Coccidioides species (Coccidioidomycosis)

MICROBIOLOGY 

Coccidioidomycosis is caused by 2 nearly identical species of Coccidioides, C. immitis and C. posadasii; both are dimorphic fungus limited to the New World (48). These fungi inhabit the desert soil within the endemic region as a mold. Within the hyphae of this mold, barrel-shaped arthroconidia form. Arthroconidia may be dislodged, become airborne, and initiate pulmonary infection when inhaled by a susceptible host. Within the host, the arthroconidia undergoes a profound morphological change in which it rounds-up and internally septates. This form is called a spherule and when seen in tissues is pathognomonic for coccidioidomycosis. Packets of endospores form within the spherule. This may be disgorged into surrounding tissue if the spherule ruptures.

EPIDEMIOLOGY 

The highest prevalence of coccidioidomycosis is in the southern San Joaquin Valley of California and in southwestern Arizona, including the Phoenix and Tucson metropolitan areas. Infection is also extant in parts of the Rio Grande Valley of Texas and in northern Mexico. It also may be acquired in other areas of southern California, Arizona, southern Nevada, southeastern Utah and southern New Mexico. Pockets of endemicity exist in Central and South America (88).

It is estimated that 150,000 cases of coccidioidomycosis occur in the United States annually (55). The vast majority of cases occur in the endemic area, and over half the cases have been reported in Arizona, where the incidence of infection has nearly quadrupled in the last decade (113). Occasionally a visitor to an endemic area may become infected and diagnosed in non-endemic areas, but the number of these cases is not known, since coccidioidomycosis is not a reportable illness in most states.

Because coccidioidomycosis is acquired via the inhalation of arthrospores, occupational or recreational activities that increase the likelihood of dust exposure may increase the likelihood of infection (77). Examples of such activities include construction or digging. Climatic variables such as rainfall, drought, windspeed, temperature, dust also affect the likelihood of exposure to the airborne fungal spores (77).

A variety of risk factors have been identified for an increased likelihood of severe or disseminated infection, but not for an increased incidence of infection. Such risk factors include: 1. Race (Filipinos and African Americans at higher risk for dissemination than Caucasians), 2. Immunosuppression either due to medication administration (such as with organ transplantation, treatment of rheumatological or other illness), acquired (such as infection with human immunodeficiency virus) 3. Underlying illnesses (such as hematological malignancies or diabetes mellitus), and 4. Pregnancy (77). Males have a greater risk of dissemination than females.

CLINICAL MANIFESTATIONS

Primary pulmonary coccidioidomycosis may present asymptomatically or with a variety of non-specific manifestations such as fever, malaise, headache, cough, chest pain, myalgia, rash (130). Symptoms may range in severity from mild to severe and life-threatening. Pulmonary coccidioidomycosis is the underlying infection in nearly 30% of patients with community acquired pneumonia within the endemic area (119). Roentgenographic studies during primary coccidioidomycosis usually demonstrate unilateral pulmonary infiltrates which generally resolve within two months. In approximately 5% of patients with primary coccidioidomycosis, pulmonary residue develop, most commonly pulmonary abscesses, which appear radiographically as nodules (12, 13). Nodules can excavate, forming either thin or thick wall cavities. Occasionally such cavities can become secondarily infected (98). Primary pneumonia with symptoms persisting longer than six weeks is termed chronic progressive pulmonary coccidioidomycosis and occurs in about 1% of all patients (51).

Chronic fibrocavitary pulmonary coccidioidomycosis is an extreme and uncommon form of chronic pulmonary coccidioidomycosis that is characterized by prolonged symptoms (mean 40 months in one series) that include cough, weight loss, fever, hemoptysis, chest pain and dyspnea. Biapical fibronodular lesions and multiple cavities with retraction similar in appearance to tuberculosis are seen in this form of infection (103).

Disseminated coccidioidomycosis occurs when infection spreads beyond the thoracic cavity and occurs in fewer than 1% of all patients. Risk factors for such dissemination have been delineated (see Epidemiology). Although dissemination of infection can result anywhere, the most common sites are the skin, soft tissue, bone, joints, the central nervous system, or combinations of these. Extrathoracic dissemination almost always occurs within twelve months of the initial pulmonary infection, although the initial infection might have been clinically silent, and radiographically resolved at the time of evaluation.

Prior to the development of specific antifungal therapy, it was recognized that untreated extrathoracic disseminated coccidioidomycosis may follow any of several clinical courses, including steady progression; persistence without progression; remittance with exacerbation; or spontaneously healing (46). Which course any particular patient might take is unpredictable. These natural history observations imply that one must be careful to not ascribe all clinical improvement in any given case of coccidioidomycosis to antifungal therapy. This is particularly applicable to localized cutaneous disease, where spontaneous improvements are well documented (46).

LABORATORY DAIGNOSIS

The diagnosis of coccidioidomycosis depends on laboratory confirmation beyond clinical impression. Several laboratory modalities are available to make the diagnosis.

Whenever Coccidioides is cultured from any site, the diagnosis of coccidioidomycosis is established; there is no known colonization state for this fungus. Culture of the fungus from respiratory secretions or other involved sites is not difficult, since Coccidioides grows well on routine bacteriologic and fungal culture media, and often, within 7 days. However, growth of the organism may take up to 21 days, so fungal cultures should be performed to allow for an extended incubation time. For many fungi, in vitro antifungal susceptibility testing is becoming more available than in the past. This type of testing for Coccidioides isolates is being evaluated (96, 114) but its clinical role is unclear at this time (105).

Identification of the spherule stage of the fungus on histopathological specimens or cytological smears also confirms a diagnosis of coccidioidomycosis. Spherules may be identified on H&E, PAS, GMS, calcofluor (105) and Papanicoulou stains (104).

For some time, there has been interest in the use of molecular probes in clinical specimens. Polymerase chair reaction assays have been developed to detect organisms in direct clinical samples, and fresh or fixed tissue (13,14,22). Further study is needed to determine the role for this type of assay in clinical diagnosis of coccidioidomycosis.

Historically, skin testing has been a measure of cell-mediated cellular immune responses to either spherulin or coccidioidin antigens (105). Unfortunately, these antigen preparations are no longer available commercially. Within the endemic area, a number of persons still give a history of coccidiodomycosis on the basis of a positive skin test.

