Cryptococcal meningitis. Because of the relatively rapid emergence of drug resistance, flucytosine is not employed as a single agent and is, therefore, only used in combination with amphotericin B or fluconazole. The desired outcome is continued absence of symptoms associated with cryptococcal meningitis and resolution or stabilization of cranial nerve abnormalities. For patients with more severe disease, a combination of fluconazole (400 mg/d) plus flucytosine (100150 mg/d) may be used for 10 weeks, followed by fluconazole maintenance therapy. Recently, lipid formulations of amphotericin B have been tested in cryptococcal meningitis and may have some toxicity profile advantages over the conventional amphotericin B formulation when used alone or possibly with flucytosine [12, 29]. Objectives. Benefits and harms. Specific recommendations for the treatment of HIV-associated cryptococcal pulmonary disease are summarized in table 2. Combination therapy of amphotericin B and flucytosine will sterilize CSF within 2 weeks of treatment in 60%90% of patients [1, 3]. Authors Anil A Panackal 1 , Kieren A Marr 2 , Peter R Williamson 3 Affiliations 1 National . The Advisory Committee on Immunization Practices recently added a category B recommendation (individual clinical decision making) for consideration of vaccination with serogroup B vaccines in healthy patients 16 to 23 years of age (preferred age of 16 to 18 years).60,61 The serogroup B vaccines are not interchangeable, so care should be taken to ensure completion of the series with the same brand that was used for the initial dose. Because CSF enterovirus polymerase chain reaction testing is more rapid than bacterial cultures, a positive test result can prompt discontinuation of antibiotic treatment, thus reducing antibiotic exposure and cost in patients admitted for suspected meningitis.34 Similarly, polymerase chain reaction testing can be used to detect West Nile virus when seasonally appropriate in areas of higher incidence. Cryptococcal meningitis usually presents as a subacute meningoencephalitis. Diagnosis of meningitis is mainly based on clinical presentation and cerebrospinal fluid analysis. definitions. Cryptococcal meningitis in an immunocompetent patient By far the most common presentation of cryptococcal disease is cryptococcal meningitis, which accounts for an estimated 15% of all AIDS-related deaths globally, three quarters of which are in sub-Saharan Africa. Yet, because of the potentially grave consequences of overlooking this illness, it is imperative to assess AIDS patients with pneumonia for possible fungal infection. Cryptococcal meningitis, mainly caused by Cryptococcus neoformans/gattii species complexes, is a lethal infection in both immunosuppressive and immunocompetent populations. Microscopy of cerebrospinal fluid Cryptococcal Meningitis: Causes, Symptoms, and Diagnosis We characterized 110 Cryptococcus strains collected from Xiangya Hospital of Central South University in China during the 6-year study period between 2013 and 2018, and performed their antifungal susceptibility testing . Taking this medication helps prevent relapses. The desired outcome is resolution of symptoms, such as cough, shortness of breath, sputum production, chest pain, fever, and resolution or stabilization of abnormalities (infiltrates, nodules, masses, etc.) It isnt found in bird droppings. These cookies perform functions like remembering presentation options or choices and, in some cases, delivery of web content that based on self-identified area of interests. A 2015 Cochrane review found a nonsignificant reduction in overall mortality (relative risk [RR] = 0.90), as well as a significant reduction in severe hearing loss (RR = 0.51), any hearing loss (RR = 0.58), and short-term neurologic sequelae (RR = 0.64) with the use of dexamethasone in high-income countries.41 The number needed to treat to decrease mortality in the S. pneumoniae subgroup was 18 and the number needed to treat to prevent hearing loss was 21.38,41 There was a small increase in recurrent fever in patients given corticosteroids (number needed to harm = 16) with no worse outcome.38,41, The best evidence supports the use of dexamethasone 10 to 20 minutes before or concomitantly with antibiotic administration in the following groups: infants and children with H. influenzae type B, adults with S. pneumoniae, or patients with Mycobacterium tuberculosis without concomitant human immunodeficiency virus infection.7,8,42,45 Some evidence also shows a benefit with corticosteroids in children older than six weeks with pneumococcal meningitis.45, Because the etiology is not known at presentation, dexamethasone should be given before or at the time of initial antibiotics while awaiting the final culture results in all patients older than six