Dexamethasone - Or Antibiotics Alone? Christie PGR... · Nervous System Infections Christine M Gamble, PharmD PGY1 Pharmacy Practice Resident Pharmacy Grand Rounds March 15, 2016

©2015 MFMER | slide-1

Dexamethasone - Or Antibiotics Alone?Adjunctive Dexamethasone Therapy for Central Nervous System InfectionsChristine M Gamble, PharmDPGY1 Pharmacy Practice Resident

Pharmacy Grand RoundsMarch 15, 2016


Objectives

• Review the mechanism of action of corticosteroids

• Discuss the role of dexamethasone in acute pneumococcal meningitis

• Discuss the role of dexamethasone in non-pneumococcal central nervous system infections


Which of the following best describes the use of dexamethasone at your practice site?

A. Not often used for bacterial meningitis or other CNS infections

B. Often started for bacterial meningitis and continued only if evidence of S.pneumoniae

C. Often started for bacterial meningitis and continued regardless of bacterial organism

D. Unsure how it is used at my practice site, or none of the above


Inflammation of the brain parenchyma

Tessier JM. Chapter 30. In: Scheld WM, ed. Youmans Neurological Surgery. :544–558https://commons.wikimedia.org/wiki/File:MRI_head_side.jpg#filelinks

https://commons.wikimedia.org/wiki/Commons:GNU_Free_Documentation_License,_version_1.2

Central Nervous System (CNS) InfectionsCentral Nervous System (CNS) Infections

MeningitisMeningitisEncephalitisEncephalitisInflammation of the

meninges


Protector of The CNS – The Blood Brain BarrierTypical CapillaryBrain Capillary

Tissue

H20

Brain

H20

Tight Junctions

Tessier JM. Chapter 30: Basic Science of Central Nervous System Infections. In: Scheld WM, ed. Youmans Neurological Surgery. :544–558


Protector of The CNS – The Blood Brain BarrierInflamed Brain CapillaryHealthy Brain Capillary

Brain

H20

Brain

H20

Tight Junctions



Inflammation in CNS Infections- Helpful or Harmful?

Brain and Spinal Cord Perfusion

Brain and Spinal Cord Perfusion

Cognitive & Functional

Disabilities or Death

Cognitive & Functional

Disabilities or Death

Presence of

Pathogen

Presence of

PathogenInflammationInflammation

Eradication of InfectionEradication of Infection

Fluid into CSF

Fluid into CSF

Increased BBB Permeability

Increased BBB Permeability

Edema & ICP Edema

& ICP

IschemiaIschemia


Leukocyte Entry

Leukocyte Entry

Antibiotic Entry

Antibiotic Entry

BBB= blood brain barrier


Corticosteroid Mechanism of Action• Inhibit BBB permeability

• Inhibit:• TNF-α• IL-1

• Inhibit other inflammatory pathways• Upstream Inhibition:

• COX-2 • Inflammatory products

• COX-1• Maintains GI mucosa

Tessier JM. Chapter 30: In: Scheld WM, ed. Youmans Neurological Surgery. :544–558Dexamethasone. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO.

van de Beek D,et al. N Engl J Med. 2004;351:1849-1859

Key mediators of BBB permeability


Dexamethasone

• Most potent glucocorticoid

• No water-retaining (mineralocorticoid) properties

• Best CSF penetration of glucocorticoids

• Long duration

Adrenal Cortical Steroids. In Drug Facts and Comparisons. 5th ed. St. Louis. 122-128,1997Czock D, et al. Clin Pharmacokinet. 2005; 44(1):61-98


Dexamethasone theoretically has the ability to improve outcomes in CNS infections through which of the following mechanisms?

A. Prevents inflammation associated with antimicrobial-mediated bacterial lysis

B. Decreases permeability of BBB through blocking the production of TNF-a and IL-1 and therefore reduces edema and ICP

C. Decreases permeability of BBB through blocking the production of TNF-a and IL-1 and therefore reduces antibiotic entry into CSF

D. A and B

E. A and C


Bacterial Meningitis


Bacterial Meningitis - Mortality

Mortality Rate 3-29% - Dependent on organism

Thigpen MC, et al. 1998-2007. N Engl J Med. 2011;364:2016-2025Tunkel, AR, et al. Mandell’s Principles and Practice of Infectious Diseases, 89, 1097-1137. e8.

