is acquired from an environmental

source. In the case of dermatophytes (ringworm fungi), the organism can be acquired

from dirt, animals, or another infected individual. The subcutaneous mycoses result

from direct inoculation of infected material, often a thorn or other vegetable matter,

through the skin. Infections of the skin and subcutaneous tissues by Aspergillus and

zygomycetes (e.g., Rhizopus, Absidia, and Mucor) have resulted from contaminated

wound dressings and cast materials.

1,5 Drug-induced disease has been observed

secondary to Saccharomyces cerevisiae (nutraceutical) administration to healthy and

immunocompromised patients or secondary to the administration of a contaminated

sterile product (i.e., Exserohilum rostratum).

Exogenous fungi colonized or carried on the hands of health-care workers can

infect patients; therefore, handwashing is emphasized for health-care workers,

particularly in critically ill patients.

6 Other than candidal infections, the systemic

mycoses are primarily the result of inhalation of dust contaminated by the infectious

spores, with a primary focus of infection in the lungs.

If local or systemic host defenses do not control the primary infection, the

organism can spread hematogenously to other organs. Some of the systemic mycoses

have defined geographic (endemic) areas where the fungus is more commonly

encountered. For example, histoplasmosis and blastomycosis occur most often in the

regions of the Red, Mississippi, and Ohio River valleys, whereas

coccidioidomycosis is endemic to the southwestern United States and the Central

Valley of California.

Host Defenses

Host defenses against fungal infection involve both nonimmune (also known as

nonspecific or natural resistance) and immune (also known as specific or acquired

resistance) mechanisms. Nonimmune resistance plays a primary role in preventing

colonization and invasion of a susceptible tissue. The normal bacterial flora of the

skin and mucous membranes prevent colonization (colonization resistance) by more

pathogenic bacteria and fungi. Patients treated with broad-spectrum antibiotics are at

a greater risk for colonization and infection by fungi. The barrier function of the intact

skin and mucous membranes is also an important defense. Skin defects (intravenous

[IV] catheters, burns, surgery, or trauma) are risk factors for local invasion and

fungemia, especially with Candida species. The translocation of yeast from the gut

into the peritoneum during the trauma of a motor vehicle accident or post-GI surgery

is also commonly associated with these infections. When these physical barriers are

breached, the polymorphonuclear leukocyte (neutrophil) and monocytes along with

defensive lectins (i.e., mannose-binding protein) provide early host defense. The

antifungal activity of neutrophils involves phagocytosis and intracellular killing but

also can include extracellular killing by secreted lysosomal enzymes. Neutropenia is

the most common neutrophil defect predisposing to fungal infection, but functional

defects of neutrophils, such as those occurring in patients with chronic granulomatous

disease of childhood and myeloperoxidase deficiency, have also been associated

with an increased frequency of fungal infections, especially with Candida and

Aspergillus. Finally, endothermy/homeothermy and ultimately febrile responses are

potent nonspecific immune defenses.

Antibody and complement have a potential role in the prevention of certain fungal

infections, but they are not the primary effectors of acquired resistance. Cellular

immunity, mediated by antigen-specific T lymphocytes, cytokines, and activated

macrophages, is the primary acquired (immune) host defense

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p. 1624

against fungi. Patients with defective cellular immunity (e.g., immunosuppressed

organ transplant recipients, patients with lymphoma and leukemia, patients with

AIDS, and those treated with corticosteroids or cytotoxic agents) are at a greatest

risk for fungal infection. Severe immunodeficiency often results in poor therapeutic

outcome despite appropriate antifungal therapy. An additional factor associated with

an increased risk for fungal infection is the use of total parenteral nutrition (TPN).

1

Interestingly, patients with specific T-cell dysfunction (i.e., HIV infection) appear to

be at an isolated risk for mucosal Candida infection, but not systemic infections.

ANTIMYCOTICS

Mechanisms of Action

Table 78-3 lists the US Food and Drug Administration (FDA)-approved topical and

systemic antimycotics for the treatment of fungal infections. Griseofulvin and

potassium iodide have limited clinical utility and are not used to treat systemic fungal

infections. Griseofulvin inhibits growth by inhibiting fungal cell mitosis caused by

the polymerization of cell microtubules, thereby disrupting mitotic spindle formation.

It has activity only against the dermatophyte fungi. The antifungal mechanism of

potassium iodide is unclear. It is effective only in the treatment of lymphocutaneous

sporotrichosis.

