Mycotic Infections in the Compromised Host Part 1

Opportunistic fungal infections have become increasingly important over the past several decades, paradoxically because advances in medical practice have improved the survival of debilitated and immunosuppressed patients. Opportunistic fungal pathogens may originate as human commensals (e.g., Candida albicans) or have an environmental reservoir (e.g., Aspergillus fumi-gatus). They may have yeast (budding, unicellular) or mold (branching, tubular hyphal cell) phenotypes. Timely diagnosis of opportunistic fungal infection depends on an understanding of host characteristics, environmental risk factors, clinical presentation, and diagnostic testing. In treatment, correction of predisposing conditions can be as important as the use of antifungal medication. Localized infections may require surgery. Immunocompromised patients require either prophylaxis or early empirical treatment during high-risk periods.

Candidiasis

Epidemiology

C. albicans is a yeast that is virtually ubiquitous in humans. Acquired at or soon after birth, it becomes part of the normal flora of the gastrointestinal and vaginal tracts. In healthy persons, overgrowth of Candida at those commensal sites is a common cause of minor skin and mucous membrane infections—notably, oral candidiasis, diaper rash in infants, and vaginal candidiasis in women. In persons with immune system aberrations or iatro-genic factors that predispose to infection, candidal infections can become invasive; the organism may enter the bloodstream and disseminate to normally sterile tissues.

C. albicans has the best adherence mechanisms of the various Candida species and is therefore the predominant yeast colonizing the mouth, gut, and vagina. Treatment with systemic antifungal drugs may result in the replacement of C. albicans by other candi-dal species and their appearance as opportunistic pathogens. This phenomenon has grown with the wider use of such agents. In particular, C. glabrata and C. krusei bloodstream infections have become more common since the introduction of fluconazole in the early 1990s.1,2 Other Candida species regarded as frequent human pathogens include C. parapsilosis, C. tropicalis, C. lusitaniae, C. dubliniensis, and C. guilliermondii.3 C. lusitaniae is notable for resistance to amphotericin. C. parapsilosis is notable for nosocomial transmission from an exogenous source, such as hyperalimentation fluids. In a hospital, a series of infections with the same non-albicans Candida species in several patients over a short period of time suggests a common nosocomial point source.

Etiology

Candidal infection often reflects a combination of environmental and host defense factors; this is especially true of localized mucocutaneous infection from overgrowth of commensal C. albicans. Wearing diapers or dentures provides an environment conducive to candidal growth, as does antibiotic treatment that reduces the commensal bacteria that normally help keep Candida in check. Host factors include the normal life phases of infancy and pregnancy (especially third trimester) and pathologic conditions such as vitamin deficiencies and malnourishment, diabetes mellitus and other endocrine abnormalities, congenital or acquired defects in cell-mediated immunity, and malignancy. Iatrogenic contributors include radiotherapy, systemic or inhaled steroids, and other immunosuppressive medications.4

Pathogenesis

Candida can reach normally sterile tissues through iatrogenic means: contamination of plastic catheters may lead to localized infection, such as peritonitis from peritoneal dialysis catheters and cystitis or upper urinary tract infection from urinary (Foley) catheters.5 Alternatively, Candida may spread from colonized surfaces to contiguous tissues. Depending on the original site, such invasion can lead to esophagitis, sinusitis, mastoiditis, and, in rare cases, primary pneumonia. A breakdown of GI mucosa through damage from cancer chemotherapy, radiation, trauma, or concurrent viral ulcers may allow a commensal Candida strain to gain access to the bloodstream. Tissue abscesses from hematogenous dissemination can form in the lung, brain, liver, spleen, kidney, bone, joints, heart valves, skin, and eye. In short, Candida infections can affect almost every organ system in the body.

Diagnosis

Clinical Manifestations

Oropharyngeal candidiasis Patients with oropharyngeal candidiasis may complain of sore throat or raw tongue; eating may be so uncomfortable that patients lose weight. Pseudomembranous candidiasis (thrush) presents as loosely adherent white patches and plaques on the buccal mucosa, palate, oropharynx, or tongue. Erythematous candidiasis presents as redness without pseudomembranes. An erythematous, smooth plaque on the dorsal surface of the tongue characterizes median rhomboid glossitis. Angular cheilitis presents as erythema, maceration, and fissuring at the corners of the mouth.

