InternalMed_Harrison

InternalMed_Harrison. Note: The oral dose is usually 200 mg bid for voriconazole and itraconazole and 400 mg bid for posaconazole suspension. The IV dose of voriconazole for adults is 6 mg/kg twice at 12-h intervals (loading doses) followed by 4 mg/kg q12h; a larger dose is required for children and teenagers. Plasma monitoring is helpful in optimizing the dosage. Caspofungin is given as a single loading dose of 70 mg and then at 50 mg/d; some authorities use 70 mg/d for patients weighing >80 kg, and lower doses are required with hepatic dysfunction. Micafungin is given as 50 mg/d for prophylaxis and as at least 150 mg/d for treatment; this drug has not yet been approved by the U.S. Food and Drug Administration (FDA) for this indication. AmB deoxycholate is given at a daily dose of 1 mg/kg if tolerated. Several strategies are available for minimizing renal dysfunction. Lipid-associated AmB is given at 3 mg/kg (AmBisome) or 5 mg/kg (Abelcet). Different regimens are available for aerosolized AmB, but none is


InternalMed_Harrison

InternalMed_Harrison. strategies are available for minimizing renal dysfunction. Lipid-associated AmB is given at 3 mg/kg (AmBisome) or 5 mg/kg (Abelcet). Different regimens are available for aerosolized AmB, but none is FDA approved. Other considerations that may alter dose selection or route include age; concomitant medications; renal, hepatic, or intestinal dysfunction; and drug tolerability.


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InternalMed_Harrison. Abbreviations: AmB, amphotericin B; ABPA, allergic bronchopulmonary aspergillosis; SAFS, severe asthma with fungal sensitization. heart valve, sinuses, and proximal areas of the lung; brain abscess; keratitis; and endophthalmitis. In allergic fungal sinusitis, removal of abnormal mucus and polyps, with local and occasionally systemic glucocorticoid treatment, usually leads to resolution. Persistent or recurrent signs and symptoms may require more extensive surgery (ethmoidectomy) and possibly local antifungal therapy. Surgery is problematic in chronic pulmonary aspergillosis, usually resulting in serious complications. Bronchial artery embolization is preferred for problematic hemoptysis.


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InternalMed_Harrison. In situations in which moderate or high risk is predicted (e.g., after induction therapy for acute myeloid leukemia), the need for antifungal prophylaxis for superficial and systemic candidiasis and for invasive aspergillosis is generally accepted. Fluconazole is commonly used in these situations but has no activity against Aspergillus species. Itraconazole capsules are ineffective, and itraconazole solution offers only modest efficacy. Posaconazole solution is more effective. Some data support the use of IV micafungin. No prophylactic regimen is completely successful.


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InternalMed_Harrison. Invasive aspergillosis is curable if immune reconstitution occurs, whereas allergic and chronic forms are not. The mortality rate for invasive aspergillosis is ~50% if the infection is treated but is 100% if the diagnosis is missed. Infection with a voriconazole-resistant strain carries a mortality rate of 88%. Cerebral aspergillosis, Aspergillus endocarditis, and bilateral extensive invasive pulmonary aspergillosis have very poor outcomes, as does invasive infection in persons with late-stage AIDS or relapsed uncontrolled leukemia and in recipients of allogeneic hematopoietic stem cell transplants. Deterioration with no therapy over 12 months Natural history FIGuRE 241-2 Comparison of the impact of itraconazole therapy (400 mg/d) and standard care on chronic cavitary pulmonary aspergillosis at 6 and 12 months. (After R Agarwal et al: Itraconazole in chronic cavitary pulmonary aspergillosis: a randomised controlled trial and systematic review of literature. Mycoses 56:559, 2013.)


InternalMed_Harrison

InternalMed_Harrison. The mortality rate for chronic cavitary pulmonary aspergillosis is ~30% 6 months after presentation, falling to ~15% annually thereafter. After 12 months with no antifungal therapy, 70% of patients have deteriorated and 30% are stable (Fig. 241-2). Therapy fails in ~30% of recipients of antifungal therapy and still more often if azole resistance is present. Both ABPA and SAFS patients respond to antifungal therapy; ~60% respond to itraconazole and ~80% to voriconazole and posaconazole (if tolerated). If the severity of asthma declines, the inhaled glucocorticoid dose can be reduced and oral glucocorticoids can be stopped. Brad Spellberg, Ashraf S. Ibrahim


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InternalMed_Harrison. Brad Spellberg, Ashraf S. Ibrahim Mucormycosis represents a group of life-threatening infections caused by fungi of the order Mucorales of the subphylum Mucoromycotina (formerly known as the class Zygomycetes). Infection caused by the Mucorales is most accurately referred to as mucormycosis, although the term zygomycosis may still be used by some sources. Mucormycosis is highly invasive and relentlessly progressive, resulting in higher rates of morbidity and mortality than many other infections. However, recent studies have suggested that mortality rates from mucormycosis have declined with newer therapies. A high index of suspicion is critical for diagnosis, and early initiation of therapy—often before confirmation of the diagnosis—is necessary to optimize outcomes. Fungi of the order Mucorales belong to seven medically relevant families (Table 242-1), all of which can cause mucormycosis.


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InternalMed_Harrison. Among the Mucorales, Rhizopus oryzae (in the family Mucoraceae) is by far the most common cause of infection in the Western Hemisphere. Less frequently isolated species of the Mucoraceae that cause a similar spectrum of infections include Rhizopus microsporus, Rhizomucor pusillus, Lichtheimia corymbifera (formerly Absidia corymbifera), Apophysomyces elegans, and Mucor species (which, despite its name, only rarely causes mucormycosis). Increasing numbers of cases of mucormycosis due to infection with Cunninghamella species (family Cunninghamellaceae) have also been reported, particularly in highly immunocompromised patients. Rare case reports have demonstrated the ability of fungi in the remaining families of the Mucorales to cause mucormycosis, although other Mucorales can be the major cause of disease in certain geographic areas (e.g., A. elegans in India and Mucor irregularis in China).


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InternalMed_Harrison. The Mucorales are ubiquitous environmental fungi to which humans are constantly exposed. These fungi cause infection primarily in patients with diabetes or defects in phagocytic function (e.g., those associated with neutropenia or glucocorticoid treatment). Patients with elevated levels of free iron, which supports fungal growth in serum and tissues, are likewise at increased risk for mucormycosis. In iron-overloaded patients with end-stage renal failure, treatment with deferoxamine predisposes to the development of rapidly fatal disseminated mucormycosis; this agent, an iron chelator for the human host, serves as a fungal siderophore, directly delivering iron to the Mucorales. Furthermore, patients with diabetic ketoacidosis (DKA) are at high risk of developing rhinocerebral mucormycosis. The acidosis causes dissociation of iron from sequestering proteins in serum, TABLE 242-1 TAxOnOMy OF FungI CAusIng MuCORMyCOsIs (suBPHyLuM MuCOROMyCOTInA, ORdER MuCORALEs)


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InternalMed_Harrison. TABLE 242-1 TAxOnOMy OF FungI CAusIng MuCORMyCOsIs (suBPHyLuM MuCOROMyCOTInA, ORdER MuCORALEs) Lichtheimiaceae Lichtheimia (formerly Mycocladus, formerly Absidia) Cunninghamellaceae Cunninghamella Thamnidiaceae Cokeromyces Mortierellaceae Mortierella Saksenaceae Saksenaea Apophysomyces Syncephalastraceae Syncephalastrum resulting in enhanced fungal survival and virulence. Nevertheless, the majority of diabetic patients who present with mucormycosis are not acidotic, and, even absent acidosis, hyperglycemia directly contributes to the risk of mucormycosis by at least three likely mechanisms: (1) hyperglycation of iron-sequestering proteins, disrupting normal iron sequestration; (2) upregulation of a mammalian cell receptor (GRP78) that binds to Mucorales, enabling tissue penetration (due to both a direct effect of hyperglycemia and increasing levels of free iron, which independently enhances GRP78 expression); and (3) induction of poorly characterized defects in phagocytic function.


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InternalMed_Harrison. Mucormycosis typically occurs in patients with diabetes mellitus, solid organ or hematopoietic stem cell transplantation (HSCT), prolonged neutropenia, or malignancy. The majority of diabetic patients are not acidotic on presentation with mucormycosis. Furthermore, patients often have no previously recognized history of diabetes mellitus when they present with mucormycosis. In these instances, presentation for mucormycosis may result in the first clinical recognition of hyperglycemia, which may have been unmasked by recent glucocorticoid use. Thus a high index of suspicion of mucormycosis must be maintained, even in the absence of a known history of diabetes, if hyperglycemia is present. In patients undergoing HSCT, mucormycosis develops at least as commonly during nonneutropenic as during neutropenic periods, probably because of glucocorticoid treatment of graft-versus-host disease. Mucormycosis can occur as isolated cutaneous or subcutaneous infection in immunologically normal


InternalMed_Harrison

InternalMed_Harrison. during neutropenic periods, probably because of glucocorticoid treatment of graft-versus-host disease. Mucormycosis can occur as isolated cutaneous or subcutaneous infection in immunologically normal individuals after traumatic implantation of soil or vegetation (e.g., due to natural disasters or motor vehicle accidents) or in nosocomial settings via direct access through IV catheters, SC injections, or maceration of the skin by a moist dressing.


InternalMed_Harrison

InternalMed_Harrison. Patients receiving antifungal prophylaxis with either itraconazole or voriconazole may be at increased risk of mucormycosis. These patients typically present with disseminated mucormycosis, the most lethal form of disease. Breakthrough mucormycosis also has been described in patients receiving posaconazole or echinocandin prophylaxis. Mucormycosis can be divided into at least six clinical categories based on clinical presentation and the involvement of a particular anatomic site: rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and miscellaneous. These categories of invasive mucormycosis tend to affect patients with specific defects in host defense. For example, patients with DKA typically develop the rhino-orbital-cerebral form and much more rarely develop pulmonary or disseminated disease. In contrast, pulmonary mucormycosis occurs most commonly in leukemic patients who are receiving chemotherapy and in patients undergoing HSCT.


