John N. Galgiani,1,2,3 Neil M. Ampel,1,2,3 Janis E. Blair,4 Antonino Catanzaro,5 Royce H. Johnson,6 David A. Stevens,7,8
and Paul L. Williams9

1Valley Fever Center for Excellence, 2Southern Arizona Veterans Affairs Health Care System, and 3University of Arizona, Tucson, and 4Mayo Clinic,Scottsdale, Arizona; and 5University of California, San Diego, 6Kern Medical Center, Bakersfield, 7Santa Clara Valley Medical Center and 8StanfordUniversity, San Jose, and 9Kaiser Permanente Medical Center, Fresno, California EXECUTIVE SUMMARY
Management of coccidioidomycosis first involves rec- Coccidioidomycosis (also known as valley fever) results ognizing that a coccidioidal infection exists, defining from inhaling the spores (arthroconidia) of Coccidioides the extent of infection, and identifying host factors that species (Coccidioides immitis or Coccidioides posadasii) predispose to disease severity. After these assessments, [1]. Most infections in the United States are acquired patients with localized acute pulmonary infections and within the major regions of endemicity of southern no risk factors for complications often require only Arizona, central or other areas of California, southern periodic reassessment to demonstrate resolution of New Mexico, and west Texas. Travelers who have re- their self-limited process. On the other hand, patients cently visited the region of endemicity or previously with extensive spread of infection or who are at high infected patients with immunosuppression who expe- risk of complications because of immunosuppression rience reactivation of latent infections can develop clin- or other preexisting factors require a variety of treat- ical disease and require medical management outsideof the region of coccidioidal endemicity [2].
ment strategies that may include antifungal drug ther- The estimated numbers of infections per year has apy, surgical debridement, or a combination of both.
risen to ∼150,000 as a result of population increases in Azole antifungals, primarily fluconazole and itracona- southern Arizona and central California. Of these in- zole, have replaced amphotericin B as initial therapy fections, one-half to two-thirds are subclinical, and vir- for most chronic pulmonary or disseminated infections.
tually all patients with these infections are protected Amphotericin B is now usually reserved for patients from second primary infections. The most common with respiratory failure due to infection with Cocci- clinical presentation of coccidioidomycosis is a self- dioides species, those with rapidly progressive cocci- limited acute or subacute community-acquired pneu- dioidal infections, or women during pregnancy. Ther- monia that becomes evident 1–3 weeks after infection.
apy often ranges from many months to years in Such illnesses are usually indistinguishable from bac- duration, and in some patients, lifelong suppressive terial or other infections without specific laboratory therapy is needed to prevent relapses.
tests, such as fungal cultures or coccidioidal serologicaltesting. For such patients, symptoms—especially fatigueinterfering with normal activities—may last for weeksto many months. Approximately 5%–10% of infectionsresult in residual pulmonary sequelae, usually nodules Received 12 July 2005; accepted 13 July 2005; electronically published 20 or peripheral thin-walled cavities. An even smaller pro- These guidelines were developed and issued on behalf of the Infectious portion of all infections result in illnesses related to chronic pulmonary or extrapulmonary infection. For Reprints or correspondence: Dr. John N. Galgiani, Valley Fever Center for Excellence, 3601 S. 6th Ave., VA Med Ctr. and Univ. of Arizona, Tucson, AZ 85723 extrapulmonary complications, estimates range as low as 0.5% of infections for persons of Caucasian ancestry, Clinical Infectious Diseases
2005; 41:1217–23
several-fold higher for persons of African or Filipino 2005 by the Infectious Diseases Society of America. All rights reserved.
ancestry (possibly also for persons of Asian, Hispanic, Treatment Guidelines for Coccidioidomycosis • CID 2005:41 (1 November) • 1217
or Native American ancestry), and as high as 30%–50% of absorption is satisfactory. Cyclodextrin suspensions of itracon- infections for heavily immunosuppressed patients, such as those azole afford greater absorption, although published clinical tri- with AIDS, lymphoma, receipt of a solid-organ transplant, or als of itraconazole for the treatment of coccidioidomycosis have receipt of rheumatologic therapies, such as high-dose corti- not used this formulation. In general, the more rapidly pro- costeroids or anti-TNF medications. Disseminated infections gressing a coccidioidal infection, the more likely amphotericin also appear to be more frequent in adults than in children.
