Infections Brian S. Schwartz, MD UCSF, Division of Infectious - - PDF document

2/17/16 1

Update in Diagnosis and Management of CNS Infections

Brian S. Schwartz, MD

UCSF, Division of Infectious Diseases

Pick a partner

• Turn to the person next to you
• Say, “Hi, my name is your name here.”
• Spend 3 minutes sharing how you

would approach the following case

2/17/16 2

Case

• 65 y/o male presents to ED by

ambulance after a seizure. He had progressive lethargy, fever, and stiff neck x 48 hrs

• Exam: 39°C, 110, 110/50, 20, 99% RA
• Oriented to person only
• Unable to touch chin to chest
• No focal neurological abnormalities

DISCUSS

• 1. CT scan yes/no?
• 2. LP when?
• 3. Empiric antibiotics (when, what)?
• 4. Steroids (yes/no, when)?
• 65 y/o male presents to ED by ambulance after a
• seizure. He had progressive lethargy, fever, and

stiff neck x 48 hrs.

• Exam: 39°C, 110, 110/50, 20, 99% RA
• Oriented to person only
• Unable to touch chin to chest
• No focal neurological abnormalities

2/17/16 3

Decision #1: CT before LP?

Yes if…

• New-onset seizure
• Immunocompromised
• Focal neurological finding
• Papilledema
• Mod-severe impaired consciousness

Hasbun R. NEJM. 2001. Gopal AK. Arch Int Med. 1999.

C T

• Y

e s

Decision #2: Antibiotics?

• When?
• CT: antibiotics up front (blood cx 1st)
• No CT: LP and then antibiotics
• What?
• Depends on which bugs….

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How quickly does the CSF sterilize after antibiotic administration?

0 ¡ 20 ¡ 40 ¡ 60 ¡ 80 ¡ 100 ¡ 0-­‑2 ¡ 2.1-­‑4 ¡ 4.1-­‑6 ¡ 6.1-­‑24 ¡ 24.1-­‑48 ¡ >48 ¡

% ¡of ¡CSF ¡sterilized ¡

Time ¡a3er ¡start ¡of ¡an5bio5cs ¡(hours) ¡

• N. ¡meningi)dis ¡
• S. ¡pneumoniae ¡

Kanegye JT. Pediatrics. 2001. 108 (5).

Could molecular diagnostics be helpful in those cases?

• 451 suspected bacterial meningitis
• 98 had antibiotics in CSF sample
• Sensitivity
• Culture: 78%
• Gram Stain: 99%
• RT-PCR: 95%

Wu et al. BMC Infectious Diseases. 2013

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18–34 Yr 35–49 Yr 50–64 Yr ≥65 Yr All adult cases

Percentage of Total Cases

100 80 90 70 60 40 30 10 50 20

Thigpen MC. NEJM.2011

Streptococcus pneumoniae Neisseria meningitidis GBS Haemophilus influenzae Listeria monocytogenes

Empiric therapy

Risk factor Pathogens Antimicrobials 2-50 yr

• N. meningitidis,
• S. pneumoniae

Vancomycin + Ceftriaxone > 50 yr

• S. pneumoniae,
• N. meningitidis,
• L. monocytogenes

Vancomycin+ Ceftriaxone + Ampicillin

Adapted from Tunkel AR. CID 2004

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Why add vanco?

0 ¡ 1 ¡ 2 ¡ 3 ¡ 4 ¡ 5 ¡ 6 ¡ 0 ¡ 5 ¡ 10 ¡ 24 ¡

Colony ¡forming ¡units/ml ¡CSF ¡ Hours ¡post ¡ini5a5on ¡of ¡therapy ¡ CFTX ¡ RIF ¡ VANCO ¡+ ¡RIF ¡ VANCO ¡ CFTX ¡+ ¡Vanco ¡

Friedland ET. AAC. 1993

Answer: Pen resistant S pneumo

Decision #3: Steroids?

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Steroids for bacterial meningitis

• When?
• Before first dose of antibiotics
• Not for patients who already received

antibiotics

• How much?
• Dexamethasone 10mg q6h x 4 days
• For which bugs?
• S pneumoniae

Tunkel et al, CID 2004:39.