In most instances of coccidioidomycosis, patients do not require biopsy procedure and sputum for culture is difficult to obtain due to a non-productive cough. Therefore, coccidioidal serology is a very common means to diagnose this infection. Whereas a positive culture or pathology result establishes a diagnosis of coccidioidomycosis, serology is suggestive but not confirmatory. A combination of a compatible illness, radiographic findings and positive serology is adequate to establish a probable diagnosis. Qualitative and quantitative serologic tests are available. In general, IgM antibodies rise in early infection, and IgG rises either concurrently or within several weeks. The serology stays positive for a variable period of time, and generally fall with resolution of illness.

Several serologic methodologies are available, and a few will be mentioned herein. The enzyme immunoassay (EIA) measures both IgM and IgG, is sensitive in early infection and has a rapid turn around time. IgM measured by EIA should be confirmed with repeated serology or immunodiffusion. Immunodiffusion and complement fixation are generally performed in reference laboratories. Complement fixing antibodies are IgG antibodies, and often rise within a few months of infection onset. These antibodies can be quantitated by a complement fixing test (CF) or an immunodiffusion (IDCF). The resulting titers fall with convalescence and can be used to follow the resolution of infection. Immunodiffusion assays can measure IgM or IgG and are reported to be very specific, and are used to confirm other serological results (105).

PATHOGENESIS 

The primary mechanism for acquiring coccidioidal infection occurs by inhalation of the airborne arthrospore. Once inhaled, the arthrospore travels the respiratory passage to the lung, to the level of the terminal bronchiole (56). Within the respiratory passages, the arthrospore undergoes a morphological change, resulting in the formation of the spherule. The spherule enlarges and septates, forming endospores, which are subsequently released. The growth and rupture of the spherule initiates the acute inflammatory response. The initial response consists of the recruitment of neutrophils and eosinophils. Later, a chronic inflammatory response is elicited, with granuloma formation, consisting of lymphocytes, histiocytes and multinucleated giant cells surrounding unruptured spherules. Pulmonary macrophages, having ingested spherules in the acute infection, may move to hilar or regional lymph nodes (56).

The innate initial immune response functions serve to slow the progress of infection, but control of the coccidioidal infection is critically dependent upon intact T lymphocyte functions (56). Persons who lack intact T lymphocyte function, such as those with advanced human immunodeficiency virus infection (2), recipients of organ transplants (17), or those receiving immunosuppressants such as corticosteroids (38), are more susceptible to severe and disseminated infections. The humoral immune system is active in producing antibodies to a variety of coccidioidal antigens, and some of these antibody responses form the basis of diagnostic serology. However, none of the humoral responses are useful for the control of infection (56).

Extrathoracic spread is manifested in less than 5% of persons. The specific details of the mechanism of spread is not clearly delineated, but may be accomplished through a transient fungemia (56).

An understanding of the vagaries of the natural history of symptomatic coccidioidal infection is essential to the managing physician, particularly because no placebo-controlled trials of antifungal therapy for coccidioidomycosis have ever been performed. Approximately 65% of all coccidioidal infections are asymptomatic, recognizable only by a durable delayed-type hypersensitivity reaction after intradermal injection of coccidioidal antigen. The other 35% of infections are symptomatic, generally associated with respiratory symptoms, and are almost always self-limited. Chronic illness results in fewer than 5% of all of those infected (51). This may manifest as chronic pneumonia or as disseminated disease, where the fungus has caused infection beyond the thoracic cavity.

SUSCEPTIBILITY IN VITRO AND IN VIVO

No standardized method exists by which the susceptibility of Coccidioides to antifungal agents can be tested in vitro. Similarly, while animal models have been used to assess various therapies after experimental infection with Coccidiodes (28, 45, 59, 80), these in vivo systems have not necessarily been predictive of results in humans. Because of this, virtually all the information on the treatment of coccidioidomycosis in humans is based on either clinical experience or on clinical trials.

ANTIMICROBIAL THERAPY  

Drug of Choice

Despite the availability of newer antifungal agents over the past several years, the treatment of coccidioidomycosis, particularly among those with chronic pulmonary infection or extrathoracic disseminated infection, has remained problematic (109). There have been no trials comparing the efficacy of amphotericin B and other antifungal agents for the treatment of coccidioidomycosis. However, given the inconvenience and toxicity of intravenous amphotericin B and the convenience and relatively low toxicity of the currently available oral antifungal agents, we believe that oral azole antifungals, such as fluconazole, itraconazole and ketoconazole, should be the therapy of choice for most cases of coccidioidomycosis. Intravenous amphotericin B should be reserved for life-threatening non-meningeal disease or for patients who fail to respond to azole therapy (Table 1).

Amphotericin B

Amphotericin B is a polyene antifungal derived from soil actinomycetes. Originally introduced in 1955 in a colloidal dispersion with deoxycholate (Fungizone ®), it was the first antifungal agent to be shown to be clinically effective for the treatment of coccidioidomycosis. It can only be administered intravenously and has numerous toxicities, including fever, rigors, phlebitis, hypokalemia, anemia and renal dysfunction (57). It has been demonstrated to be fungicidal in vitro against Coccidioides at concentrations of < 0.5 µg/ml but has never been demonstrated to be more than fungistatic in vivo, either in animal models or in humans.

Although there is general consensus that amphotericin B is effective therapy in patients with serious pulmonary or disseminated coccidioidomycosis, no placebo-controlled trial proving its efficacy in coccidioidomycosis has ever been done. A summary of the efficacy of amphotericin B in the treatment of coccidioidomycosis was reported by Hardenbrok and Barriere (66). These authors identified 103 patients treated with amphotericin B in 34 separate publications. There was a favorable clinical response in 70% of patients. This summary is complemented by over three decades of unpublished experience that support the concept that amphotericin B is effective therapy for many cases of serious pulmonary and non-meningeal disseminated coccidioidomycosis.

There is also a developed consensus that treatment with amphotericin B in patients with chronic pulmonary or disseminated coccidioidomycosis should be long enough to achieve symptomatic benefit and a decline in serum complement fixation (IgG) antibody titer to at least <1:16. The total dose of amphotericin B required to achieve this effect in any given patient is undefined but in a study of eleven patients with chronic pulmonary coccidioidomycosis, treatment failure was associated with receiving a total dose of intravenous amphotericin B of <39 mg/kg, or 2.7 gm in a 70 kg patient (103). Extrathoracic coccidioidomycosis has generally been treated with total doses of intravenous amphotericin B ranging from 2.5 to 3.0 gm. The efficacy of amphotericin B for bone and joint coccidioidomycosis is not fully established. Iger reviewed 112 such cases between 1964 and 1976. Of these, only 12 patients were judged to have done well (70). Other investigators have also not been convinced of the efficacy of amphotericin B for bone and joint coccidioidomycosis (127).