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InternalMed_Harrison. Rhino-Orbital-Cerebral Disease Rhino-orbital-cerebral mucormycosis continues to be the most common form of the disease. Most cases occur in patients with diabetes, although such cases (probably due to glucocorticoid use) are increasingly being described in the transplantation setting, often along with glucocorticoid-induced diabetes mellitus. The initial symptoms of rhino-orbital-cerebral mucormycosis are nonspecific and include eye or facial pain and facial numbness followed by the onset of conjunctival suffusion and blurry vision. Fever may be absent in up to half of cases. White blood cell counts are typically elevated as long as the patient has functioning bone marrow. If untreated, infection usually spreads from the ethmoid sinus to the orbit, resulting in compromise of extraocular muscle function and proptosis, typically with chemosis. Onset of signs and symptoms in the contralateral eye, with resulting bilateral proptosis, chemosis, vision loss, and ophthalmoplegia, is ominous,


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InternalMed_Harrison. function and proptosis, typically with chemosis. Onset of signs and symptoms in the contralateral eye, with resulting bilateral proptosis, chemosis, vision loss, and ophthalmoplegia, is ominous, suggesting the development of cavernous sinus thrombosis.


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InternalMed_Harrison. Upon visual inspection, infected tissue may appear to be normal during the earliest stages of fungal spread, then progressing through an erythematous phase, with or without edema, before the onset of a violaceous appearance and finally the development of a black necrotic eschar. Infection can sometimes extend from the sinuses into the mouth and produce painful necrotic ulcerations of the hard palate, but this is a late finding that suggests extensive, well-established infection.


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InternalMed_Harrison. Pulmonary Disease Pulmonary mucormycosis is the second most common manifestation. Symptoms include dyspnea, cough, and chest pain; fever is often but not invariably present. Angioinvasion results in necrosis, cavitation, and/or hemoptysis. Lobar consolidation, isolated masses, nodular disease, cavities, or wedge-shaped infarcts may be seen on chest radiography. High-resolution chest CT is the best method for determining the extent of pulmonary mucormycosis and may demonstrate evidence of infection before it is seen on chest x-ray. In the setting of cancer, where mucormycosis may be difficult to differentiate from aspergillosis, the presence of ≥10 pulmonary nodules, pleural effusion, or concomitant sinusitis makes mucormycosis more likely. It is critical to distinguish mucormycosis from aspergillosis as rapidly as possible because treatments for these infections differ. Indeed, voriconazole— the first-line treatment for aspergillosis—exacerbates mucormycosis in mouse and fly models of


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InternalMed_Harrison. as rapidly as possible because treatments for these infections differ. Indeed, voriconazole— the first-line treatment for aspergillosis—exacerbates mucormycosis in mouse and fly models of infection.


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InternalMed_Harrison. Cutaneous Disease Cutaneous mucormycosis may result from external implantation of the fungus or conversely from hematogenous dissemination. External implantation–related infection has been described in the setting of soil exposure from trauma (e.g., in a motor vehicle accident or natural disaster), penetrating injury with plant material (e.g., a thorn), injections of medications (e.g., insulin), catheter insertion, contamination of surgical dressings, and use of tape to secure endotracheal tubes. Cutaneous disease can be highly invasive, penetrating into muscle, fascia, and even bone. In mucormycosis, necrotizing fasciitis carries a mortality rate approaching 80%. Necrotic cutaneous lesions in the setting of hematogenous dissemination also are associated with an extremely high mortality rate. However, with prompt, aggressive surgical debridement, isolated cutaneous mucormycosis has a favorable prognosis and a low mortality rate.


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InternalMed_Harrison. Gastrointestinal Disease In the past, gastrointestinal mucormycosis occurred primarily in premature neonates in association with disseminated disease and necrotizing enterocolitis. However, there has been a marked increase in case reports describing adults with neutropenia or other immunocompromising conditions. In addition, gastrointestinal disease has been reported as a nosocomial process following administration of medications mixed with contaminated wooden applicator sticks. Nonspecific abdominal pain and distention associated with nausea and vomiting are the most common symptoms. Gastrointestinal bleeding is common, and fungating masses may be seen in the stomach at endoscopy. The disease may progress to visceral perforation, with extremely high mortality rates.


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InternalMed_Harrison. Disseminated and Miscellaneous Forms of Disease Hematogenously disseminated mucormycosis may originate from any primary site of infection. The most common site of dissemination is the brain, but metastatic lesions may also be found in any other organ. The mortality rate associated with dissemination to the brain approaches 100%. Even without central nervous system (CNS) involvement, mortality rates for disseminated mucormycosis exceed 90%. Miscellaneous forms of mucormycosis may affect any body site, including bones, mediastinum, trachea, kidneys, and (in association with dialysis) peritoneum.


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InternalMed_Harrison. A high index of suspicion is required for diagnosis of mucormycosis. Unfortunately, autopsy series have shown that up to half of cases are diagnosed only post-mortem. Because the Mucorales are environmental isolates, definitive diagnosis requires a positive culture from a sterile site (e.g., a needle aspirate, a tissue biopsy specimen, or pleural fluid) or histopathologic evidence of invasive mucormycosis. A probable diagnosis of mucormycosis can be established by culture FIGuRE 242-1 Histopathology sections of Rhizopus oryzae in infected brain. A. Broad, ribbon-like, nonseptate hyphae in the parenchyma (arrows) and a thrombosed blood vessel with extensive intravascular hyphae (arrowhead) (hematoxylin and eosin). B. Extensive, broad, ribbon-like hyphae invading the parenchyma (Gomori methenamine silver).


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InternalMed_Harrison. from a nonsterile site (e.g., sputum or bronchoalveolar lavage) when a patient has appropriate risk factors as well as clinical and radiographic evidence of disease. However, given the urgency of administering therapy early, the patient should be treated while confirmation of the diagnosis is awaited.


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InternalMed_Harrison. Biopsy with histopathologic examination remains the most sensitive and specific modality for definitive diagnosis (Fig. 242-1). Biopsy reveals characteristic wide (≥6to 30-μm), thick-walled, ribbon-like, aseptate hyphal elements that branch at right angles. Other fungi, including Aspergillus, Fusarium, and Scedosporium species, have septa, are thinner, and branch at acute angles. Because artificial septa may result from folding of tissue during processing (which may also alter the appearance of the angle of branching), the width and the ribbon-like form of the fungus are the most reliable features distinguishing mucormycosis. The Mucorales are visualized most effectively with periodic acid–Schiff or methenamine silver stain or, if the organism burden is high, with hematoxylin and eosin. While histopathology can identify the Mucorales, specific species can be identified only by culture. Polymerase chain reaction (PCR) is being investigated as a diagnostic tool for mucormycosis but is


InternalMed_Harrison

InternalMed_Harrison. While histopathology can identify the Mucorales, specific species can be identified only by culture. Polymerase chain reaction (PCR) is being investigated as a diagnostic tool for mucormycosis but is not yet approved by the U.S. Food and Drug Administration (FDA) for this purpose and is not generally available.


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InternalMed_Harrison. Unfortunately, cultures are positive in fewer than half of cases of mucormycosis. Nevertheless, the Mucorales are not fastidious organisms and tend to grow quickly (i.e., within 48 h) on culture media. The likely explanation for the low sensitivity of culture is that the Mucorales form long filamentous structures that are killed by tissue homogenization—the standard method for preparing tissue cultures in the clinical microbiology laboratory. Thus the laboratory should be advised when a diagnosis of mucormycosis is suspected, and the tissue should be cut into sections and placed in the center of culture dishes rather than homogenized. There is also substantial variability among isolates in optimal growth temperature, so growth at both room temperature and 37°C is advisable.


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InternalMed_Harrison. Imaging techniques often yield subtle findings that underestimate the extent of disease. For example, the most common finding on CT or MRI of the head or sinuses of a patient with rhino-orbital mucormycosis is sinusitis that is indistinguishable from bacterial sinusitis. It is also common to detect no abnormalities in sinus bones despite clinical evidence of progressive disease. MRI is more sensitive (~80%) for detecting orbital and CNS disease than is CT. High-risk patients should always undergo endoscopy and/or surgical exploration, with biopsy of the areas of suspected infection. If mucormycosis is suspected, initial empirical therapy with a polyene antifungal agent should be initiated while the diagnosis is being confirmed.


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InternalMed_Harrison. Other mold infections, including aspergillosis, scedosporiosis, fusariosis, and infections caused by the dematiaceous fungi (brown-pigmented 1352 soil organisms), can cause clinical syndromes identical to mucormycosis. Histopathologic examination usually allows distinction of the Mucorales from these other organisms, and a positive culture permits definitive species identification. As stated above, it is important to distinguish the Mucorales from these other fungi, as the preferred antifungal treatments differ (i.e., polyenes for the Mucorales vs. expanded-spectrum triazoles for most septate molds). The entomophthoromycoses caused by Basidiobolus and Conidiobolus also can cause identical clinical syndromes. These fungi may appear similar to the Mucorales on histopathology and can be reliably distinguished from the latter only by culture. In a patient with sinusitis and proptosis, orbital cellulitis and cavernous sinus thrombosis caused by bacterial pathogens (most commonly


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InternalMed_Harrison. be reliably distinguished from the latter only by culture. In a patient with sinusitis and proptosis, orbital cellulitis and cavernous sinus thrombosis caused by bacterial pathogens (most commonly Staphylococcus aureus, but also streptococcal and gram-negative species) must be excluded. Klebsiella rhinoscleromatis is a rare cause of an indolent facial rhinoscleroma syndrome that may appear similar to mucormycosis. Finally, the Tolosa-Hunt syndrome causes painful ophthalmoplegia, ptosis, headache, and cavernous sinus inflammation; biopsies and clinical follow-up may be needed to distinguish the Tolosa-Hunt syndrome from mucormycosis by the lack of progression of the former entity.


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InternalMed_Harrison. The successful treatment of mucormycosis requires four steps: (1) early diagnosis; (2) reversal of underlying predisposing risk factors, if possible; (3) surgical debridement; and (4) prompt anti-fungal therapy. Early diagnosis of mucormycosis is critical, since early initiation of therapy is associated with improved survival rates. It is also crucial to reverse (or prevent) underlying defects in host defense during treatment (e.g., by stopping or reducing the dosage of immunosuppressive medications or by rapidly restoring euglycemia and normal acid-base status). Finally, iron administration to patients with active mucormycosis should be avoided, as iron exacerbates infection in animal models. Blood transfusion typically results in some liberation of free iron due to hemolysis, so a conservative approach to red blood cell transfusions is advisable.


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InternalMed_Harrison. Blood vessel thrombosis and resulting tissue necrosis during mucormycosis can result in poor penetration of antifungal agents to the site of infection. Therefore, debridement of all necrotic tissues is critical for eradication of disease. Surgery has been found (by logistic regression and in multiple case series) to be an independent variable for favorable outcome in patients with mucormycosis. Limited data from a retrospective study support the use of intraoperative frozen sections to delineate the margins of infected tissues, with sparing of tissues lacking evidence of infection. A multidisciplinary team, including an internist, an infectious disease specialist, and surgical specialists whose expertise is relevant to the sites of infection, is typically required for the management of mucormycosis.


