CENTER FOR DRUG SAFETY AND
EFFECTIVENESS SEMINAR SERIES
IMPACT OF THE 2012 FUNGAL MENINGITIS
OUTBREAK UPON PATIENTS WHO WERE
EXPOSED BUT DID NOT DEVELOP
INFECTION
Shmuel Shoham MD, FACP
Assistant Professor of Medicine
Johns Hopkins University School of Medicine
CASE




59 year old man with chronic back pain. Received
lumbar spine injection with potentially contaminated
steroids in mid August.
Back pain increased and he underwent L3, L4, L5
laminectomy and fusion with hardware placement on
October 8th. The surgery was successful, with
improvement in his lower back pain and radicular
symptoms.
October 10th he developed a headache with
photophobia nausea,
photophobia,
nausea confusion,
confusion and possibly some
hallucinations.
Imaging showed fluid collection, CSF showed pleocytosis
CASE (continued)
(
)





CSF sent for cultures
started on IV voriconazole, liposomal amphotericin
Liposomal
p
amphotericin
p
was discontinued after a
couple of days because of acute kidney injury.
Around October 15th, a lumbar paraspinal fluid
collection was identified and drained. Fluid sent to
CDC
O b 19th,
October
19 h patient
i was discharged
di h
d home
h
on orall
voriconazole. But, this had to be stopped due to
liver toxicity
CASE (continued)
(
)




All cultures negative
Admitted to JHH with large spinal collection that
was drained and discovered to be a CSF leak
Patient discharged to home, but readmitted with
cholecystitis
Now home again
CASE






31-year-old man with chronic back pain in the thoracic area
08/31/12 steroid injection to spine
Contacted by health department and pain clinic and referred to ED for
headaches
10/7/12:
/ /
He underwent a diagnostic lumbar puncture, which she
described as very painful and then had a large amount of CSF
withdrawn. He felt unwell after tap with headaches, mental haze
leading
g to MVA,, nausea,, vomiting
g and left elbow swelling
g
Over next two weeks he was evaluated in ED on multiple occasions, was
diagnosed with a CSF leak, underwent a tap of left elbow and had a
blood patch.
Elbow with olecranon bursitis, probably related to leaning down hard
on table during time of lumbar puncture
Overview
1
1.
2
2.
3.
4.
5
5.
6.
Contaminated steroid injection outbreak: current
status
Recommendations for evaluation and treatment of
exposed patients
Clinical description of some non
non-infected
infected patients
Broader implications of these patients
Research approach to addressing this issue
Barriers, so far
Fatal Exserohilum Meningitis and Central Nervous
System Vasculitis after Cervical Epidural
Methylprednisolone Injection
Lyons J, et al. Ann Intern Med. 2012
Products linked to outbreak
New
e England
g a d Compounding
Co pou d g Center
Ce e
 Methylprednisolone Acetate (PF) 80 mg/ml Injection,
Lot #05212012@68, BUD 11/17/2012
 Methylprednisolone Acetate (PF) 80 mg/ml Injection,
Lot #06292012@26, BUD 12/26/2012
 Methylprednisolone Acetate (PF) 80 mg/ml Injection,
Lot #08102012@51, BUD 2/6/2013
14,000
14
000 persons potentially
t ti ll exposed
d to
t
medications from at least one of these lots
Map of Healthcare Facilities that Received Three Recalled Lots of
Methylprednisolone Acetate (PF) from New England Compounding Center
on September
S t b 26,
26 2012
http://www.cdc.gov/hai/outbreaks/meningitis-facilities-map.html
Maryland Healthcare Facilities that Received Three Recalled Lots of
Methylprednisolone Acetate (PF) from New England Compounding Center on
S
September
b 26,
26 2012
BALTIMORE PAIN MANAGEMENT
410-682-5040
BALTIMORE, MD
BERLIN INTERVENTIONAL PAIN
MANAGEMENT
410-641-3759
BERLIN, MD
BOX HILL SURGERY CENTER
410-877-8141
ABINGDON,, MD
GREENSPRING SURGERY CENTER
410-653-0077
BALTIMORE, MD
HARFORD COUNTY ASC, LLC
410-538-7000
EDGEWOOD, MD
PAIN MEDICINE SPECIALISTS
410 825 6945
410-825-6945
TOWSON MD
TOWSON,
SURGCENTER OF BEL AIR
410-638-5523
BEL AIR, MD
Fungal
g Infections: Epidemiology
p
gy Curve.
Smith RM et al. N Engl J Med 2012.
Persons with Fungal Infections Linked to Epidural
Steroid Injections, by State
Cases: 664
Deaths: 40
http://www.cdc.gov/hai/outbreaks/meningitis-map-large.html
Attack Rates
Smith RM et al. N Engl J Med 2012
Fungal Infections Associated with Contaminated
Methylprednisolone in Tennessee
Kainer MA et al. N Engl
g J Med 2012.
Presentation
Frequency
(%)
Meningitis alone
73
Cauda equina syndrome/focal infection
15
Posterior circulation stroke
12
Symptom
Frequency
(%)
Headache
73
Back pain
50
Neurological
48
Nausea
39
Stiff neck
29
Sample
p letter
We are sending this letter because you were administered a drug
produced
d d by
b the
th New
N England
E l dC
Compounding
di C
Center
t (NECC) th
thatt has
h been
b
recalled.
Although we do not know whether the specific drug you received was
precaution, we want you
y to know the symptoms
y p
of
contaminated, as a p
possible infection and urge you to contact your healthcare provider
immediately if you experience any of these symptoms.
You received medication that was injected into your body site. Signs and
symptoms of meningitis include fever
fever, headache,
headache stiff neck,
neck nausea and
vomiting, photophobia (sensitivity to light) and altered mental status.
Symptoms for other possible infections may include fever; swelling,
increasing pain, redness, warmth at injection site…
If you hhave any off these
th
symptoms,
t
you should
h ld seekk medical
di l care so th
thatt
you can be properly evaluated.
Diagnostic Testing CSF

