Fungal meningitis medical therapy: Difference between revisions

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{{CMG}}; '''Assistant Editor(s)-in-Chief:''' [[User:Rim Halaby|Rim Halaby]]
{{CMG}}; '''Assistant Editor(s)-in-Chief:''' [[User:Rim Halaby|Rim Halaby]]
==Overview==
==Overview==
Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of high dose [[Antifungal drug|antifungals]]. In addition, frequent lumbar punctures are recommended in order to relieve the increased intracranial pressure<ref name="pmid15838017">{{cite journal| author=Bicanic T, Harrison TS| title=Cryptococcal meningitis. | journal=Br Med Bull | year= 2004 | volume= 72 | issue=  | pages= 99-118 | pmid=15838017 | doi=10.1093/bmb/ldh043 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15838017  }} </ref>.
Fungal meningitis, such as [[Cryptococcal Meningitis|cryptococcal meningitis]], is treated with long courses of high dose [[Antifungal drug|antifungals]]. In addition, frequent lumbar punctures are recommended in order to relieve the increased intracranial pressure<ref name="pmid15838017">{{cite journal| author=Bicanic T, Harrison TS| title=Cryptococcal meningitis. | journal=Br Med Bull | year= 2004 | volume= 72 | issue=  | pages= 99-118 | pmid=15838017 | doi=10.1093/bmb/ldh043 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15838017  }} </ref>.


==Medical Therapy==
==Medical Therapy==
*The treatment of fungal meningitis, such as cryptococcal meningitis, is a long course of high dose [[Antifungal drug|antifungals]]. The most commonly administered [[Antifungal drug|antifungals]] are [[amphotericin B]] and [[flucytosine]]<ref>{{cite journal |author=Gottfredsson M, Perfect JR |title=Fungal meningitis |journal=Seminars in Neurology |volume=20 |issue=3 |pages=307–22 |year=2000 |pmid=11051295| doi = 10.1055/s-2000-9394}}</ref>. Other [[Antifungal drug|antifungals]] that can be used are miconazole and fluconazole.
*The treatment of fungal meningitis, such as [[Cryptococcal Meningitis|cryptococcal meningitis]], is a long course of high dose [[Antifungal drug|antifungals]]. The most commonly administered [[Antifungal drug|antifungals]] are [[amphotericin B]] and [[flucytosine]]<ref>{{cite journal |author=Gottfredsson M, Perfect JR |title=Fungal meningitis |journal=Seminars in Neurology |volume=20 |issue=3 |pages=307–22 |year=2000 |pmid=11051295| doi = 10.1055/s-2000-9394}}</ref>. Other [[Antifungal drug|antifungals]] that can be used are [[miconazole]] and [[fluconazole]].
*Increased intracranial pressure is a common finding in [[fungal meningitis]]. Therefore, it is recommended to do frequent, ideally daily, lumbar punctures to relieve the intracranial pressure.<ref name="pmid15838017">{{cite journal| author=Bicanic T, Harrison TS| title=Cryptococcal meningitis. | journal=Br Med Bull | year= 2004 | volume= 72 | issue=  | pages= 99-118 | pmid=15838017 | doi=10.1093/bmb/ldh043 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15838017  }} </ref>
*Increased [[intracranial pressure]] is a common finding in [[fungal meningitis]]. Therefore, it is recommended to do frequent, ideally daily, [[Lumbar puncture|lumbar punctures]] to relieve the intracranial pressure.<ref name="pmid15838017">{{cite journal| author=Bicanic T, Harrison TS| title=Cryptococcal meningitis. | journal=Br Med Bull | year= 2004 | volume= 72 | issue=  | pages= 99-118 | pmid=15838017 | doi=10.1093/bmb/ldh043 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15838017  }} </ref>
 
 
 
 