The 12 antifungal drugs used commonly for systemic disease fall into five

structural classes that act by four mutually exclusive mechanisms. Amphotericin B

(AmB) and nystatin (a polyene macrolide) act principally by binding to ergosterol in

the fungal cell membrane, effectively creating pores in the cell membrane and leading

to the depolarization of the membrane and cell leakage.

7 AmB binds with greater

affinity to ergosterol than to cholesterol.

8 This phenomenon is believed to be

mediated through both hydrophilic hydrogen bonding and hydrophobic, nonspecific

van der Waals forces. Investigations using P

32 nuclear magnetic resonance

spectroscopy document that the presence of the double bond in the side chain of

ergosterol (not present in cholesterol) accounts for the greater affinity of AmB for

ergosterol.

7 AmB, however, also binds to sterols of mammalian cells (i.e.,

cholesterol), which may account for most of the toxic effects of AmB or reduced

toxicity (i.e., circulating cholesterol). Alteration in the lipid content of the pathogens

membrane may play a role in the development of resistance,

9 although other factors

are also important.

10 The cidal antifungal effects of AmB are, however, not only

owing to cell leakage resulting from ergosterol binding, but also owing to immune

stimulation and oxygen-dependent killing.

8,11

5-Flucytosine, a fluorinated cytosine analog, acts principally by inhibiting nucleic

acid synthesis. It is actively transported into susceptible cells by the enzyme cytosine

permease, where it is deaminated to the toxic metabolite 5-fluorouracil. Fluorouracil,

when converted to 5-fluorouridine triphosphate, functions as an antimetabolite. It is

incorporated into fungal RNA, where it is substituted for uracil and thereby disrupts

protein synthesis. 5-Fluorouracil can also be converted to fluorodeoxyuridine

monophosphate, which inhibits thymidylate synthase and thus disrupts DNA

synthesis.

12

The azole antifungals and the allylamines (naftifine and terbinafine) inhibit sterol

biosynthesis by interference with either cytochrome (CYP) P450–dependent

lanosterol C14-demethylase (azoles) or squalene epoxidase (allylamines), critical

enzymes in the biosynthesis of ergosterol.

13,14 The superior affinity of the triazoles

(fluconazole, itraconazole, isavuconazole, posaconazole, and voriconazole) for

fungal versus mammalian enzymes, as compared with the imidazoles (ketoconazole

and miconazole), accounts for their reduced toxicity and improved efficacy.

13 The

consequence of sterol biosynthesis inhibition is a faulty cell membrane with altered

permeability. In general, the allylamines and older azoles are fungistatic. The newer

triazoles (voriconazole and posaconazole) demonstrate fungicidal activity against

some fungal species. The clinical relevance of in vitro fungicidal versus fungistatic

action is the subject of considerable debate. Nevertheless, it seems logical that

fungicidal action, if it can also be achieved in vivo, is preferred in

immunosuppressed hosts.