Amphotericin B in the management of coccidioidomycosis has had its biggest impact in the treatment of meningitis (44). The combined use of intravenous amphotericin B with direct injection of amphotericin B into the cerebrospinal fluid (CSF), in doses of 1 mg three times weekly, has reduced mortality in this disease to between 30 and 50% and even resulted in true cures, defined as a CSF white blood cell concentration of < 20 cells/µl with normal protein and glucose concentrations and undetectable complement fixation antibody (73). Doses as high as 2 mg per injection have been recommended to speed treatment (75), although many patients are unable to tolerate this because of severe headache. Complications of coccidioidal meningitis include obstructive and nonobstructive hydrocephalus (99), vasculitic events leading to stroke, progressive arachnoiditis and parenchymal space-occupying brain lesions. These all may occur during therapy (10, 125). In addition, injection of amphotericin B directly into the CSF may also lead to complications. When administered intrathecally by cisternal puncture, brain stem puncture and subarachnoid hemorrhage may occur. Whenever amphotericin B is administered intrathecally, arachnoiditis, secondary bacterial infection, or CSF obstruction may occur. This includes when administered through a ventricular, cisternal, or lumbar reservoir, or by lumbar puncture using hydrobaric technique. Hence, despite its efficacy, the complications of direct delivery of amphotericin B into the CSF make its use problematic in coccidioidal meningitis.

Because of the dose-limiting toxicity of amphotericin B as formulated with deoxycholate, newer alternatives with other lipid formulations that allow for higher doses and less toxicity have undergone recent study. Two studies have been reported in abstract form, one using lipid-complexed amphotericin B (ABLC, Abelcet ®) (106), and another using amphotericin B in colloidal dispersion with cholesteryl sulfate (ABCD, Amphotec ®) (69). Both agents appeared to have efficacy and reasonable safety in the treatment of coccidioidomycosis. These agents can clearly be useful in cases of disseminated disease (74). However, current unpublished studies and case reports are too limited to draw conclusions and further data are needed before the use of newer amphotericin B formulations can be recommended for initial management of coccidioidomycosis (61). Because renal dysfunction appears to be less frequent with the newer amphotericin B formulations (116), they should be considered in patients with preexisting renal disease or in those who develop it during amphotericin B deoxycholate therapy. Recently, Clemons and colleagues presented data that suggests that intrathecal administration of ABCD in a rabbit model of coccidioidal meningitis was clinically and histologically less toxic than injection of amphotericin B deoxycholate (29).

Azole Antifungal Agents

Azole antifungals are synthetic agents that differ significantly in chemistry, site of action, pharmacokinetics, and toxicity from amphotericin B (32). All azoles differ from amphotericin B in that they are all orally absorbable. Most are fungistatic against Coccidioides. The newer azole antifungals, namely posaconazole (84) and voriconazole (81), have been used in the treatment of coccidioidomycosis refractory to other antifungal therapy with some success (5, 25 33, 93, 94, 110).

Because of significant drug interactions as well as suppression of adrenal and gondal testosterone synthesis (32, 112), the use of ketoconazole for the treatment of coccidioidomycosis has been supplanted by newer triazole antifungal agents, fluconazole and itraconazole. Unlike ketoconazole, the triazoles lack significant effects on androgen synthesis (32). Although no comparative trials have been done, the new triazoles appear to have greater efficacy in the treatment of coccidioidomycosis than ketoconazole (51).

Fluconazole, a relatively low molecular weight bistriazole, is characterized by moderate water solubility, good oral absorption not dependent on gastric acidity, and relatively few drug interactions. While it exists in both intravenous and oral formulations, oral absorption is very high and leads serum levels that are equivalent to intravenous infusion. In a study conducted by the Mycoses Study Group of 73 patients with non-meningeal disseminated coccidioidomycosis, 19 patients had soft-tissue disease, 40 had chronic pulmonary disease, and 14 had skeletal or joint disease. Forty-nine had underlying conditions with immunocompromising characteristics including seven patients with HIV infection. Patients initially received 200 mg daily; this was increased to 400 mg daily in those not clinically responding. Overall, there was a 67% response rate, with the best response in those with soft tissue and skeletal or joint disease. However, relapses occurred in approximately 30% of patients after the fluconazole was discontinued (24).

Fluconazole has also been found to be effective therapy for coccidioidal meningitis (53). In another Mycoses Study Group trial, patients were treated with 400 mg of fluconazole daily for up to 4 years. Of the 47 evaluable patients, 37 patients (75%) responded favorably to treatment, including those with HIV infection. Improvement was maximal within the first 4 to 8 months of therapy. However, most patients responding to therapy continued to demonstrate modest abnormalities in CSF findings through 20 months of therapy.

traconazole shares structural similarities with ketoconazole, and like it, has numerous drug interactions. Itraconazole therapy, particularly at high doses, may be associated with gastrointestinal upset, hypertension, hypokalemia, peripheral edema (32) and congestive heart failure (1). It exists in two oral preparations, capsule and liquid, and also as an intravenous formulation with cyclodextrin (124). The oral capsule has variable absorption and the degree of absorption can be increased with food. On the other hand, the oral solution is better absorbed and absorption is increased when no food is taken with it. Concomitant use of grapefruit juice may decrease the absorption of oral itraconazole and should be avoided (91).

A Mycoses Study Group trial examined 49 patients with nonmeningeal chronic coccidioidal pulmonary disease or disseminated disease treated with itraconazole 400 mg daily. Forty-four patients completed a minimum of six months of therapy and were evaluable. Of these, 25 (57%) achieved a clinical remission. Treatment failure occurred in 16 (36%) patients and three (7%) patients did not complete therapy because of drug toxicity. Of the 25 patients who attained remission, 11 completed at least one year of post-treatment follow-up observation and four (36%) relapsed. All relapses occurred at the site of primary disease.

Although itraconazole does not achieve significant levels in the CSF, it does appear to possess efficacy in treating coccidioidal meningitis. In a small series, Tucker and colleagues found that four of five patients with coccidioidal meningitis treated with itraconazole 400 mg per day alone responded to therapy. An additional five patients received concomitant intrathecal amphotericin B with oral itraconazole and all five had a favorable response (117). An animal model of coccidioidal meningitis has also demonstrated that itraconazole was equivalent to fluconazole in efficacy (107).