===[[Antimicrobial agent|Antimicrobial Regimens]]===
===='''[[Pathogen]]-directed antimicrobial therapy'''====
The pathogen specific antifungal therapy for fungal meningitis is shown in the table below:<ref name="pmid20166817">{{cite journal| author=Bariola JR, Perry P, Pappas PG, Proia L, Shealey W, Wright PW et al.| title=Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era. | journal=Clin Infect Dis | year= 2010 | volume= 50 | issue= 6 | pages= 797-804 | pmid=20166817 | doi=10.1086/650579 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20166817  }} </ref><ref name="pmid15736018">{{cite journal| author=Wheat LJ, Musial CE, Jenny-Avital E| title=Diagnosis and management of central nervous system histoplasmosis. | journal=Clin Infect Dis | year= 2005 | volume= 40 | issue= 6 | pages= 844-52 | pmid=15736018 | doi=10.1086/427880 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15736018  }} </ref><ref name="pmid26392507">{{cite journal| author=Morgand M, Rammaert B, Poirée S, Bougnoux ME, Tran H, Kania R et al.| title=Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole. | journal=Antimicrob Agents Chemother | year= 2015 | volume= 59 | issue= 12 | pages= 7857-61 | pmid=26392507 | doi=10.1128/AAC.01506-15 | pmc=4649149 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26392507  }} </ref>


{| class="wikitable"
{| class="wikitable"
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!Alternate therapy
!Alternate therapy
|-
|-
|''Aspergillus''
|''[[Cryptococcus]]''
|'''[[Human Immunodeficiency Virus (HIV)|HIV-infection]]'''
'''''(Induction/consolidation)''''':
* [[Amphotericin B]] [[deoxycholate]] 0.7-1.0 mg/kg/day IV '''plus''' [[flucytosine]] 25 mg/kg PO QID for at least 2 weeks
{{then}}  [[fluconazole]] 400 mg/day PO/IV (6 mg/kg/day);
* Lipid formulations of [[amphotericin B]] may be substituted for [[Amphotericin B]] [[deoxycholate]] if necessary: [[liposomal amphotericin B]] 3-4 mg/kg/day IV and [[amphotericin B]] lipid complex 5 mg/kg/day IV.
'''''(Maintenance):'''''
* [[Fluconazole]] 200 mg/day
 
'''''Solid organ transplant:'''''
* Lipid formulations of [[amphotericin B]] ([[liposomal amphotericin B]] 3-4 mg/kg/day IV or [[amphotericin B]] lipid complex 5 mg/kg/day IV) '''plus''' [[flucytosine]] 25 mg/kg PO QID for at least 2 weeks
{{then}}  [[fluconazole]] 400-800 mg/day PO/IV (6-12 mg/kg/day) for 8 weeks  {{then}}  [[fluconazole]] 200-400 mg/day for 6-12 months
 
'''''Non-[[HIV]], non-[[organ transplant]]:'''''
* [[Amphotericin B]] [[deoxycholate]] 0.7-1.0 mg/kg/day IV plus [[flucytosine]] 25 mg/kg QID for at least 4 weeks
{{then}}  [[fluconazole]] 200 mg/day (3 mg/kg) for 6-12 months
|'''[[HIV]]-infection'''
 
'''''(Induction/consolidation):'''''
* [[Amphotericin B]] [[deoxycholate]] 0.7-1.0 mg/kg/day IV or  lipid formulations of [[amphotericin B]] ([[liposomal Amphotericin B]] 3-4 mg/kg/day IV and [[amphotericin B]] lipid complex 5 mg/kg/day IV) monotherapy for 4-6 weeks;
* [[Amphotericin B]] [[deoxycholate]] 0.7 mg/kg/day IV plus [[fluconazole]] 800 mg/day PO/IV for 2 weeks {{then}} [[fluconazole]] 800 mg/day for a minimum of 8 weeks;
* [[fluconazole]] (≥800 mg/day) PO/IV '''plus''' [[flucytosine]] 25 mg/kg PO QID for 6 weeks
 
'''''(Maintenance):'''''
* [[Itraconazole]] 200 mg PO BID
 
'''''Solid organ transplant:'''''
* If [[flucytosine]] not used, then consider extension of induction with  lipid formulations of [[amphotericin B]] for at least 4-6 weeks.
 
