on 07-May-2022 (Sat)

dete Konvention darüber, was genau mit „Change Management“ gemeint sein soll, existiert nicht. Die Abgrenzungen dessen, was mit „Change“ genau

Second, liposomal amphotericin B (AmBisome) at 3 to 6 mg/kg/day and probably amphotericin B lipid complex at 5 mg/ kg/day have had treatment successes similar to that of amphotericin B deoxycholate, with reduced toxicity. 352,353 In patients with renal dysfunc- tion or at risk for renal dysfunction, the lipid products of amphotericin B are frequently recommended. For example, they are used as primary therapy in transplant recipients. 331

In fact, lipid formulations of ampho- tericin B may also be advantageous in all patients with cryptococcal meningitis in that they are less likely to require adjustments of the induction regimen that can produce a negative impact on treatment outcome. 354,355

Flucytosine has been used alone in treatment of cryptococcal meningitis, 358 but frequent development of direct drug resistance on monotherapy has meant that it cannot be recommended as a single agent for treatment of this infection. It is primarily used in combination therapy with conventional amphotericin B or lipid formulations of amphotericin B, 349,350,359–362 and doses in patients with normal renal function are typically 100 mg/kg/day but will need to be adjusted in those with renal dysfunction. Drug levels should be monitored to keep 2-hour postdose levels under 100 μg/mL, 363 or careful follow-up of complete blood counts should be performed, to reduce the development of bone marrow depression in those with risk for this toxicity, such as patients with renal dysfunction or those receiving high doses of polyenes

Azoles have been used effectively in the management of cryptococcal meningitis. For instance, fluconazole has been used extensively in cryptococcal meningitis because of its excellent CSF pharmacokinetics and long-term oral safety. 367–371 Clinical trials have shown that it penetrates well into CSF and is excellent for use in the consolidation and suppressive phases of cryptococcal meningitis management. 372,373 However, it tends to be fungistatic and is probably best used in the stage of infection in which there is a low burden of yeasts in the CSF, and thus is not recommended for the primary induction phase of therapy for meningitis when a polyene is available for use

Itraconazole, despite its poor CSF penetration and inconsistent oral bioavailability, has been successfully used in the treatment of cryptococcal meningitis. 374,375 However, it has been shown to be inferior to fluconazole for the suppressive phase of treatment. 364 Its place in therapy for cryptococcal meningitis is probably as a less-than-ideal alternative to first-line therapy with fluconazole in the consolidation and suppressive phases of management if the drug levels are monitored.

The relatively new triazoles—voriconazole, posacon- azole, and isavuconazole—have been studied in a small number of refractory cases of cryptococcosis with moderate success, 314,376,377 but it is not clear whether they possess any advantage over fluconazole

The antifungal class of β-glucan synthase inhibitors, such as caspo- fungin, micafungin, and anidulafungin, does not possess reliable anticryptococcal activity and is not to be used for management of cryptococcal infections.

Combination therapy for the management of cryptococcal meningitis has been extremely well studied. The combination of amphotericin B and flucytosine has become the standard therapy for meningitis, and in patients without AIDS it usually sterilizes CSF after 2 weeks of therapy. In fact, it clears CSF yeast counts significantly faster than amphotericin B alone, amphotericin B plus fluconazole, or all three agents together. 378

A standard algorithm for the management of cryptococcal meningitis in patients with HIV is a three-stage regimen. 360 Induction-phase treat- ment is initiated with amphotericin B 0.7 mg/kg/day plus flucytosine 100 mg/kg/day for at least 2 weeks. In resource-limited environments, a 1-week induction combination of a polyene plus flucytosine appears to be effective, with a better outcome than prolonged polyene therapy. 380 Patients who have responded clinically may be switched to fluconazole 400 to 800 mg/day for 8 to 10 weeks as a consolidation phase. Finally, a suppressive phase is begun with fluconazole 200 mg once daily

The use of suppressive- or maintenance-phase therapy for cryptococcal meningitis became a concept during the pre-ART AIDS epidemic, when 50% to 60% of patients relapsed after therapy was stopped. With the use of fluconazole, daily suppression was better than that obtained with intermittent amphotericin B or itraconazole, and there was a reduction in the relapse rates to less than 5%. 372,373

Recent data in several studies have shown that administration of ART, with its ability to produce immune reconstitution (rising CD4 counts and lower HIV loads), allows antifungal therapy to be stopped after 1 to 2 years in patients with a CD4 count above 100/μL for at least 3 months, a nondetectable viral load, and a negative or low serum cryptococcal antigen. 383,384

Patients without AIDS can be given either a 4-week induction-phase regimen of amphotericin B, with or without initial flucytosine, or, more commonly, the previously mentioned regimen used for AIDS patients of 2 weeks. If induction therapy includes only a polyene, this phase should be extended at least another 2 weeks.

In transplant recipients with known renal toxicity issues, a lipid polyene formulation is favored with flucytosine for a 2-week induction period. These patients can then receive a consolidation phase of fluconazole 400 to 800 mg/day for 8 weeks and finally be placed on suppressive doses of fluconazole 200 mg/ day.

Criteria for stopping therapy are not well defined but include resolu- tion of initial symptoms, negative CSF cultures from several milliliters of CSF, normal CSF glucose, and a prolonged asymptomatic period of 6 months to 1 year.

A negative CSF or serum cryptococcal antigen does not appear to be required to discontinue therapy.

ecause there was a 15% to 25% relapse rate before the AIDS epidemic, primarily occurring in the first year after stopping therapy, most patients will receive at least 12 months of suppressive fluconazole therapy.