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InternalMed_Harrison. Primary therapy for mucormycosis should be based on a polyene antifungal agent (Table 242-2), except perhaps for mild localized infection (e.g., isolated suprafascial cutaneous infection) that has been eradicated surgically in an immunocompetent patient. Amphotericin B (AmB) deoxycholate remains the only licensed antifungal agent for the treatment of mucormycosis. However, lipid formulations of AmB are significantly less nephrotoxic, can be administered at higher doses, and are probably more effective than AmB deoxycholate for this purpose. Liposomal amphotericin B (LAmB) is preferred to amphotericin B lipid complex (ABLC) for management of CNS infection on the basis of retrospective survival data and superior brain penetration; there is no clear advantage of either agent for non-CNS infections.


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InternalMed_Harrison. aPrimary therapy should generally include a polyene. Non-polyene-based regimens may be appropriate for patients who refuse or are intolerant of polyene therapy or for relatively immunocompetent patients with mild disease (e.g., isolated suprafascial cutaneous infection) that can be surgically eradicated. bProspective randomized trials are necessary to confirm the suggested benefit (from animal and small retrospective human studies) of combination therapy for mucormycosis. Dose escalation of any echinocandin is not recommended because of a paradoxical loss of benefit of combination therapy at echinocandin doses of ≥3 mg/kg qd. Abbreviations: ABLC, AmB lipid complex; AmB, amphotericin B; CNS, central nervous system; LAmB, liposomal AmB. Source: Modified from B Spellberg et al: Clin Infect Dis 48:1743, 2009.


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InternalMed_Harrison. Abbreviations: ABLC, AmB lipid complex; AmB, amphotericin B; CNS, central nervous system; LAmB, liposomal AmB. Source: Modified from B Spellberg et al: Clin Infect Dis 48:1743, 2009. The optimal dosages for antifungal treatment of mucormycosis are not known. Starting dosages of 1 mg/kg per day for AmB deoxycholate and 5 mg/kg per day for LAmB and ABLC are commonly given to adults and children. Dose escalation of LAmB to 7.5 or 10 mg/kg per day for CNS mucormycosis may be considered in light of the limited penetration of polyenes into the brain. Because of auto-induction of metabolism, which results in paradoxically lower drug levels, there is no advantage to escalating the LAmB dose above 10 mg/kg per day, and doses of 5 mg/kg per day are probably adequate for non-CNS infections. ABLC dose escalation above 5 mg/ kg per day is not advisable given the lack of relevant data and the drug’s potential toxicity.


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InternalMed_Harrison. Echinocandin–lipid polyene combinations improved survival rates among mice with disseminated mucormycosis (including CNS disease) and were associated with significantly better outcomes than polyene monotherapy in a small retrospective clinical study involving patients with rhino-orbital-cerebral mucormycosis. Although combination therapy may be considered on the basis of these limited data sets, definitive clinical trials are needed to establish whether it offers any real advantage over monotherapy for mucormycosis. Echinocandins should be administered at standard, FDA-approved doses, since dose escalation has resulted in paradoxical loss of efficacy in preclinical models.


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InternalMed_Harrison. In contrast to deferoxamine, the iron chelator deferasirox is fungicidal against clinical isolates of the Mucorales. In mice with DKA and disseminated mucormycosis, combination deferasirox-LAmB therapy resulted in synergistic improvement of survival rates and reduced the fungal burden in brain. Unfortunately, a randomized, double-blind, phase 2 safety clinical trial of adjunctive therapy with deferasirox (plus LAmB) documented excess mortality in the patients treated with deferasirox. It is noteworthy that the study population included primarily patients with active malignancy, and few patients in the study had diabetes mellitus as their only risk factor. Deferasirox is therefore contraindicated as therapy in patients with active malignancy, but its role in patients who have diabetes mellitus without malignancy (the setting in which its preclinical efficacy was optimal) remains uncertain.


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InternalMed_Harrison. Posaconazole is the only FDA-approved azole with in vitro activity against the Mucorales. However, pharmacokinetic/pharmacodynamic data raise concerns about the reliability with which adequate in vivo levels of orally administered posaconazole are attained. Furthermore, posaconazole is inferior in efficacy to AmB for the treatment of murine mucormycosis and is not superior to placebo for treatment of murine infection with R. oryzae. Moreover, posaconazole-polyene combination therapy is not superior to polyene monotherapy for mucormycosis in mice, and no comparative data are available for combination therapy in humans. The roles of recombinant cytokines and neutrophil transfusions in the primary treatment of mucormycosis are not clear, although it is intuitive that earlier recovery of neutrophil counts should improve survival rates. Limited data indicate that hyperbaric oxygen may be useful in centers with the appropriate technical expertise and facilities.


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InternalMed_Harrison. In general, antifungal therapy for mucormycosis should be continued until resolution of clinical signs and symptoms of infection and resolution of underlying immunosuppression. For patients with mucormycosis who are receiving immunosuppressive medications, secondary antifungal prophylaxis is typically continued for as long as the immunosuppressive regimen is administered. The role of radiographic follow-up in determining prognosis and therapeutic duration is being studied. Analysis of data from the phase 2 DEFEAT Mucor study indicated that early radiographic progression (within the first 2 weeks) did not predict long-term mortality risk, nor did early radiographic stability/regression predict long-term survival. Therefore, caution should be used in reacting to short-term, serial radiographic results, and greater emphasis should be placed on clinical response, particularly within the first 2–4 weeks after initiation of therapy. Carol A. Kauffman


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InternalMed_Harrison. Carol A. Kauffman Dimorphic fungi exist in discrete environmental niches as molds that produce conidia, which are their infectious form. In tissues and at temperatures of >35°C, the mold converts to the yeast form. Other endemic mycoses—histoplasmosis, coccidioidomycosis, and blastomycosis—are discussed in Chaps. 236, 237, and 238, respectively.


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InternalMed_Harrison. SPOROTRICHOSIS Etiologic Agent Sporothrix schenckii is a thermally dimorphic fungus that is found worldwide in sphagnum moss, decaying vegetation, and soil. Epidemiology and Pathogenesis Sporotrichosis most commonly infects persons who participate in outdoor activities such as landscaping, gardening, and tree farming. Infected animals can transmit S. schenckii to humans. An outbreak of sporotrichosis in Rio de Janeiro that began in 1998 and that has involved >2000 people has been traced to cats, which are highly susceptible to this infection. Sporotrichosis is primarily a localized infection of skin and subcutaneous tissues that follows traumatic inoculation of conidia. Osteoarticular sporotrichosis is uncommon, occurring most often in middle-aged men who abuse alcohol, and pulmonary sporotrichosis occurs almost exclusively in persons with chronic obstructive pulmonary disease who have inhaled the organism from the environment. Dissemination occurs rarely, almost always in markedly


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InternalMed_Harrison. occurs almost exclusively in persons with chronic obstructive pulmonary disease who have inhaled the organism from the environment. Dissemination occurs rarely, almost always in markedly immunocompromised patients, especially those with AIDS.


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InternalMed_Harrison. Clinical Manifestations Days or weeks after inoculation, a papule develops at the site and then usually ulcerates but is not very painful. Similar lesions develop sequentially along the lymphatic channels proximal to the original lesion (Fig. 243-1). Some patients develop a fixed cutaneous lesion that can be verrucous or ulcerative and that remains localized without lymphatic extension. The differential diagnosis of lymphocutaneous sporotrichosis includes nocardiosis, tularemia, nontuberculous mycobacterial infection (especially that due to Mycobacterium marinum), and leishmaniasis. Osteoarticular sporotrichosis can present as chronic synovitis or septic arthritis. Pulmonary sporotrichosis must be differentiated from tuberculosis and from other fungal pneumonias.


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InternalMed_Harrison. FIGuRE 243-1 Several nodular lesions that developed after a young boy pricked his index finger with a thorn. A culture yielded S. schenckii. (Courtesy of Dr. Angela Restrepo.) 1354 Numerous ulcerated skin lesions, with or without spread to visceral organs (including the central nervous system [CNS]), are characteristic of disseminated sporotrichosis. Diagnosis S. schenckii usually grows readily as a mold when material from a cutaneous lesion is incubated at room temperature. Histopathologic examination of biopsy material shows a mixed granulomatous and pyogenic reaction, and tiny oval or cigar-shaped yeasts are sometimes visualized with special stains. Serologic testing is not useful.


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InternalMed_Harrison. Treatment and Prognosis Guidelines for the management of the various forms of sporotrichosis have been published by the Infectious Diseases Society of America (Table 243-1). Itraconazole is the drug of choice for lymphocutaneous sporotrichosis. Fluconazole is less effective; voriconazole and posaconazole have not been used for sporotrichosis. Saturated solution of potassium iodide (SSKI) also is effective for lymphocutaneous infection and costs much less than itraconazole. However, SSKI is poorly tolerated because of adverse reactions, including metallic taste, salivary gland swelling, rash, and fever. Terbinafine appears to be effective but has been used in few patients. Treatment for lymphocutaneous sporotrichosis is continued for 2–4 weeks after all lesions have resolved, usually for a total of 3–6 months. Pulmonary and osteoarticular forms of sporotrichosis are treated with itraconazole for at least 1 year. Severe pulmonary infection and disseminated sporotrichosis, including that


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InternalMed_Harrison. total of 3–6 months. Pulmonary and osteoarticular forms of sporotrichosis are treated with itraconazole for at least 1 year. Severe pulmonary infection and disseminated sporotrichosis, including that involving the CNS, are treated initially with amphotericin B (AmB), which is followed by itraconazole after improvement has been noted. Lifelong suppressive therapy with itraconazole is required for AIDS patients. The success rate for treatment of lymphocutaneous sporotrichosis is 90–100%, but other forms of the disease respond poorly to antifungal therapy.


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InternalMed_Harrison. aThe starting dosage is 5–10 drops tid in water or juice. The dosage is increased weekly by 10 drops per dose, as tolerated, up to 40–50 drops tid. bThe dosage of lipid AmB is 3–5 mg/kg daily; the higher dosage should be used when the central nervous system is involved. cThe dosage of AmB deoxycholate is 0.6–1.0 mg/kg daily. Abbreviations: AmB, amphotericin B; SSKI, saturated solution of potassium iodide; TMPSMX, trimethoprim-sulfamethoxazole.