'''''Non-HIV, non-organ transplant:'''''
* Lipid formulations of [[amphotericin B]] ([[liposomal amphotericin B]] 3-4 mg/kg/day IV or [[amphotericin B]] lipid complex 5 mg/kg/day IV) can be substituted in those unable to tolerate [[Amphotericin B]] [[deoxycholate]];
* if [[flucytosine]] not used, then consider extension of [[Amphotericin B]] [[deoxycholate]] or  lipid formulations of [[amphotericin B]] induction for at least 2 additional weeks.
|-
|''[[Aspergillus]]''
|
|
* [[Voriconazole]] 6 mg/kg IV q12h on day 1  
* [[Voriconazole]] 6 mg/kg IV q12h on day 1  
{{then}} 4 mg/kg q12h; further conversion to oral therapy may be considered.
{{then}} 4 mg/kg q12h; further conversion to oral therapy may be considered.
* Typical oral dosing is 200 mg q12h but is dependent on therapeutic drug monitoring.
* Typical oral dosing is 200 mg q12h but is dependent on therapeutic drug monitoring.
* Total duration of therapy has not been defined. Multiple factors must be considered, including extent of disease, response to therapy, and underlying immune status of the host.
* Total duration of therapy has not been defined. Multiple factors must be considered, including extent of disease, response to therapy, and underlying [[Immune system|immune status]] of the host.
|
|
* [[Liposomal amphotericin B]] 3-5 mg/kg/day IV, [[amphotericin B]] lipid complex 5 mg/kg/day IV, [[itraconazole]] 200 mg PO BID, or [[posaconazole]] 200 mg PO q6h.  
* [[Liposomal amphotericin B]] 3-5 mg/kg/day IV, [[amphotericin B]] lipid complex 5 mg/kg/day IV, [[itraconazole]] 200 mg PO BID, or [[posaconazole]] 200 mg PO q6h.  
* Combination therapy with [[voriconazole]] and an [[echinocandin]] such as [[caspofungin]] 70 mg IV on day 1 and 50 mg/day IV thereafter may be considered.
* Combination therapy with [[voriconazole]] and an [[echinocandin]] such as [[caspofungin]] 70 mg IV on day 1 and 50 mg/day IV thereafter may be considered.
|-
|-
|''Candida''
|''[[Candida]]''
|
|
* Lipid formulations of [[amphotericin B]] 3-5 mg/kg/day +/− [[flucytosine]] 25 mg/kg QID for ∼3 weeks  
* Lipid formulations of [[Amphotericin B]] 3-5 mg/kg/day +/− [[Flucytosine]] 25 mg/kg QID for ∼3 weeks  
{{then}}  [[fluconazole]] 400-800 mg/day PO/IV (6-12 mg/kg/day)
{{then}}  [[Fluconazole]] 400-800 mg/day PO/IV (6-12 mg/kg/day)
* Treatment continued until clinical signs and symptoms resolved and CNS and radiographic abnormalities have normalized.
* Treatment continued until clinical signs and symptoms resolved and [[CNS]] and radiographic abnormalities have normalized.
|
|
* [[Fluconazole]] 400-800 mg/day PO/IV (6-12 mg/kg/day)
* [[Fluconazole]] 400-800 mg/day PO/IV (6-12 mg/kg/day)
|-
|-
|''Blastomyces''
|''[[Blastomyces]]''
|
|
* Lipid formulations of [[amphotericin B]] 5 mg/kg/day for 4-6 weeks  
* Lipid formulations of [[Amphotericin B]] 5 mg/kg/day for 4-6 weeks  
{{then}}  [[fluconazole]] 800 mg/day PO/IV
{{then}}  [[Fluconazole]] 800 mg/day PO/IV
* Treatment for at least 12 months and until resolution of CSF abnormalities
* Treatment for at least 12 months and until resolution of [[CSF]] abnormalities
|
|
* Alternative [[azole]] considerations include [[itraconazole]] 200 mg PO BID to TID and [[voriconazole]] 200-400 mg PO BID.
* Alternative [[azole]] considerations include [[itraconazole]] 200 mg PO BID to TID and [[voriconazole]] 200-400 mg PO BID.
|-
|-
|''Coccidioides''
|''[[Coccidioides spp|Coccidioides]]''
|
|
* [[Fluconazole]] 400 mg/day PO/IV. Some use higher doses of [[fluconazole]], up to 1,000 mg/day up-front.
* [[Fluconazole]] 400 mg/day PO/IV. Some use higher doses of [[Fluconazole]], up to 1,000 mg/day up-front.
* [[Azole]] therapy is typically continued indefinitely.
* [[Azole]] therapy is typically continued indefinitely.
|
|
Line 56: Line 89:
* [[Intrathecal]] [[amphotericin B]] [[deoxycholate]]. dosing ranges from 0.1 to 1.5 mg per dose given daily to weekly.
* [[Intrathecal]] [[amphotericin B]] [[deoxycholate]]. dosing ranges from 0.1 to 1.5 mg per dose given daily to weekly.
|-
|-
|''Cryptococcus''
|''tfExserohilum''
|'''HIV-infection'''
'''''(Induction/consolidation)''''':
* [[Amphotericin B]] [[deoxycholate]] 0.7-1.0 mg/kg/day IV plus [[flucytosine]] 25 mg/kg PO QID for at least 2 weeks
{{then}}  [[fluconazole]] 400 mg/day PO/IV (6 mg/kg/day);
* Lipid formulations of [[amphotericin B]] may be substituted for [[Amphotericin B]] [[deoxycholate]] if necessary: [[liposomal amphotericin B]] 3-4 mg/kg/day IV and [[amphotericin B]] lipid complex 5 mg/kg/day IV.
'''''(Maintenance):'''''
* Fluconazole 200 mg/day
 