Gastrointestinal candidiasis Esophageal candidiasis causes painful swallowing, a feeling of obstruction on swallowing, and substernal or retrosternal chest pain. Thrush may also be evi-dent.6 Candidiasis elsewhere in the GI tract presents as pain in the abdominal quadrant where the affected organs are located.

Genital candidiasis Candidal vaginitis may present as intense pruritus of the vulva and a cervical discharge that can vary from scant to thick and white. There may be edema of the vulva and erythema of the vagina and labia that extends onto the perineum.

Balanitis can begin as itching or burning, with vesicles or white patches on the penis. Plaques may extend onto the thighs, buttocks, and scrotum.

Diaper rash Candida diaper rash causes itching and maceration in the perianal area that may spread to the entire skin region of diaper contact. Satellite lesions may be present. Girls may have a vaginal discharge.

Hematogenous candidiasis Patients with hematogenous Candida infection and major organ involvement may have fever, with or without additional manifestations in the organ system involved (central nervous system, lungs, heart, urinary tract, bones, joints, liver, spleen, gallbladder, or eyes). Even in the absence of ocular symptoms, patients with positive blood cultures for Candida should have a dilated eye examination to look for the white cotton ball-like chorioretinitis lesions of hematogenous Candida endophthalmitis, which can result in permanent blindness unless treated appropriately.

Candiduria A laboratory report of Candida in the urine may represent contamination of the sample by vaginal flora, colonization of a urinary catheter or the lower urinary tract, or infection. Asymptomatic colonization of the lower urinary tract is the most common source of candiduria; treatment is of questionable value in such patients, because the candiduria may resolve without treatment or return despite initially successful treatment.7,8 Systemic antifungal treatment is typically reserved for symptomatic patients and for those who are at increased risk for Candida infection; this population includes recent renal transplant recipients, patients with neutropenia, patients with diabetes, and those undergoing genitourinary tract manipulation.

Laboratory Tests

Candidal lesions can be so distinctive that diagnosis does not require testing. When the appearance is uncertain, pseudomem-branes should be scraped and sent for staining and culture. Fungal forms (4 to 6 ^m oval yeast cells, pseudohyphae, and hy-phae) can be visualized using 40x to 100x magnification after staining with potassium hydroxide—with or without calcoflu-or—or with Gram stain. Culture plates specific for yeast include bromocresol green and Sabouraud dextrose agar, although can-didal organisms are easily cultured on blood agar. In immuno-suppressed patients, endoscopy specimens from esophageal and other GI sites should be submitted for viral culture in addition to fungal culture, because such patients can have concurrent her-pesvirus infections.

Diagnosis of hematogenous and major organ candidiasis requires culture of blood, radiographic imaging of the organ system involved, and culture of any localized fluid collections. Blood culture is used for diagnosis of fungemia, catheter-related infection, vascular infection, endocarditis, and liver and spleen infection. Even repeated cultures—both of blood and of biopsy tissue—are often negative in visceral (hepatosplenic) candidia-sis, however.

The current generation of automated blood culture systems has improved the ability to detect Candida, and Candida species are now the fourth most common nosocomial bloodstream isolate. When culture growth is noted, a germ tube test can be performed to distinguish C. albicans from other species of Candida. The organism is inoculated into serum and incubated for 2 to 3 hours at 37° C. If an elongated hypha (a germination tube) is seen extending from the yeast, the species is C. albicans.

Antifungal susceptibility testing should be requested for the first bloodstream isolate from a new infection episode. Susceptibility testing is available for azoles (e.g., fluconazole, voricona-zole) but not for echinocandins.