The Mycoses Study Group has published a trial comparing fluconazole to itraconazole for the therapy of non-meningeal coccidioidomycosis. In this randomized, placebo-controlled, multicenter study containing 198 subjects, fluconazole, 400 mg each day, was compared to itraconazole, 200 mg twice each day. After eight months of therapy, 50% of those receiving fluconazole demonstrated a clinical response, while 63% of those on itraconazole responded. The difference between the two treatments was not statistically significant. After 12 months of therapy, 72% of subjects on itraconazole responded compared to 57% of those on fluconazole, a result that just reached statistical significance. The response of those with skeletal infections on itraconazole was twice that of fluconazole. At all time points examined, the response to itraconazole was always greater than to fluconazole. Both treatments resulted in a significant number of relapses (28% for fluconazole, 18% for itraconazole) once therapy was stopped. Finally, serum levels of drug did not predict clinical response and three patients responded despite having undetectable serum azole levels. The authors cautiously conclude fluconazole and itraconazole are therapeutically equivalent. However, the data suggest that itraconazole, particularly for skeletal coccidioidomycosis, has increased efficacy (54).

The role of voriconazole in the treatment of coccidiodidmycosis is not clear. At this time, there are no published in vitro or in vivo studies examining the efficacy of voriconazole in the treatment of Coccidioides infections (55), although this agent has shown efficacy in the salvage treatment of selected patients (6, 33, 93, 94).

Posaconazole is a new triazole with potent activity versus Coccidioides species in vitro and in murine models (60). Its role in the treatment of coccidioidomycosis is not yet extablished. A multinational open label trial of posaconazole for the treatment of invasive fungal infection refractory to previous treatment, found that 11 of 15 patients had a successful response to posaconazole 400 mg twice daily (4 complete responses, 7 partial responses)(110). In a multicenter trial to study the safety and tolerability of posaconazole, 20 patients with chronic pulmonary or non meningeal disseminated coccidioidomycosis with little to no treatment experience were treated with 400 mg daily; 17 of 20 (85%) had a satisfactory response to treatment (25). Posaconazole has been well tolerated in these studies. Currently a multicenter trial comparing fluconazole 400 mg daily with posaconazole 400 mg twice daily for the treatment of chronic pulmonary or nonmeningeal disseminated coccidioidomycosis has begun enrollment.

Therapy for Specific Coccidioidal Diseases

Therapy for coccidioidomycosis is notoriously idiosyncratic. However, general guidelines for the treatment of coccidioidomycosis can and have been formulated. Recently, an updated consensus statement was published on the management of the various clinical manifestations of coccidioidomycosis (55). This statement serves as a useful reference for any clinician managing coccidioidomycosis.

Primary Focal Pneumonia

Although antifungal therapy is often prescribed for primary focal coccidioidal pneumonia in the non-immunocompromised patient, there are no data which indicate that treatment either shortens the course of the acute disease or prevents later dissemination (51). Based on this, we do not recommend routine antifungal therapy for primary coccidioidal pneumonia in such patients. However, certain factors may mitigate this decision (109). Antifungal therapy may be considered for severely ill patients, patients with high complement fixation (IgG) serum antibody titers (1:16) or high inoculum exposures, such as occur in laboratory accidents or field anthropology infections (88), or extensive or enlarging pulmonary processes. Underlying conditions that may also prompt initiation of therapy include immunosuppression (innate or acquired), diabetes mellitus, preexisting cardiopulmonary disease, or pregnancy. Persons of Filipino or African American descent have a higher risk of dissemination, a factor that should be considered in the treatment decision.

If antifungal therapy is prescribed, an oral azole is most appropriate. A dose of at least 400 mg per day should be given. A notable exception is in the treatment of pregnant women with coccidioidomycosis (see discussion below), since azoles carry a risk of fetal malformation. The length of therapy is undefined but should continue at least until symptoms have improved. Many authorities commonly prescribe a two-to three-month course of azole therapy at a minimum. Because dissemination may still occur after a course of therapy, the patient should be followed every two to three months during the first year following cessation of therapy and evaluated for signs and symptoms of extrathoracic dissemination with periodic reassessment of serologic status using complement fixation titers.

Residual Coccidioidal Pulmonary Lesions

In general, residual manifestations of pulmonary coccidioidomycosis do not require therapy but occasionally can become management problems, either because of confusion with other diseases or because of complications associated with the lesions themselves.

Nodules

Nodules are one result of primary coccidioidal pneumonia and represent undrained pulmonary abscesses. They are usually single and less than 4 cm in diameter (40). In the coccidioidal endemic area, coccidioidomycosis is the cause of solitary pulmonary nodules in up to 60% of patients (50, 97). They require no therapy but often cannot be differentiated from malignant lesions (86). There are several approaches to their management. First, the nodule can be biopsied. If accessible, percutaneous fine needle aspiration is a useful technique and yields the diagnosis in up to half the patients. Histological examination is more sensitive than culture (27, 50). In cases where the nodule is not accessible or definitive diagnosis is not established by needle aspiration even after multiple attempts, either thorascopic or open lung biopsy can be performed.

In some patients, it may be reasonable to follow the nodule radiographically over time. Patients who are candidates for this approach are individuals with a low risk for pulmonary malignancy who live in the coccidioidal endemic area and have a positive coccidioidal serology or history of a previously positive coccidioidal skin test (128). If the size of the nodule decreases over time in such a patient, it is most likely to be a coccidioidal nodule.

Cavities

Coccidioidal cavities result from necrosis and excavation of pulmonary nodules. They are usually solitary, in the upper lung fields, may either be thin-walled without surrounding in filtration or thick-walled with surrounding in filtration, and are usually less than 4 cm in diameter. In most patients, cavities will progressively decrease in size within two years and no therapy is required (40). However, in a small number of patients, cavities may be associated with complications.

Hemoptysis occurs in approximately 15% of patients with cavities and is usually self-limited (40). For such cases, particularly if the sputum culture is positive forCoccidioides species,, antifungal therapy is indicated. If the patient is otherwise stable, an oral azole at a dose of 400 mg per day is an appropriate treatment. Treatment should continue for three to six months from the time the hemoptysis abates. Occasionally, hemoptysis is massive and life-threatening. In these cases, immediate surgical resection of the cavity is indicated. In such cases, although there are no data, we would recommend adjunctive antifungal chemotherapy. One approach is to give intravenous amphotericin B to a total dose of 500 to 1000 mg. Alternatively, fluconazole at a daily oral dose of 400 mg could be given. With oral fluconazole, the duration of therapy requires individualization, but we recommend a course of at least three months.

Another complication associated with coccidioidal cavities is secondary infection. This is usually manifests as the development of a productive cough with an air-fluid level within the cavity. Cavities can be secondarily infected with bacteria or with other fungi, particularly Aspergillus species. Rarely, a coccidioidal mycetoma containing hyphal elements may form within a coccidioidal cavity (98,115). Management involves empiric antibiotics for cavities secondarily infected with bacteria. For fungal mycetomas, particularly those associated with recurrent hemoptysis, surgical resection is the treatment of choice (23).