B will be selected by most authorities for initial therapy. Con- Although virtually any site in the body may be involved, ex- versely, subacute or chronic presentations are more likely to be trapulmonary dissemination most frequently involves the skin, treated initially with an azole antifungal.
the skeletal system, and the meninges [3–6].
Newly available antifungal agents of possible benefit for the Objective.
The objective of this practice guideline is to pro- treatment of refractory coccidioidal infections are voriconazole vide recommendations for which patients with coccidioido- and caspofungin. Voriconazole has not been approved by the mycosis are likely to benefit from treatment and which therapies United States Food and Drug Administration (FDA) for the are most appropriate for various forms of infection.
treatment of coccidioidomycosis. Although there are no reports Treatment options.
of voriconazole therapy for experimental coccidioidal infec- broad spectrum of illness. At one end of that spectrum, it may tions, case reports have suggested that voriconazole may be produce a mild respiratory syndrome or an uncomplicated effective in selected patients [7–9]. Caspofungin has been ef- community-acquired pneumonia, either of which may resolve fective in treating experimental murine coccidioidomycosis spontaneously. At the other end of that spectrum, infection [10], but in vitro susceptibility of isolates varies widely [11], may result in progressive pulmonary destruction or lesions in and there is only 1 report regarding its value [12]. Posaconazole, other parts of the body. Because severity varies widely, the not yet approved by the FDA, was shown to be an effective optimal management strategies also vary widely among indi- treatment in a small clinical trial [13] and in patients with vidual patients. Although the vast majority of patients who refractory infections [14]. Its efficacy relative to other triazole present with early infections will resolve their infection without specific antifungal therapy, management should routinely in- Combination therapy with members of different classes of clude repeated patient encounters every 3–6 months for up to antifungal agents has not been evaluated in patients, and there 2 years, either to document radiographic resolution or to iden- is a hypothetical risk of antagonism [15]. However, some cli- tify evidence of pulmonary or extrapulmonary complications nicians feel that outcome in severe cases is improved when as early as possible. Patients who present with severe pneu- amphotericin B is combined with an azole antifungal. If the monia soon after infection warrant antifungal therapy. Patients patient improves, the dosage of amphotericin B can be slowly who develop chronic pulmonary or disseminated disease also decreased while the dosage of azole is maintained.
warrant antifungal therapy, which is typically prolonged—po- Despite there being several antifungal therapies available for tentially lifelong—especially in patients with overt immuno- treatment of coccidioidomycosis, occasional patients have ex- compromising conditions. Exact management guidelines for ceptionally widespread, debilitating, and potentially life-threat- these clinical forms will vary according to disease type and, to ening complications, either at the time of first diagnosis or an extent, must be individualized. For example, the role of despite therapy. This is especially true for patients with coc- surgical debridement, which, in some patients, is a critical com- cidioidal meningitis. Because of the regional nature of coccid- ponent of therapy, is not addressed in this guideline. However, ioidomycosis, many of the clinicians most familiar with such all patients with progressive or disseminated disease will require problems practice in the southwestern regions of endemnicity.
some combination of periodic physical examinations, labora- Occasionally seeking advice or obtaining a second opinion from tory studies, and imaging studies to guide management a specialist who is particularly familiar with coccidioidomycosis may be of benefit in formulating a treatment plan that best fits Specific antifungal drugs and their usual dosages for treat- ment of coccidioidomycosis include amphotericin B deoxy- Outcomes.
Desired outcomes of treatment are resolution cholate (0.5–1.5 mg/kg per day or alternate day administered of signs and symptoms of infection, reduction of serum con- intravenously), lipid formulations of amphotericin B (2.0–5.0 centrations of anticoccidioidal antibodies, and return of func- mg/kg or greater per day administered intravenously), keto- tion of involved organs. It would also be desirable to prevent conazole (400 mg every day administered orally), fluconazole relapse of illness on discontinuation of therapy, although cur- (400–800 mg/day administered orally or intravenously), and rent therapy is often unable to achieve this goal.
itraconazole (200 mg twice per day or 3 times per day admin- Evidence to support recommendations.
istered orally). If itraconazole is used, measurement of itra- ability of antifungal therapy, initial uncomplicated pulmonary conazole concentration in serum samples may determine if infections in the absence of comorbidity resolved in at least 1218 • CID 2005:41 (1 November) • Galgiani et al.