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InternalMed_Harrison. Abbreviations: AmB, amphotericin B; SSKI, saturated solution of potassium iodide; TMPSMX, trimethoprim-sulfamethoxazole. Etiologic Agent, Epidemiology, and Pathogenesis Paracoccidioides brasiliensis is a thermally dimorphic fungus that is endemic in humid areas of Central and South America, especially in Brazil. A striking male-to-female ratio varies from 14:1 to as high as 70:1 (in rural Brazil). Most patients are middle-aged or elderly men from rural areas. Paracoccidioidomycosis develops after the inhalation of aerosolized conidia encountered in the environment. For most patients, disease rarely develops at the time of the initial infection but appears years later, presumably after reactivation of a latent infection.


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InternalMed_Harrison. Clinical Manifestations Two major syndromes are associated with paracoccidioidomycosis: the acute or juvenile form and the chronic or adult form. The acute form is uncommon, occurs mostly in persons <30 years old, and manifests as disseminated infection of the reticuloendothelial system. Immunocompromised individuals also manifest this type of rapidly progressive disease. The chronic form of paracoccidioidomycosis accounts for ∼90% of cases and predominantly affects older men. The primary manifestation is progressive pulmonary disease, primarily in the lower lobes, with fibrosis. Ulcerative and nodular mucocutaneous lesions in the nares and mouth—another common manifestation of chronic paracoccidioidomycosis—must be differentiated from leishmaniasis (Chap. 251) and squamous cell carcinoma (Chap. 105).


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InternalMed_Harrison. Diagnosis The diagnosis is established by growth of the organism in culture. A presumptive diagnosis can be made by detection of the distinctive thick-walled yeast, with multiple narrow-necked buds attached circumferentially, in purulent material or tissue biopsies. Treatment and Prognosis Itraconazole is the treatment of choice for paracoccidioidomycosis (Table 243-1). Ketoconazole is also effective but more toxic; voriconazole and posaconazole have been used with success in a few cases. Sulfonamides also are effective and are the least costly agents, but the response is slower and the relapse rate higher. Seriously ill patients should be treated with AmB initially. Patients with paracoccidioidomycosis have an excellent response to therapy, but pulmonary fibrosis is often progressive in those with chronic disease.


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InternalMed_Harrison. Etiologic Agent, Epidemiology, and Pathogenesis Penicillium marneffei is a thermally dimorphic fungus that is endemic in the soil in certain areas of Vietnam, Thailand, and several other southeastern Asian countries. The epidemiology of penicilliosis is linked to bamboo rats, which are infected with the fungus but rarely manifest disease. The disease occurs most often among persons living in rural areas in which the rats are found, but there is no evidence for transmission of the infection directly from rats to humans. Infection is rare in immunocompetent hosts, and most cases are reported in persons who have advanced AIDS. Infection results from the inhalation of conidia from the environment. The organism converts to the yeast phase in the lungs and then spreads hematogenously to the reticuloendothelial system.


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InternalMed_Harrison. Clinical Manifestations The clinical manifestations of penicilliosis mimic those of disseminated histoplasmosis and include fever, fatigue, weight loss, dyspnea, diarrhea (in some cases), lymphadenopathy, hepatosplenomegaly, and skin lesions, which appear as papules that often umbilicate and resemble molluscum contagiosum (Chap. 220e). Diagnosis Penicilliosis is diagnosed by culture of P. marneffei from blood or from biopsy samples of skin, bone marrow, or lymph node. The organism usually grows within 1 week as a mold that produces a distinctive red pigment. Histopathologic examination of tissues and smears of blood or material from skin lesions shows oval or elliptical yeast-like organisms with central septation and can quickly establish a presumptive diagnosis.


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InternalMed_Harrison. Treatment and Prognosis Patients who have severe disease should be treated initially with AmB until their condition improves; therapy can then be changed to itraconazole (Table 243-1). Patients who have mild symptoms can be treated from the start with itraconazole. For patients with AIDS, suppressive therapy with itraconazole is recommended until immune reconstitution (related to successful therapy for HIV infection with antiretroviral drugs) is evident. Disseminated penicilliosis is usually fatal if not treated. With treatment, the mortality rate is ∼10%.


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InternalMed_Harrison. In these common soil organisms (also called dematiaceous fungi), melanin causes the hyphae and/or conidia to be darkly pigmented. The term phaeohyphomycosis is used to describe any infection with a pigmented mold. This definition encompasses two specific syndromes—eumycetoma and chromoblastomycosis—as well as all other types of infections caused by these organisms. It is important to note that eumycetomas can be caused by hyaline molds as well as brown-black molds and that only about half of all mycetomas are due to fungi. Actinomycetes cause the remainder (Chap. 199). Most of the involved fungi cause localized subcutaneous infections after direct inoculation, but disseminated infection and serious focal visceral infections also occur, especially in immunocompromised patients.


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InternalMed_Harrison. Etiologic Agents A large number of pigmented molds can cause human infection. All are found in the soil or on plants, and some cause economically important plant diseases. The most common cause of eumycetoma is Madurella species. Fonsecaea and Cladophialophora species are responsible for most cases of chromoblastomycosis. Disseminated infection and focal visceral infections are caused by a variety of dematiaceous fungi; Alternaria, Exophiala, Curvularia, and Wangiella species are among the more common molds reported to cause human infection. Recently, Exserohilum species have caused a large outbreak of severe, sometimes fatal CNS and osteoarticular infections following the injection of methylprednisolone contaminated with this fungus.


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InternalMed_Harrison. Epidemiology and Pathogenesis Eumycetoma and chromoblastomycosis are acquired by inoculation through the skin. These two syndromes are seen almost entirely in tropical and subtropical areas and occur mostly in rural laborers who are frequently exposed to the organisms. Other infections with dematiaceous molds are acquired by inhalation, by traumatic inoculation into the eye or through the skin, or by injection of contaminated medication. Melanin is a virulence factor for all the pigmented molds. Several organisms, specifically Cladophialophora bantiana and Rhinocladiella mackenziei, are neurotropic and likely to cause CNS infection. In an immunocompromised patient or when a pigmented mold is injected directly into a deep structure, these organisms become opportunists, invading blood vessels and mimicking better-known opportunistic infections, such as aspergillosis.


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InternalMed_Harrison. Clinical Manifestations Eumycetoma is a chronic subcutaneous and cutaneous infection that usually occurs on the lower extremities and that is characterized by swelling, development of sinus tracts, and the appearance of grains that are actually colonies of fungi discharged from the sinus tract. As the infection progresses, adjacent fascia and bony structures become involved. The disease is indolent and disfiguring, progressing slowly over years. Complications include fractures of infected bone and bacterial superinfection. Chromoblastomycosis is an indolent subcutaneous infection characterized by nodular, verrucous, or plaque-like painless lesions that occur predominantly on the lower extremities and grow slowly over months to years. There is hardly ever extension to adjacent structures, as is seen with eumycetoma. Long-term consequences include bacterial superinfection, chronic lymphedema, and (rarely) the development of squamous cell carcinoma.


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InternalMed_Harrison. Dematiaceous molds are the most common cause of allergic fungal sinusitis and a less common cause of invasive fungal sinusitis. Keratitis occurs with traumatic corneal inoculation. Even in many immunocompromised patients, inoculation through the skin generally produces localized cyst-like, nodular lesions at the entry site. However, other immunocompromised patients develop pneumo-1355 nia, brain abscess, or disseminated infection. Epidural injection of Exserohilum-contaminated steroids has led to meningitis, basilar stroke, epidural abscess or phlegmon, vertebral osteomyelitis, and arachnoiditis.


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InternalMed_Harrison. Diagnosis The specific diagnosis of infection with a pigmented mold is established by growth of the organism in culture. However, in eumycetoma, a tentative clinical diagnosis can be made when a patient presents with a lesion characterized by swelling, sinus tracts, and grains. Histopathologic examination and culture are necessary to confirm that the etiologic agent is a mold and not an actinomycete. In chromoblastomycosis, the diagnosis rests on the histologic demonstration of sclerotic bodies (dark brown, thick-walled, septate fungal forms that resemble large yeasts) in the tissues; culture establishes which pigmented mold is causing the infection. For other infections, growth of the organism is essential to differentiate infection with a hyaline mold (e.g., Aspergillus or Fusarium) from that due to a pigmented mold. No serologic assays for pigmented molds are available. Polymerase chain reaction (PCR) assays are increasingly used in the diagnosis of infection due to pigmented molds


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InternalMed_Harrison. that due to a pigmented mold. No serologic assays for pigmented molds are available. Polymerase chain reaction (PCR) assays are increasingly used in the diagnosis of infection due to pigmented molds but are available only through fungal reference laboratories.


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InternalMed_Harrison. Treatment and Prognosis Treatment of eumycetoma and chromoblastomycosis involves both surgical extirpation of the lesion and use of antifungal agents. Surgical removal of the lesions of both eumycetoma and chromoblastomycosis is most effective if performed before extensive spread has occurred. In chromoblastomycosis, cryosurgery and laser therapy have been used with variable success. The antifungal agents of choice are itraconazole, voriconazole, and posaconazole. The most experience has accrued with itraconazole; less experience has been gained with the newer azoles, which are active in vitro and have been reported to be effective in a few patients. Flucytosine and terbinafine also have been used to treat chromoblastomycosis. Chromoblastomycosis and eumycetoma are chronic indolent infections that are difficult to cure but are not life-threatening.


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InternalMed_Harrison. Disseminated and focal visceral infections are treated with the appropriate antifungal agent; the choice of agent is based on the location and extent of the infection, in vitro testing, and clinical experience with the specific infecting organism. AmB is not effective against many of these organisms but has been used successfully against others. The most experience has accrued with itraconazole in the treatment of localized infections. Voriconazole is increasingly used when infections are disseminated or involve the CNS because this drug reaches adequate concentrations within the CNS and because both IV and well-absorbed oral formulations are available. The role of posaconazole has not been established but will likely expand. Disseminated and focal visceral infections, especially those involving the CNS, are associated with high mortality rates.


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InternalMed_Harrison. Two genera of hyaline (nonpigmented) molds, Fusarium and Scedosporium, and one yeast-like genus, Trichosporon, have become prominent pathogens among immunocompromised patients. Infections caused by Fusarium and Scedosporium species overlap with invasive aspergillosis in their clinical manifestations, and, when seen in tissues, these organisms appear similar to Aspergillus. In the immunocompetent host, these fungi cause localized infections of skin, skin structures, and subcutaneous tissues, but their role as causes of infection in immunocompromised patients will be emphasized in this section.