weeks with suspected bacterial meningitis. Among HIV-infected patients with elevated CSF pressures, a poorer clinical response was noted among patients whose pressure increased between baseline and week 2 of treatment; benefit from management of intracranial pressure is inferred from reduced mortality in this population [22]. The presentation of pulmonary cryptococcosis can range from asymptomatic nodular disease to severe acute respiratory distress syndrome (ARDS). During the early 1970s, flucytosine was established as an orally bioavailable agent with potent activity against C. neoformans; however, this activity was lost rapidly because of the development of resistance when the drug was used as monotherapy [2]. In cases where repeated lumbar punctures or use of a lumbar drain fail to control elevated pressure symptoms, or when persistent or progressive neurological deficits are present, a ventriculoperitoneal shunt is indicated [21, 22] (BII). Guidelines for Diagnosing, Preventing and Managing Cryptococcal Disease Maintain isolation precautions as necessary with bacterial meningitis. Lumbar punctures are relatively inexpensive. Uniform success cannot be anticipated with existing therapy; however, since the mortality associated with cryptococcal meningitis can be up to 25% among persons with AIDS, the use of therapies that result in even modest levels of success are worthy. The Bacterial Meningitis Score has a sensitivity of 99% to 100% and a specificity of 52% to 62%, and appears to be the most specific tool available currently, although it is not widely used.2527 The score can be calculated online at http://reference.medscape.com/calculator/bacterial-meningitis-score-child. CDC twenty four seven. When flucytosine was added to amphotericin B as combination therapy, overall outcome of therapy was improved and the duration of treatment could be reduced from 10 weeks to 46 weeks, depending on the status of the host [1, 3]. The classic triad of meningitis is fever, headache, and neck stiffness. The antibiotic or combination of antibiotics depends on the type of bacteria causing the infection. Working with health programs to introduce and implement cryptococcal screening and treatment, Helping health programs assess costs and impact of cryptococcal screening activities, Supporting training of clinical and laboratory staff on diagnosing, treating, and managing cryptococcal infection and cryptococcal meningitis, Collaborating with partners to improve access to cryptococcal diagnostics and antifungal drugs. Recognition of cryptococcal meningitis in HIV-infected patients requires a high index of suspicion. Treatment should not be delayed if there is lag time in the evaluation. Outcomes. Outcomes. Most cases of aseptic meningitis are viral and require supportive care. Owing to the intense fungal burden and large amount of replication in patients with HIV disease, adjunctive steroid therapy is not recommended for HIV-infected patients (DIII). To screen people living with HIV for early cryptococcal infection and cryptococcal meningitis, healthcare facilities and laboratories must have access to the reliable tests. In both HIV-negative and HIV-positive patients with cryptococcal meningitis, elevated intracranial pressure occurs in excess of 50% of patients [22]. Healthline Media does not provide medical advice, diagnosis, or treatment. Drug acquisition costs are high for antifungal therapies administered for life. Early, appropriate treatment of cryptococcal meningitis reduces both morbidity and mortality. . Copyright 2023 American Academy of Family Physicians. Drug-related toxicities and development of adverse drug-drug interactions are the principal harms of therapeutic intervention. Reprints or correspondence: Dr. Michael S. Saag, University of Alabama at Birmingham, 908 20th Street South, Birmingham, AL 35294-2050 (. Radiographic imaging of the brain is recommended prior to performance of the initial lumbar puncture to rule out the presence of a space-occupying lesion [21] (BII). All patients should be monitored closely for evidence of elevated intracranial pressure and managed in a fashion similar to HIV-positive patients (see below). See permissionsforcopyrightquestions and/or permission requests. There are no controlled clinical trials describing the outcome of therapy for AIDS-related cryptococcal pneumonia (table 2). Specific pathogens are more prevalent in certain age groups, but empiric coverage should cover most possible culprits. Update: Recommendations for healthcare workers can be found at Ebola For Clinicians. Aggressive management of elevated intracranial pressure is perhaps the most important factor in reducing mortality and minimizing morbidity of acute cryptococcal meningitis. A lumbar puncture is recommended after 2 weeks of treatment