95% of patients. Randomized, prospective clinical trials of an- available at considerably lower cost. For managing critically ill tifungal drugs have not been completed to determine whether patients with coccidioidomycosis, there are considerable ad- drug therapy hastens the resolution of immediate symptoms ditional costs, including intensive care support for many days or prevents subsequent complications.
or weeks. In a recent Centers for Disease Control and Preven- Published reports of intravenous amphotericin B treatment tion (CDC) analysis, hospital costs in Arizona during 1998– of chronic pulmonary or extrapulmonary nonmeningeal coc- 2001 were a mean of $33,762 per patient with coccidioido- cidioidomycosis are limited to small numbers of patients treated in open-label, nonrandomized studies [13]. Coccidioidal men- Validation.
Below are descriptions of management strat- ingitis treatment with intrathecal amphotericin B has been re- egies for several manifestations of coccidioidomycosis. A re- ported as the accumulated experience of individual investiga- vision of the original Practice Guidelines for Coccidioidomy- cosis [29] was circulated among the authors. Subsequently The response of symptomatic chronic pulmonary and ex- revised drafts were reviewed for comment by members of the trapulmonary disseminated infections to several oral azole an- Arizona Infectious Diseases Society (6–7 March 2004) and by tifungal agents has been studied in large, multicentered, open- health care professionals who attended the 48th Annual Coc- label, nonrandomized trials by the Mycoses Study Group, as cidioidomycosis Study Group Meeting (held on 3 April 2004).
well as by other investigators [17–26]. The majority of patients The strength of and evidence for recommendations, expressed in these studies were treated for periods ranging from months using the Infectious Diseases Society of America–US Public to years and exhibited decreased numbers of symptoms, im- Health Service grading system for ranking recommendations proved appearance of chest radiographs or extrapulmonary le- in clinical guidelines (table 1), is shown following each specific sions, decreased concentrations of complement fixing-type an- tibodies in their serum or CSF samples, and sputum culturesthat converted from positive for Coccidioides species to negative.
Follow-up cultures of samples obtained from extrapulmonary Primary Respiratory Infection
lesions often would have required invasive procedures and fre- Primary infections due to Coccidioides species most frequently quently were not carried out. Moreover, when therapy was manifest as community-acquired pneumonia 1–3 weeks after stopped, these abnormalities often recurred, suggesting that exposure [30, 31]. Distinguishing coccidioidomycosis from sterilization of lesions was not accomplished. A randomized other etiologies is usually difficult without specific laboratory trial of oral itraconazole (200 mg administered twice per day) confirmation, such as detection of anticoccidioidal antibodies versus oral fluconazole (400 mg administered every day) has in serum samples [32] or identification of Coccidioides species been published [27]. In the primary analysis, there was no in sputum samples or another respiratory specimen. Therefore, difference between these 2 treatments when analyzed at the 8- residents of and recent travelers to regions where community- month time point. Subanalyses indicated that itraconazole ther- acquired pneumonia is endemic should be evaluated for Coc- apy may be more potent in the treatment of skeletal lesions cidioides species as a possible etiologic agent. Coccidioides spe- and superior when analyzed at 12 months overall.
cies are listed by the CDC as Select Agents, and their growth Values.
Principal value is afforded to patients who receive in culture requires handling in a secure and contained fashion treatment. Coccidioidomycosis is not contagious by the respi- ratory route and therefore control of individual infections will Uncomplicated acute coccidioidal pneumonia.
not have additional public health benefit.
to manage primary respiratory coccidioidal infections is an Benefits, harms, and costs.
unsettled issue because of the lack of prospective controlled mycosis in itself may benefit a patient by (1) reducing the use trails. For many (if not most) patients, management may rely of unnecessary antibacterial therapies, (2) avoiding further di- on periodic reassessment of symptoms and radiographic find- agnostic evaluations, (3) allaying patient anxiety about an oth- ings to assure resolution without antifungal treatment. On the erwise uncertain respiratory condition, and (4) affording pa- other hand, some authorities propose treatment of all symp- tomatic patients to decrease the intensity or duration of symp- treatment of complications will decrease the amount of tissue toms. Although physicians speculate that early treatment may destruction and resulting morbidity. Effective therapy is po- decrease the frequency or severity of dissemination, there are no data to support this speculation (C-III). Several special cir- Use of amphotericin B often engenders untoward effects.