'''''Solid organ transplant:'''''
* Lipid formulations of [[amphotericin B]] ([[liposomal amphotericin B]] 3-4 mg/kg/day IV or [[amphotericin B]] lipid complex 5 mg/kg/day IV) '''plus''' [[flucytosine]] 25 mg/kg PO QID for at least 2 weeks
{{then}}  [[fluconazole]] 400-800 mg/day PO/IV (6-12 mg/kg/day) for 8 weeks  {{then}}  [[fluconazole]] 200-400 mg/day for 6-12 months
 
'''''Non-HIV, non-organ transplant:'''''
* [[Amphotericin B]] [[deoxycholate]] 0.7-1.0 mg/kg/day IV plus [[flucytosine]] 25 mg/kg QID for at least 4 weeks
{{then}}  [[fluconazole]] 200 mg/day (3 mg/kg) for 6-12 months
|'''HIV-infection'''
'''(Induction/consolidation):'''
* [[Amphotericin B]] [[deoxycholate]] 0.7-1.0 mg/kg/day IV or  lipid formulations of [[amphotericin B]] ([[liposomal Amphotericin B]] 3-4 mg/kg/day IV and [[amphotericin B]] lipid complex 5 mg/kg/day IV) monotherapy for 4-6 weeks;
* [[Amphotericin B]] [[deoxycholate]] 0.7 mg/kg/day IV plus [[fluconazole]] 800 mg/day PO/IV for 2 weeks {{then}} [[fluconazole]] 800 mg/day for a minimum of 8 weeks;
* [[fluconazole]] (≥800 mg/day) PO/IV '''plus''' [[flucytosine]] 25 mg/kg PO QID for 6 weeks
 
'''(Maintenance):'''
* [[Itraconazole]] 200 mg PO BID
 
'''Solid organ transplant:'''
* If [[flucytosine]] not used, then consider extension of induction with  lipid formulations of [[amphotericin B]] for at least 4-6 weeks.
 