Differential diagnosis

In patients with mucocutaneous manifestations that do not fit the classic picture of C. albicans infection, non-albicans candidal species, bacteria, mold, and viruses need to be considered. Bacterial infection is especially likely in patients with findings such as abscesses or fever, whereas viral infection may be present in those with ulcerations of the mucosal surface. Infections in severely debilitated patients may have multiple copathogens. Can-didiasis must also be distinguished from noninfectious syndromes such as aphthous ulcers.

Treatment

Active Infection

Management of candidal infections should include attempts to correct any factors that can predispose to candidal overgrowth. In some cases, this will involve local measures: with diaper rash, for example, the affected areas should be kept dry. Other cases require general measures, such as tighter control of glucose levels in diabetic patients or minimizing the number and dosage of antibacterial or immunosuppressive medications.

Antifungal drug therapy for candidiasis may be topical or systemic11 [see Table 1]. For mucocutaneous infections in particular, it is important to try topical agents before giving systemic ones. The use of topical agents can prevent the replacement of C. albicans with other candidal strains and the development of drug resistance, and it avoids the side effects of systemic treatment.

When systemic treatment is required, fluconazole is often the drug of choice for C. albicans infections. C. glabrata infections should be considered fluconazole resistant and treated with a different agent until sensitivities are known. Importantly, C. kru-sei is innately resistant to fluconazole, so infections caused by this organism should be treated with a different agent.

In the first years of the 21st century, several new antifungal agents have gained important roles in the treatment of candidiasis and other fungal infections. Voriconazole, a new triazole with wide-spectrum antifungal activity and high bioavailability, has proved effective as empirical antifungal therapy in patients with neutropenia and persistent fever.12 Caspofungin is the first in a new class of antifungal agents called echinocandins, which inhibit synthesis of an integral component of the fungal cell wall, |-(1,3)-D-glucan. The Food and Drug Administration has approved caspofungin for the first-line treatment of candidemia, esophageal candidiasis, and other Candida infections (e.g., intraabdominal abscesses, peritonitis, and pleural space infections).13,14 A comparison study found caspofungin to be at least as effective as amphotericin B for the treatment of invasive candidiasis and, more specifically, candidemia.15 Caspofungin is also approved by the FDA for the empirical treatment of presumed fungal infection in febrile neutropenic patients, and it appears to be as effective as, as well as generally better tolerated than, liposomal amphotericin B when used for this purpose.16 Micafungin, the second echinocandin to become clinically available, is approved by the FDA for intravenous treatment of esophageal candidiasis and for Candida prophylaxis in hematopoietic stem cell transplant recipients.17,18

Adjunctive measures are important in controlling severe can-didal infections and in boosting the immune function of severely debilitated patients. For patients with catheter-related infections, strong consideration should be given to catheter removal from any affected site (intravascular, genitourinary, and peritoneal) if possible. Neutropenic patients may benefit from colony-stimulating factors or granulocyte transfusions. In patients with a central venous catheter, infections accompanied by tenderness or erythema along the catheter tunnel tract may require surgical de-bridement of the tract. Macroabscesses may require surgical drainage or debulking. Patients with recurrent positive cultures despite receiving both systemic medication and adjunctive measures should be reexamined clinically and radiologically to look for an occult focus of Candida organisms, such as an infected thrombus or abscess. 