Any presentation of disseminated cryptococcosis should probably follow the recommendations for cryptococcal meningitis. On the other hand, cryptococcosis confined to the lung in previously healthy persons responds well to fluconazole at 200 to 400 mg/day for 3 to 6 months. 67,368,369

Nonimmunosuppressed patients with endobronchial colonization but without radiologic evidence of pulmonary parenchymal disease do not require antifungal treatment. However, if the patient is symptomatic, immunocompromised, or at risk for immunosuppression, treatment should be started.

CNS cryptococcomas are treated with a prolonged combination of amphotericin B and flucytosine for the induction phase and then tend to be treated for longer periods with fluconazole, but they rarely need surgical removal. 385 MRI scans of the brain may not show a decrease in lesion size for many months after treatment is started and even stopped. Edema around a lesion, if present, decreases more rapidly. 329

Identifying a relapse or persistent infection can be difficult in patients with cryptococcal infections. The two clearest signs of relapse after at least 4 weeks of an established antifungal regimen, which suggest a change in management, are (1) development of new clinical signs and symptoms and (2) repeat positive cultures.

The persistence of a positive India ink examination or changing versus fixed polysaccharide antigen titers are not precise indications of relapse.

IRIS in cryptococcosis must be considered. 239 It is marked by a rapid return of an inflammatory response that may produce new symptoms, such as fever, headaches with or without increasing intracranial pressure, and increased number of host cells in the CSF. This syndrome may occur from several weeks to months to a year after beginning ART or after immunosuppressive dose reduction in transplant recipients.

It is still not certain when it is best to initiate ART during the treatment of cryptococcal meningitis to prevent this syndrome, but recommendations range from 2 to 10 weeks after the start of antifungal therapy, and at present it is beneficial to not start ART during the induction phase of treatment. 331

It is important to recognize that IRIS is not an indication of direct antifungal failure and might be improved with empirical corticosteroid therapy in seriously ill patients with CNS disease

A critical management issue in cryptococcal meningitis is the role of increased intracranial pressure. 387,388 Patients with severe infection often present with CSF opening pressures in excess of 250 mm of CSF and rapidly progressing signs of cerebral edema. Clinicians need to particularly respond to high opening pressures and symptoms rather than a specific elevated opening pressure measurement.

The pathophysiology for this elevated sub- arachnoid pressure even as antifungal treatment is started remains uncertain, but there is a suggestion of CSF outflow obstruction through the arachnoid villi by clumping of yeasts. 388

In retrospective reviews, corticosteroid treatment for elevated intracranial pressure without IRIS was not found to be generally useful. 387,388 In fact, a recent study confirms the lack of value for routine early use of corticosteroids in cryptococcal meningitis during induction therapy, with more disabilities, adverse events, and reduced antifungal killing of yeasts with the use of corticosteroids. 392

Thus cases need to be examined on an individual basis for use of corticosteroids during the diagnosis of IRIS. Unfortunately, despite interventions, blindness, permanent dementia, or death may still result.

It is vital to distinguish cerebral edema from classic hydrocephalus. The latter is diagnosed by the presence of dilated cerebral ventricles and dementia, with or without gait ataxia or urinary incontinence. CSF pressure may or may not be elevated. A loculated temporal horn of the lateral cerebral ventricle may present as a space-filling mass and cause transfalciform herniation. Symptoms of hydrocephalus need to be identified in the follow-up management period and can occur months after the initial diagnosis.

No evidence suggests that a shunt placement after institution of appropriate antifungal therapy presents a foreign body that impairs cure, but it needs to be placed after the start of the antifungal regimen

Every attempt to improve the immunity of the patient with cryptococ- cosis should be made. For example, a goal is to reduce the routine daily dose of prednisone to less than or equal to 20 mg/day during therapy.

The most important prognostic factor for success in the treatment of cryptococcosis remains the ability to control the patient’s underlying disease. In fact, it has been shown that cancer victims have shorter survival than patients with AIDS because of the inability to control their underlying neoplasm. 396

Ironically, the group with the worst prognosis is the non-HIV, nontransplant recipient group, which likely represents the variety of underlying diseases or delay in making the diagnosis, or both. 397

Several studies have examined the prognostic features of cryptococcal meningitis, 42,349,359 and a summary of the different populations, treatment modalities, and end point evaluations suggests that there are three major prognostic findings: (1) burden of yeasts at presentation, (2) poor inflammatory response, and (3) level of the patient’s sensorium at presentation. For example, a poor prognosis is indicated by a strongly positive India ink examination, a high polysaccharide antigen titer (≥ 1 : 1024), and a poor inflammatory response in the CSF (<8

For instance, poor prognostic underlying conditions are severe liver disease or a hematologic malignancy. 10 Multiple studies have identified the poor prognosis of patients with liver diseases, and this likely reflects both end-organ disease and delayed diagnosis. 401

In most cases in developed countries, the immediate mortality rate (at 6 months to a year) of cryptococcal meningitis unfortunately still remains at 10% to 25%. 103,403 In underdeveloped countries with limited resources, the mortality rate at 6 months can reach from 50% to 100%. 333

First, in the pre-ART era, fluconazole prophylaxis in patients with AIDS and CD4 counts under 100 cells/μL has been shown to be effective in reducing the incidence of cryptococcosis. 404–406

Second, active immunization with a vaccine in high-risk patients has been considered. A cryptococcal GXM–tetanus toxoid conjugate vaccine that protected mice has been developed, 407 and several new potential protective antigens have been identified. 408

Third, the use of protective serotherapy with specific monoclonal antibodies 409,410 could be considered in high-risk patients, but protection would require repeated injections.