Dexamethasone for Bacterial Meningitis

• Double-blinded RCT in adults from the Netherlands
• Dexamethasone 10 mg q6h vs. placebo x 4d
• 1° outcome: Death or neurological disability

de Gans J. NEJM 2002

Dex Placebo RR of poor outcome

All

15% 25% 0.59 (0.37-0.94), p=0.03

• S. pneumoniae

26% 52% 0.50 (0.30-0.83), p=0.006

• N. meningitidis

8% 11% 0.75 (0.21-2.63), p=0.74

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What do you do next and in what order?

• 1. Blood cultures

2. Vanco + Ceftriaxone + Amp + Steroids

• 3. CT scan
• 4. LP

Case continued

• Rx: Ceftriaxone, Vanco, Amp, Decadron
• CT was normal
• LP:
• WBC: 450 (90% PMNs)
• Glucose: 50 (Serum:170);CSF/serum=0.3
• Protein: 120
• Gram stain: Gram positive diplococci
• Culture: negative
• Blood cultures: no growth

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Definitive antimicrobial therapy ¡

Pathogen ¡ Primary ¡ Duration of Rx ¡

• S. pneumoniae ¡

10-14 days ¡

Pen MIC ≤0.1 µg/ml ¡ Penicillin ¡ Pen MIC 0.1-1.0 µg/ml ¡ Ceftriaxone ¡ Pen MIC >0.1-1.0 µg/ml

¡ Vanco + Ceftriaxone ¡

• N. meningitidis ¡

7 days ¡

Pen MIC ≤0.1 µg/ml ¡ Penicillin G ¡ Pen MIC 0.1-1.0 µg/ml ¡ Ceftriaxone ¡

• L. monocytogenes ¡

Ampicillin ¡

≥21 days ¡

Adapted from Tunkel AR. CID 2004 ¡

IDSA algorithm for management of bacterial meningitis

Indication for head CT

YES NO Blood cx + Lumbar puncture Blood cx Steroids and empiric antimicrobials Steroids and empiric antimicrobials CSF suggestive of bacterial meningitis Head CT w/o mass lesion

• r herniation

Lumbar puncture Refine therapy

Tunkel AR. CID 2004

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Tricky scenarios…

Empiric therapy for penicillin allergic?

• What type of reaction?
• Non-IgE mediated: Cephalosporin OK
• IgE-mediated (hives, anaphylaxis)
• Alternate Rx, consider desensitization

https://en.wikipedia.org/wiki/Urticaria

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If it is IgE mediated…

Empiric:

Vancomycin + (Aztreonam or Meropenem)

Directed:

Pathogen Alternative treatment

• S. pneumoniae

Meropenem or fluoroquinolone

• N. meningitidis

Aztreonam, fluoroquinolone

• L. monocytogenes TMP-SMX, meropenem

Adapted from Tunkel AR. CID 2004

If it is IgE mediated…

Empiric:

Vancomycin + (Aztreonam or Meropenem)

Directed:

Pathogen Alternative treatment

• S. pneumoniae

Vancomycin, fluoroquinolone

• N. meningitidis

Aztreonam, fluoroquinolone

• L. monocytogenes TMP-SMX, meropenem

Adapted from Tunkel AR. CID 2004

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N meningitidis – prophylaxis?

• Who needs prophylaxis?
• Household members
• Direct exposure to oral secretions
• What to give?
• Rifampin 600 mg q12 x 2 days
• Ciprofloxacin 500 mg x 1
• Ceftriaxone 250 mg IM x 1

http://www.cdc.gov/MMWR/preview/mmwrhtml/00046263.htm

Preventing spread of

• f N meningitidis (inpatient)
• Droplet precautions
• DCed after 24h ceftriaxone

http://www.cdc.gov/MMWR/preview/mmwrhtml/00046263.htm

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Patient with meningitis, 7 days post meningioma resection

• What bugs are your worried about?
• MRSA
• Resistant Gram negative rods
• Empiric regimen?
• Vancomycin

PLUS

• Cefepime or Meropenem

Fever and HA x 5 days; Lymphs in CSF?