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InternalMed_Harrison. Etiologic Agent, Epidemiology, and Pathogenesis Fusarium spe cies, which are found worldwide in soil and on plants, have emerged as major opportunists in markedly immunocompromised patients. Most human infections follow inhalation of conidia, but ingestion and direct inoculation also can lead to disease. An outbreak of severe Fusarium keratitis among soft contact lens wearers was traced back to a particular brand of contact lens solution and 1356 individual contact lens cases that had been contaminated. Disseminated infection is reported most often in patients who have a hematologic malignancy, are neutropenic, have received a stem cell or solid organ transplant, or have a severe burn.


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InternalMed_Harrison. Clinical Manifestations In immunocompetent persons, Fusarium species cause localized infections of various organs. These organisms commonly cause fungal keratitis, which can extend into the anterior chamber of the eye; cause loss of vision; and require corneal transplantation. Onychomycosis due to Fusarium species, while basically an annoyance in immunocompetent patients, is a source of subsequent hematogenous dissemination and should be aggressively sought and treated in neutropenic patients. In profoundly immunocompromised patients, fusariosis is angioinvasive, and clinical manifestations mimic those of aspergillosis. Pulmonary infection is characterized by multiple nodular lesions. Sinus infection is likely to lead to invasion of adjacent structures. Disseminated fusariosis occurs primarily in neutropenic patients with hematologic malignancies and in allogeneic stem cell transplant recipients, especially those with graft-versus-host disease. Disseminated fusariosis differs from


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InternalMed_Harrison. in neutropenic patients with hematologic malignancies and in allogeneic stem cell transplant recipients, especially those with graft-versus-host disease. Disseminated fusariosis differs from disseminated aspergillosis in that skin lesions are extremely common with fusariosis; the lesions are nodular or necrotic, are usually painful, and appear over time in different locations (Fig. 243-2).


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InternalMed_Harrison. Diagnosis The diagnostic approach usually includes both documentation of the growth of Fusarium species from involved tissue and demonstration of invasion by histopathologic techniques that show septate hyphae in tissues. The organism is difficult to differentiate from Aspergillus species in tissues; thus, identification with culture is imperative. An extremely helpful diagnostic clue is growth in blood cultures, which are positive in as many as 50% of patients with disseminated fusariosis. There are no serologic assays for Fusarium. PCR techniques have proved useful but are available only through fungal reference laboratories.


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InternalMed_Harrison. Treatment and Prognosis Fusarium species are resistant to many anti-fungal agents. A lipid formulation of AmB (at least 5 mg/kg daily), voriconazole (200–400 mg twice daily), or posaconazole (300 mg daily) is recommended. Many physicians use both a lipid formulation of AmB and either voriconazole or posaconazole because susceptibility information is not available when therapy must be initiated. Serum drug levels should be monitored with either azole to ensure that absorption is adequate and with voriconazole to avoid toxicity. Mortality rates for disseminated fusariosis have been as high as 85%. With the improved antifungal therapy now available, mortality rates have fallen to ∼50%. However, if neutropenia persists, the mortality rate approaches 100%. FIGuRE 243-2 Painful necrotic foot lesion that developed over a week in a woman who had acute leukemia and who had been neu-tropenic for 2 months. Fusarium species were grown from a punch biopsy. (Courtesy of Dr. Nessrine Ktaich.)


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InternalMed_Harrison. SCEDOSPORIOSIS Etiologic Agent The genus Scedosporium includes several pathogens. The major causes of human infections are Scedosporium apiospermum, which in its sexual state is termed Pseudallescheria boydii, and S. prolificans. The S. apiospermum complex encompasses several species but will be referred to here simply as S. apiospermum. Epidemiology and Pathogenesis S. apiospermum is found worldwide in temperate climates in tidal flats, swamps, ponds, manure, and soil. This organism is known as a cause of pneumonia, disseminated infection, and brain abscess in near-drowning victims. S. prolificans is also found in soil but is more geographically restricted. Infection occurs predominantly through inhalation of conidia, but direct inoculation through the skin or into the eye also can occur.


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InternalMed_Harrison. Clinical Manifestations Among immunocompetent persons, Scedosporium species are a prominent cause of eumycetoma. Keratitis as a result of accidental corneal inoculation is a sight-threatening infection. In patients who have hematologic malignancies (especially acute leukemia with neutropenia), recipients of solid organ or stem cell transplants, and patients receiving glucocorticoids, Scedosporium species are angioinvasive, causing pneumonia and widespread dissemination with abscesses. Pulmonary infection mimics aspergillosis; nodules, cavities, and lobar infiltrates are common. Disseminated infection involves the skin, heart, brain, and many other organs. Skin lesions are not as common or as painful as those of fusariosis.


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InternalMed_Harrison. Diagnosis Diagnosis depends on the growth of Scedosporium species from involved tissue and the demonstration of invasion by histopathologic techniques that show septate hyphae in tissues. Culture evidence is essential because Scedosporium species are difficult to differentiate from Aspergillus in tissues. Demonstration of tissue invasion is essential because these ubiquitous environmental molds can be mere contaminants or colonizers. S. prolificans can grow in blood cultures, but S. apiospermum usually does not. There are no serologic assays for Scedosporium. PCR techniques have proved useful but are available only through fungal reference laboratories.


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InternalMed_Harrison. Treatment and Prognosis Scedosporium species are resistant to AmB, echinocandins, and some azoles. Voriconazole is the agent of choice for S. apiospermum, and posaconazole also has been used for this infection. S. prolificans is resistant in vitro to almost every available antifungal agent; the addition of agents such as terbinafine to a voriconazole regimen has been attempted because in vitro data suggest possible synergy against some strains of S. prolificans. Mortality rates for invasive S. apiospermum infection are ∼50%, but those for invasive S. prolificans infection remain as high as 85–100%. TRICHOSPORONOSIS Etiologic Agent The genus Trichosporon contains many species, some of which cause localized infection of hair and nails. The major pathogen responsible for invasive infection is Trichosporon asahii. Trichosporon species grow as yeast-like colonies in vitro; in vivo, however, hyphae, pseudohyphae, and arthroconidia can also be seen.


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InternalMed_Harrison. Epidemiology and Pathogenesis These yeasts are commonly found in soil, sewage, and water and in rare instances can colonize human skin and the human gastrointestinal tract. Most infections follow fungal inhalation or entry via central venous catheters. Systemic infection occurs almost exclusively in immunocompromised hosts, including those who have hematologic malignancies, are neutropenic, have received a solid organ transplant, or are receiving glucocorticoids. Clinical Manifestations Disseminated trichosporonosis resembles invasive candidiasis, and fungemia is often the initial manifestation of infection. Pneumonia, skin lesions, and sepsis syndrome are common. The skin lesions begin as papules or nodules surrounded by erythema and progress to central necrosis. A chronic form of infection mimics hepatosplenic candidiasis (chronic disseminated candidiasis).


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InternalMed_Harrison. Diagnosis The diagnosis of systemic Trichosporon infection is established by growth of the organism from involved tissues or from blood. Histopathologic examination of a skin lesion showing a mixture of yeast forms, arthroconidia, and hyphae can lead to an early presumptive diagnosis of trichosporonosis. The serum cryptococcal antigen latex agglutination test may be positive in patients with disseminated trichosporonosis because T. asahii and Cryptococcus neoformans share polysaccharide antigens. Treatment and Prognosis Rates of response to AmB have been disappointing, and many Trichosporon isolates are resistant in vitro. Voriconazole appears to be the antifungal agent of choice and is used at a dosage of 200–400 mg twice daily. The mortality rates for disseminated Trichosporon infection have been as high as 70% but are decreasing with the use of newer azoles, such as voriconazole; however, patients who remain neutropenic are likely to succumb to this infection.


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InternalMed_Harrison. Fungal infections of the skin and skin structures are caused by molds and yeasts that do not invade deeper tissues but rather cause disease merely by inhabiting the superficial layers of skin, hair follicles, and nails. These agents are the most common cause of fungal infections of humans but only rarely cause serious infections. YEAST INFECTIONS Etiologic Agents The lipophilic yeast Malassezia is dimorphic in that it lives on the skin in the yeast phase but transforms to the mold phase as it causes disease. Most species require exogenous lipids for growth. Epidemiology and Pathogenesis Malassezia species are part of the indigenous human flora found in the stratum corneum of the back, chest, scalp, and face—areas rich in sebaceous glands. Disease is more common in humid areas. The organisms do not invade below the stratum corneum and generally elicit little if any inflammatory response.


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InternalMed_Harrison. Clinical Manifestations Malassezia species cause tinea versicolor (also called pityriasis versicolor), folliculitis, and seborrheic dermatitis. Tinea versicolor presents as flat round scaly patches of hypoor hyperpigmented skin on the neck, chest, or upper arms. The lesions are usually asymptomatic but can be pruritic. They can be mistaken for vitiligo, but the latter is not scaly. Folliculitis occurs over the back and chest and mimics bacterial folliculitis. Seborrheic dermatitis manifests as erythematous pruritic scaly lesions in the eyebrows, moustache, nasolabial folds, and scalp. The scalp lesions are termed cradle cap in babies and dandruff in adults. Seborrheic dermatitis can be severe in patients with advanced AIDS. Fungemia and disseminated infection occur rarely with Malassezia species—almost always in premature neonates receiving parenteral lipid preparations through a central venous catheter.


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InternalMed_Harrison. Diagnosis Malassezia infections are diagnosed clinically in most cases. If scrapings are collected on a microscope slide on which a drop of potassium hydroxide has been placed, a mixture of budding yeasts and short septate hyphae is seen. In order to culture M. furfur from those patients in whom disseminated infection is suspected, sterile olive oil must be added to the medium.


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InternalMed_Harrison. Treatment and Prognosis Topical creams and lotions, including selenium sulfide shampoo, ketoconazole shampoo or cream, terbinafine cream, and ciclopirox cream, are effective in treating Malassezia infections and are usually given for 2 weeks. Mild topical steroid creams are sometimes used to treat seborrheic dermatitis. For extensive disease, itraconazole (200 mg/d) or fluconazole (200 mg/d) can be used for 5–7 days. The rare cases of fungemia caused by Malassezia species are treated with AmB or fluconazole, prompt removal of the catheter, and discontinuance of parenteral lipid infusions. Malassezia skin infections are benign and self-limited, although recurrences are the rule. The outcome of systemic infection depends on the host’s underlying conditions, but most infected infants do well. DERMATOPHYTE (MOLD) INFECTIONS Etiologic Agents The molds that cause skin infections in humans include the genera Trichophyton, Microsporum, and Epidermophyton.