to assess the status of CSF sterilization. Treatment decisions should not be based routinely or exclusively on cryptococcal polysaccharide antigen titers in either the serum or CSF [31, 34] (AI). For selected patients who have responded very well to HAART, consideration might be given to discontinuing secondary antifungal prophylaxis after 1218 months of successful suppression of HIV viral replication (CIII). Classic symptoms of pneumonitis, including cough, fever, and sputum production, may be present, or pleural symptoms may predominate. Fluconazole is well-tolerated; nausea, abdominal pain, and skin rash are the most common adverse effects. Occasionally patients who present with extremely high opening pressures (>400 mm H2O) may require a lumbar drain, especially when frequent lumbar punctures are required to or fail to control symptoms of elevated intracranial pressure. Costs. Beginning in the 1980s, orally bioavailable azole antifungal agents with activity against C. neoformans were introduced, in particular, itraconazole and fluconazole. For those individuals with non-CNS-isolated cryptococcemia, a positive serum cryptococcal antigen titer >1 : 8, or urinary tract or cutaneous disease, recommended treatment is oral azole therapy (fluconazole) for 36 months. More Information. Patients are usually treated with two antifungal agents and the . Examination findings that may indicate meningeal irritation include a positive Kernig sign, positive Brudzinski sign, neck stiffness, and jolt accentuation of headache (i.e., worsening of headache by horizontal rotation of the head two to three times per second). Prospective clinical trials and carefully conducted observational studies show that potent antiretroviral therapy reduces the incidence of opportunistic infections [2527]. (2005). Cryptococcosis - Infectious Diseases - Merck Manuals Professional Edition The elevated intracranial pressure in this setting is thought to be due, in part, to interference with CSF reabsorption in the arachnoid villi, caused by high levels of fungal polysaccharide antigen or excessive growth of the organism per se. Meningitis is an inflammatory process involving the meninges. Recommendations. These materials are intended to support cryptococcal screen-and-treat programs. This trial was terminated by an independent data safety monitoring board after preliminary results revealed a CSF culture relapse rate of 4% among patients receiving fluconazole (200 mg/d), compared with 24% relapse among itraconazole (200 mg/d) recipients [17]. Meningitis - National Institute of Neurological Disorders and Stroke Among patients with normal baseline opening pressure (<200 mm H2O), a repeat lumbar puncture should be performed 2 weeks after initiation of therapy to exclude elevated pressure and to evaluate culture status. They are called Cryptococcus neoformans (C. neoformans) and Cryptococcus gattii (C. gattii). However, patients with nonpulmonary, extraneural (e.g., bone or skin) disease require specific antifungal therapy. Cryptococcal disease that develops in patients with HIV infection always warrants therapy. Learn how it can, Recurrent meningitis is a rare condition that happens when meningitis goes away and comes back again. 7, 8 Droplet isolation precautions should be instituted for the first 24 hours of . Such testing is generally best used in cases of relapse or in cases of refractory disease. On the basis of experience of treating cryptococcal meningitis in HIV disease, it is reasonable to follow a similar induction, consolidation, and suppression strategy, since previous strategies reported failure rates of 15%20% with 6 weeks of treatment with combination amphotericin B/5-flucytosine [3]. Drug acquisition costs are high for antifungal therapies administered for life. AIDS Clinical Trials Group 320 Study Team, Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection, Combination therapy with fluconazole and flucytosine for cryptococcal meningitis in Ugandan patients with AIDS, Cryptococcal meningitis: outcome in patients with AIDS and patients with neoplastic disease, Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis, Itraconazole compared with amphotericin B plus flucytosine in AIDS patients with cryptococcal meningitis, Utility of serum and CSF cryptococcal antigen in the management of cryptococcal meningitis in AIDS patients, 34th Annual Meeting of the Infectious Diseases Society of America (Denver), Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel, Use of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS, High-dose fluconazole therapy for cryptococcal meningitis in patients with AIDS, 2000 by the Infectious Diseases Society of America. The prevention of progression to cryptococcal meningitis is the principal goal of therapy in this population. These