• 31 y/o M c/o 5 days of severe HA
• Sore throat, malaise, fever, chills
• PMH: none; Meds: Acetaminophen
• SH: Sacramento, 1 female partner
• Exam: T-38.6, pain w/ neck flexion
• LP: WBC 228 (96% L),Gluc 63, Protein 76

Case created by Jen Babik

2/17/16 14

CSF findings

WBCs

PMNs %

Glucose

(CSF/serum)

Protein

(mg/dL)

Bacterial meningitis 500-10K >85 < 0.4 < 200 Aseptic meningitis 10-500 <50 WNL <100 Encephalitis 0-1000 <50 WNL < 100 Chronic meningitis 100-500 <50 < 0.4 > 200

DDx Aseptic Meningitis/Lymphocytic Pleocytosis

• Bacterial
• Bacterial meningitis (10%)
• Partially treated bacterial meningitis
• Listeria (<25%)
• Mycobacteria
• Spirochetes: Syphilis, Lyme, Lepto
• Other: Brucella, RMSF, Q fever
• Para-meningeal focus of infection

(brain/epidural abscess)

• Viral
• Arboviruses (West Nile Virus)
• Enteroviruses
• Herpesviruses (HSV, VZV, CMV, EBV)
• Acute HIV
• Others (LCMV, Measles, Mumps)
• Fungal
• Crypto
• Endemic fungi (e.g., cocci)
• Parasites
• Toxoplasma gondii
• Helminths (eg

neurocystercircosis)

• Amoeba (eg Balamuthia)
• Non-infectious
• Medications (e.g., NSAIDs,

Abx)

• Rheumatologic Disease (e.g.,

SLE, sarcoid)

• Carcinomatous meningitis

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DDx Aseptic Meningitis: Most Common Infections

• Bacterial
• Syphilis
• Lyme
• Viral
• Enteroviruses
• HSV, VZV
• Acute HIV
• West Nile virus

Diagnostics:

• Serum
• RPR
• HIV Ab and VL
• West Nile IgM/IgG
• Lyme Ab (if risk factors)
• CSF
• VDRL
• Enterovirus PCR
• HSV/VZV PCR
• West Nile IgM/IgG

Case created by Jen Babik

Back to the Case…

• CSF HSV, VZV PCR negative
• RPR negative
• HIV Ab negative
• HIV VL 120,000
• Diagnosis: Acute HIV Infection

Case created by Jen Babik

2/17/16 16

Progressive headache x 3 weeks

• 56 y/o male c/o 3 wks of progressive

HA, fatigue, low grade fevers, confusion

• PMH: Diabetes, HTN
• SH: Phoenix, AZ; construction worker
• Exam: T-38.1, pain w/ neck flexion
• LP:
• WBC: 190 (85% lymphs), TP: 420, Gluc 39

CSF findings

WBCs

PMNs %

Glucose

(CSF/serum)

Protein

(mg/dL)

Bacterial meningitis 500-10K >85 < 0.4 < 200 Aseptic meningitis 10-500 <50 WNL <100 Encephalitis 0-1000 <50 WNL < 100 Chronic meningitis 100-500 <50 < 0.4 > 200

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Chronic meningitis

• Definition: >4 weeks of symptoms
• LP: Lymphs, low glucose, high protein
• History important!
• DDx: TB, crypto, cocci, histo, etc.
• Work up:
• LP, CrAg, AFB/fungal Cx, Cocci IgM, HIV
• Empiric Rx: RIPE + steroids (+/- fluc)

Case continued

• Serum and CSF Coccidiodes immitis

titers; 1:256 and 1:8

• 2 months ago had pneumonia while

working at a new construction site with lots of dust

• Started on fluconazole

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Take home points: meningitis

• CT scan before LP in patients w/:
• Seizure, altered MS, neuro deficits, IS, papilledema
• Give Abx immediately if going to CT
• Add Ampicillin if >50 yr or IS for Listeria
• Steroids before Abx, only S pneumo
• Aseptic: WNV, HSV, entero…syphilis, acute HIV
• Chronic: TB, cocci, consider empiric Rx

2/17/16 19

Case: 63 y/o F with ESRD on HD c/o 3 wks of lower back pain

• PMH: ESRD on HD
• Meds:
• Metoprolol
• Nephrovite
• SH:
• Teacher
• no IVDU

37.5, 89, 154/66, 16 Skin: L forearm AVF, no

erythema/TTP

Back: TTP L2-L3 Neuro: normal

http://www.medpagetoday.com/Nephrology/ESRD/52319

• Spend 2 minutes discussing next steps:
• Radiographic testing?
• Laboratory testing?
• 63 year-old male with ESRD on HD has

3 weeks of progressive back pain, tender to palpation over L2-3

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Vertebral osetomyelitis/discitis is hard to diagnose?