cumstances are usually considered to warrant initiation of ther- Surgical risks depend on the specific procedure.
apy. Chief among these is concurrent immunosuppression, such The cost of antifungal medication can be as high as $20,000 as that which accompanies AIDS, receipt of an organ transplant, per year of treatment. Recently, generic fluconazole has become therapy with high-dose corticosteroids, or receipt of inhibitors Treatment Guidelines for Coccidioidomycosis • CID 2005:41 (1 November) • 1219
Infectious Diseases Society of America–US Public Health Service Grading System for ranking recommendations
in clinical guidelines.
Good evidence to support a recommendation for use; should always be offered Moderate evidence to support a recommendation for use; should generally be offered Poor evidence to support a recommendation; optional Moderate evidence to support a recommendation against use; should generally not be offered Good evidence to support a recommendation against use; should never be offered Evidence from у1 properly randomized, controlled trial Evidence from у1 well-designed clinical trial, without randomization; from cohort or case- controlled analytic studies (preferably from 11 center); from multiple time-series; or fromdramatic results from uncontrolled experiments Evidence from opinions of respected authorities, based on clinical experience, descriptive of TNF (such as etanercept or infleximab). Also, other patients tablishing the nodule’s etiology at a future time. Identifying who are likely to handle pulmonary coccidioidal infection less dissemination is accomplished with histologic examination and well include those with diabetes mellitus or preexisting cardio- culture of suspicious skin lesions, analysis of aspirates of joint pulmonary disease (A-II). The diagnosis of primary infection effusions, and lumbar puncture of patients who develop pro- during pregnancy, especially in the third trimester or imme- gressively severe or persistent headaches, mental status changes, diately postpartum, frequently prompts the initiation of treat- or other meningeal signs. Although extrapulmonary dissemi- ment (A-III). During pregnancy, amphotericin B is the treat- nation is infrequent, early detection of patients in whom dis- ment of choice because fluconazole (and likely other azole semination does occur would afford benefit by earlier initiation antifungals) are teratogenic (A-III). Persons of Filipino or Af- of treatment and a resulting reduction in tissue destruction.
rican descent have a higher risk for dissemination, and this Diffuse pneumonia.
may also be taken into consideration (B-III). Finally, patients infiltrates produced by Coccidioides species suggest either an who are judged to have exceptionally severe primary infections underlying immunodeficiency state with concurrent fungemia may be more likely to benefit from treatment than those pa- or an exposure to a high inoculum of fungal spores, as may tients with a more mild illness. Although opinion varies as to occur as a result of laboratory accidents or at archeology sites.
the most-relevant factors for judging severity of illness, com- In such patients, therapy is usually begun either with ampho- monly used indicators include weight loss of 110%, intense tericin B or high-dose fluconazole. Amphotericin B is more night sweats persisting longer than 3 weeks, infiltrates involving frequently used as initial therapy if significant hypoxia is present more than one-half of one lung or portions of both lungs, or if deterioration is rapid (A-III). Several weeks of therapy are prominent or persistent hilar adenopathy, anticoccidiodial often required to produce clear evidence of improvement. After complement-fixing antibody concentrations in excess of 1:16 this time, during convalescence, amphotericin B therapy may (as determined by a reference method or equivalent titer) [32], be discontinued and replaced with treatment with an oral azole inability to work, symptoms that persist for 12 months, or age antifungal (B-III). In combination, the total length of therapy 155 years. Commonly prescribed therapies include currently should be at least 1 year, and for patients with severe immu- available oral azole antifungal agents at dosages of 200–400 mg nodeficiency, oral azole therapy should be continued as sec- per day. Courses of typically recommended treatment range ondary prophylaxis (A-III). Because diffuse pneumonia due to Coccidioides species is usually a manifestation of fungemia, pa- As the patient’s illness improves, either with or without an- tients should be evaluated for the possibility of other extra- tifungal therapy, continued monitoring at 1–3-month intervals pulmonary lesions that may also require attention.