Organism Percentage of Total US Cases

US Mortality Rate

Streptococcus pneumoniae 58% 18-26%Neisseria meningitidis 14% 3-13%Haemophilus influenzae 7% 3-7%

Listeria monocytogenes 3% 15-29%


Bacterial Meningitis - Morbidity

Edmond K, et al. Lancet Infect Dis. 2010; May; 10(5):317-328.

Organism Risk for at Least One Major Sequelae

Streptococcus pneumoniae 24.7%Neisseria meningitidis 7.2%Haemophilus influenzae 9.5%

Major Sequelae Fraction of All Major Sequelae Reported

Hearing Loss 33.3%Seizures 12.6%Motor Deficits 11.6%Cognitive Impairment 9.1%


Evidence Supporting Adjunctive Steroids in Bacterial Meningitis

2015200219621950s

Case studies show hydrocortisone + antibiotics

= better outcomes vs. antibiotics alone

Retrospective Study N=120

Steroids + antibiotics = better outcomes vs.

antibiotics alone. Benefit not seen if steroid

delayed 5 days

Prospective Double-Blinded, Randomized

Placebo-Controlled Trial N= 301

Cochrane Database Meta Analysis

N= 4121 patients

Gross HP, et al. Med Bull (Ann Arbor). 1956 Aug;22(8):329-31Ribble JC, et al. Am J Med. 1958 Jan;24(1):68-79, Hoh, TK, et al. Singapore Med J. 1962 Jun;3:73-7

De Gans, et al. N Engl J Med 2002; 347: 1549-1556Brouwer MC, et al. Cochrane Database Syst Rev. 2015 Sep 12;9:CD004405


2002 De Gans, et al. Prospective, Randomized, Double-Blind, Multicenter, Placebo-

Controlled Trial

Adults with Acute Bacterial Meningitis

N=301

Placebo

Dexamethasone 10mg q6h x 4 days.

1st Dose 15-20 minutes before or with the first

dose of antibiotic.

De Gans, et al. N Engl J Med 2002; 347: 1549-1556

Unfavorable Outcome, Death, Hearing Loss at 8 weeks


Primary Endpoint: Unfavorable Outcome

Glasgow Outcome Scale5 = Mild or No Disability: able to return to work or school

4 = Moderate Disability: able to live independently but unable to return to work or school

3 = Severe Disability: follows commands but unable to live independently

2 = Vegetative State

1 = Death

:

Unfavorable Outcome


Score <5 on the Glasgow Outcome Scale at 8 weeks


ResultsAll Patients

Endpoint- no. (%) Dexamethasone(N = 157)

Placebo(N = 144) P-Value

Unfavorable Outcome 23 (15%) 36 (25%) P=0.03Death 11 (7%) 21 (15%) P=0.04Hearing Loss 9% 12% P=0.54

S.pneumoniae Subgroup




N.meningitidis Subgroup






Adverse Events:

All Patients



GastrointestinalBleeding 2 (1%) 5 (3%) P=0.27

Hyperglycemia 50 (32%) 37 (26%) P=0.24Herpes Zoster 6 (4%) 4 (3%) P=0.75Fungal Infection 8 (5%) 4 (3%) P=0.38



Author’s Conclusions

Early Treatment with dexamethasone (prior to or with the first dose of antibiotic) improves

outcomes in adults with acute bacterial meningitis and does not increase the risk of gastrointestinal

bleeding.



Author’s Recommendation• Recommend dexamethasone for all adults with

acute bacterial meningitis – regardless of infecting organism

• Rationale• Events were rare in N.meningitidis subgroup• Study was not powered to show difference in

subgroups• Benefit cannot be ruled out in subgroups• Dexamethasone did not increase adverse events



2015 Cochrane Review• Meta-analysis of 25 studies

• N= 4121 participants with acute bacterial meningitis

• Primary Endpoints• 1. Mortality• 2. Hearing Loss• 3. Neurological Sequelae

• New epilepsy• Severe ataxia• Severe memory or concentration disturbance

Brouwer MC, et al. Cochrane Database Syst Rev. 2015;9:CD004405 PMID: 26362566


All Patients: Mortality- no (%)Corticosteroids

(N= 2064)Placebo

(N= 2057) RR (95% CI)

367 (17.8%) 409 (19.9%) 0.90 (0.80-1.01)

All Patients: Mortality



Mortality by Species Subgroup

Mortality By Species

Causative Species # Studies # ParticipantsCorticosteroids vs.