Fourth, a preemptive treatment strategy in areas of high cryptococcal prevalence and HIV infection, by using cryptococcal antigen screening with ART introduction, may be cost-effective in managing or preventing cryptococcal disease. 411

Finally, high-risk patients can attempt to avoid high-risk environments, such as sites where large numbers of yeasts might be aerosolized from bird droppings

Cryptococcus neoformans meningoencephalitis is the most frequently encountered manifestation of cryptococcosis.

The term "meningoencephalitis" is more appropriate than "meningitis" since histopathologic examination has demonstrated that the brain parenchyma is almost always involved

he basis for the tropism for the CNS is uncertain, but a number of hypotheses have been proposed:

● The cerebrospinal fluid (CSF) is a favorable growth medium for the organism as it lacks the factors present in serum that inhibit cryptococcal growth [1]. In the serum, the organism activates the alternative complement pathway, but complement activity in the CSF is very low [2].

● Dopamine levels in the CNS may promote cryptococcal virulence by serving as a substrate for melanin production by the organism [3]. (See "Microbiology and epidemiology of Cryptococcus neoformans infection".)

● Production of mannitol by the organism may contribute to brain edema and inhibit phagocyte function [4].

● C. neoformans appears to evade the host innate immune system and invade through the blood-brain barrier [5].

The inflammatory response in the brain is generally milder than that seen in bacterial meningoencephalitis

Most patients with cryptococcal meningitis are immunocompromised. The most common forms of immunosuppression other than HIV include glucocorticoid therapy, solid organ transplantation, cancer (particularly hematologic malignancy), and other conditions such as sarcoidosis and hepatic failure

Other risk factors include the use of the tyrosine kinase inhibitor, ibrutinib [6], and the development of anti-granulocyte-macrophage colony stimulating factor (anti-GM-CSF) antibodies [7].

Although many patients have risk factors for disease, in a multicenter retrospective study of 157 cases of central nervous system cryptococcosis in HIV-negative patients, 30 percent had no apparent underlying condition [ 8]

Some patients have symptoms for up to several months prior to diagnosis, whereas others present with an acute illness of only a few days. Most patients present with signs and symptoms of subacute meningoencephalitis; fever is observed in approximately 50 percent of cases [8-10]. Typically, headache, lethargy, personality changes, and memory loss develop over two to four weeks. Patients may also present with disseminated disease.

Among solid organ transplant recipients, cryptococcal infection occurs in an average of 2.8 percent of patients [11,12]. The median time to disease onset is 21 months after transplantation; 68 percent of cases occur >1 year after transplantation. Central nervous system involvement and disseminated infection have been documented in 52 to 61 percent of patients with cryptococcal infection [11,13]. Approximately 25 percent of transplant recipients with C. neoformans disease have fungemia [11,14]

The disease should be suspected in any immunocompromised patient with fever, headache, and signs or symptoms referable to the central nervous system (CNS). C. neoformans should also be considered in immunocompetent individuals presenting with subacute to chronic meningitis

Lumbar puncture with measurement of the opening pressure and careful evaluation of the cerebrospinal fluid (CSF) with India ink, polymerase chain reaction (PCR) CSF testing, and/or cryptococcal antigen testing should suggest the diagnosis in most cases. Culture nearly always establishes the diagnosis

The opening pressure may be markedly elevated. Almost 70 percent of AIDS patients with cryptococcal meningoencephalitis have opening pressures >200 mmH₂0 on the initial lumbar puncture [9]. Increased intracranial pressure is observed less frequently in non–HIV-infected patients

Cell counts of the CSF are characteristically low in HIV-associated infection (0 to 50 cells/microL), and higher in non-HIV cases (20 to 200 cells/microL). Mononuclear cells predominate in both HIV-infected and noninfected patients (50 to 80 percent)

Low glucose levels and elevated protein levels are frequently observed. Inflammatory cell counts have a lymphocytic predominance. Some patients present with normal CSF protein and glucose values [15]

Examination of the CSF with India ink demonstrates encapsulated yeast forms in approximately 75 percent of HIV-infected patients and in 50 percent of non-HIV-infected patients [16,17]. Gram stain is usually not sufficient since the organisms stain poorly and can be confused with host cells (picture 1A-C).

The diagnosis of cryptococcal meningoencephalitis is established by culturing the organism from the CSF. Cultures are positive in about 90 percent of non-AIDS patients. C. neoformans usually takes three to five days to grow in the laboratory. At least 3 to 5 mL of CSF should be used for culture; the yield may be increased by culturing more than 15 mL of CSF [16,18]

Cryptococcal antigen testing is a useful tool in the diagnosis of cryptococcal meningoencephalitis. Antigen testing can be collected in the CSF or the serum and can be quantified by evaluating serial dilutions.

The height of the antigen titer generally correlates with the burden of organisms. However, serial measurement of antigen titers is not a reliable indicator of response to therapy.

CSF cryptococcal antigen should be sent in addition to CSF culture when cryptococcal meningoencephalitis is suspected. Antigen test results are generally available soon after the lumbar puncture is performed and can help make the diagnosis before the culture results are complete.

The antigen test is very sensitive and specific in the CSF. In a study of five antigen tests (four latex agglutination assays and one enzyme-linked immunoassay), all had sensitivities ranging from 93 to 100 percent and specificities of 93 to 98 percent compared with culture [ 19].

False-positive CSF cryptococcal antigen results have been reported rarely following exposure of samples to disinfectants or soap or after samples were placed into an anaerobic transport vial [21-23].