for 1 year or longer is advised to assess the resolution of pul-monary infiltrates and to identify, as early as possible, thosepatients who develop infection outside of the chest. Monitoring Pulmonary Nodule, Asymptomatic
usually should include patient interviews, physical examina- If a stable solitary nodule is determined to be due to Coccidioides tions (as appropriate), serologic tests, and radiographic ex- species by noninvasive means or by fine-needle aspiration, spe- aminations. Determining pulmonary lesions that evolve into cific antifungal therapy or resection is unnecessary (E-II). Sim- residual nodules is useful because it obviates the need for es- ilarly, in the absence of significant immunosuppression, anti- 1220 • CID 2005:41 (1 November) • Galgiani et al.
fungal therapy is not recommended if the lesion is completely management approaches are less uniform and may include resected and the diagnosis is determined from the excised tissue.
courses of therapy with amphotericin B or oral azole antifungal Stability can be determined by repeated radiographic exami- drugs prior to surgery or chest tube drainage without surgery nation of the chest for 2 years demonstrating no change in the size of the nodule. Should enlargement of the nodule occur,reevaluation with sputum cultures and measurement of coc- Chronic Progressive Fibrocavitary Pneumonia
cidioidal serum antibodies may help to determine whether the Initial treatment with oral azole antifungal agents is recom- patient’s infection is active and warrants therapy. Consideration mended (A-II). If the patient improves sufficiently, therapy also should be given to the possibility of cancer coexistent with should be continued for at least 1 year. If therapy is not sat- the coccidioidal infection, in which case resection of the nodule isfactory, switching to an alternative azole antifungal, raising the dosage of the azole, or therapy with amphotericin B arealternative strategies (B-III). Surgical resection may be a useful Pulmonary Cavity
option for refractory lesions that are well localized or in cases Asymptomatic.
Many cavities caused by Coccidioides species in which significant hemoptysis has occurred.
are benign in their course and do not require intervention.
Such cavities may harbor viable fungus, and cultures of samples Disseminated Infection (Extrapulmonary)
of sputum or other respiratory secretions commonly yield col- Nonmeningeal.
Initial therapy is usually initiated with oral onies of Coccidioides species. Many authorities do not consider azole antifungal agents, most commonly fluconazole or itra- these characteristics of asymptomatic cavities sufficient reason conazole (A-II). Clinical trials have used 400 mg per day of to initiate treatment. Moreover, in the absence of controlled ketoconazole, itraconazole, or fluconazole. Some experts rec- clinical trials, evidence is lacking that antifungal therapy has a ommend higher dosages (up to 2000 mg per day of fluconazole; salutary effect on the course of asymptomatic coccidioidal cav- up to 800 mg per day of itraconazole, administered in 200-mg ities (B-III). With the passage of time, some cavities disappear, doses) (B-III). Amphotericin B is recommended for alternative obviating the need for intervention. Although an indefinite therapy, especially if lesions are appearing to worsen rapidly follow-up period without intervention is appropriate for many and are in particularly critical locations, such as the vertebral patients, eventual resection from 1 to several years after the column (B-III). Amphotericin B dosage is similar to that for cavity is identified may be recommended to avoid future com- diffuse coccidioidal pneumonia, although the duration of ther- plications, especially if the cavity is still detectable after 2 years, apy may be longer. In patients experiencing failure of conven- if it demonstrates progressive enlargement, or if it is imme- tional deoxycholate amphotericin B therapy or experiencing diately adjacent to the pleura (B-III).
intolerable drug-related toxicities, lipid amphotericin B for- Symptomatic.
Complications of coccidioidal cavities in- mulations have been demonstrated to be safe and to cause less clude local discomfort, superinfection with other fungi or pos- nephrotoxicity and may be considered. Animal model studies sibly bacteria, or hemoptysis. Should these complications occur, have indicated that the higher amphotericin B dosages that can oral therapy with azole antifungals may result in improvement, be given via lipid formulations produce results superior to those although recurrence of symptoms (at least in some patients) seen with the maximally tolerated deoxycholate amphotericin may occur on cessation of therapy. If a bacterial superinfection B [35–37]. However, there have been no clinical trials assessing is present, treatment for several weeks with an oral antibacterial the efficacy of lipid formulations of amphotericin B.
may also reduce symptoms. However, such therapies usually Combination therapy with amphotericin B and an azole has do not result in the closure of the cavity. In cases in which the been administered to some patients, especially when infection surgical risks are not unusually high, resection of localized cav- is widespread or in cases in which there has been disease pro- ities is likely to resolve the problem and may be recommended gression during treatment with a single agent. Although com- as an alternative approach to chronic or intermittent therapy.
bination therapy may improve responses, there is no evidence Ruptured.