Pyopneumothorax results when a subpleural cavity ruptures into the pleural space, resulting in pneumothorax associated with an exudative pleural effusion. This is a local complication of coccidioidomycosis and does not necessarily indicate dissemination of infection or poor prognosis. Prompt surgical closure of the bronchopleural defect is required (35). Most clinicians would use antifungal therapy adjunctively with surgery but the type and length of such therapy is not established. We recommend the same approach to antifungal chemotherapy as when surgery is performed for hemoptysis.

Chronic Pulmonary, Diffuse Pulmonary, and Extrathoracic Disseminated Disease

These forms of coccidioidomycosis always require antifungal therapy. Because there are no comparative trials of any antifungal agents in coccidioidomycosis, there is great latitude in the treatment approach. Based on clinical experience, we recommend using amphotericin B or liposomal amphotericin as initial therapy for any patient who appears fulminantly ill and requires hospitalization. On the other hand, for less ill patients, an oral azole agent appears to be a reasonable initial choice. In all cases of azole therapy, the minimum starting daily starting dose is 400 mg. Many clinicians start at higher doses than this, for example 800 mg per day, and reduce the dose to 400 mg per day as the patient responds.

Chronic Progressive Pneumonia

This form of coccidioidomycosis is characterized by pulmonary symptoms for more than six weeks, a chest radiograph demonstrating persistent pulmonary parenchymal abnormalities, a positive sputum culture for Coccidioides species and positive coccidioidal serologic tests (14). Amphotericin B, ketoconazole, fluconazole, itraconazole, have shown efficacy in treating chronic, progressive coccidioidal pneumonia. Since most patients with chronic pneumonia do not require hospitalization, initial therapy with an oral azole is a reasonable choice. Although no comparative trial has been published, review of all the separate trials would suggest that ketoconazole is inferior to fluconazole and itraconazole (51). Therefore, we would recommend either fluconazole or itraconazole at a dose of 400 mg per day orally as initial therapy (24, 62). If the patient fails to respond over a one-month period, doses can be increased. There is a subset of patients that will not respond to first-line azole antifungal therapy at any dose. For these patients, an amphotericin B preparation should be initiated.

Some patients with chronic radiographic abnormalities, particularly biapical cavitary changes, have minimal pulmonary symptoms. It is unclear if these patients will benefit from antifungal therapy. A reasonable approach to such patients is close follow-up without therapy. Worsening symptoms, with progressive chest radiographic findings, particularly in association with a positive sputum culture for Coccidioides species, rising coccidioidal serologic titers, or systemic symptoms are factors favoring initiating antifungal therapy.

Diffuse, Reticulonodular Pneumonia

Diffuse pulmonary involvement is a rare but severe complication of coccidioidal infection. It is usually the initial manifestation of coccidioidomycosis rather than a progression from primary, focal pneumonia. It may mimic bacterial pneumonia with septic shock (8, 82). While the chest radiographic pattern has been described as "military" (58), the precise term should be "reticulonodular", since both nodules and interstitial in filtrates are seen. Diffuse pulmonary involvement most commonly occurs in patients with underlying immunosuppressive conditions, such as those with AIDS, those with cancer undergoing chemotherapy, or those on chronic corticosteroid therapy (4), but may be seen in patients without underlying immunosuppression who have been exposed to a large coccidioidal inoculum (9, 78). It is often associated with fungemia and undoubtedly represents a severe form of dissemination (4, 58). Prognosis is grave with death commonly occurring within one month of diagnosis (4).

There are no controlled trials of any form of antifungal therapy for this manifestation of coccidioidomycosis. Based on our clinical experience, we recommend beginning intravenous amphotericin B deoxycholate at 1.0 to 1.5 mg/ kg/ day. If renal dysfunction is present, a lipid-formulation of amphotericin B at 5.0 mg/ kg/ day is reasonable. Many clinicians would combine amphotericin B with a triazole antifungal agent. Recommendations regarding combining amphotericin B with azoles have been previously discussed. If the patient stabilizes with initial therapy, the frequency of infusion of amphotericin B can be reduced to three times per week at the same dosage. Alternatively, if the patient is clinically stable and no longer requires hospitalization, either fluconazole in a dose from 400 and 800 mg daily or itraconazole at a dose from 400 to 600 mg daily can be started. For fluconazole, doses up to 2000 mg daily may be safe and demonstrate increased efficacy (42). While on maintenance dosage, the patient must be followed very closely for relapse.

Extrathoracic Dissemination

The most common sites of dissemination beyond the thoracic cavity in coccidioidomycosis are the soft tissues, bones, joints, skin and meninges. Because meningitis requires a unique therapeutic approach, it will be discussed separately. All forms of disseminated coccidioidomycosis require antifungal therapy. In severely ill patients with soft tissue, bone or joint disease, particularly if it is at multiple sites, we would recommend initiating therapy with intravenous amphotericin B deoxycholate at doses of 1.0 to 1.5 mg/kg/day. Once the patient is clinically stable, therapy with an oral azole at a dose of at least 400 mg per day should be given. For less severely ill patients, initiation of therapy with fluconazole at 400-800 mg daily or itraconazole at 400-600 mg daily appear to be reasonable choices. Patients should be carefully monitored for clinical response and for drug toxicity. When higher doses of antifungals are initially used, downward modification within three to six months is usually possible as the patient responds. In our experience, in rare cases patients may fail to respond to either fluconazole or itraconazole at high doses but may, paradoxically, respond to ketoconazole. The duration of therapy is discussed above.

Meningitis

Coccidioidal meningitis, if untreated, is almost universally fatal (120). Intravenous amphotericin B is ineffective in the treatment of coccidioidal meningitis. However, as mentioned previously, repeated direct injection of amphotericin B into the CSF has been shown to result in improved outcome (44, 75). However, even with careful management, mortality with intrathecal administration of amphotericin B is still 30 to 50% (75) and toxicity is significant. Since they became available, oral azole agents have been tested for efficacy in the treatment of coccidioidal meningitis. Results for ketoconazole have been disappointing. Although some patients may respond at relatively high doses (34), most patients do not (51).

The new triazoles, itraconazole and fluconazole, appear to be major breakthroughs in the management of coccidioidal meningitis and have emerged as the initial choices for therapy for coccidioidal meningitis. However, there are several important caveats regarding their use. First, responses, particularly improvements in CSF parameters, can be slow. Second, a major complication of coccidioidal meningitis is hydrocephalus. Failure to identify this can lead to significant morbidity despite appropriate antifungal therapy (99). It is as yet unknown if patients with evidence of continued CSF inflammation during therapy will, over time, be at increased risk for the development of hydrocephalus or other complications. Third, there are data that suggest that treatment for coccidioidal meningitis, at least with azole therapy, should be life-long (39).