If a lumbar puncture cannot be performed expediently, serum cryptococcal antigen testing can be helpful to support the diagnosis if positive. However, it cannot be reliably used to rule out cryptococcal meningoencephalitis in patients without HIV. Because patients without HIV tend to have a lower cryptococcal burden, the sensitivity of serum antigen testing is lower than in patients with HIV [24]

False-negative serum cryptococcal antigen tests can also occur with samples that contain a large amount of antigen (the prozone phenomenon) if the laboratory is using a latex agglutination assay and doesn't pretreat the sample with pronase [ 19].

Among organ transplant recipients, patients with CNS or disseminated cryptococcosis are more likely to have a positive serum cryptococcal antigen result than patients with limited pulmonary disease [ 14].

False-positive serum cryptococcal antigen tests can occur in the setting of infections due to the fungus Trichosporon asahii (formerly Trichosporon beigelii) or the bacterial genera Stomatococcus or Capnocytophaga [25-27].

A multiplex PCR assay has been found to be useful for the diagnosis of cryptococcal meningitis in patients with HIV infection (>90 percent sensitivity and specificity) [28]. However, with the lower burden of CSF yeasts in many patients without AIDS, this test may be less sensitive [29,30]

The diagnosis of cryptococcal meningoencephalitis is occasionally made by recovering C. neoformans from an extraneural site before CNS disease is suspected. This is especially true in patients with HIV infection who have a high likelihood of extraneural disease involving the respiratory tract, urinary tract, or bloodstream at the same time as CNS infection. As an example, blood cultures have been positive for cryptococci in approximately two-thirds of HIV-associated cases of meningoencephalitis [18].

Therefore, lumbar puncture should be considered for patients with positive serum cryptococcal antigen or extraneural culture to rule out CNS involvement. Immunocompetent individuals with only pulmonary involvement who have no CNS signs or symptoms may not require a lumbar puncture prior to treatment.

Radiographic imaging of the brain with computed tomography (CT) or magnetic resonance imaging (MRI) prior to lumbar puncture is important in the setting of focal neurologic signs, papilledema, or impaired mentation. MRI is more effective than CT for identifying CNS cryptococcal lesions [31]

Radiographic images frequently show no abnormality or cerebral atrophy without obstruction or other pathology [32]. Less commonly, hydrocephalus may be seen. Mass lesions are seen in about 10 percent of patients with CNS cryptococcal infections [9]. Acute and subacute cerebral infarcts have also been described [10,33]

Some brain lesions persist radiographically for long periods even in those who have had a good clinical response to therapy [32]. Lesions that develop surrounding edema during effective therapy are typically due to an immunologic response associated with control of infection, the so-called immune reconstitution inflammatory syndrome [33].

Patients with cryptococcal meningoencephalitis require a prolonged course of antifungal therapy (induction, consolidation, and maintenance phases) [1,2]. Additional therapeutic interventions include managing intracranial pressure, reducing immunosuppressive therapy, and controlling immune reconstitution inflammatory syndromes (IRIS)

Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated disease (eg, involvement of at least two noncontiguous sites or cryptococcal antigen titer ≥1:512) should be treated with the same antifungal regimens as those used to treat central nervous system disease, even in the setting of normal findings on cerebrospinal fluid examination

Induction antifungal therapy — The preferred antifungal regimen for induction therapy is the same for organ transplant and nonorgan transplant patients. Data on the use of antifungal regimens for HIV-uninfected hosts are largely extrapolated from larger studies of patients with HIV infection.

Preferred regimen — For nonpregnant adults, we suggest that induction therapy consist of a lipid formulation of amphotericin B plus flucytosine:

● Either liposomal amphotericin B (3 to 4 mg/kg intravenously [IV] per day) or amphotericin B lipid complex (5 mg/kg IV per day) can be used.

● Flucytosine should be administered as 100 mg/kg/day orally in four divided doses (adjusted for renal function). (See "Pharmacology of flucytosine (5-FC)", section on 'Dosing'.)

This regimen should be administered for at least two weeks. However, for some patients the duration should be extended for four to six weeks.

Lipid formulations of amphotericin B, rather than amphotericin B deoxycholate, are preferred as first-line therapy in organ transplant recipients due to the frequency of reduced renal function in such patients (approximately 25 percent have creatinine >2 mg/dL) and the risk of nephrotoxicity associated with concurrent use of amphotericin B deoxycholate and calcineurin inhibitors.

There are fewer data regarding the use of lipid formulations of amphotericin B preparations in nontransplant patients. The 2010 Infectious Disease Society of America (IDSA) guidelines suggest that induction therapy for HIV-uninfected, nontransplant hosts with cryptococcal meningoencephalitis consists of amphotericin B deoxycholate (0.7 to 1 mg/kg IV daily) plus flucytosine (100 mg/kg/day orally in four divided doses). However, lipid formulations of amphotericin B with flucytosine have become the favored induction regimen for such patients in resource-available health care systems to minimize the risk of toxicity and reduce treatment interruptions, since it is critically important to complete an uninterrupted induction regimen to optimize clinical outcomes [5].