Collect a large volume of CSF (10
(10-15
15 mL)
 gram stain, bacterial and fungal cultures
 If WBC >5,
>5 consider sending CSF to CDC for PCR
PCR.
 All cultures should be incubated for at least 2
weekss prior
wee
p o too discarding.
d sca d g.
CDC Guidance for asymptomatic patients who received their last
epidural or paraspinal injection with contaminated steroid product1
within
i hi the
h last
l 6 weeks
k (42
( 2 days)
d )

Option
p
1:
Clinical monitoring
 lumbar puncture should the patient become symptomatic.


Option 2. Estimated to reduce the maximal risk of
stroke or death from approximately 0.4% to 0.3% in
comparison to option 1
Perform lumbar puncture
 If the patient remains asymptomatic, consider repeating
weekly
kl lumbar
l b punctures untill 6 weeks
k (42 days)
d ) have
h
passed since the last epidural or paraspinal injection with
contaminated steroid product

Exserohilum rostratum
Agent
MIC
Voriconazole
0.06 to 4 μg/mL
(0.5-2 μg/mL in current outbreak)
AmB
0.03 to 1 μg/mL
posaconazole
0.015 to 8 μg/mL
itraconazole
0.015 to 16 μg/mL
Treatment recommendations

Antifungal
 Voriconazole:
standard recommendation
 Voriconazole + AmB: severe or progressive cases