PlaceboRR (95% CI)

H. influenzae 11 825 0.76 (0.53-1.09)

S. pneumoniae 17 1132 0.84 (0.72-0.98)N. meningitidis 13 618 0.71 (0.35-1.46)



Hearing Loss


All Patients: Any Hearing Loss- no (%)Corticosteroids

(N= 1424)Placebo

(N= 1361) RR (95% CI)

197 (13.8%) 259 (19.0%) 0.74 (0.63-0.87)


Neurologic Sequelae*

Endpoint # Studies # ParticipantsCorticosteroids

vs. PlaceboRR (95% CI)

Short-term Neurologic Sequelae(Discharge - 6 weeks post discharge) 13 1756 0.83 (0.69-1.00)

Long-term Neurologic Sequelae(6 weeks – 12 months post discharge) 13 1706 0.90 (0.74-1.10)


*New epilepsy, severe ataxia, or severe memory or concentration disturbance


Gastrointestinal Bleeding

Adverse Event # Studies # ParticipantsCorticosteroids

vs. PlaceboRR (95% CI)

Gastrointestinal Bleeding 16 2560 1.45 (0.86-2.45)



2015 Cochrane Review Conclusion

• Dexamethasone:

• Significantly reduced mortality in patients with S. pneumoniae meningitis, but not other species

• Significantly reduced hearing loss in bacterial meningitis

• Significantly reduced rates of short term neurologic sequelae, but not long-term neurologic sequelae

• Did not lead to increased gastrointestinal bleeding



IDSA Approach Regarding Steroids in Bacterial Meningitis

Clin Infect Dis. 2004 Nov 1;39(9):1267-84.

Suspicion for Bacterial MeningitisSuspicion for Bacterial Meningitis

Blood Cultures and Lumbar Puncture* STAT

Blood Cultures and Lumbar Puncture* STAT

*no lumbar puncture if papilledema, delay in performance of lumbar puncture, or selected focal neurologic defects.

Dexamethasone + Empiric AntibioticsDexamethasone + Empiric Antibiotics

G+ dipplococci on CSF gram stain, or blood or CSF culture positive for S. pneumoniae?

G+ dipplococci on CSF gram stain, or blood or CSF culture positive for S. pneumoniae?

Yes

Continue TherapyContinue Therapy Discontinue DexamethasoneDiscontinue Dexamethasone

No

IDSA= Infectious Disease Society of America


Why S. pneumoniae?


• Produces pneumolysin

• Pore-forming toxin

• Increased BBB permeability

• Direct neuronal cell death

Brain Capillary

Tight Junctions

S.pneumo

Pneumolysin


Which of the following are appropriate dexamethasone regimens for suspected pneumococcal meningitis?

A. 0.15 mg/kg IV q6h x 4 days initiated 10-20 minutes before start of antimicrobialsB. 0.15 mg/kg IV q6h x 4 days initiated at the same time as antimicrobialsC. 0.15 mg/kg IV q6h x 4 days initiated after the start of antimicrobialsD. A and BE. B and C


Tuberculous Meningitis


Tuberculous meningitis (TBM)

• Mycobacterium tuberculosis• Currently 2 billion people are infected with TB

infection (1/3 of the world’s population)• 10% develop clinical disease

• Prevalence: 0.7% of all reported TB cases are TBM

• 200-300 cases annually in the US• Higher incidence in developing countries

Centers for Disease Control. Available at: http://www.cdc.gov/tb/topic/globaltb/default.htmVan TTT, et al. J. Epidemiol Community Health 2014;68: 195-196

Ramachandran TS. Tuberculous Meningitis. Medscape Reference® 2014


Typical Outcomes in Tuberculous Meningitis

Death 50.00%

Complete Neurological

Recovery21.50%

Cognitive Impairment

28.50%

Kalita J et al. (2007). Eur J Neurol 14: 33–37Thwaites GE et al. (2005). Lancet Neurol 4: 160–170


Evidence Supporting Adjunctive Steroids in Tuberculous Meningitis

2000 200419941950s

Case series show cortisone + streptomycin improved

prognosis vs. streptomycin alone

RCT N=47 Showed better neurological outcomes and

Faster Recovery with Dexamethasone + anti-tuberculosis therapy vs.

tuberculosis therapy alone

Cochrane Meta Analysis N=595 Dexamethasone

decreased death and disability patients ≤14

years of age. No difference found for

subgroup patients >14 years of age (not

enough data)

RCT N= 545 patients only >14

years of age. Dexamethasone vs.