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InternalMed_Harrison. DERMATOPHYTE (MOLD) INFECTIONS Etiologic Agents The molds that cause skin infections in humans include the genera Trichophyton, Microsporum, and Epidermophyton. These organisms, which are not components of the normal skin flora, 1357 can live within the keratinized structures of the skin—hence the term dermatophytes.


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InternalMed_Harrison. wide, and infections with these organisms are extremely com mon. Some organisms cause disease only in humans and can be transmitted by person-to-person contact and by fomites, such as hairbrushes or wet floors, that have been contaminated by infected individuals. Several species cause infections in cats and dogs and can readily be transmitted from these animals to humans. Finally, some dermatophytes are spread from contact with soil. The characteristic ring shape of cutaneous lesions is the result of the organisms’ outward growth in a centrifugal pattern in the stratum corneum. Fungal invasion of the nail usually occurs through the lateral or superficial nail plates and then spreads throughout the nail; when hair shafts are invaded, the organisms can be found either within the shaft or surrounding it. Symptoms are caused by the inflammatory reaction elicited by fungal antigens and not by tissue invasion. Dermatophyte infections occur more commonly in male than in female patients, and


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InternalMed_Harrison. it. Symptoms are caused by the inflammatory reaction elicited by fungal antigens and not by tissue invasion. Dermatophyte infections occur more commonly in male than in female patients, and progesterone has been shown to inhibit dermatophyte growth.


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InternalMed_Harrison. Clinical Manifestations Dermatophyte infection of the skin is often called ringworm. This term is confusing because worms are not involved. Tinea, the Latin word for worm, describes the serpentine nature of the skin lesions and is a less confusing designation that is used in conjunction with the name of the body part affected—e.g., tinea capitis (head), tinea pedis (feet), tinea corporis (body), tinea cruris (crotch), and tinea unguium (nails, although infection at this site is more often termed onychomycosis).


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InternalMed_Harrison. Tinea capitis occurs most commonly in children 3–7 years old. Children with tinea capitis usually present with well-demarcated scaly patches in which hair shafts are broken off right above the skin; alopecia can result. Tinea corporis is manifested by well-demarcated, annular, pruritic, scaly lesions that undergo central clearing. Usually one or several small lesions are present. In some cases, tinea corporis can involve much of the trunk or manifest as folliculitis with pustule formation. The rash should be differentiated from contact dermatitis, eczema, and psoriasis. Tinea cruris is seen almost exclusively in men. The perineal rash is erythematous and pustular, has a discrete scaly border, is without satellite lesions, and is usually pruritic. The rash must be differentiated from intertriginous candidiasis, erythrasma, and psoriasis.


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InternalMed_Harrison. Tinea pedis also is more common among men than among women. It usually starts in the web spaces of the toes; peeling, maceration, and pruritus are followed by development of a scaly pruritic rash along the lateral and plantar surfaces of the feet. Hyperkeratosis of the soles of the feet often ensues. Tinea pedis has been implicated in lower-extremity cellulitis, as streptococci and staphylococci can gain entrance to the tissues through fissures between the toes. Onychomycosis affects toenails more often than fingernails and is most common among persons who have tinea pedis. The nail becomes thickened and discolored and may crumble; onycholysis almost always occurs. Onychomycosis is more common in older adults and in persons with vascular disease, diabetes mellitus, and trauma to the nails. Fungal infection must be differentiated from psoriasis, which can mimic onychomycosis but usually has associated skin lesions.


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InternalMed_Harrison. Diagnosis Many dermatophyte infections are diagnosed by their clinical appearance. If the diagnosis is in doubt, as is often the case in children with tinea capitis, scrapings should be taken from the edge of a lesion with a scalpel blade, transferred to a slide to which a drop of potassium hydroxide is added, and examined under a microscope for the presence of hyphae. Cultures are indicated if an outbreak is suspected or the patient does not respond to therapy. Culture of the nail is especially useful as an aid to decisions about both diagnosis and treatment. Treatment and Prognosis Dermatophyte infections usually respond to topical therapy. Lotions or sprays are easier than creams to apply to large or hairy areas. Particularly for tinea cruris, the affected Terbinafine 250 mg/d for 1–2 weeks Adverse reactions minimal with short treatment period


InternalMed_Harrison

InternalMed_Harrison. Terbinafine 250 mg/d for 1–2 weeks Adverse reactions minimal with short treatment period Itraconazolea 200 mg/d for 1–2 weeks Adverse reactions minimal with short treatment period except for drug interactions aItraconazole capsules require food and gastric acid for absorption, whereas itraconazole solution is taken on an empty stomach.


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InternalMed_Harrison. area should be kept as dry as possible. When patients have extensive skin lesions, oral itraconazole or terbinafine can hasten resolution (Table 243-2). Terbinafine interacts with fewer drugs than itraconazole and is generally the first-line agent. Onychomycosis does not respond to topical therapy, although ciclopirox nail lacquer applied daily for a year is occasionally beneficial. Itraconazole and terbinafine both accumulate in the nail plate and can be used to treat onychomycosis (Table 243-2). These agents are more effective and better tolerated than griseofulvin and ketoconazole. The major decision to be made with regard to therapy is whether the extent of nail involvement justifies the use of systemic antifungal agents that have adverse effects, may interact with other drugs, and are costly. Treating for cosmetic reasons alone is discouraged. Relapses of tinea cruris and tinea pedis are common and should be treated early with topical creams to avoid development of more extensive


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InternalMed_Harrison. costly. Treating for cosmetic reasons alone is discouraged. Relapses of tinea cruris and tinea pedis are common and should be treated early with topical creams to avoid development of more extensive disease. Relapses of onychomycosis follow treatment in 25–30% of cases.


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InternalMed_Harrison. Henry Masur, Alison Morris Pneumocystis is an opportunistic pathogen that is an important cause of pneumonia in immunocompromised hosts, particularly those with HIV infection (Chap. 226), and in individuals with organ transplants, those with hematologic malignancies, and those receiving immunosuppressive therapy. The organism was discovered in rodents in 1906 and was initially believed to be a protozoan. Because Pneumocystis cannot be cultured, our understanding of its biology has been limited, but molecular techniques have demonstrated that the organism is actually a fungus. Formerly known as Pneumocystis carinii, the species infecting humans has been renamed Pneumocystis jirovecii.


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InternalMed_Harrison. P. jirovecii pneumonia (PCP) came to medical attention when cases were reported in malnourished orphans in Europe during World War II. The disease was later recognized in other immunosuppressed populations but was rare in the era before HIV/AIDS and before intensive immunosuppressive therapy for organ transplantation and autoimmune disorders. In 1981, PCP was first reported in men who had sex with men and in IV drug users who had no obvious cause of immunosuppression. These cases were subsequently recognized as the first cases of what came to be known as the acquired immunodeficiency syndrome (AIDS) (Chap. 226). The incidence of PCP increased dramatically as the AIDS epidemic grew: without chemoprophylaxis or antiretroviral therapy (ART), 80–90% of patients with HIV/AIDS in North America and Western Europe ultimately develop one or more episodes of PCP. While its incidence declined with the introduction of anti-Pneumocystis prophylaxis and combination ART, PCP has continued to be a


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InternalMed_Harrison. and Western Europe ultimately develop one or more episodes of PCP. While its incidence declined with the introduction of anti-Pneumocystis prophylaxis and combination ART, PCP has continued to be a leading cause of AIDS-associated morbidity in the United States and Western Europe, particularly in individuals who do not know they are infected with HIV until they are profoundly immunosuppressed and in HIV-infected patients who are not receiving ART or PCP prophylaxis.


InternalMed_Harrison

InternalMed_Harrison. PCP also develops in HIV-uninfected patients who are immunocompromised secondary to hematologic or malignant neoplasms, stem cell or solid organ transplantation, and immunosuppressive medications. The incidence of PCP depends on the degree of immunosuppression. PCP is increasingly reported among individuals receiving tumor necrosis factor α inhibitors and antilymphocyte monoclonal antibodies for rheumatologic or other diseases. While clinical PCP in immunocompetent hosts has not been clearly documented, studies have shown that Pneumocystis organisms can colonize the airways of children and adults who are not overtly immunocompromised. The relevance of these organisms to acute or chronic syndromes, such as chronic obstructive pulmonary disease (COPD), in immunocompetent patients is being investigated. In some developing countries, the incidence of PCP among


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InternalMed_Harrison. In some developing countries, the incidence of PCP among HIV-infected individuals has been found to be lower than that in industrialized countries. This lower incidence may be due to competing mortality from infectious diseases such as tuberculosis and bacterial pneumonia, which typically occur before patients become immunosuppressed enough to develop PCP. Geographic variations in Pneumocystis exposure and underdiagnosis also may explain the apparent lower frequency of PCP in some countries.


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InternalMed_Harrison. PATHOGENESIS AND PATHOLOGY Life Cycle and Transmission The life cycle of Pneumocystis involves both sexual and asexual reproduction, and the organism exists as a trophic form, a cyst, and a precyst at various points. Serologic and molecular studies have demonstrated that most humans are exposed to Pneumocystis early in life. It was historically thought that Pneumocystis developed from reactivation of latent infection, but de novo infections from environmental sources and person-to-person transmission occur as well. Outbreaks of PCP suggest that nosocomial transmission can take place, and studies with rodents show that immunocompetent animals can serve as reservoirs for transmission of P. carinii (the infecting species in rodents) to immunocompetent and immunosuppressed animals. However, Pneumocystis organisms are species specific, and thus humans are infected only by other humans who transmit P. jirovecii; humans cannot be infected with animal species of Pneumocystis such as P. murina


InternalMed_Harrison

InternalMed_Harrison. organisms are species specific, and thus humans are infected only by other humans who transmit P. jirovecii; humans cannot be infected with animal species of Pneumocystis such as P. murina (mice) or P. oryctolagi (rabbits). The utility of respiratory isolation in preventing transmission from patients with PCP to other immunosuppressed individuals has been debated; no clear evidence exists, although it seems prudent to isolate patients with active PCP from other immunosuppressed patients.


