The mortality rate and recurrence rate of novel cryptococcal meningitis are high, and antifungal drugs are not only toxic, but also prone to failure. With the combination of antifungal drugs and staged treatment, combined with local treatment and immunotherapy, the success rate of treatment has been improved, and the occurrence of adverse drug reactions and sequelae has been reduced. The progress of treatment is now reviewed. 1.Antifungal treatment (1) Combination application of antifungal drugs Combination of drugs can produce synergistic effects to improve the efficacy, reduce the generation of drug-resistant strains, reduce the role of drug side effects, thereby shortening the treatment time and reducing sequelae. The combination of dicloxacillin B and 5-fluorocytosine is the most studied and accepted treatment option. Most immunocompetent patients can be cured within 6 weeks with this combination. It has been shown that patients who received this regimen within 2 weeks of disease onset had a significantly lower recurrence rate at one year than those treated with dicitomycin B alone. The combination of disulfiramycin B (0.7-1 mg/kg daily) and 5-flucytosine (100 mg/kg daily) was more effective than disulfiramycin B alone (P = 0.006), disulfiramycin B plus fluconazole (P = 0.02) or the combination of all three drugs (P = 0.02), with the fastest cerebrospinal fluid regression. In contrast, the combination of fluconazole and 5-fluorocytosine was not effective in treating the first patient, so it was only used as an alternative treatment to diphenomycin B. (2) Phased treatment of antifungal drugs Acute phase: It can be divided into induction phase and consolidation phase. The classical treatment for cryptococcal meningitis without human immunodeficiency virus (H IV) infection is: diphenomycin B (0.7 mg/kg daily), plus 5-fluorocytosine (1,000 mg/kg daily), after 2 weeks of induction treatment, followed by fluconazole (4,000 mg daily), which is maintained for at least 10 weeks. The consolidation period should be maintained for at least 10 weeks. After 2 weeks of induction therapy, a lumbar puncture should be performed to check whether the cryptococci have been killed in the cerebrospinal fluid. If the cerebrospinal fluid culture is not negative after 2 weeks, the induction period should be extended, and then the treatment should be continued with fluconazole for 6 to 12 weeks. For patients who cannot tolerate fluconazole, itraconazole (20 mg twice daily) may be substituted. In immunocompromised patients, the above treatment is still ineffective in 15% to 20% of cases, so the duration of treatment should be prolonged by using diphenhydramine B (0.7-1 mg/kg daily) plus 5-fluorocytosine (1,000 mg/kg daily) for 6-10 weeks during the induction period and fluconazole (4,000-8,000 mg daily) for at least 8-10 weeks during the consolidation period. In patients with A IDS-associated cryptococcal meningitis, the immune function is severely suppressed, and in the acute phase, dicloxacillin B (0.7-1 mg/kg/day) can be given in combination with 5-fluorocytosine (1,000 mg/kg/day in 4 oral doses) for 2 weeks or more, or dicloxacillin B (0.7-1 mg/kg/day) alone if 5-fluorocytosine is not tolerated. After 2 weeks of successful induction therapy, fluconazole (40 mg orally once daily) is administered for 8 weeks or until cerebrospinal fluid cultures are free of cryptococci. The combination of fluconazole (4,000-8,000 mg/day) and 5-fluorocytosine (1,000 mg/kg/day in four oral doses) has been shown to be effective in the treatment of A IDS-associated cryptococcal meningitis, but it is only used as an alternative to diphenhydramine B because of its toxic side effects. In patients with severe renal impairment or multiple organ dysfunction, the induction phase can be treated with liposomal diphenomycin B instead of regular diphenomycin B, regardless of their immune function. The liposomes are 70 times less toxic than Dictyomycin B, which makes them more tolerable and can be used in patients with severe fungal infections with multiple organ dysfunction. In a randomized study, liposomal disulfiramycin B (4 mg/kg daily) cleared the fungus in 73% of patients with cryptococcal meningitis, and the cerebrospinal fluid was negative in 7-14 d. Regular disulfiramycin B cleared the fungus in only 38% of patients, and the cerebrospinal fluid was negative in 21 d. Maintenance Cryptococcal meningitis without H IV infection Non-H IV infected patients are treated with fluconazole (200 mg daily) for 6-12 months, regardless of immune function. Diphenomycin B can also be used for maintenance treatment by injection of Diphenomycin B (1 mg/kg daily, 1 to 3 times a week). Because of its toxic effects and the complexity of its