'''Non-HIV, non-organ transplant:'''
* Lipid formulations of [[amphotericin B]] ([[liposomal amphotericin B]] 3-4 mg/kg/day IV or [[amphotericin B]] lipid complex 5 mg/kg/day IV) can be substituted in those unable to tolerate [[Amphotericin B]] [[deoxycholate]];
* if [[flucytosine]] not used, then consider extension of [[Amphotericin B]] [[deoxycholate]] or  lipid formulations of [[amphotericin B]] induction for at least 2 additional weeks.
|-
|''Exserohilum''
|
|
* [[Voriconazole]] 6 mg/kg IV every 12h with assessment of [[voriconazole]] trough concentrations on day 5 of therapy with adjustment to achieve trough of 2-5 mcg/ml. IV therapy should be initiated in most cases with transition to PO therapy once improving and clinically stable.
* [[Voriconazole]] 6 mg/kg IV every 12h with assessment of [[voriconazole]] trough concentrations on day 5 of therapy with adjustment to achieve trough of 2-5 mcg/ml.  
* Total duration of therapy is unknown and will depend on extent of infection, response to therapy, and underlying immune status of the host.  
* IV therapy should be initiated in most cases with transition to PO therapy once improving and clinically stable.
* Total duration of therapy is unknown and will depend on extent of infection, response to therapy, and underlying [[Immune system|immune status]] of the host.  
* Minimum duration of 3-6 months.
* Minimum duration of 3-6 months.
|
|
Line 97: Line 99:
* Doses of [[liposomal amphotericin B]] up to 7.5 mg/kg/day IV may be considered in patients who continue to do poorly.
* Doses of [[liposomal amphotericin B]] up to 7.5 mg/kg/day IV may be considered in patients who continue to do poorly.
|-
|-
|''Histoplasma''
|''[[Histoplasma capsulatum|Histoplasma]]''
|
|
* [[Liposomal amphotericin B]] 5 mg/kg/day IV for 4-6 weeks  
* [[Liposomal amphotericin B]] 5 mg/kg/day IV for 4-6 weeks  
{{then}} [[itraconazole]] 200 mg BID to TID for at least 1 year and until resolution of [[CSF]] abnormalities including ''[[Histoplasma capsulatum|Histoplasma]]'' antigen levels.
{{then}} [[itraconazole]] 200 mg BID to TID for at least 1 year and until resolution of [[CSF]] abnormalities including ''[[Histoplasma capsulatum|Histoplasma]]'' [[antigen]] levels.
|
|
* [[Amphotericin B]] [[deoxycholate]] 0.7-1.0 mg/kg/day is an alternative to [[liposomal amphotericin B]] in patients at low risk of [[nephrotoxicity]].
* [[Amphotericin B]] [[deoxycholate]] 0.7-1.0 mg/kg/day is an alternative to [[liposomal amphotericin B]] in patients at low risk of [[nephrotoxicity]].
|-
|-
|
| colspan="3" |'''KEY:'''
|'''KEY:'''
IV, intravenous;  
IV, intravenous; AmB, amphotericin B; ABLC, amphotericin B lipid complex; PO, per os, oral administration; BID, twice daily; LFAmB, lipid formulations of amphotericin B; TID, three times daily; QID, four times daily; AmBd, amphotericin B deoxycholate.
|
|}
 
 


PO, per os, oral administration;


BID, twice daily;


TID, three times daily;


QID, four times daily;
|}


==References==
==References==
Line 125: Line 127:
[[Category:Neurology]]
[[Category:Neurology]]
[[Category:Disease]]
[[Category:Disease]]
[[Category:Emergency mdicine]]
[[Category:Up-To-Date]]
[[Category:Infectious disease]]

Latest revision as of 21:47, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Rim Halaby

Overview

Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of high dose antifungals. In addition, frequent lumbar punctures are recommended in order to relieve the increased intracranial pressure[1].