15

Table 78-3

Antifungal Agents Approved for Use

Agent (Brand Name) Formulation

Systemic Agents

Amphotericin B (Abelcet, AmBisome, Amphotec) IV

Amphotericin B-deoxycholate (generic) IV

Anidulafungin (Eraxis) IV

Caspofungin (Cancidas) IV

Fluconazole (Diflucan) IV, tablet, oralsuspension

Fluorocytosine [Flucytosine] (Ancobon) Capsule

Griseofulvin (generic) Tablet, oralsuspension

Isavuconazole (Cresemba) IV, oral capsule

Itraconazole (Sporanox) IV, capsule, oralsolution

Ketoconazole (Nizoral) Tablet

Micafungin (Mycamine) IV

Posaconazole (Noxafil) IV, oralsuspension, oral gastroresistant tablet

Potassium iodide Solution

Terbinafine (Lamisil) Tablet, oral granules

Voriconazole (Vfend) IV, tablet, oralsuspension

Topicals, Class I

Amphotericin B Cream, lotion, ointment, oralsuspension

a

Butenafine (Lotrimin Ultra) Cream

Butoconazole (Gynazole) Vaginal cream

Ciclopirox (Loprox) Cream, gel, lotion, shampoo, solution, suspension

Clioquinol (Vioform) Cream, ointment

Clotrimazole Cream, lotion, lozenge, solution, tablet, vaginal cream

Econazole (Spectazole) Cream

Ketoconazole (Nizoral) Cream, foam, gel, shampoo

Miconazole Aerosol liquid and powder, buccal tablet, cream, lotion,

ointment, powder, suppository, vaginal tablet

Naftifine (Naftin) Cream, gel

Nystatin Cream, mouthwash, ointment, powder, suspension,

tablet

Oxiconazole (Oxistat) Cream, lotion

Povidone iodine Aerosol, douche, gel, ointment, solution, suppository

Sodium thiosulfate (Exoderm) Lotion

Sulconazole (Exelderm) Cream, solution

Terbinafine (Lamisil) Cream, spray

Terconazole (Terazol 7) Cream, suppository

Tioconazole (Vagistat) Ointment

Tolnaftate (generic) Aerosol, cream, gel, powder, solution

Undecylenic acid Powder

aNo longer available in the United States.

IV, intravenous.

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Lipopeptides, which are potent antifungal agents, include the structural class of

echinocandins (anidulafungin, micafungin, and caspofungin). All share a common

mechanism. They act by interfering with 1,3-β-D-glucan, preventing the synthesis of

essential cell wall polysaccharides that protect the cell from osmotic and structural

stresses. The result is inhibition of fungal cell wall biosynthesis. Targeting the cell

wall (as opposed to the cell membrane, which is the target of polyene, azole, and

allylamine antifungals) imparts greater selectivity for fungal versus mammalian cells;

thus, echinocandins class of antifungals has fewer toxicities than other antifungal

classes.

16

Antifungal Spectrum and Susceptibility Testing

The Clinical and Laboratory Standards Institute (CLSI) recommends standardized

broth dilution (M27-A3) and disk diffusion (M44-A2, M44-S3, and M51-A) methods

for determining in vitro antifungal susceptibilities for yeasts.

17 These methods

stipulate test medium, inoculum size and preparation, incubation time and

temperature, end-point reading, and quality control limits for AmB, flucytosine,

fluconazole, ketoconazole, and itraconazole. Minimum inhibitory concentration

(MIC) values for use in clinical interpretation are specified for fluconazole,

voriconazole, itraconazole, flucytosine, and the echinocandins against Candida

species after 24 hours of incubation. For azole, a susceptible-dose-dependent (SDD) break point was developed based on data supporting a trend toward better

response with higher drug concentrations for isolates with higher MIC.

18 The

fluconazole S-DD range is 4 to 8 mcg/mL for C. albicans, Candida parapsilosis, and

Candida tropicalis and ≤32 mg/L for C. glabrata. Itraconazole and voriconazole SDD ranges are 0.25 to 0.5 mg/L for C. albicans. Owing to the rapid development of

resistance and limited data on correlation of MIC with outcome for flucytosine

monotherapy, proposed interpretive break points for this agent are based on a

combination of historic data and results from animal studies. Candida isolates with a

flucytosine MIC ≤4 mcg/mL are considered susceptible, and isolates with MIC >16

mcg/mL are considered resistant. Limitations of the M27-A methodology have

precluded the development of AmB interpretive break points nor have interpretive

criteria been proposed for ketoconazole MIC. Candida are generally susceptible to

MIC <0.25 mcg/mL and resistant to >1 mcg/mL, except for C. parapsilosis and

Candida guilliermondii that have higher susceptibility (<2 mcg/mL) and resistant (>8

mcg/mL) values. Commercial kits are available for antifungal susceptibility testing,

which utilize broth microdilution, colorimetric, and agar-based techniques.

19–21

University of Texas Health Science Fungal Testing Laboratory has historically tested

fungi susceptibilities and reports current break points and epidemiologic cutoff

values.

An E-Test (AB Biodisk; Piscataway, NJ) is a commercially available antifungal

gradient strip. Difficulties in end point determination using this method result from

frequent, nonuniform growth of the fungus on the agar medium; yet, when properly

performed, correlation between the E-Test and M27-A methods has been satisfactory

for the azole antifungal agents against most Candida.

19 Other techniques under

development for antifungal susceptibility testing for yeasts include flow cytometry

and direct measurement of alterations in ergosterol synthesis.

20 Flow cytometry

detects the activity of the test antifungal drug through identification of subtle dosage–

response effects on specific cell parameters as cells within the prepared inoculum

pass through a beam of light. Test results may be available in as few as 4 hours.

Interlaboratory reproducibility or correlation between test results and clinical

outcomes has not been well studied.

21