administration, it should only be used in patients who are receiving fluconazole but have recurrent attacks or those who cannot tolerate fluconazole. IDS combined with cryptococcal meningitis A IDS-associated cryptococcal meningitis has a recurrence rate of 50% to 60% with initial treatment, and most authors advocate lifelong maintenance therapy. Fluconazole (200 mg orally once daily) at the end of the consolidation period is the most effective maintenance therapy for A IDS with cryptococcal meningitis. If fluconazole is not tolerated, itraconazole (200 mg orally twice daily) can be used. In a randomized controlled study, the cerebrospinal fluid relapse rate was 4% in patients treated with maintenance fluconazole (200 mg daily) and 24% in those treated with itraconazole. Patients who did not receive maintenance therapy and antiretroviral therapy had a relapse rate of 37% to 60%. For AIDS patients, the underlying cause of opportunistic infections such as Cryptococcus neoformans is the continuous replication and proliferation of H IV, resulting in a low immune function. Therefore, along with active antifungal therapy, highly active antiretroviral therapy (HAART) should be given to control H IV replication and prevent the recurrence of Cryptococcal meningitis. It has been shown that patients who respond well to HAART can stop prophylactic antifungal therapy 12 to 18 months after successful suppression of H IV replication. If the CD4 cell count is >100 cells/L, prophylactic therapy can be discontinued. However, after discontinuation of prophylactic therapy, the patient should be closely monitored and laboratory tests should be performed. If the CD4 cell count suddenly decreases or the number of viruses increases and the antigen agglutination test is positive, fluconazole should be reintroduced. Although discontinuation of prophylactic therapy can reduce drug interactions and decrease the patient’s medication burden, it is only suitable for patients on HAART for a long time. 2, immunotherapy Studies have shown that immune function is closely related to deep fungal infections, and antifungal agents alone are sometimes ineffective, with poor results and high recurrence rates. Therefore, in recent years, people proposed antifungal drugs combined with immunotherapy. It has been proved that the combination of gamma-interferon and diclofenac B is more effective than single antifungal agent in the treatment of Cryptococcosis infection. The results of animal experiments and preliminary clinical trials showed that the combination of anti-cryptococcal monoclonal antibodies could rapidly clear cryptococcal polysaccharide antigens in blood and significantly reduce brain edema and mortality. The new cryptococcal monoclonal antibodies and fungal vaccines have been successful in experimental animal models with low cellular and humoral immune function, and the immunized animals have gained temporary or permanent cellular immune function, which has laid a solid foundation for further immunization of immunodeficient patients. 3, local treatment (1) intrathecal injection Indications: intrathecal injection is only recommended abroad as a remedial measure for refractory patients who have failed systemic antifungal therapy; in China, it is used to treat patients who cannot reach the effective dose with early systemic medication or cannot tolerate high dose of intravenous dicitomycin B (0. 7 mg/kg daily), and those who have adverse reactions to intravenous medication or whose infection is still severe. Intrathecal injection of dicitomycin B can be used in patients who cannot tolerate large doses of intravenous dicitomycin B (0.7 mg/kg/day) or who have adverse reactions to intravenous administration or whose infection is still severe. The initial dose of intrathecal dicitomycin B is 0.05-0.1 mg, and then the dose is increased by 0.1-0.2 mg, and the highest dose is 1 mg. 2-2.5 mg of dexamethasone is added to each intrathecal injection, and the intrathecal injection can be given once a day at the beginning, and then changed to once every other day or twice a week after 3-5 times, and the total amount is 15-20 mg. It has also been reported that intrathecal injection of dicitomycin B can be discontinued until the cerebrospinal fluid smear and culture turn negative or the titer of cryptococcal antigen decreases significantly to below 1:1 6 or negative. The highest total dosage of dicentrin B was 4 8. 8 2 mg, and the average dosage was 28. 