Medical Therapy

Antimicrobial Regimens

Pathogen-directed antimicrobial therapy

The pathogen specific antifungal therapy for fungal meningitis is shown in the table below:[3][4][5]


ANTIFUNGAL THERAPY IN FUNGAL MENINGITIS
Type of fungal meningitis Preferred therapy Alternate therapy
Cryptococcus HIV-infection

(Induction/consolidation):

THEN fluconazole 400 mg/day PO/IV (6 mg/kg/day);

(Maintenance):

Solid organ transplant:

THEN fluconazole 400-800 mg/day PO/IV (6-12 mg/kg/day) for 8 weeks THEN fluconazole 200-400 mg/day for 6-12 months

Non-HIV, non-organ transplant:

THEN fluconazole 200 mg/day (3 mg/kg) for 6-12 months

HIV-infection

(Induction/consolidation):

(Maintenance):

Solid organ transplant:

  • If flucytosine not used, then consider extension of induction with lipid formulations of amphotericin B for at least 4-6 weeks.

Non-HIV, non-organ transplant:

Aspergillus

THEN 4 mg/kg q12h; further conversion to oral therapy may be considered.

  • Typical oral dosing is 200 mg q12h but is dependent on therapeutic drug monitoring.
  • Total duration of therapy has not been defined. Multiple factors must be considered, including extent of disease, response to therapy, and underlying immune status of the host.
Candida

THEN Fluconazole 400-800 mg/day PO/IV (6-12 mg/kg/day)

  • Treatment continued until clinical signs and symptoms resolved and CNS and radiographic abnormalities have normalized.
Blastomyces

THEN Fluconazole 800 mg/day PO/IV

  • Treatment for at least 12 months and until resolution of CSF abnormalities
Coccidioides
  • Fluconazole 400 mg/day PO/IV. Some use higher doses of Fluconazole, up to 1,000 mg/day up-front.
  • Azole therapy is typically continued indefinitely.
tfExserohilum
  • Voriconazole 6 mg/kg IV every 12h with assessment of voriconazole trough concentrations on day 5 of therapy with adjustment to achieve trough of 2-5 mcg/ml.
  • IV therapy should be initiated in most cases with transition to PO therapy once improving and clinically stable.
  • Total duration of therapy is unknown and will depend on extent of infection, response to therapy, and underlying immune status of the host.
  • Minimum duration of 3-6 months.
Histoplasma

THEN itraconazole 200 mg BID to TID for at least 1 year and until resolution of CSF abnormalities including Histoplasma antigen levels.

KEY:

IV, intravenous;

PO, per os, oral administration;

BID, twice daily;

TID, three times daily;

QID, four times daily;

References

  1. ↑ 1.0 1.1 Bicanic T, Harrison TS (2004). "Cryptococcal meningitis". Br Med Bull. 72: 99–118. doi:10.1093/bmb/ldh043. PMID 15838017.
  2. ↑ Gottfredsson M, Perfect JR (2000). "Fungal meningitis". Seminars in Neurology. 20 (3): 307–22. doi:10.1055/s-2000-9394. PMID 11051295.
  3. ↑ Bariola JR, Perry P, Pappas PG, Proia L, Shealey W, Wright PW; et al. (2010). "Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era". Clin Infect Dis. 50 (6): 797–804. doi:10.1086/650579. PMID 20166817.
  4. ↑ Wheat LJ, Musial CE, Jenny-Avital E (2005). "Diagnosis and management of central nervous system histoplasmosis". Clin Infect Dis. 40 (6): 844–52. doi:10.1086/427880. PMID 15736018.
  5. ↑ Morgand M, Rammaert B, Poirée S, Bougnoux ME, Tran H, Kania R; et al. (2015). "Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole". Antimicrob Agents Chemother. 59 (12): 7857–61. doi:10.1128/AAC.01506-15. PMC 4649149. PMID 26392507.

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