There will still be some patients who fail to respond to oral triazole therapy. Recent data suggest that 800 mg or higher daily doses of fluconazole may be more clinically effective than 400 mg daily (22) and, as mentioned above, even higher doses of fluconazole can be used. For those patients who fail to respond to even high-dose azole therapy, intrathecal amphotericin B is recommended. Many experts continue concomitant azole therapy with intrathecal amphotericin B in the setting of recalcitrant coccidioidal meningitis. Some experts recommend initial management of patients with coccidioidal meningitis to include both intrathecally administered amphotericin B and an oral azole antifungal. There is no clinical evidence that such a combination is antagonistic (111). We suggest that anyone treating coccidioidal meningitis either have considerable experience themselves or seek the advice from someone who does.

Underlying Diseases

HIV Infection

Within the endemic region, coccidioidomycosis is a major cause of opportunistic infection among individuals infected with HIV. Risk of infection is closely associated with degree of immunodeficiency, as reflected by a CD4 lymphocyte count < 250/µl. On the other hand, a prior history of coccidioidomycosis, residence in the coccidioidal endemic area for more than 4 years and a positive coccidioidal skin test do not predispose HIV-infected patients to develop active coccidioidomycosis (3). These data suggest that the development of active coccidioidomycosis in HIV-infected patients in the endemic area is most likely due to new infection and not reactivation of latent disease. Outside the endemic region, coccidioidomycosis among HIV-infected individuals is uncommon (72) and virtually always represents reactivation of a previously clinically quiescent infection.

The presentation of coccidioidomycosis in the vast majority of HIV-infected patients is pulmonary. The most common presentation is a diffuse, reticulonodular pneumonia. As noted above, this presentation indicates overwhelming dissemination with fungemia and is associated with an extremely high mortality (3, 47). Although there are no studies regarding therapy for this form of coccidioidomycosis, we recommend amphotericin B deoxycholate at doses of 1.0 to 1.5 mg/kg/day. In those patients who survive longer than 1 month, it is reasonable to reduce the administration of amphotericin B to twice or three-times a week or to place the patient on an oral azole agent (i. e. 400 to 800 mg daily of fluconazole). Because many patients with HIV infection have relative achlorhydria (76), fluconazole, whose absorption does not depend on gastric acid (131), is preferred to ketoconazole and itraconazole. Patients placed on an oral azole after responding to amphotericin B must be monitored very closely for recrudescence of disease by clinical examination, chest radiograph and coccidioidal serologic tests.

The second most common presentation of coccidioidomycosis in the HIV-infected patient is focal pulmonary pneumonia. This presentation is clinically indistinguishable from primary coccidioidomycosis in hosts without HIV infection and usually occurs in relatively immunocompetent patients with CD4 lymphocyte counts > 250/µl (46). The course of this form of coccidioidomycosis is usually benign with prompt response to antifungal therapy. Treatment with an oral azole at 400 mg each day is recommended for all such patients. While there are no studies, we recommend life-long therapy, as do others (26).

A small subset of HIV-infected patients will develop extrathoracic dissemination, particularly meningitis and soft-tissue infection (47). For reasons that are unclear, bone and joint coccidioidomycosis in patients with HIV infection is very uncommon. HIV-infected patients with specific sites of extrathoracic dissemination are generally clinically stable and not profoundly immunosuppressed. They should be managed in the same way as patients without HIV infection with the exception that therapy be continued life-long.

A unique manifestation of coccidioidomycosis among patients with HIV infection is the development of positive coccidioidal serologic tests, particularly of the complement fixation (IgG) type, without evidence of active clinical infection. Analysis of these cases indicates an extremely high risk for the development of clinical illness over time (7). Because of this, we recommend treatment with fluconazole at 400 mg each day and close clinical and serologic follow-up of these patients.

Transplantation

Allogeneic organ transplantation is clearly associated with an increased risk for the development of active coccidioidomycosis (17, 30, 64, 65, 68). This risk is highest in those who have a prior history of active coccidioidomycosis or who have positive coccidioidal serologic tests at the time of transplantation, suggesting that most active coccidioidomycosis in these patients is due to reactivation of prior infection (65). Active disease is most likely to occur in the first six months after transplantation, when immunosuppressive therapy is greatest. The use of oral azole for the prevention of coccidioidomycosis in solid organ transplantation in patients with a history of prior coccidioidal infection or positive serology at the time of transplantation appears to reduce this risk (18, 21, 64).

Patients with a history of active coccidioidomycosis can safely undergo transplantation provided that the coccidioidal infection is completely controlled from a clinical, radiographic and serologic standpoint (19). The duration of antifungal treatment is not clear,and probably depends on the status of the infection at the time of transplantation. In one transplant program within the endemic area, patients with a history of remote, serologically negative coccidioidomycosis receive 6 months of prophylaxis, and those with positive serology at the time of transplantation are advised to take lifelong prophylaxis. The results of this program have shown encouraging results (19).

Oral azoles are reasonable to use in this situation, but it is important to realize that they may interfere with the metabolism of cyclosporine and tacrolimus. Extraordinarily high levels of calcineurin inhibitaor with resultant renal failure have complicated the treatment of coccidioidomycosis in organ transplant recipients (17, 32).

Pregnancy

The risk of severe, symptomatic coccidioidomycosis is increased during pregnancy. The risk of disease and dissemination is particularly high when infection is newly acquired during the second or third trimester (85, 92, 108, 121). Women with a prior history of coccidioidomycosis or stable coccidioidomycosis at the time they become pregnant rarely develop worsening or active disease during pregnancy (11, 122). Infants born of mothers with active coccidioidomycosis are rarely affected.

Mortality from active coccidioidomycosis during pregnancy appears to be significantly reduced by the use of intravenous amphotericin B (92). A review of instances where amphotericin B was used during pregnancy for a variety of fungal infections revealed no untoward effects in the majority of women or their newborns. However, sustained hypokalemia as well as decreases in renal function have been reported in some mothers and infants (37). The safety and teratogenicity of the oral azoles during pregnancy are of concern. A study examining repeated low doses of fluconazole for vaginal candidiasis found no increase in adverse events among pregnant women or their offspring (71). However, a case report described congenital malformations in the newborn of a women who became pregnant while on fluconazole for coccidioidal meningitis and in whom the fluconazole was continued throughout pregnancy. While the malformations were consistent with an autosomal recessive disorder, they were also similar to some defects in organogenesis seen in animal models studying the effect of fluconazole during pregnancy (79). Subsequently, there have been three more cases of similar congenital anomalies associated with women receiving fluconazole for coccidioidomycosis during pregnancy (95).