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InternalMed_Harrison. Role of Immunity Defects in cellular and/or humoral immunity predispose to development of PCP. CD4+ T cells are critical in host defense against Pneumocystis. For HIV-infected patients, the incidence is inversely related to the CD4+ T cell count: at least 80% of cases occur at counts of <200 cells/μL, and most of these cases develop at counts of <100 cells/μL. CD4+ T cell counts are less specific and thus less useful in predicting the risk of PCP in HIV-uninfected, immunosuppressed patients. Lung Pathology Pneumocystis has a unique tropism for the lung. It is presumably inhaled into the alveolar space. Clinically apparent pneumonia occurs only if an individual is immunocompromised. Pneumocystis proliferates in the lung, provoking a mononuclear cell


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InternalMed_Harrison. FIGuRE 244-1 Direct microscopy of Pneumocystis pneumonia. A. Transbronchial lung biopsy stained with hematoxylin and eosin shows eosinophilic alveolar filling. B. Methenamine silver–stained bronchoalveolar lavage (BAL) fluid. C. Giemsa-stained BAL fluid. D. Immunofluorescent stain of BAL fluid. response. The alveoli become filled with proteinaceous material, and alveolar damage results in increased alveolar-capillary injury and surfactant abnormalities. Stained lung sections typically show foamy, vacuolated alveolar exudates composed largely of viable and nonviable organisms (Fig. 244-1A). Interstitial edema and fibrosis may develop, and organisms can be seen in the alveolar space with silver or other stains. Moreover, the organisms can be seen when tissue is subjected to colorimetric or immunofluorescent staining (Fig. 244-1B–D).


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InternalMed_Harrison. CLINICAL FEATuRES Clinical Presentation PCP presents as acute or subacute pneumonia that may initially be characterized by a vague sense of dyspnea alone but that subsequently manifests as fever and nonproductive cough with progressive shortness of breath ultimately resulting in respiratory failure and death. Extrapulmonary manifestations of PCP are rare but can include involvement of almost any organ, most notably lymph nodes, spleen, and liver. Physical Examination The physical examination findings in PCP are nonspecific. Patients have decreased oxygen saturation—at rest or with exertion—that, without treatment, progresses to severe hypoxemia. Patients may initially have a normal chest examination and no adventitious sounds but later, without treatment, develop diffuse rales and signs of consolidation. Oral thrush in a patient with HIV infection indicates an increased risk for PCP.


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InternalMed_Harrison. Laboratory Findings The results of routine laboratory tests are nonspecific in PCP. Serum levels of lactate dehydrogenase (LDH) are often elevated due to pulmonary damage; however, a normal LDH level does not rule out PCP, nor is an elevated LDH value specific for PCP. The peripheral white blood cell count may be elevated, but the increase is usually modest. Hepatic and renal function are typically normal.


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InternalMed_Harrison. Radiographic Findings Although the initial chest radiograph may be normal when patients have mild symptoms, the classic radiographic appearance of PCP consists of diffuse bilateral interstitial infiltrates that are perihilar and symmetric (Fig. 244-2A)—yet another finding that is not specific for PCP. The interstitial infiltrates can progress to alveolar filling (Fig. 244-2B). High-resolution chest CT shows diffuse ground-glass opacities in virtually all patients with PCP (Fig. 244-2C). A normal chest CT essentially rules out the diagnosis of PCP. Cysts and pneumothoraces are common chest radiographic findings (Fig. 244-2D). A wide variety of atypical radiographic findings have been described, including asymmetric patterns, upper lobe infiltrates, mediastinal adenopathy, nodules, cavities, and effusions.


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InternalMed_Harrison. The optimal sample for diagnostic examination depends on how ill the patient is and what resources are available. Before the 1990s, diagnoses of PCP were usually established by open lung biopsy; later, transbronchial lung biopsy was employed. Hematoxylin and eosin staining of pulmonary FIGuRE 244-2 Radiographs in Pneumocystis pneumonia. A. Posterior-anterior chest radiograph showing symmetric interstitial infiltrates. B. Posterior-anterior chest radiograph showing symmetric alveolar infiltrates (courtesy of Alison Morris). C. CT image demonstrating symmetric interstitial infiltrates and ground-glass opacities. D. CT image showing symmetric interstitial infiltrates, ground-glass opacities, and pneumatoceles.


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InternalMed_Harrison. tissue demonstrates a foamy alveolar infiltrate and a mononuclear interstitial infiltrate (Fig. 244-2A). This appearance is pathognomonic for PCP even though the organisms cannot be specifically identified with this stain. The diagnosis is typically established in lung tissue or pulmonary secretions by highly specific staining of the cyst—e.g., with methenamine silver (Fig. 244-2B), toluidine blue O, or Giemsa (Fig. 244-2C)—or by staining with a specific immunofluorescent antibody (Fig. 244-2D).


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InternalMed_Harrison. The demonstration of organisms in bronchoalveolar lavage fluid is almost 100% sensitive and specific for PCP in patients with either HIV infection or immunosuppression of other etiologies. The organisms are identified with the specific stains indicated above for lung biopsy. While expectorated sputum or throat swabs have very low sensitivity, an induced sputum sample obtained and interpreted by an experienced provider can be highly sensitive and specific. The reported sensitivity of induced sputum for PCP is widely variable (55–90%), however, and is dependent on both the characteristics of the patient and the experience of the center conducting the test.


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InternalMed_Harrison. Recently, many laboratories have offered polymerase chain reaction (PCR) testing of respiratory specimens for Pneumocystis. However, these PCR tests are so sensitive that it is difficult to distinguish patients with colonization (i.e., those whose acute lung disease is due to some other process but who have low levels of Pneumocystis DNA in the lungs) from those with acute pneumonia due to Pneumocystis. Such PCR tests on appropriate samples may be more useful for ruling out a diagnosis of PCP if they are negative than for definitively attributing the disease to Pneumocystis. There has been considerable interest in serologic tests such as assays for (1→3)-β-D-glucan, levels of which are frequently elevated in patients with PCP. However, no serologic assays developed to date offer substantial sensitivity or specificity.


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InternalMed_Harrison. Untreated, PCP is invariably fatal. Patients with HIV infection often have an indolent course that presents as mild exercise intolerance or chest tightness without fever or cough and a normal or nearly normal posterior-anterior chest radiograph, with progression over days, weeks, or even a few months to fever, cough, diffuse alveolar infiltrates, and profound hypoxemia. Some patients with HIV infection and most patients with other types of immunosuppression have more acute disease that progresses over a few days to respiratory failure. Rare patients also develop distributive shock. A few unusual patients present with extrapulmonary manifestations in the skin or soft tissue, retina, brain, liver, kidney, or spleen that are nonspecific in presentation and can be diagnosed only by histology.


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InternalMed_Harrison. Factors that influence mortality risk include the patient’s age and degree of immunosuppression as well as the presence of preexisting lung disease, a low serum albumin level, the need for mechanical ventilation, and the development of pneumothorax. With advances in supportive critical care, the prognosis for patients with PCP who require intubation and respiratory support has improved and now depends to a large extent on comorbidities and the prognosis of the underlying disease. Since patients typically do not respond to therapy for 4–8 days, supportive care for a minimum of 10 days is a reasonable consideration if such support is compatible with the patient’s wishes and the prognosis of comorbidities. Patients whose condition continues to deteriorate after 3 or 4 days or has not improved after 7–10 days should be reevaluated to determine whether other infectious processes are present (either having been missed on initial evaluation or having developed during treatment) or whether


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InternalMed_Harrison. after 7–10 days should be reevaluated to determine whether other infectious processes are present (either having been missed on initial evaluation or having developed during treatment) or whether noninfectious processes (e.g., congestive heart failure, pulmonary emboli, pulmonary hypertension, drug toxicity, or a neoplastic process) are causing pulmonary dysfunction.


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TREATMEnT p. jirovecii Pneumonia

InternalMed_Harrison. TREATMEnT p. jirovecii Pneumonia


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InternalMed_Harrison. The treatment of choice for PCP is trimethoprim-sulfamethoxazole (TMP-SMX), given either IV or PO for 14–21 days (Table 244-1). TMP-SMX, which interferes with the organism’s folate metabolism, is at least as effective as alternative agents and is better tolerated. However, TMP-SMX can cause leukopenia, hepatitis, rash, and fever as well as anaphylactic and anaphylactoid reactions, and patients with HIV infection have an unusually high incidence of hypersensitivity to TMP-SMX. Monitoring of serum drug levels is useful if renal function or toxicities are issues. Maintenance of a 2-h post-dose sulfamethoxazole level of 100–150 μg/mL has been associated with a successful outcome. Resistance to TMP-SMX cannot be measured by organism growth inhibition in the laboratory because Pneumocystis cannot be cultured. However, mutations in the target gene for sulfamethoxazole that confer in vitro sulfa resistance to other organisms have been found in Pneumocystis. The clinical relevance of these


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InternalMed_Harrison. be cultured. However, mutations in the target gene for sulfamethoxazole that confer in vitro sulfa resistance to other organisms have been found in Pneumocystis. The clinical relevance of these mutations for the response to therapy is unknown. Sulfadiazine plus pyrimethamine, an oral regimen more often used


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InternalMed_Harrison. Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; TMP-SMX, trimethoprimsulfamethoxazole. for treatment of toxoplasmosis, also is highly effective. Dapsone 1361 plus pyrimethamine or dapsone plus trimethoprim also can be used. Intravenous pentamidine or the combination of clindamycin plus primaquine is an option for patients who cannot tolerate TMP-SMX and for patients in whose treatment TMP-SMX appears to be failing. Pentamidine must be given IV over at least 60 min to avoid potentially lethal hypotension. Adverse effects can be severe and irreversible and include renal dysfunction, dysglycemia (life-threatening hypoglycemia that can occur days or weeks after initial infusion and be followed by hyperglycemia), neutropenia, and torsades des pointes. Clindamycin plus primaquine is effective, but primaquine can be given only by the oral route—a disadvantage for patients who cannot ingest or absorb oral drugs.


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InternalMed_Harrison. A major advance in therapy for PCP was the recognition that glucocorticoids could improve survival rates among HIV-infected patients with moderate to severe disease (room air PO2, <70 mmHg; or alveolar-arterial oxygen gradient, ≥35 mmHg). Glucocorticoids appear to reduce the pulmonary inflammation that occurs after specific therapy is started and organisms begin to die, eliciting inflammation. Therapy with glucocorticoids should be the standard of care for patients with HIV infection and probably is also effective for patients with other immunodeficiencies. This treatment should be started for moderate or severe disease when therapy for PCP is initiated, even if the diagnosis has not yet been confirmed. If HIV-infected or HIV-uninfected patients are receiving high-dose glucocorticoids when they develop PCP, there are theoretical advantages to increasing or decreasing the steroid dose, but there is no convincing evidence on which to base any specific strategy.