Flucytosine is used as an adjunct to amphotericin B for the first two weeks of therapy because the combination of agents provides greater early fungicidal activity than amphotericin B alone [6-9]. The absence of flucytosine is associated with lack of cerebrospinal fluid (CSF) sterilization at week two and treatment failure [10,11]. Combination therapy with amphotericin B plus flucytosine also results in lower mortality compared with amphotericin B monotherapy or combination therapy with amphotericin B plus fluconazole [8,9]

Duration of preferred regimen — The minimum duration of induction therapy with amphotericin B and flucytosine is two weeks. However, the ultimate duration depends upon the presence of serious neurologic complications (eg, persistent headaches, seizures, ocular and auditory manifestations), radiographic evidence of brain parenchymal involvement (eg, cryptococcomas), the patient's underlying condition, and the response to therapy.

For immunocompromised hosts without neurologic complications or parenchymal involvement, a repeat lumbar puncture (LP) is typically performed after two weeks of induction therapy, and the response to therapy is assessed by the presence or absence of fungal growth [8,12]. Serial evaluation of CSF or serum cryptococcal antigen (CrAg) is not appropriate for evaluating response to therapy as CrAg does not correlate with CSF sterilization at two weeks or outcome at 180 days [2,13,14]

However, it can take several weeks for culture results to be finalized, and this delay makes decision-making difficult when determining the ultimate duration of treatment. Thus, we use certain prognostic factors to dictate the treatment approach while awaiting culture results.

• We transition patients to consolidation therapy pending the results of the two-week CSF cultures if the cultures are anticipated to be negative based upon a clear clinical response to treatment and favorable baseline CSF studies, such as a low starting fungal burden by quantitative CSF yeast counts (eg, <5 log10 colony-forming units [CFU]/mL) and/or CrAg titer (≤1:160) [1].

This approach has generally been used for organ transplant recipients. In a small prospective study of CNS cryptococcosis in transplant patients, the median time to CSF sterilization was 10 days (mean, 16 days) [14]. Guidelines have typically favored a four-week induction course for all HIV-uninfected, nonorgan transplant recipients, since they tend to have a worse clinical outcome [1,15,16] (see 'Prognosis' below); however, we feel a two-week induction course is reasonable for such patients who have had a rapid response.

• For all others, we continue the induction regimen pending the results of the cultures. If the cultures are negative at two weeks, the patient can then be transitioned to consolidation therapy. Although laboratories often keep cultures for three to four weeks to detect fungal growth, most persistently positive cryptococcal cultures grow within two weeks in patients who are on therapy

Patients whose CSF cultures return positive should reinitiate (or continue) the induction regimen with serial lumbar punctures every two weeks until the CSF becomes sterile

However, certain immunocompetent hosts may transition to consolidation therapy without a repeat LP at two weeks. Such patients include those who were without severe symptoms at baseline, were diagnosed early, did not develop new symptoms, and demonstrated a clear clinical response after two weeks of combination antifungal therapy. In this setting, it is reasonable to administer a two-week induction course, and then transition to consolidation therapy with fluconazole at a high dose (800 mg [12 mg/kg] per day orally) for eight weeks [1].

Patients with neurologic complications — For HIV-uninfected individuals who have or develop neurologic complications on treatment, induction therapy should be extended for at least six weeks (or four weeks after the culture is negative) [18]

If flucytosine is not available or tolerated, we typically administer amphotericin B with fluconazole (800 mg [12 mg/kg] per day orally) for two weeks of induction therapy.

Other options include extending the duration of amphotericin B so that patients receive at least four to six weeks of induction therapy [1], or, in cases with a high fungal burden of disease (or relapse), administering higher doses of liposomal amphotericin B (6 mg/kg/day). However, these alternative approaches are not ideal.

In addition, a randomized controlled trial that compared doses of 3 mg/kg and 6 mg/kg of liposomal amphotericin B in patients with AIDS found that the higher dose was safe, but not more efficacious than the lower dose [ 19]

If lipid formulations of amphotericin B are not available, amphotericin B deoxycholate (0.7 mg/kg/day) should be used. This agent is known to be effective for the treatment of cryptococcal disease and is generally well tolerated for two weeks when administered with adjunctive saline infusions [6,7,20]

If no amphotericin B formulations are tolerated or available, fluconazole (800 to 1200 mg orally per day) plus flucytosine (100 mg/kg orally per day in four divided doses) can be administered for the two-week induction period. This regimen can also be continued until two-week CSF culture returns negative and/or up to 10 weeks in severe cases [1,21-23]. Liver function tests should be monitored closely when this combination is used.

If flucytosine cannot be given, higher doses of fluconazole (eg, 1200 mg orally per day in patients with normal renal function) can be administered for at least 10 weeks or until CSF culture results are negative, followed by maintenance therapy with fluconazole (200 to 400 mg orally daily). However, fluconazole monotherapy for induction therapy is generally not recommended.

Following induction therapy, consolidation therapy with fluconazole (400 to 800 mg [6 to 12 mg/kg] orally daily) should be administered for eight weeks.

Although the 400 mg dose of fluconazole can be used as consolidation therapy for many patients, we prefer the 800 mg dose for those non-organ transplant patients who were deemed to be at low risk for therapeutic failure as described above, and who received only two weeks of induction therapy.

Consolidation therapy should then be followed by maintenance therapy with fluconazole (200 to 400 mg orally daily) [1]. Maintenance azole therapy is generally given for one year after diagnosis. Longer therapy may be warranted for those receiving very high doses of immunosuppressive agents (eg, those receiving >40 mg/day of prednisone or persistently using biologic modifiers such as alemtuzumab); for such patients, the duration of maintenance therapy is determined on a case-by-case basis. Maintenance therapy may also need to be extended for those who have radiographic evidence of cryptococcomas.