Based on these data, women who become pregnant who are already on therapy with an oral azole for coccidioidomycosis should be switched to intravenous amphotericin B. Women with histories of previous coccidioidomycosis prior to pregnancy but on no therapy should be followed closely for the development of active disease. Therapy with intravenous amphotericin B is recommended for women who acquire primary coccidioidomycosis during pregnancy, particularly if infection occurs during the second or third trimester. If disease is non-meningeal, we would recommend intravenous amphotericin B for the remainder of the pregnancy at a dose of from 0.7 to 1.0 mg/kg three times weekly. For meningeal disease, we would recommend intravenous combined with intrathecal amphotericin B. After parturition, oral fluconazole or itraconazole may be started and the amphotericin B discontinued. It is strongly recommended that an infectious diseases consultant knowledgeable in the treatment of coccidioidomycosis be involved in the management of such cases.

Other Conditions

Patients with malignancy undergoing cancer chemotherapy (20, 38,101) and patients on chronic corticosteroid therapy or other immunosuppressive agents (4, 101) have a very high risk of developing disseminated disease after primary coccidioidal infection. In addition, they have an increased risk of relapsing once antifungal therapy is discontinued. Similarly, patients with chronic renal failure undergoing dialysis, while at no greater risk for acquiring primary coccidioidomycosis, have a very high risk of developing disseminated disease after initial infection (30). We recommend beginning antifungal therapy for primary coccidioidomycosis in all such patients and following them closely for dissemination. Many clinicians would favor continuing antifungal therapy indefinitely even after the primary infection was documented to clear.

Genetic factors may place certain patients at a higher risk for developing severe and disseminated coccidioidomycosis (83). For example, there are data suggesting that men are far more likely than women to develop symptomatic as well as disseminated disease (4, 41, 88). Early studies also demonstrated a propensity for blacks, Filipinos and Asians to develop disseminated coccidioidomycosis. Two studies have demonstrated an increased risk for symptomatic coccidioidomycosis among non-whites during an epidemic of coccidioidomycosis which occurred after a severe dust storm (49, 126). A more recent study of an outbreak in Kern County, California found similar increased risks among blacks (100). Pappagianis has recommended that particular care be used in the management of such patients in "anticipation of possible dissemination" (88). We would recommend following any such patient with pulmonary coccidioidomycosis very closely for dissemination, especially if that patient is male. Whether early antifungal treatment prevents subsequent dissemination is not known. We have seen several cases where it has not. However, many clinicians would begin oral azole therapy for these patients. The length of such therapy is not known. Whether antifungal therapy is started or not, such patients should be monitored for at least one year after their initial presentation to ensure that disseminated or persistent disease has not occurred.

Persons with diabetes mellitus may be at increased risk for more severe pulmonary disease, particularly pulmonary cavitation, but data is mixed regarding predisposition to disseminated disease (88, 102). For these patients, many clinicians begin therapy with an oral azole agent at 400 mg daily in a diabetic patient with primary pulmonary coccidioidomycosis. The length of such therapy and whether it would prevent subsequent pulmonary complications are not known.

Combination Therapy

Amphotericin B plus Azoles

The utility of combining amphotericin B with azole antifungal agents for the treatment of fungal diseases has been recently reviewed by Sugar (111). While concern has existed that such a combination might be antagonistic, no clinical evidence supports this contention for most clinical situations. Moreover, the combination of amphotericin B with fluconazole has become a relatively common clinical practice. In the absence of extensive data, Sugar has suggested that combination therapy may be used after careful consideration of the particular clinical situation and with close documentation of the clinical outcome (111).

The combination of amphotericin B and azoles for the treatment of coccidioidomycosis has never been formally studied. However, anecdotal clinical experience and review of specific literature suggests that the combination of amphotericin B and fluconazole in particular may be useful in certain instances. This combination has been most frequently used in the management of recalcitrant coccidioidal meningitis (63, 117, 118) and has often resulted in a reduction in the amount of amphotericin B required to achieve clinical improvement. Hence, the combination of amphotericin B and an azole antifungal, particularly fluconazole, may be considered in any case of disseminated coccidioidomycosis, particularly meningitis, where there is a clear lack of clinical response to single-agent therapy.

ADJUNCTIVE THERAPY

The role of surgery has diminished since the advent of sensitive imaging technology, such as CT scan and MRI, as well as with the development of oral antifungal therapy. In the past, management of a large soft tissue coccidioidal mass would have included immediate surgical drainage. Currently, it is reasonable in a clinically stable patient to give antifungal chemotherapy and follow the size of the mass radiographically. In addition, whether or not surgical management is cautious or aggressive is often based on the experience and expertise of the local surgeon, and this varies from community to community.

Surgical intervention is clearly indicated under certain circumstances in coccidioidomycosis. First, it is required for the closure of a bronchopleural fistula associated with pyopneumothorax. CSF shunts, either lumbar or ventricular, are necessary for the patient with coccidioidal meningitis and hydrocephalus. Surgical removal of a cavity is required for the patient with severe hemoptysis or for a cavity that is enlarging while on antifungal chemotherapy, particularly if the cavity is adjacent to the pleura. Surgical debridement and drainage may be required for any extrapulmonary site of infection that fails to improve with chemotherapy. However, surgery is almost always required when coccidioidomycosis involves the spine. Outcome of combined medical management with surgery appears to be better than medical management alone (67, 129).

ENDPOINTS FOR MONITORING THERAPY

The total length of time a patient with chronic pulmonary or disseminated coccidioidomycosis should receive antifungal therapy is undefined. Relapse occurs in up to one-third of patients with either chronic progressive pneumonia or with extrathoracic disseminated disease once antifungal therapy is discontinued (24, 54, 62). Nonetheless, many clinicians would stop therapy for at least six to twelve months when there is no evidence of clinical disease and coccidioidal serological tests are significantly improved or negative. Expression of delayed-type hypersensitivity after coccidioidal skin testing may also portend lack of relapse (87). Unfortunately, this skin test is no longer available. All patients who have their therapy discontinued should be monitored closely for evidence of disease recrudescence during the first year after therapy is discontinued. Life-long antifungal therapy should be given to patients with meningitis and to patients with underlying cellular immune defects. Life-long oral azole therapy may also be reasonable for some patients with non-meningeal disseminated disease, particularly if they have already demonstrated a propensity to relapse, are racially predisposed to severe disease, are skin-test negative, have exhibited multiple sites of dissemination, or have had debilitating disease at one extrathoracic site.