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InternalMed_Harrison. No definitive trials have defined the best therapeutic algorithm for patients in whom TMP-SMX treatment for PCP is failing. If no other treatable infectious or noninfectious processes are detected and pulmonary dysfunction appears to be due to PCP alone, many authorities would switch from TMP-SMX to either IV pentamidine or IV clindamycin plus oral primaquine. Some authorities would add the second drug or drug combination to TMP-SMX rather than switching regimens. If patients are not already receiving them, glucocorticoids should be added to the regimen; the dosage and regimen, which are usually chosen empirically, depend on what glucocorticoid regimen (if any) the patient was receiving when PCP therapy was begun.


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InternalMed_Harrison. For patients with HIV infection who present with PCP before the initiation of ART, ART should be started within the first 2 weeks of therapy for PCP in most cases. Immune reconstitution inflammatory syndrome (IRIS) can occur, however, and the decision to initiate ART thus requires considerable expertise in terms of optimal timing relative to PCP recovery as well as in the other factors that are relevant when ART is initiated in any patient.


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InternalMed_Harrison. The most effective method for preventing PCP is to eliminate the cause of immunosuppression by withdrawing immunosuppressive therapy or treating the underlying cause, e.g., HIV infection. Patients who are susceptible to PCP benefit from chemoprophylaxis during the period of susceptibility. For patients with HIV infection, CD4+ T cell counts are a reliable marker of susceptibility, and counts below 200 cells/μL are an indication to start prophylaxis (Table 244-2). For patients with HIV infection who are not receiving ART, oral candidiasis or prior PCP also is an indication for chemoprophylaxis, regardless of CD4+ T cell count. For such patients not receiving ART, any prior episode of an AIDS-defining illness or pneumonia should encourage the use of chemoprophylaxis. However, patients who are not adherent to ART are not likely to take PCP chemoprophylaxis.


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InternalMed_Harrison. For patients without HIV infection, there is no laboratory parameter, including the CD4+ T cell count, that predicts susceptibility to PCP with adequate positive and negative accuracy. The period of susceptibility is usually estimated on the basis of experience with the Drug(s) Dose, Route Comments TMP-SMX 1 tablet (doubleor Incidence of hypersensisingle-strength) qd PO tivity is high. Rechallenge for nonlife-threatening hypersensitivity; consider dose-escalation protocol. optimal absorption. Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; TMP-SMX, trimethoprimsulfamethoxazole.


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InternalMed_Harrison. optimal absorption. Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; TMP-SMX, trimethoprimsulfamethoxazole. underlying disease and immunosuppressive regimen. Patients receiving a prolonged course of high-dose glucocorticoids appear to be particularly susceptible to PCP. The glucocorticoid exposure threshold that warrants chemoprophylaxis is controversial, but such preventive therapy should be strongly considered for any patient receiving more than the equivalent of 20 mg of prednisone daily for 30 days. TMP-SMX is the most effective prophylactic drug: few patients experience a PCP breakthrough when they are reliably taking a recommended TMP-SMX chemoprophylactic regimen. Several TMPSMX regimens have been used successfully. One double-strength tablet daily is the regimen with which there is the most experience, but either one single-strength tablet daily or one double-strength tablet two or three times weekly also has been recommended for various populations of patients.


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InternalMed_Harrison. For patients who cannot tolerate TMP-SMX (usually because of hypersensitivity or bone marrow suppression), alternative drugs include daily dapsone, weekly dapsone-pyrimethamine, and monthly aerosol pentamidine. Patients who develop hypersensitivity to TMP-SMX can sometimes tolerate the drug if a gradual dose-escalation protocol is used. Dapsone cross-reacts with sulfonamides in a substantial fraction of patients and therefore is rarely useful in patients with a history of life-threatening reactions to TMP-SMX. Aerosolized pentamidine is highly effective, but it is not as effective as TMP-SMX and may not provide protection in areas of the lung that are not well ventilated. Atovaquone is also effective and well tolerated; however, this drug is available only as an oral preparation, and gastrointestinal absorption is unpredictable in patients with abnormal gastrointestinal motility or function.


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InternalMed_Harrison. 245e-1 Laboratory Diagnosis of Parasitic Infections Sharon L. Reed, Charles E. Davis The cornerstone for the diagnosis of parasitic infections is a thorough history of the patient’s illness. Epidemiologic aspects of the illness are especially important because the risks of acquiring many parasites T. saginata are morphologically indistinguishable from those of Taenia solium (the cause of cysticercosis), motility is an important distinguishing characteristic. Microscopic examination of feces is not complete until direct wet mounts have been evaluated and concentration techniques as well as permanent stains have been applied. Before accepting a report of negativity for ova and parasites as final, the physician should insist that the laboratory undertake each of these procedures. Some intestinal parasites are more readily detected in material other than feces. For example, examination of duodenal contents is sometimes necessary to 245e SECTIon 17 PRoTozoAL AnD HELmInTHIC InfECTIonS:


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InternalMed_Harrison. parasites are more readily detected in material other than feces. For example, examination of duodenal contents is sometimes necessary to 245e SECTIon 17 PRoTozoAL AnD HELmInTHIC InfECTIonS: GEnERAL ConSIDERATIonS are closely related to occupation, recreation, or travel to areas of high endemicity. Without a basic knowledge of the epidemiology and life cycles of the major parasites, it is difficult to approach the diagnosis of parasitic infections systematically. Accordingly, the medical classification of important human parasites in this chapter emphasizes their geographic distribution, their transmission, and the anatomic location and stages of their life cycle in humans. The text and tables are intended to serve as a guide to the correct diagnostic procedures for the major parasitic infections; in addition, the reader is referred to other chapters that contain more comprehensive information about each infection (Chaps. 247–260). Tables 245e-1, 245e-2, and 245e-3 summarize the


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InternalMed_Harrison. infections; in addition, the reader is referred to other chapters that contain more comprehensive information about each infection (Chaps. 247–260). Tables 245e-1, 245e-2, and 245e-3 summarize the geographic distributions, the anatomic locations, and the methods employed for the diagnosis of flatworm, roundworm, and protozoal infections, respectively.


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InternalMed_Harrison. In addition to selecting the correct diagnostic procedures, physicians must counsel their patients to ensure that specimens are collected properly and arrive at the laboratory promptly. For example, the diagnosis of bancroftian filariasis is unlikely to be confirmed by the laboratory unless blood is drawn near midnight, when the nocturnal microfilariae are active. Laboratory personnel and surgical pathologists should be notified in advance when a parasitic infection is suspected. Continuing interaction with the laboratory staff and the surgical pathologists increases the likelihood that parasites in body fluids or biopsy specimens will be examined carefully by the most capable individuals.


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InternalMed_Harrison. Most helminths and protozoa exit the body in the fecal stream. Many laboratories now use a stool collection kit with instructions for patients to transfer portions of the sample directly into bacterial carrier medium and fixative, which increases yield. If kits are not available, the patient should be instructed to collect feces in a clean waxed or cardboard container and to record the time of collection on the container. Refrigeration will preserve trophozoites for a few hours and protozoal cysts and helminthic ova for several days. Contamination with water (which could contain free-living protozoa) or with urine (which can damage trophozoites) should be avoided. Fecal samples should be collected before ingestion of barium or other contrast agents for radiologic procedures and before treatment with antidiarrheal agents and antacids; these substances change the consistency of the feces and interfere with microscopic detection of parasites. Because of the cyclic shedding of most


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InternalMed_Harrison. treatment with antidiarrheal agents and antacids; these substances change the consistency of the feces and interfere with microscopic detection of parasites. Because of the cyclic shedding of most parasites in the feces, a minimum of three samples collected on alternate days should be examined. Examination of a single sample can be up to 50% less sensitive.


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InternalMed_Harrison. Analysis of fecal samples entails both macroscopic and microscopic examination. Watery or loose stools are more likely to contain protozoal trophozoites, but protozoal cysts and all stages of helminths may be found in formed feces. If adult worms or tapeworm segments are observed, they should be transported promptly to the laboratory or washed and preserved in fixative for later examination. The only tapeworm with motile segments is Taenia saginata, the beef tapeworm, which patients sometimes bring to the physician. Because the ova of detect Giardia lamblia, Cryptosporidium, and Strongyloides larvae. Use of the “cellophane tape” technique to detect pinworm ova on the perianal skin sometimes also reveals ova of T. saginata deposited perianally when the motile segments disintegrate (Table 245e-4).


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InternalMed_Harrison. Two routine solutions are used to make wet mounts for identification of the various life stages of helminths and protozoa: physiologic saline for trophozoites, cysts, ova, and larvae and dilute iodine solution for protozoal cysts and ova. Iodine solution must never be used to examine specimens for trophozoites because it kills the parasites and thus eliminates their characteristic motility. The two most common concentration procedures for detecting small numbers of cysts and ova are formalin-ether sedimentation and zinc sulfate flotation. The formalin-ether technique is preferable because all parasites sediment but not all float. Slides permanently stained for trophozoites should be prepared before concentration. Additional slides stained for cysts and ova may be made from the concentrate.


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InternalMed_Harrison. In many instances, especially in the differentiation of Entamoeba histolytica from other amebas, identification of parasites from wet mounts or concentrates must be considered tentative. Permanently stained smears allow study of the cellular detail necessary for definitive identification. The iron-hematoxylin stain is excellent for critical work, but trichrome staining, which can be completed in 1 h, is a satisfactory alternative that also reveals parasites in specimens preserved in polyvinyl alcohol fixative. Modified acid-fast staining and fluorescent auramine microscopy are useful adjuncts for detection and identification of several intestinal protozoa, including Cryptosporidium and Cyclospora, while direct fluorescent antibody testing is in common use for Cryptosporidium and Giardia. Microsporidia, which cause chronic diarrhea in HIV-infected patients, may be missed unless a special modified trichrome stain or fluorescent screening with calcofluor white is requested (Table


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InternalMed_Harrison. Microsporidia, which cause chronic diarrhea in HIV-infected patients, may be missed unless a special modified trichrome stain or fluorescent screening with calcofluor white is requested (Table 245e-3).


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InternalMed_Harrison. Invasion of tissue by protozoa and helminths renders the choice of diagnostic techniques more difficult. For example, physicians must understand that aspiration of an amebic liver abscess rarely reveals