Table 1 Treatment of Infections Caused by Candida Species

Infection	Drug	Dosage	Relative Efficacy	Comments
Denture stomatitis	Fluconazole	100-400 mg p.o. daily for 1-14 days	First-choice agent	Remove dentures at night
Gingivostomatitis	Nystatin	Swish 4-6 ml of 100,000 units/ml q.i.d., or suck 200,000-unit lozenges q.i.d., daily for 2 wk	First-choice topical agent	—
	Clotrimazole	Suck 10 mg troches five times daily for 2 wk	Alternative topical agent	Less bitter than nystatin
	Gentian violet	Apply 1% solution to oropharynx once, repeat weekly as needed	Alternative topical agent	Stains tissue
	Fluconazole	100-400 mg p.o. daily for 1-14 days	First-choice systemic agent	May lead to replacement of C. albi-cans with other Candida strains
	Itraconazole	100 mg p.o., b.i.d., or 200 mg daily of oral solution for 14 days	Alternative systemic agent	Capsule absorption improved by acidic stomach contents
	Amphotericin	0.5 mg/kg I.V. daily for 2 wk beyond the last clinical symptoms, then once or twice weekly as maintenance	Alternative systemic agent	—
Sinusitis/ mastoiditis	Fluconazole	400-800 mg p.o. or I.V. daily for 3 wk	First-choice agent	—
	Amphotericin	0.5 mg/kg I.V. daily for 3 wk	Alternative agent	—
	Itraconazole	200 mg p.o. or I.V. twice daily or 400 mg daily of oral solution for 3 wk	Alternative agent	Capsule absorption improved by acidic stomach contents
Pneumonia	Amphotericin	0.5 mg/kg I.V. daily for 2 wk ± 50 mg nebulized daily	First-choice agent	—
	Fluconazole	400-800 mg p.o. or I.V. daily for 2 wk	Alternative agent	—
	Itraconazole	200 mg p.o. or I.V. b.i.d., or 400 mg daily of oral solution for 2 wk	Alternative agent	Capsule absorption improved by acidic stomach contents
	Flucytosine	25 mg/kg p.o., q.i.d., for duration of amphotericin therapy	Adjunct to amphotericin	Follow levels and adjust dose for renal insufficiency
Meningitis				Remove foreign bodies
	Amphotericin	0.7-1.0 mg/kg I.V. daily for 2-6 wk ± 1 mg intrathecal or intraventricular daily	First-choice agent	—
	Flucytosine	37.5 mg/kg p.o., q.i.d., for duration of amphotericin therapy	Adjunct to amphotericin	Follow levels and adjust dose for renal insufficiency
	Fluconazole	400-800 mg p.o. or I.V. daily for duration of risk factors that led to infection	First-choice agent	May be used for maintenance after amphotericin
Brain macroabscess		[See Meningitis, above] ; continue therapy until lesion has resolved		Debulk or drain abscess
Esophageal infection		Continue all therapy for 2 wk after clinical resolution		—
	Fluconazole	100-400 mg p.o. daily	First-choice oral systemic agent	—
	Micafungin	150 mg daily I.V	First-choice I.V. systemic agent	—
	Itraconazole	100-200 mg p.o., b.i.d., or 200^00 mg daily of oral solution	Alternative agent	Capsule absorption improved by acidic stomach contents
	Caspofungin	50 mg daily by slow I.V. infusion	Alternative agent	Reduce dose for hepatic insufficiency
	Voriconazole	200 mg q. 12 hr p.o.	Alternative agent	Taken s 1 hr before or after meal
	Amphotericin	0.5 mg/kg I.V. daily	Alternative agent	—
Liver/spleen infection				Correct neutropenia
	Amphotericin	0.5-1.0 mg/kg I.V. daily until fevers have resolved and lesions appear smaller on CT scan	First-choice agent	—
	Fluconazole	6-12 mg/kg p.o. or I.V. daily for the duration of lesions on serial CT scans	First-choice agent	May be used for maintenance after amphotericin