Surgical debridement
 Abscess,

osteomyelitis
Length of Rx
A
minimum of 3 months of antifungal treatment (or
longer) should be considered
Antifungal
g Therapy:
py Voriconazole
 Dose:
ose:
6 mg/kg
g/ g eve
every
y 12 hours.
ou s.
 IV preferred to oral, especially early on.
 Measure serum voriconazole trough
g on dayy 5 of Rx and
aim for a trough of around 2 to 5 mcg/ml
 Monitor liver function tests closely
 Be aware of multiple drug interactions
 Warn patients of neuropsychiatric symptoms,
phototoxicity
Antifungal Therapy: Voriconazole
AND A
Amphotericin
h t i i B
 Indications
d ca o s
 Severe
disease
 Patients who do not improve or who experience clinical
deterioration while on voriconazole monotherapy
 Formulation:
liposomal AmB (AmBisome®)
 Dose:
D
5
to 6 mg/kg/day
 Consider 7.5 mg/kg/d if patient is not improving
 Monitoring

Renal and liver function and electrolytes
voriconazole

Neuropsychiatric
 Mild
visual changes
 Psychosis

Skin
 Photosensitivity
 Skin

cancer
Hepatic
 Hepatitis,

liver failure
Drug interactions
Amphotericin
p
B

Infusion related toxicity
 Shakes,

chills, chest pain
Renal and electrolytes
 Decreased
GFR
 Hypokalemia, hypomagnesemia

Hepatotoxicity
CSF evaluation


Pain at LP site
CSF leak
 Headache
 Mental
status changes
 Secondary infection
Early Clinical Observations in Prospectively Followed
Patients With Fungal Meningitis Related to Contaminated
Kerkering T, et al. Ann Intern Med. 2012
Epidural
p
Steroid Injections
j
Fungal Infections Associated with Contaminated
Methylprednisolone in Tennessee
Kainer MA et al. N Engl J Med 2012.
Typical patient receiving
antifungals



Medically
Immunocompromised
Well connected to
multidisciplinary
healthcare team
Medically
knowledgeable
Typical patient involved in spinal
injection outbreak



Older
Chronic pain
Care distributed over
multiple providers
Broader implications
p
of the two cases


Information regarding
g
g adverse events occurring
g in
the uninfected group is essential in order to gain a
better understanding of impact of this outbreak.
This information will be useful to multiple
stakeholders. These include patients and their
caregivers clinicians,
caregivers,
clinicians government officials and
payers as they confront the needs of those directly
affected by this current outbreak and prepare to
apply the lessons learned to prevent and manage
future ones.
Hypothesis
yp

We hypothesize that there is a large proportion of
exposed patients who do not have an infection, but
have experienced
p
adverse events related to the
outbreak.
Objectives
j

Descriptive
p
epidemiology
p
gy and clinical outcomes



Patient characteristics (e.g. age, gender, reason for injection, site
of injection, vial number, number of injections, co-morbid
conditions,, concomitant medications))
Utilization of medical resources (e.g. additional outpatient visits,
emergency department visits, inpatient hospitalization, lumbar
puncture,, imaging,
p
g g, antifungal
g therapy,
py, laboratoryy testing)
g)
Adverse experiences (AE) related to evaluation and therapy:



Lumbar puncture AE (e.g. headache, dural leak requiring blood
p
patch)
)
Antifungal therapy AE (e.g. renal, hepatic, neuropsychiatric,
cutaneous)
Psychological sequelae, missed days of work, quality of life
Objectives
j
((continued))

Analysis of risks for:
 AE
related to antifungal therapy
 AE related to lumbar puncture
 Adverse psychological sequelae
Planned approach:
pp

Primary sources of data
 List
of exposed patients:
 Through
g
providers,
p
, health department
p
records,, CDC
 Methods:
 Patient

interviews
Phone based structured survey with validation of the response)
 Review
of medical records
Planned approach:
pp

Secondary sources of data
 Utilization
of administrative health plan claims data
(blue health intelligence, united healthcare database,
Medicare)
 Review of pharmacy databases
Barriers

Primary data sources
 Access
to patients: providers are scared
 Health departments and patient confidentiality issues

Secondary data sources:
 Identifying
exposed patients and accurately cross
referencing with desired outcome measures