Prior to the use of fluconazole for maintenance therapy, the rate of relapse of cryptococcal meningoencephalitis in HIV-uninfected patients ranged from 15 to 25 percent; most relapses occur within six months [18]. The use of consolidation and maintenance therapy has been associated with a very low relapse rate. As an example, in a prospective study of 79 solid organ transplant recipients in whom maintenance therapy was employed for a median of 183 days, the risk of relapse was 1.3 percent [14]

For pregnant women, it is reasonable to administer induction therapy for four weeks. Antifungal treatment should be continued throughout pregnancy. Immunologic alterations associated with pregnancy may increase the severity of cryptococcosis in pregnant women, and the mortality rate can approach 25 percent [24]. In addition, immune reconstitution inflammatory syndrome (IRIS) can occur in the postpartum period [25,26]. Indeed, nearly half of the cryptococcal cases reported in pregnancy presented with symptomatic disease in the third trimester or postpartum period [24]

The specific regimen should be tailored to the stage of pregnancy.

● Initial treatment of pregnant women with CNS or disseminated disease consists of amphotericin B deoxycholate (0.7 to 1.0 mg/kg IV daily) or a lipid formulation of amphotericin B (liposomal amphotericin B [3 to 4 mg/kg IV daily] or amphotericin B lipid complex [5 mg/kg IV daily]) [1].

Flucytosine should not be used during the first trimester of pregnancy. If the patient presents during the second or third trimester, the use of flucytosine should be determined on a case-by-case basis.

For consolidation therapy, it is appropriate to administer fluconazole during the second and third trimesters to ensure continuous antifungal therapy. However, fluconazole should be avoided during the first trimester since it has been associated with birth defects [30,31].

Treatment of children with CNS or disseminated disease consists of amphotericin B deoxycholate (1.0 mg/kg IV daily) plus flucytosine (100 mg/kg orally per day in four divided doses) for two weeks, followed by fluconazole (10 to 12 mg/kg orally per day) for eight weeks [1].

Cerebral cryptococcomas can cause significant morbidity, are difficult to treat, and require prolonged antifungal therapy [39,40]. They are more common in the setting of Cryptococcus gattii infection than C. neoformans infection [39,41,42]. The management of cryptococcomas associated with C. gattii infection is discussed separately. (See "Cryptococcus gattii infection: Treatment", section on 'Cerebral cryptococcomas'.)

Antifungal therapy – Induction therapy for cerebral cryptococcomas should consist of a lipid formulation of amphotericin B (liposomal amphotericin B [3 to 4 mg/kg IV daily] or amphotericin B lipid complex [5 mg/kg IV daily]) plus flucytosine (100 mg/kg per day orally in four divided doses) for at least six weeks [1]. Consolidation and maintenance therapy for cerebral cryptococcoma consists of fluconazole (400 to 800 mg orally daily) for 18 months

Adjunctive therapies – Glucocorticoids may be administered in the setting of mass effect and surrounding edema, especially if there are neurologic deficits. If glucocorticoids are used, the doses should be tapered gradually to prevent "a rebound" IRIS.

Surgical removal (open or stereotactic guided) may be necessary for large (≥3 cm) lesions and lesions with mass effect with substantial surrounding edema. Surgery may also be needed in the setting of optic nerve involvement and in cases unresponsive to prolonged or repeated induction antifungal therapy [40,45,46]

Amphotericin B – Although the lipid formulations of amphotericin B are less toxic than conventional amphotericin B, monitoring for toxicity should mirror that used for amphotericin B deoxycholate, with daily monitoring of blood counts and chemistries. In patients who develop renal dysfunction despite appropriate hydration, transitioning off or interrupting polyene therapy becomes a bedside decision. In general, the risks and benefits of switching to an alternative regimen should be considered when creatinine levels rise above 3 mg/dL in a patient with initial normal kidney function

Flucytosine – Careful attention to serum flucytosine (5-FC) levels is also warranted to avoid bone marrow toxicity, particularly in patients with renal dysfunction. Measurement of serum 5-FC concentrations is recommended, when available, after three to five doses, and should be obtained two hours after a dose has been administered [1]. Guidelines for the treatment of cryptococcal infections recommend peak concentrations between 30 and 80 mcg/mL; concentrations >100 mcg/mL should be avoided [1]. Serum drug concentrations should be repeated if renal function worsens, or if leukopenia or thrombocytopenia occur.

All patients receiving 5-FC should undergo regular monitoring of complete blood counts (CBC). In settings in which serum 5-FC concentrations are not available, CBC monitoring two to three times per week provides an indirect method of screening for excessive dosing. An otherwise unexplained reduction in the neutrophil or platelet count may reflect 5-FC toxicity, and either the drug should be stopped or the dose reduced

Control of intracranial pressure is one of the most critical determinants of outcome for cryptococcal meningoencephalitis [18,48]. The intracranial pressure should be measured at the time of initial lumbar puncture. If the pressure is ≥25 cm of cerebrospinal fluid (CSF) and there are symptoms of increased intracranial pressure during induction therapy, CSF drainage should be performed to reduce the pressure by 50 percent (if extremely high) or to a normal pressure of ≤20 cm [1]

Therapeutic lumbar drainage should be repeated daily in the setting of clinical symptoms and persistent pressure elevations ≥25 cm of CSF until stabilized for >2 days

Mannitol and acetazolamide are not appropriate agents for control of elevated intracranial pressure in the setting of cryptococcal meningoencephalitis [52]. In addition, there is no benefit of administering glucocorticoids, except in the setting of an immune reconstitution inflammatory syndrome (IRIS) [48].