cookies may also be used for advertising purposes by these third parties. Thank you for taking the time to confirm your preferences. To reduce mortality from cryptococcal infection, CD4 testingis also needed to identify patients with low CD4 counts, who are at highest risk for cryptococcal meningitis. PDF CRYPTOCOCCOSIS Thank you for submitting a comment on this article. Regardless of the treatment chosen, it is imperative that all patients with pulmonary and extrapulmonary cryptococcal disease have a lumbar puncture performed to rule out concomitant CNS infection. Bacterial meningitis droplet precautions: What to know Routine studies should include the following: measurement of CSF opening pressure (with the patient in the lateral recumbent position); collection of sufficient CSF for fungal culture (3 mL); and the measurement of CSF cryptococcal antigen titer, glucose level, protein level, and cell count with differential (5 mL total). Guidelines for diagnosing, preventing and managing cryptococcal disease It may be prudent to use doses of 200 mg of itraconazole twice daily (BIII). Patients with isolated or asymptomatic cryptococcal antigenemia without meningitis and low serum CrAg titers (i.e., <1:320 using LFA) can be treated in a similar fashion as patients with mild to moderate symptoms and only focal pulmonary cryptococcosis with fluconazole 400 to 800 mg per day (BIII). Ketoconazole has in vitro activity against C. neoformans, but is generally ineffective in the treatment of cryptococcal meningitis and should be used rarely, if at all, in this setting [10] (CIII). Cookies used to enable you to share pages and content that you find interesting on CDC.gov through third party social networking and other websites. This specific species is an emerging pathogen and is best known for the 2013 outbreak in the U.S. Pacific Northwest. INTRODUCTION. Cryptococcal Meningitis - StatPearls - NCBI Bookshelf Cryptococcal meningitis is a fungal infection that is most commonly thought of as an opportunistic infection affecting immunocompromised patients, classically patients with Human Immunodeficiency (HIV) infection. Patients with a positive culture at 2 weeks may require a longer course of induction therapy. Bicanic T, et al. Considerations for Bioterrorist Threats, Table 4. You will be subject to the destination website's privacy policy when you follow the link. In response to important new evidence that became available in 2021, these new guidelines strongly recommend a single high dose of liposomal amphotericin B as part of the preferred induction regimen for the treatment of cryptococcal meningitis in people . As a result, most clinicians are uncertain about which agents to use for which underlying disease state, in what combination, and for what duration. See additional information. Costs. Symptoms are those of pneumonia, meningitis, or involvement of skin, bones, or viscera. Benefits and harms. In the most recent large comparative study of this disease, the overall mortality was 6%; in contrast, previous treatment studies experienced mortality rates of 14%25% [11, 13]. Ketoconazole is generally ineffective in the treatment of cryptococcosis in HIV-infected patients and should probably be avoided [10, 30] (DII). Whether the CNS disease is associated with involvement of other body sites, treatment remains the same. Etiologies range in severity from benign and self-limited to life-threatening with potentially severe morbidity. If any test is positive for C. neoformans, then a CSF examination is recommended to exclude cryptococcal meningitis. Meningitis can be caused by different germs, including bacteria, fungi, and viruses. Therapy with amphotericin B (0.71 mg/kg/d) for 2 weeks, followed by 810 weeks of fluconazole (400800 mg/d), is followed with 612 months of suppressive therapy with a lower dose of fluconazole (200 mg/d) (BIII). This fungus is found in soil around the world. We avoid using tertiary references. Worldwide, approximately 1 million new cases of cryptococcal meningitis occur each year, resulting in 625,000 deaths. Common manifestations in this setting include papilledema, hearing loss, loss of visual acuity, pathological reflexes, severe headache, and abnormal mentation. Amphotericin B, flucytosine, and fluconazole are antifungal medications shown to improve survival in patients with cryptococcal infections. The differential diagnosis is broad (Table 1). EPIC | Eukaryotic Pathogens Innovation Center Some reports describe the successful use of flucytosine (100 mg/kg/d for 612 months) as therapy for pulmonary cryptococcal disease; however, concern about the development of resistance to flucytosine when used alone limits its use in this setting [2, 5] (DII). You can review and change the way we collect information below. Additional costs