Rupture of a coccidioidal cavity into the pleural that such an approach is superior to treatment with a single space, resulting in a pyopneumothorax, is an infrequent but agent, and for other fungal infections, there are examples of serious complication of a necrotizing coccidioidal pneumonia antagonism with combination therapy [38], as has been dem- [34]. In young, otherwise-healthy patients, surgical closure by onstrated in vitro with Coccidioides species [11].
lobectomy with decortication is the preferred management (A- Surgical debridement or stabilization is an occasionally im- II). Antifungal therapy is recommended for treatment, partic- portant, if not critical, adjunctive measure. Factors that favor ularly in cases with delay of diagnosis and coexistent diseases a recommendation for surgical intervention are large size of (C-III). For patients in whom the diagnosis was delayed a week abscesses, progressive enlargement of abscesses or destructive or more or for patients in whom there are coexistent diseases, lesions, presence of bony sequestrations, instability of the spine, Treatment Guidelines for Coccidioidomycosis • CID 2005:41 (1 November) • 1221
or impingement on critical organs (such as a pericardial ef- Management of Patients Infected with HIV-1
fusion on the heart) or tissues (such as an epidural abscess on Before the introduction of HAART, coccidioidomycosis was a major opportunistic infection in the area of endemicity among Meningitis.
Therapy with oral fluconazole is currently pre- individuals infected with HIV-1 [45]. The incidence of clinically ferred by most clinicians. The dosage used in reported clinical apparent coccidioidal infection has since decreased. Prevention trials was 400 mg per day (A-II). Some physicians begin therapy of coccidioidomycosis among HIV-1–infected patients living in with 800 or 1000 mg per day of fluconazole (B-III). Itracon- the area of coccidioidal endemicity by prophylactic use of an azole, administered in dosages of 400–600 mg per day, has also antifungal is not effective for most patients [46]. Treatment is been reported to be comparably effective [39] (B-II). Some recommended for all patients with HIV-1 infection and pe- physicians also initiate therapy with intrathecal amphotericin ripheral blood CD4+ lymphocyte counts !250 cells/mL who have B in addition to an azole on the basis of their belief that re- clinically active coccidioidomycosis. Therapy should be con- sponses are more prompt with this approach. The dose and tinued as long as the CD4+ cell count is !250 cells/mL [45, 47].
duration of intrathecal amphotericin B in this circumstance However, it may be reasonable to stop therapy in those patients ranges between 0.1 mg and 1.5 mg per dose (C-III). Patients with higher CD4+ cell counts if there is clinical evidence of who respond to azole therapy should continue this treatment control of the coccidioidal infection (except for patients with indefinitely [40] (A-III). Hydrocephalus nearly always requires meningitis, for whom therapy should be life-long).
a shunt for decompression (A-III). Hydrocephalus may developregardless of the therapy being used and need not require Acknowledgments
switching to alternative therapy (B-III). Patients who do not Financial support.
Supported in part by the US Office of Veterans respond to fluconazole or itraconazole would be candidates for intrathecal amphotericin B therapy with or without continu- Potential conflicts of interest.
Schering and has lectured for Pfizer. J.N.G. has received research support ation of azole treatment. The intrathecal dosage of amphoter- or has been a consultant for Pfizer, Janssen, Merck, Schering, Enzon, and icin B normally ranges between 0.1 mg and 1.5 mg per dose, Lilly. R.H.J. has received grant support from Pfizer; is a member of the administered at intervals ranging from daily to weekly, begin- speakers’ bureaus for Sanofi-Aventis, Enzon, and Merck; and has been onthe speakers’ bureau of Bristol Myers-Squibb and Bayer. D.A.S. has received ning at a low dosage and increasing the size of the dosage until research support from and has been a consultant for Janssen, Ortho- the appearance of patient intolerance (indicated by severe vom- McNeil, Pfizer, Gilead, Enzon, and Schering. All other authors: no conflicts.
iting, prostration, or transient dose-related mental status) [16].
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Treatment Guidelines for Coccidioidomycosis • CID 2005:41 (1 November) • 1223


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