Placebo

2008

Updated Cochrane Meta Analysis

Showing benefit for all age groups

Ashby M and Grant H (1955) Lancet 268: 65–66Kumarvelu S et al. (1994) Tuber Lung Dis 75: 203–207Prasad K, et al. Cochrane Database Syst Rev 2000;3:CD00224Thwaites GE et al. (2004) N Engl J Med 351: 1741–1751Prasad K, et al. Cochrane Database Syst Rev 2008

Shane SJ and Riley C (1953). N Engl J Med 249: 829–834


2004 Thwaites GE et al.Prospective, Randomized, Double-Blinded, Multicenter Trial in

Vietnam

Patients >14 years of age with tuberculous

meningitisN= 545

Thwaites GE et al. N Engl J Med 2004; 351: 1741–1751

Dexamethasone + Anti-Tuberculosis

Therapy

Placebo + Anti-Tuberculosis

Therapy

Severe Disability and Adverse Events at 9 Months


Glasgow Coma Scale Stratification

• Grade I Disease: Score 15

• Grade II Disease: Score 11-14.

• Grade III Disease: Score <11

Institute of Neurological Sciences NHS Greater Glasgow and Clyde. Glasgowcomascale.orgThwaites GE et al. N Engl J Med 2004; 351: 1741–1751

• Glasgow Coma Score

• Range 3-15

• Score 15 • obeys commands• oriented to time,

place and person• opens eyes

spontaneously• 3 = totally unresponsive

Stratification in Study


Treatment Specifics

Rifampin +Isoniazid +

Pyrazinamide + Streptomycin

Rifampin + Isoniazid +

Pyrazinamide

X 3 months X 6 months

Dexamethasone IV 0.3 mg/kg/day

If Grade II – III Disease: 8 week taper

Dexamethasone IV0.4 mg/kg/day

If Grade I disease: 6 week taperPlacebo

Placebo



Results: Baseline Characteristics

Characteristic Dexamethasone(N = 274)

Placebo(N = 271)

Median Age - years 36 35 Age Range - years 15-88 15-84Male % 61.3% 60.1%Median Glasgow Coma Score 14 14



Results: Composite Primary Endpoint

0%

10%

20%

30%

40%

50%

60%

70%

Placebo Dexamethasone

49.4%44.2%

P=0.22Death or Severe

Disability at 9 Months

Thwaites GE et al. (2004) N Engl J Med 351: 1741–1751


Results: Other Endpoints

Endpoint- no. (%) At 9 Months

Dexamethasone(N = 274)


*Death or Severe Disability 121 (44.2%) 132 (49.4%) P=0.22

Death 87 (31.8%) 112 (41.3%) P=0.01

**Severe Disability -- (18.2%) -- (13.8%) P=0.27

***Serious Adverse Events 26 (9.5%) 45 (16.6%) P=0.02• Severe Hepatitis 0 8 (3%) --• GI Bleeding 3 (1.1%) 3 (1.1%) --• Bacterial Sepsis 1 (0.4%) 3 (1.1%) --

*Primary Endpoint**Out of survivors***Any event causing or threatening to cause prolonged hospital stay



Author’s Conclusions

In tuberculous meningitis, adjunctive dexamethasone improves survival in

patients over 14 years of age without an increase in adverse events, but it likely

does not prevent severe disability



Central Nervous System TB Guidelines

National Institute for Health and Care Excellence. Jan 13, 2016. https://www.nice.org.uk/guidance/ng33/resources/tuberculosis-1837390683589

MMWR June 20, 2003 / 52 (RR11);1-77

Guideline DexamethasoneRecommendation

NICE

At the start of anti-TB treatment regimen, offer dexamethasone initially at a high dose with

gradual withdrawal over 4-8 weeks.