This approach to managing increased intracranial pressure is extrapolated from literature describing HIV patients with cryptococcal meningoencephalitis. Among 55 patients with CSF pressure >35 cm, increased incidence of papilledema (29 percent) and impaired mentation (18 percent) were observed [48]. Among 12 patients who died in the first two weeks of therapy, 91 percent had baseline intracranial pressure ≥25 cm. Among the 161 patients treated by CSF lumbar drainage to reduce the pressure, there were fewer cases of clinical failure and patients reported relief of severe headache; recurrence of elevated pressure was associated with worsening symptoms

Reducing immunosuppressive therapy may be beneficial for control of cryptococcal infection. As an example, tyrosine kinase inhibitors, such as ibrutinib, should be stopped until infection is shown to be controlled.

The optimal approach to management of the immunosuppressive regimen in organ transplant recipients with cryptococcosis is uncertain. Reducing immunosuppressants over time in a step-wise fashion following initiation of antifungal therapy is appropriate [54]. It may be helpful to reduce corticosteroids before calcineurin inhibitors, since the latter class has direct anticryptococcal activity in vitro [55,56]

For patients with persistent or worsening symptoms, distinguishing between persistent or relapsed cryptococcal infection, immune reconstitution inflammatory syndrome (IRIS), and other infections or complications can be difficult [54,57].

Clinical manifestations, inflammatory cerebrospinal fluid (CSF) values, positive India ink exams, and positive cryptococcal antigen titer may be present in both IRIS and cryptococcal infection. The most important distinguishing feature is that patients with active infection have positive CSF cultures, whereas patients with IRIS have sterile CSF cultures.

In a study where polymerase chain reaction (PCR) testing using a Biofire Film Array Meningitis/Encephalitis Panel was performed on eight HIV-infected individuals with symptomatic recurrence of cryptococcal meningitis, a positive PCR was associated with relapse/persistence while a negative PCR was associated with no growth, suggesting that the symptoms might be an IRIS [ 58].

Persistent infection refers to persistently positive CSF cultures after four weeks of appropriate antifungal therapy. Relapse of infection refers to resolution of infection followed by subsequent recurrence as demonstrated by both recovery of viable cryptococci from a sterile site and recrudescence of signs and symptoms at a previous site of disease. Most cases are attributable to inadequate primary therapy (dose and/or duration) or insufficient adherence to consolidation or maintenance fluconazole therapy

Risk factors for relapse include [59]:

● Low initial CSF white blood cell counts

● Persistently low CSF glucose concentration after four weeks of therapy

● Treatment with prednisone (≥20 mg) or equivalent that continues after completion of antifungal therapy

Initial management of persistent or relapsed infection should include evaluation of immunosuppressive therapy and management of increased intracranial pressure. (See 'Control of intracranial pressure' above and 'Modulating immunosuppression' above.)

Repeat induction phase therapy should be reinstituted for a longer course (4 to 10 weeks) and a repeat lumbar puncture should be performed after two weeks of therapy. The amphotericin B dose may also be increased; liposomal amphotericin B has been used at 6 mg/kg intravenously (IV) daily for treating cryptococcal meningitis [19]; for amphotericin B deoxycholate, the upper limit of the dosing range is 1 mg/kg IV daily.

The fungal isolates of patients who relapsed should be evaluated for changes in the minimum inhibitory concentration (MIC) from the original isolate; a ≥3-dilution difference suggests development of drug resistance. A fluconazole MIC of ≥16 mcg/mL or a flucytosine MIC of ≥32 mcg/mL has typically been considered resistant and alternative agents should be considered [60]. However, there are no validated MIC breakpoints for drug susceptibility in cryptococcosis, and on a practical basis, only isolates with extremely high MICs for fluconazole and flucytosine (ie, ≥64 mcg/mL) should probably be considered resistant

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If the organism is not responding to fluconazole but has a low MIC to voriconazole (≤1 mcg/mL), then voriconazole can be administered (loading doses of 6 mg/kg IV twice daily or 400 mg orally twice daily on the first day, then 200 to 300 mg orally twice daily for 10 to 12 weeks). Posaconazole (loading dose of 300 mg orally twice daily on the first day, followed by 300 mg orally once daily thereafter) is an alternative but achieves poor levels in the CSF. Isavuconazole (200 mg three times daily for two days followed by 200 mg once daily) has also been reported to have antifungal activity in patients with cryptococcosis but achieves minimal levels in the CSF [61]

The use of interferon-gamma as adjunctive therapy during primary (not salvage) treatment has been evaluated; its efficacy was encouraging but not definitive [64,65]. It may be a reasonable consideration for use in true refractory cases with persistent positive cultures

Onset of IRIS in solid organ transplant recipients has been described as a mean of six weeks after initiation of antifungal therapy [53]. Manifestations may include fever, lymphadenitis, and signs and symptoms of meningitis. Acute respiratory distress syndrome can also be a manifestation of IRIS in immunocompromised individuals.

The most important distinguishing feature is that patients with active infection have positive CSF cultures, whereas patients with IRIS have sterile CSF cultures. Some studies suggest that PCR positivity in CSF may help predict positive cultures [58]

Patients with IRIS should continue antifungal therapy. Those with minor manifestations can be managed with supportive care; symptoms frequently resolve spontaneously in days to weeks

There are limited data to suggest a specific dosing regimen. Some providers administer dexamethasone, starting at a dose of approximately 0.3 mg/kg/day IV (20 to 24 mg IV for most normal and overweight patients) during week 1, and then tapering the dose over the course of six weeks (eg, 0.2 mg/kg/day IV during week 2; followed by oral administration of 0.1 mg/kg/day during week 3; 3 mg/day during week 4; 2 mg/day during week 5; and 1 mg/day during week 6) [66]. However, other clinicians empirically use prednisone, starting at approximately 1 mg/kg/day (60 to 80 mg/day for most normal and overweight patients) and then tapering over four to six weeks

IRIS occurs most commonly in HIV-infected patients with initiation of antiretroviral therapy, although it has also been described in solid organ transplant recipients [41,53,67-69].