are accrued for the monthly monitoring of therapies during maintenance therapy. Although some preliminary evidence suggests lower relapse rates of opportunistic infections when patients have been successfully treated with potent antiretroviral therapy, until proven otherwise, maintenance therapy for cryptococcal meningitis should be administered for life (AI). Practice Guidelines for the Management of Cryptococcal Disease Early, appropriate treatment of non-CNS pulmonary and extrapulmonary cryptococcosis in HIV-infected patients reduces morbidity and prevents progression to potentially life-threatening CNS disease. This test cannot be used to rule out bacterial meningitis.7. If you do not allow these cookies we will not know when you have visited our site, and will not be able to monitor its performance. Maintenance therapy. Amphotericin B (0.71 mg/kg given iv daily for 2 weeks) combined with flucytosine, 100 mg/kg given orally in 4 divided doses per day, is the initial treatment of choice [11, 13, 18, 29] (AI). The principal intervention for reducing elevated intracranial pressure is percutaneous lumbar drainage [21, 22] (AII). Serum procalcitonin, serum C-reactive protein, and CSF lactate levels can be useful in distinguishing between aseptic and bacterial meningitis.2833 C-reactive protein has a high negative predictive value but a much lower positive predictive value.28 Procalcitonin is sensitive (96%) and specific (89% to 98%) for bacterial causes of meningitis.29,30 CSF lactate also has a high sensitivity (93% to 97%) and specificity (92% to 96%).3133 CSF latex agglutination testing for common bacterial pathogens is rapid and, if positive, can be useful in patients with negative Gram stain if LP was performed after antibiotics were administered. Youll typically receive amphotericin B intravenously, meaning directly into your veins. Combination therapy with fluconazole (400800 mg/d) and flucytosine (100 mg/kg/d in 4 divided doses) has been shown to be effective in the treatment of AIDS-associated cryptococcal meningitis [16, 29]. Nevertheless, amphotericin B can be employed safely and effectively; only 3% of patients will have toxic side effects of a magnitude that requires it to be discontinued within the first 2 weeks of therapy [11]. Vancomycin hydrochloride, alone or in combination with rifampin, may be used if resistant strains of bacteria are identified. Pilot studies that have investigated fluconazole with flucytosine as initial therapy yielded unsatisfactory outcomes [7]. According to the U.S. Centers for Disease Control and Prevention (CDC), infections by C. neoformans occur yearly in about 0.4 to 1.3 cases per 100,000 people in the general healthy population. CDC is not responsible for Section 508 compliance (accessibility) on other federal or private website. One large cohort study found a 4.5% mortality rate and a 30.9% rate of complications, such as developmental delay, seizure disorder, or hearing loss, for childhood encephalitis and meningitis combined.50 Tuberculous meningitis also has a higher mortality rate (19.3%) with a higher risk of neurologic disease in survivors (53.9%).51 A recent prospective cohort study also found that males had a higher risk of unfavorable outcomes (odds ratio = 1.34) and death (odds ratio = 1.47).52, Complications from bacterial meningitis also vary by age (Table 71,11,12,46,5356 ). For patients with elevated baseline opening pressure, lumbar drainage should remove enough CSF to reduce the opening pressure by 50%. Your Guide to Salmonella Meningitis and How to Spot It, Group B Streptococcal (GBS) Meningitis: Symptoms, Treatment, Outlook, and More. The Centers for Disease Control and Prevention (CDC) cannot attest to the accuracy of a non-federal website. For both immunocompetent and immunocompromised patients with significant renal disease, lipid formulations of amphotericin B may be substituted for amphotericin B during the induction phase [12] (CIII). All information these cookies collect is aggregated and therefore anonymous. The format of this section was changed to improve readability and accessibility. The study will help to identify safer and more effective drugs that target cryptococcal infections like the life-threatening meningo-encephalitis in an immunocompromised host. In HIV-infected patients, evaluation of the CSF reveals minimal inflammation (frequently, few leukocytes; and normal levels of glucose and protein) but uncontrolled fungal growth in the CSF. Add Droplet Precautions for the first 24 hours of appropriate antimicrobial therapy if invasive Group A streptococcal disease is suspected, Centers for Disease Control and Prevention. Repeating the LP can identify resistant pathogens, confirm the diagnosis if initial results were negative, and determine the length of treatment for