Table 1 Treatment of Infections Caused by Candida Species

Infection	Drug	Dosage	Relative Efficacy	Comments
Spleen infection		[See Liver/Spleen Infection, above]		May require splenectomy
				Remove peritoneal catheter
Peritoneum infection	Amphotericin	0.5-1.0 mg/kg I.V. daily until fevers have resolved and peritoneal fluid appears less infected, for 3-4 wk after last positive culture	First-choice agent	—
	Fluconazole	6-12 mg/kg p.o./I.V. daily until fevers have resolved and peritoneal fluid appears less infected, for 3-4 wk after last positive culture	First-choice agent	May be used for maintenance after amphotericin
	Caspofungin	50 mg daily by slow I.V. infusion, for 3-4 wk after last positive culture	Alternative agent	Reduce dose for hepatic insufficiency
Cystitis, uncomplicated				Asymptomatic candiduria may represent colonization or specimen contamination rather than infection, and may not require treatment; remove urinary catheter
	Fluconazole	200 mg p.o./I.V. on first day, then 100 mg p.o. daily for 4 more days	First-choice agent	If poor response, rule out fungus ball in renal pelvis
	Amphotericin	Bladder irrigation with 5 mg in 100 ml water at 42 ml/hr for 1-2 days, or 0.3 mg/kg I.V. once	Alternative agent	If poor response, rule out fungus ball in renal pelvis
Pyelonephritis	Amphotericin	0.5-1.0 mg/kg I.V. daily for 2 wk, or longer if fevers have not resolved	First-choice agent	Resolve concomitant nephrolithiasis
	Voriconazole	6 mg/kg q. 12 hr for first 24 hr, then 3-4 mg/kg q. 12 hr; when oral medication tolerated, 200 mg p.o., q. 12 hr for 2-4 wk after cultures become negative	First-choice agent	Oral form taken > 1 hr before or after meal
Renal/perinephric abscess	Amphotericin	0.5-1.0 mg/kg I.V. daily until several weeks after scan shows resolution of abscess	First-choice agent	Drain abscess
	Voriconazole	6 mg/kg q. 12 hr for first 24 hr, then 3^ mg/kg q. 12 hr; when oral medication tolerated, 200 mg p.o., q. 12 hr until several weeks after scan shows resolution of abscess	First-choice agent	Oral form taken > 1 hr before or after meal
				Stop antibacterial agents
	Clotrimazole	One applicator per vagina each evening for 3-7 days	First-choice topical agent	—
Vulva/cervix infection	Gentian violet	Apply 0.25%-1% solution to vagina two to three times daily for 3 days	Alternative topical agent	Stains tissue
	Fluconazole	100^00 mg p.o. daily for 1-14 days	First-choice systemic agent	—
	Itraconazole	100 mg p.o., b.i.d, or 200 mg daily of oral solution for 14 days	Alternative systemic agent	Capsule absorption improved by acidic stomach contents
				Reduce predisposing factors
Balanitis/ balanoposthitis	Clotrimazole	1% cream applied twice daily for 1 wk	First-choice topical agent	—
	Fluconazole	Single oral 150 mg dose	First-choice systemic agent	—
				Keep affected area dry
Diaper/perianal rash	Nystatin	Cream or powder applied after every diaper change for 1 wk	First-choice topical agent	—
	Miconazole	Ointment applied after every diaper change for 1 wk	First-choice topical agent	—
				May require surgery
Osteomyelitis/ septic arthritis	Amphotericin	0.5-1.0 mg/kg I.V. daily for 4-12 wk	First-choice agent	Follow ESR
	Flucytosine	25 mg/kg p.o., q.i.d., for duration of amphotericin therapy	Adjunct to amphotericin	Follow levels and adjust dose for renal insufficiency
	Fluconazole	6-12 mg/kg p.o. daily for 1-6 mo	Maintenance	Follow ESR