For patients in whom antifungal therapy is discontinued, we recommend a clinical, serologic and radiographic reevaluation every two to three months after therapy is discontinued for at least one year. If treatment is continued, low doses of azole antifungals (< 400 mg/day) may be sufficient to prevent relapse. The clinical examination should particulary focus on the areas where coccidioidal lesions existed previously. Coccidioidal serology should be obtained; an increase in the titer of complement fixation (IgG) antibody by more than two-fold should lead to consideration of reinitiation of antifungal chemotherapy, even if the patient is clinically well. To date, there are no known clinical or serologic parameters that predict which patients are likely to relapse once therapy is discontinued.

VACCINES 

A study examining the efficacy of intramuscular injection of formalin-killed spherules (FKS) could not demonstrate a significant protective effect of vaccine compared to saline placebo (89). At this time, there is no available vaccine for coccidioidomycosis, but efforts to develop one are currently on-going (31, 90).

PREVENTION AND INFECTION CONTROL MEASURES

Because coccidioidomycosis is ubiquitous in the environment within the endemic region, there is no way to completely prevent infection among those living in these areas. For individuals susceptible to severe infection, such as those with underlying cellular immunodeficiency, extensive or close contact with native soils should be avoided (26).

Persons with coccidioidomycosis are not infectious to others. Infection may rarely occur in association with handling of contaminated fomites where drainage from a coccidioidal infection has dried and allowed the growth of mycelia to occur (43). Because of this, special care should be taken when changing dressing from draining coccidioidal lesions.

Finally, coccidioidomycosis can be a significant laboratory hazard since the infectious mycelial form grows on artificial media. Because of this, clinical specimens suspected of containing C. immitis or C. posadasii should be handled under Biosafety Level (BSL)-2 containment and cultures known to contain the fungus should be handled under BSL-3 containment (123).

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Table 1: Summary of Treatment for Coccidioidomycosis

Infection Characteristics	Moderate/Severe Infection	Mild/Absent Symptoms
Pulmonary Coccidioidomycosis    Acute pulmonary infection               Diffuse coccidioidal pneumonia                       Chronic progressive fibrocavitary coccidioidomycosis                 Asymptomatic nodule or cavity   Symptomatic cavity	Fluconazole     400 mg daily     ≥3-6 months    Itraconazole      200 mg BID      ≥3-6 months    LAMB 1,2 or AMB 1,3   Consider initiating treatment with LAMB1,2 or AMB1,3 until clinically stabilized. Fluconazole     400 mg daily     ≥12months    Itraconazole      200 mg BID      ≥12 months       Fluconazole     400 mg daily     ≥12 months5    Itraconazole      200 mg BID      ≥12 months5   If unresponsive to treatment, alternate azole4, or LAMB 1,2or AMB 1,3   NA   Fluconazole     400 mg daily Itraconazole      200 mg BID Consider surgical resection	No antifungal therapy. Periodic reassessment             Fluconazole     400 mg daily     ≥12months    Itraconazole      200 mg BID      ≥12 months               Fluconazole     400 mg daily     12 months5    Itraconazole      200 mg BID      12 months 5  If unresponsive to treatment, alternate azole4, or LAMB 1,2 or AMB 1,3   Observe for stability   Fluconazole     400 mg daily Itraconazole      200 mg BID Consider surgical resection
Disseminated Coccidioidomycosis   Skin and/or Soft tissue coccidioidomycosis           Skeletal coccidioidomycosis             Meningeal coccidioidomycosis	Fluconazole5,7     400 -800 mg daily Itraconazole5,7      200 mg BID-TID LAMB 1,2 or AMB 1,3 May require debridement   Debridement Itraconazole5,6,7      200 mg BID-TID Fluconazole5,7     400-800 mg daily LAMB 1,2 or AMB 1,3   Fluconazole ≥800  mg daily, consider decrease to 600-400 mg daily with clinical improvement.  Lifelong treatment. Shunt for hydrocephalus Alternative: another azole4, IT AMB	Fluconazole5,7     400 – 800 mg daily Itraconazole5,7      200 mg BID-TID LAMB 2 or AMB3 May require debridement   Debridement Itraconazole5,6,7      200 mg BID-TID Fluconazole5,7     400 -800 mg daily LAMB 1,2 or AMB 1,3   Fluconazole ≥800  mg daily, consider decrease to 600-400 mg daily with clinical improvement.  Lifelong treatment. Shunt for hydrocephalus Alternative: another azole4, IT AMB

      1 For severe or rapidly progressive infection, many experts recommend the use of amphotericin B, either lipid associated or deoxycholate

      2 Lipid associated amphotericin B 2.0-5.0 or more mg/kg/day by intravenous infusion

      3 Amphotericin B deoxycholate 0.5-1.5 mg/kg/day or on alternate days by intravenous infustion

      4 Alternate azole treatment could include fluconazole, itraconazole, voriconazole, posaconazole

      5Duration of treatment depends on clinical response.  A sustained response may take months to years to achieve.

      6Itraconazole was found to have a better clinical response in skeletal coccidioidmycosis than fluconazole.

      7Higher doses may be required: consider ≥800 mg daily azole dose

 

    NA, Not applicable

    IT AMB, intrathecal amphotericin B

    BID, twice daily

    TID, three times daily

What's New?

Ampel et al. Factors and Outcomes Associated with the Decision to Treat Primary Pulmonary Coccidioidomycosis. Clin Infect Dis. 2009 Jan 15;48(2):172-8.

Kim M, Blair J, et al. Coccidioidal Pneumonia, Phoenix, Arizona, USA, 2000–2004. Emerg Infect Dis. 2009 Mar;15:397-401.

Stevens DA, et al.  Expert Opinion: What To Do When There Is Coccidioides Exposure in a Laboratory. Clin Infect Dis 2009;49:919-923.

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Epidemiology

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Review articles

Blair JE. Coccidioides Species in Transplant Recipients.

Adhikari P, Mietzner T.  Cell Mediated Immunity. 2008.

Galgiani JN, et al.  Practice Guidelines for the Treatment of Goccidioidomycosis.  Clin Infect Dis 2005;41:1217-1223.

Gauthier G, et al.  Insights into Fungal Morphogenesis and Immune Evasion.  Microbe 2008;3(9):416-423.

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Hirschmann JV.  The Early History of Coccidioidomycosis: 1892-1945.  Clin Infect Dis 2007:44;1202-1207.

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Coccidioides species (Coccidioidomycosis)