neonates with a gram-negative bacterial pathogen until CSF sterilization is documented.7,47, Prognosis varies by age and etiology of meningitis. Empiric antibiotics should be directed toward the most likely pathogens and should be adjusted by patient age and risk factors. HILLARY R. MOUNT, MD, AND SEAN D. BOYLE, DO. It is associated with a variety of complications including disseminated disease as well as neurologic complications . Aseptic and Bacterial Meningitis: Evaluation, Treatment, and Prevention These cookies perform functions like remembering presentation options or choices and, in some cases, delivery of web content that based on self-identified area of interests. C. neoformans infection statistics. If you do not allow these cookies we will not know when you have visited our site, and will not be able to monitor its performance. However, in people with weakened immune systems, such as those living with HIV, Cryptococcus can stay hidden in the body and later cause a serious (but not contagious) brain infection called cryptococcal meningitis. Treatment options for cryptococcal disease in HIV-infected patients. Michael S. Saag, Richard J. Graybill, Robert A. Larsen, Peter G. Pappas, John R. Perfect, William G. Powderly, Jack D. Sobel, William E. Dismukes, Mycoses Study Group Cryptococcal Subproject, Practice Guidelines for the Management of Cryptococcal Disease, Clinical Infectious Diseases, Volume 30, Issue 4, April 2000, Pages 710718, https://doi.org/10.1086/313757. All Rights Reserved. Studies evaluating the effectiveness of amphotericin B, with or without flucytosine, have elucidated the optimal length of therapy for HIV-negative, immunocompromised and immunocompetent hosts. CM usually occurs in people who have a compromised immune system. cryptococcal, or other . Is There a Link Between Meningitis and COVID-19? Causes In most cases, cryptococcal meningitis is caused by the fungus Cryptococcus neoformans. Most people who develop CM already have severely compromised immune systems. The most troublesome toxic side effect is renal injury, including elevation of the serum creatinine, hypokalemia, hypomagnesemia, and renal tubular acidosis. It is clear that all HIV-infected patients require treatment, since they are at high risk for disseminated infection. Ventriculoperitoneal shunts may become secondarily infected with bacteria; however, this is an uncommon complication. Indeed, few studies have been conducted that specifically evaluate outcomes among HIV-infected patients with pulmonary or non-CNS disease. Because clinical findings are also unreliable, the diagnosis relies on the examination of cerebrospinal fluid obtained from lumbar puncture. To ensure that appropriate empiric precautions are implemented always, hospitals must have systems in place to evaluate patients routinely according to these criteria as part of their preadmission and admission care. The objective of treatment is eradication of the infection and control of elevated intracranial pressure. PDF Communicable Disease Management Protocol Viral Meningitis/Encephalitis Additional costs are accrued for monthly monitoring and supervision of therapies associated with most of the recommended regimens. Patients may also present with neurological deficits, altered mental status, and seizures, indicating increased intracranial pressure (ICP). We take your privacy seriously. U.S. Centers for Disease Control and Prevention (CDC), bmb.oxfordjournals.org/content/72/1/99.full, cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html, hivinsite.ucsf.edu/InSite?page=md-agl-crypcoc, mayoclinic.org/diseases-conditions/meningitis/basics/definition/con-20019713, Bacterial, Viral, and Fungal Meningitis: Learn the Difference, Recurrent Meningitis: A Rare but Serious Condition, Understanding the Meningitis Vaccine: What It Is and When You Need It. Transmission Precautions | Appendix A | Isolation Precautions Lateral flow assay is a reliable, rapid, and inexpensive test that can be used on a small sample of blood or spinal fluid to detect cryptococcal antigen. Most patients with cryptococcal meningoencephalitis are immunocompromised. HIV-infected patients with elevated intracranial pressure do not differ clinically from those with normal opening pressure, except that neurological manifestations of disease are more severe among those with higher pressures [21, 22]. Treatment of tuberculous, cryptococcal, or other fungal meningitides is beyond the scope of this article, but should be considered if risk factors are present (e.g., travel to endemic areas, immunocompromised state, human immunodeficiency virus infection). In cases where fluconazole cannot be given, itraconazole is an acceptable, albeit less effective, alternative [9, 33] (B, I).
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