• Median time to Dx: 48 days
• Fever only present in 13%

Nolla JM. Arthritis and Rheumatisim. 2002

Clues to infectious etiology

• f back/neck pain?
• History
• Constitutional symptoms
• Recent S aureus infection
• Exam
• TTP over vertebrae
• Fever (low sensitivity)
• Labs
• Elevated CRP/ESR

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Next steps?

• Radiographic testing?
• Spine films? Dx compression fracture
• MRI? sensitive for osteo/discitis
• Laboratory testing?
• CRP? Sensitive for osteo/discitis

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Next decisions (2 min)

• Urgent surgical therapy?
• How to make micro Dx?
• Empiric antibiotic regimen?

Is surgical therapy indicated?

• Immediate indication
• Progressive neurologic deficits
• Other
• Progressive deformity and/or instability
• Persistent/recurrent infection
• Worsening pain despite appropriate Rx

N

• u

r g e n t s u r g e r y

2/17/16 23

How to make a microbiologic diagnosis?

• CT guided biopsy

How to make a microbiologic diagnosis?

• CT guided biopsy (50% sens)

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How to make a micro diagnosis?

• CT guided biopsy (50% sens)
• Blood cultures

How to make a micro diagnosis?

• CT guided biopsy (50% sens)
• Blood cultures (50% sens)
• Ok to wait on antibiotics
• If no immediate neuro threat
• If no bacteremia

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Empiric therapy: common pathogens?

S aureus 48%

GNR 23%

Strep 9%

Polymicrobial 8% S epi 7% Other 5%

McHenry et al CID 2002

Empiric therapy: common pathogens?

S aureus 48%

GNR 23%

Strep 9%

Polymicrobial 8% S epi 7% Other 5%

McHenry et al CID 2002

Ceftriaxone Vanco Vanco Vanco

2/17/16 26

Directed therapy

• Treatment usually 6 weeks
• Go to the guidelines…

2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults (Berbari E Clinical Infectious Diseases 2015

• r IDSA website)

Oral RX for S aureus vertebral osteo?

• Open-label RCT, pts with vert osteo
• Treatment: 6 wks v. 12 wks
• Most common regimen (47%):
• IV Nafcillin x 2 wk à

à FQ + Rifampin x 4/10 wk

Bernard et al. Lancet. 2015

6 wk (%) 12 wk (%) (n) 176 175 Cure 160 (91) 159 (91)

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Other infectious causes?

• Bacteria
• Tuberculosis
• Brucellosis
• Fungi
• Cocci
• Consider work-up if...
• Epi risk factors
• MRI findings
• Anterior body 1st –

disc sparing

• >2 vertebrae

Follow-up?

• Patient completed 6 wks of Rx
• Presents with continued back pain
• CRP: 4 (2-7 normal)
• MRI:
• Persistent BM edema/disc enhancement

consistent with discitis/osteomyelitis

• Unchanged from prior study (7 weeks ago)

2/17/16 28

What do you do next?

• Extend antibiotics?
• Surgery consult?
• Re-biopsy?
• Reassurance?

Follow-up?

• Back pain may persist
• MRI often not helpful
• Bone changes remain for many months
• CRP correlates with disease
• Recs:
• No follow-up MRI needed if CRP normal

and no constitutional symptoms

2/17/16 29

Epidural abscess

B

• Etiology
• Sequela of vertebral osteo/discitis
• Hematogenous to epidural alone
• Clinical
• Fever + Back Pain +/- Neuro Sx
• Diagnosis: MRI > CT
• Treatment
• Neuro deficit à urgent surgery
• Other à antibiotics (4 wks)

Take home discitis/ vertebral osteo

• Hard to diagnose: Back pain +
• Vert tender, recent bacteremia, fever, high CRP
• Micro Dx: CT guided biopsy
• Rx: 6 wks, S aureus: FQ/Rifampin
• Routine follow-up MRI not helpful
• Assuming CRP normal