In one study of 89 solid organ transplant recipients with cryptococcosis, 14 percent developed signs and symptoms suggestive of IRIS [ 69]. CNS disease and discontinuation of a calcineurin inhibitor were independently associated with IRIS. Among patients with CNS disease, those with neuroimaging abnormalities were more likely to develop IRIS.

In patients with no obvious underlying immune deficiencies, worsening of symptoms can also occur, despite mycologic control of the infection [41,70,71]. Investigators have labelled this aggravated immune response "post-infectious inflammatory response syndrome" (PIIRS) [72]. Patients with PIIRS respond to systemic courses of steroids just as patients with IRIS do

The most important prognostic factors are the nature of the underlying immunosuppression and/or the concurrent disease. As an example, relapse rates among solid organ transplant recipients are very low [14]; in contrast, the mortality rate in those with cirrhosis is extremely high [71].

The prognosis among patients with malignancy and liver disease is also worse than those with immunosuppression due to glucocorticoid therapy [17] or anti-granulocyte-macrophage colony stimulating factor (GM-CSF) auto-antibodies [75]

Other factors conferring poor prognosis include: positive India ink examination of the cerebrospinal fluid (CSF); CSF white blood cell count <20/microL; initial CSF or serum cryptococcal antigen titer >1:32; and/or high opening pressure on lumbar puncture [ 59].

The major causes of community-acquired bacterial meningitis in adults in developed countries are Streptococcus pneumoniae, Neisseria meningitidis, and, primarily in patients over age 50 years or those who have deficiencies in cell-mediated immunity, Listeria monocytogenes.

The major causes of health care-associated bacterial meningitis are staphylococci and aerobic gram-negative bacilli

Patients with bacterial meningitis are usually quite ill and often present soon after symptom onset

The classic triad of acute bacterial meningitis consists of fever, nuchal rigidity, and a change in mental status, usually of sudden onset. However, an appreciable number of patients do not have all three features

Initial blood tests should include a complete blood count with differential and platelet count and two aerobic blood cultures of appropriate volume (ideally, prior to the initiation of antimicrobial therapy). Serum electrolytes and glucose, blood urea nitrogen, and creatinine concentrations are helpful in determining the cerebrospinal fluid- (CSF) to-blood glucose ratio.

Coagulation studies may be indicated, especially if petechiae or purpuric lesions are noted.

Blood cultures are often positive and can be useful in the event that CSF cannot be obtained before the administration of antimicrobials. Approximately 50 to 90 percent of patients with bacterial meningitis have positive blood cultures.

Every patient with suspected meningitis should have CSF obtained unless a lumbar puncture (LP) is contraindicated. A CT scan is sometimes performed before LP to exclude a mass lesion or increased intracranial pressure, which rarely leads to cerebral herniation during subsequent CSF removal. However, a screening CT scan is not necessary in the majority of patients.

A CT scan of the head before LP should be performed in adult patients with suspected bacterial meningitis who have one or more of the following risk factors (see 'Indications for CT scan before LP' above):

• Immunocompromised state (eg, HIV infection, immunosuppressive therapy, solid organ or hematopoietic stem cell transplantation)

• History of central nervous system (CNS) disease (mass lesion, stroke, or focal infection)

• New onset seizure (within one week of presentation)

• Papilledema

• Abnormal level of consciousness

• Focal neurologic deficit

If LP is delayed or deferred, blood cultures should be obtained and antimicrobial therapy should be administered empirically before the imaging study, followed as soon as possible by the LP. In addition, dexamethasone (0.15 mg/kg intravenously every six hours) should be given shortly before or at the same time as the antimicrobial agents if the preponderance of clinical and laboratory evidence suggests bacterial meningitis with a plan to stop therapy, if indicated, when the evaluation is complete.

Adjunctive dexamethasone should not be given to patients who have already received antimicrobial therapy because it is unlikely to improve patient outcome.

The usual CSF findings in patients with bacterial meningitis are a white blood cell (WBC) count of 1000 to 5000/microL (range of <100 to >10,000) with a percentage of neutrophils usually greater than 80 percent, protein of 100 to 500 mg/dL (1000 to 5000 mg/L), and glucose <40 mg/dL (2.22 mm/L; with a CSF:serum glucose ratio of ≤0.4). Despite these typical CSF findings, the spectrum of CSF values in bacterial meningitis is so wide that the absence of one of more of the typical findings is of little value (table 4).

Acute bacterial meningitis should be suspected in adults who present with fever and signs of meningeal inflammation. Isolation of a bacterial pathogen from the CSF (by culture or other diagnostic techniques) confirms the diagnosis of bacterial meningitis. Isolation of bacteria from blood cultures in a patient with CSF pleocytosis also confirms the diagnosis, even if the CSF culture remains negative.

The clinical and laboratory findings of bacterial meningitis overlap with those of meningitis caused by viruses, mycobacteria, fungi, or protozoa. Differentiation of these disorders from bacterial meningitis requires careful examination of CSF parameters (table 4), neuroimaging (when indicated), as well as consideration of any epidemiologic factors that would raise the possibility of specific bacterial or nonbacterial CNS infections