Consider 6 weeks if stage I diseaseConsider 8 weeks if stage II-III disease

ATS/CDC/IDSADexamethasone x 6 weeks“Strongly Recommended”

(A1 Rating)


Which of the following CNS infections is an FDA-approved indication for dexamethasone?

A. S. pneumoniae meningitisB. N. meningitidis meningitisC. H. influenzae meningitisD. M. tuberculosis meningitisE. HSV encephalitis


Herpes Simplex Virus (HSV) Encephalitis


HSV Encephalitis• Most common fatal CNS viral infection in the

western hemisphere• Neurological emergency

• High mortality • 70% if untreated• 20-50% with antivirals

Tyler KL (2004) Herpes 11 (Suppl 2): S57A–S64ABaringer JR et al. (1976) Arch Neurol 33: 442–446

Eisenstein LE et al. (2004). Heart Lung 33: 196–197Schmutzhard E (2001) J Neurol 248: 469–477

Cinque P et al. (1996). J Neurol Neurosurg Psychiatry 61: 339–345


Studies of Adjunctive Steroids in HSV Encephalitis

2016200720052003

Studies of acyclovir + methylprednisolone in mice show reduced chronic brain

abnormalities on MRI vs. acyclovir alone

Retrospective Trial of 45 patients studies outcomes

of using steroids in the acute stage of HSV

encephalitis

In mice, dexamethasone +

acyclovir controls viral replication and restricts neuronal cell death vs.

acyclovir alone. Delaying steroids for 3

days is better than early treatment

GACHE Trial (in progress). Randomized,

Double-Blinded, Placebo Controlled Trial of Acyclovir +

Dexamethasone vs. Acyclovir + Placebo

Meyding-Lamade UK et al. (2003). J Neurovirol 9: 118–125Kamei S et al. (2005) J Neurol Neurosurg Psychiatry 76: 1544–1549


Corticosteroids in HSV Encephalitis

Study Type Outcomes Methods VariablesExamined

Results

Retrospective chart review of 45 patients with HSV encephalitis

• No Sequelae• Mild Sequelae• Moderate Sequelae

(motor, speech, memory limitations, or epilepsy)

• Severe Sequelae(requiring supportive care)

• Death

Logisticregression to identify predictors of good outcome

Sex, Age,

Glasgow Coma Score,

Protein concentration

in CSF, Corticosteroid Administration

Three variableslinked to better

outcome1. Patient Age

2. Baseline Glasgow Coma

Score 3. Steroid

administration in the acute

stage

Kamei S et al. (2005) J Neurol Neurosurg Psychiatry 76: 1544–1549


HSV Encephalitis Guidelines

Tunkel AR, et al. Clin Infect Dis. 2008 Aug 1;47(3):303-27

Guideline DexamethasoneRecommendation

IDSA

“Use of adjunctive corticosteroids was assessed in one non-randomized, retrospective

study of 45 patients with herpes simplex encephalitis treated with acyclovir. Although a worse outcome was observed in patients who

were not treated with corticosteroids, these results need to be confirmed before this

adjunctive treatment can be recommended.”


Other Encephalitis Types

Encephalitis Causative Species

CorticosteroidsBeneficial?

Varicella Zoster Virus Consider (C-III)Ebstein Barr Virus Consider (C-III)Cerebral malaria NoHelminthic encephalitis* Consider (B-III)

*If caused by Baylisascaris procyonis or Taenia solium

Tunkel AR, et al. Clin Infect Dis. 2008 Aug 1;47(3):303-27


Summary• S.pneumoniae meningitis

• Dexamethasone 0.15mg/kg q6hrs x 4 days strongly recommended

• M.tuberculosis meningitis• Stage I Disease:

• Dexamethasone 6 week taper strongly recommended

• Stage II-III Disease:• Dexamethasone 8 week taper strongly

recommended

• HSV encephalitis• Despite the lack of randomized controlled trials,

evidence exists that supports the use of dexamethasone


[email protected]

Documents

Dexamethasone - Or Antibiotics Alone? Christie PGR... · Nervous System Infections Christine M Gamble, PharmD PGY1 Pharmacy Practice Resident Pharmacy Grand Rounds March 15, 2016