Table 1 Treatment of Infections Caused by Candida Species

Infection	Drug	Dosage	Relative Efficacy	Comments
Endocarditis/ pericarditis				May require surgery
	Amphotericin	0.5-1.0 mg/kg I.V. daily, often continued for 6-10 wk after corrective surgery	First-choice agent	Follow ESR
	Flucytosine	25-37.5 mg/kg p.o., q.i.d., for duration of amphotericin therapy	Adjunct to amphotericin	Follow levels and adjust dose for renal insufficiency
	Fluconazole	6-12 mg/kg p.o. daily for 1-6 mo	Maintenance	Follow ESR
Chronic mucocutaneous candidiasis	Ketoconazole	400 mg p.o. daily for 3-9 mo	—	Take with food
Folliculitis	Fluconazole	100-400 mg p.o. daily for 1-6 wk	First-choice agent	—
	Econazole	1% cream rubbed into affected area twice daily	Adjunctive agent	—
	Ketoconazole	400 mg p.o. daily for 1-6 wk	Alternative agent	Take with food
	Itraconazole	200 mg p.o. daily for 1-6 wk	Alternative agent	—
Paronychia/ onychomycosis				Avoid moisture
	Fluconazole	6-12 mg/kg p.o. daily for 2-6 mo	First-choice agent	—
	Itraconazole	200 mg p.o. daily for 2-6 mo	Alternative agent	Capsule absorption improved by acidic stomach contents
Keratitis				May require adjunctive penetrating keratoplasty
	Natamycin	1 drop 5% suspension every 1-2 hr for first 2 days, then decrease gradually over 3 wk	First-choice agent	—
	Fluconazole	0.2% topical, 1 drop to affected eye q. 5 min for four doses for 4-6 wk	Alternative agent	—
Endophthalmitis	Amphotericin	Intravitreal 0.005-0.010 mg in 0.1 ml once, with repeat dosing based on ophthalmologic opinion	Ophthalmologist will make decision to use	Advanced vitritis may require systemic amphotericin and/or vitrectomy
	Voriconazole	6 mg/kg q. 12 hr for first 24 hr, then 3-4 mg/kg q. 12 hr; when oral medication tolerated, 200 mg p.o., q. 12 hr; duration determined by ophthalmologist
	Caspofungin	50 mg daily by slow I.V. infusion; duration determined by ophthalmologist
Systemic infection				Halt fungemia
	Amphotericin	0.5-1.0 mg/kg I.V. daily for 7 days after the last positive blood culture, then switch to fluconazole, 6-12 mg/kg p.o. daily for 7 additional days; fluconazole may be continued longer if neutropenia has not resolved; if the Candida species recovered is resistant to fluconazole, continue amphotericin for a total of 14 days after the last positive blood culture	First choice for patients who are neutropenic, deteriorating, or otherwise unstable	Use lipid formulation, not generic, for patients with nephrotoxicity or infusion toxicity; remove catheters and replace at new sites; check for metastatic lesions (e.g., endophthalmitis)
	Fluconazole	6-12 mg/kg I.V. or p.o. daily for 14 days after the last positive culture	First choice for stable patients who are not neutropenic	Remove catheters and replace at new sites; check for metastatic lesions (e.g., endophthalmitis)
	Caspofungin	50 mg daily by slow I.V. infusion for 14-28 days after the last positive culture	Alternative agent	Reduce dose for hepatic insufficiency
	Voriconazole	6 mg/kg q. 12 hr for first 24 hr, then 3-4 mg/kg q. 12 hr; when oral medication tolerated, 200 mg p.o., q. 12 hr for 14-28 days after the last positive culture	Alternative agent	Oral form taken > 1 hr before or after meal
Prevention of candi-diasis in hemato-poietic stem cell transplant recipients	Micafungin	50 mg I.V. daily until 5 days after engraftment	—	—

Note: Major pathogens include C. albicans, C. tropicalis, C. parapsilosis, and C. pseudotropicalis. C. lusitaniae and C. guilliermondii are usually resistant to amphotericin. C. glabrata and C. krusei are usually resistant to fluconazole. ESR—erythrocyte sedimentation rate

Table 2 Treatment of Infections Caused by Cryptococcus Species

Infection Site	Drug	Dosage	Relative Efficacy	Comments
	Amphotericin	0.7-1.0 mg/kg I.V. daily for AIDS patients, 0.5-0.8 mg/kg I.V. daily for non-AIDS patients; continue for 2-6 wk	First-choice agent	Continue until patient is stable and afebrile
CNS	Flucytosine	37.5 mg/kg p.o., q.i.d., for duration of amphotericin therapy	Adjunct to amphotericin	Adjust dose for renal insufficiency
	Fluconazole	6 mg/kg p.o. daily for 8-10 wk, then 3 mg/kg for duration of suppressed cell-mediated immunity	Maintenance/prophylaxis	—
	Fluconazole	6 mg/kg I.V./p.o. daily for 2-6 mo	First-choice agent	—
Pulmonary	Amphotericin	0.5-1.0 mg/kg I.V. daily for 2-6 wk, then change to fluconazole	Alternative agent	—