21 mg. Efficacy: The data showed that dicentrin B intravenous drip with intrathecal injection can shorten the treatment cycle significantly, and the efficacy is remarkable, even in the case of high cranial pressure, intrathecal injection can still be used, and the cure rate and efficacy are significantly better than the non-intrathecal injection group. The reason is that intrathecal injection can rapidly increase the concentration of dicentrin B in the central nervous system, which can rapidly reduce the number of cryptococci in the CSF, reduce the fungal reactive cranial hypertension crisis, and gain time for treatment, which can reduce the total amount of dicentrin B drip, improve the success rate of rescue and treatment, and reduce the occurrence of toxic effects and adverse reactions and sequelae. (2) Lateral ventricular drainage and intracerebroventricular injection Indications ①Patients with severe cryptococcal meningitis who are not treated with intravenous drip alone or who have relapsed should be promptly treated with lateral ventricular drainage and intracerebroventricular injection. ②If the cerebrospinal fluid pressure continues to rise, and mannitol cannot lower the intracranial pressure satisfactorily, and there is ventricular dilatation, ventricular drainage should be performed promptly; however, ventricular size is not a contraindication to ventricular drainage. (3) Severe visual impairment and hydrocephalus. The total duration of treatment (66 d) was significantly shorter than that of patients without ventricular drainage (101 d), and all four patients who received intraventricular injection were cured and none of them had recurrence. The incidence of cranial hypertension in patients with cryptococcal meningitis exceeds 50%, with the highest mortality rate within 2-4 weeks of diagnosis, which is closely related to the significant increase in cranial hypertension. Aggressive management of cranial hypertension may reduce mortality in this group of patients. Internal treatment such as corticosteroids, acetazolamide and mannitol are ineffective in cryptococcal meningitis, mainly by intermittent release of cerebrospinal fluid through lumbar puncture, lumbar catheter drainage, lateral ventricular drainage or closed ventriculoperitoneal shunt. (1) Lumbar puncture for release of cerebrospinal fluid For patients with intracranial pressure > 2. 4 kPa, the most common method is regular lumbar puncture for release of cerebrospinal fluid, which should be done daily at first to maintain the intracranial pressure in the normal range. At most, 1 0-3 0 ml of cerebrospinal fluid can be slowly drained daily, and lumbar puncture can be stopped when the cerebral pressure is normal for several days. Imaging should be performed prior to lumbar puncture to exclude intracranial occupying lesions. If long-term cerebrospinal fluid discharge is required, closed ventriculothoracic shunt can be considered. (2) Lumbar catheter drainage is an important method to reduce intracranial hypertension. For patients with intracranial pressure > 3. 9kPa and frequent lumbar puncture cannot effectively control the symptoms of cranial hypertension, lumbar catheter drainage is needed. Lumbar catheter drainage should remove enough cerebrospinal fluid to reduce the open cerebral pressure by 50%. Lumbar catheter drainage with prolonged access to the outside world can easily be combined with bacterial infection, so the patient needs to be admitted to the intensive care unit when the lumbar catheter is drained. (3) Lateral ventricular drainage If the cerebrospinal fluid pressure continues to rise, and the above measures cannot satisfactorily reduce intracranial pressure, and there is ventricular enlargement, ventricular drainage should be performed promptly; ventricular size is not a contraindication to ventricular drainage. The above three measures can lower the cranial pressure, and can also be performed simultaneously with intrathecal or intracerebroventricular injection therapy. (4) Ventriculo-abdominal shunt For those neurological defects with unsatisfactory control of cranial hypertension, recurrent brain herniation or persistent or progressive aggravation, ventriculo-abdominal shunt should be considered. Ventriculoperitoneal shunts are also prone to bacterial infection, but this complication is uncommon, and with antifungal therapy, shunts are usually not associated with Cryptococcus neoformans infection. A number of factors can affect the outcome and prognosis of novel cryptococcal meningitis, including ① rapid disease progression; ② late diagnosis and treatment; ③ low host immune function; ④ severe involvement of the central nervous system; ⑤ significant increase in intracranial pressure; ⑥ persistent low sugar content in the cerebrospinal fluid, white blood cell count < 20×1 06 /L and positive cryptococcal antigen in the CSF. High titers were positive. With the improvement of treatment methods, the efficacy of new cryptococcal meningitis has been gradually improved.