Transcript “What empiric antifungal antibiotic would you use for meningitis?”

“What empiric antifungal
antibiotic would you use for
meningitis?”
UNC Wednesday Conference
Case #1
Kees van Dam
HPI
 25
yo Caucasian female with history of
severe Cystic Fibrosis underwent a
double lung transplant on 1/10/07.

On 1/11/07 she underwent evacuation of
a left sided hemothorax as well as
takedown and revision of the left
pulmonary artery anastomosis.
HPI
 Post-operative
course further complicated
by episode of asystole after central line
placement (sp) resuscitation.
 Renal
failure thought to be due to
tacrolimus. Patient had been on CVVHD
since 12307.
HPI
 She
was difficult to “wean” from ventilator
but on 2/5/07 was successfully extubated.
 She
 She
had been on TPN during this time.
has required epogen for anemia and
has had several blood transfusions, most
recently on 2/8/07
HPI
the night of the 9th, an RN was
drawing blood from the patient who
appeared confused and asked RN what
she was doing. Patient then began staring
into space and gasping for breath. She
was given narcan for possible dilaudid OD.
She had twitching all over for a few hours.
She was intubated. Neurology called, MRI
of brain performed.
 During
MRI: 2/9/2007
 1.
Leptomeningeal enhancement, most
prominently seen over the posterior
parietal and occipital lobes.
HPI
 Critical
Care Fellow on Transplant Service
was preparing for LP and called ID Fellow
on call with question “What empiric
antifungals should we place this patient on
after LP?”
Past Medical History
 Cystic
fibrosis:
 Severe pulmonary disease on 4L via NC
continuously
 Portal gastropathy
 Hepatic disease
 Pancreatic insufficiency
 H/O Multi-drug resistant pseudomonas.
 Massive hemoptysis in 2005.
 Hypertrophic pulmonary osteoarthropathy
Social History
 She
was living nearby in a temporary
house with her father prior to transplant
surgery. Had worked as social worker in
the midwest. No etoh, no tobacco. Travel
history unknown.
Family History
 M:
alive. Has mitral valve prolapse.
F: alive. No pmhx.
Sibs: older brother no pmhx.
extended family members w/ CF
Medications: Antibiotics

Tobramycin 160mg IV X 1 on 01/25/07
 Fluconazole 50 IV QD started 01/23/07 02/04/07
 Ciprofloxacin 400mg IV qhs 1/25/07  present
Cefepime 1g IV Q12H--> changed 2grams iv q 12-->

Vancomycin 1 gram IV 2/9/07-->
 Flagyl 500 mg q 6 2/9/07-->
 Acyclovir 250mg iv qday 2/907-->
 Abelcet 300mg iv qday 2/9/07-->

Nystatin swish

Chlorhexadine mouth care
Other Medications:

Insulin gtt

Dilaudid PCA
Heparin gtt (off)
 Dopamine gtt
Cyclosporine 6mg/hr (gtt started 01/21/07)


Methylprednisolone 10mg/12.5mg I bid
Azathioprine 100mg IV qd

Nexium 40mg QD

Epoetin 4000units m/w/f

Bupivicane via thoracic epidural

Albuterol MDI q6

ADEK vitamins po bid

Ativan

TPN --stopped today
Allergies
 AUGMENTIN
 Keflex
 Chloramphenicol
 Azithromyicn
PE
 Tmax 37.5 maps 50-80 ,pulse in 80s, rr 18-20
pox 98 on 4L until intubation Now on SIMV
100% 10/5 Tv 500

Primary team exam:

General: “jerking”

HEENT: NC/AT, pupils ovoid, not reactive

CV: RRR, NL no mgr
Lung: good air mvt
 Abd: soft, no bs
Ext: 2+ LE edema, clubbing present
Labs:









CO2 22
BUN 26 H
Creatinine 1.6 H
Albumin 1.6
Bilirubin (total) 4.7
Biliruin (direct) 4.2
AST 66
ALT 51
Alk P 671
GGT 314

WBC 3.2
HGB 8.4
HCT 24.7
Platelets 53

Microbiology:

2/9/07: CVAD TEMP BLOOD pending
2/9/07: peripheral Blood pending




CXR:
Labs:

LP: opening pressure 20cmH20:


CSF ANALYSIS
tube #14
YELLOW


RBC 7635
TNC 15 20

Neutrophils 11 %
Lymphocytes 22 %
Monocytes 67 %

Protein 295
Glucose 63
Labs:
 CSF:
Gram stain
 1+ PMN’s
2+ YEAST
Discussion
Micro:



CF BAL 1/31/07: right
Probable Smooth Pseudomonas aeruginosa 3+
FURTHER I.D. BY CONSULTATION ONLY

NOTE 1/19/07 BAL RLML had been sent for

VIRAL, AFB AND FUNGAL cultures and had failed to grow any
organism other than candida.



Probable Stenotrophomonas maltophilia 1+
FURTHER I.D. BY CONSULTATION ONLY
PNEUMOCYSTIS DF NEGATIVE
CMV PCR, QUAL NEGATIVE


1/25/07 SPUTUM INDUCED
Smooth Pseudomonas aeruginosa 2+

TICARC/CLAVULAN R
PIPER/TAZOBACT S
IMIPENEM R
CEFEPIME R
CEFTAZIDIME R
GENTAMICIN R
TOBRAMYCIN I
AMIKACIN R
TRIMETH/SULFAMET R
LEVOFLOXACIN R











CF BAL 1/19/07:RLML:
Probable coagulase-negative Staphylococcus
species 1+

2 Probable Smooth Pseudomonas aeruginosa
I.D. BY CONSULTATION ONLY



CF ADULT BAL
2007-01-19 at 0820 Site: RLML

Probable Smooth Pseudomonas aeruginosa

<10,000 ORGANISMS/ML

Micro:

CF TRACHEAL (PRE-TRANSPLANT LUNGS) 1/10/07:


1 Smooth Pseudomonas aeruginosa

4+


PIPERACILLIN MIC 8 S
TICARC/CLAV MIC 64 S

MEROPENEM R

PIP/TAZO MIC 8 S


IMIPENEM R
IMIPENEM MIC 1 S


CEFEPIME MIC 8 S
CEFTAZIDIME MIC 2 S




GENTAMICIN MIC 32 R
TOBRAMYCIN MIC 32 R
AMIKACIN R
TRIMETH/SULFAMET R


CIPROFLOXACIN R
CIPROFLOXAC MIC 0.25 S

LEVOFLOXACIN R



COLISTIN MIC 2
AMIKACIN MIC 4 S
AZTREONAM MIC 16 I









2 Mucoid Pseudomonas aeruginosa 4+
TICARC/CLAVULAN S
PIPER/TAZOBACT S
CEFTAZIDIME S
GENTAMICIN R
TOBRAMYCIN S
TRIMETH/SULFAMET R
CIPROFLOXACIN S
LEVOFLOXACIN S
3 Stenotrophomonas maltophilia


<1+
3 COLONIES





TICARC/CLAV MIC 64 I
CEFTAZIDIME MIC >=256 R
TRIMETH/SULFAMET S
LEVOFLOXACIN R
MINOCYCLINE S
Course:
 ID Abx
recs:
 ABELCET
5MG/KG IV QD
 FLUCYTOSINE 25MG/KG QDAY WITH
FLUCONAZOLE 400MG IV X1
5MG/KG IV GANCYCLOVIR QOD
 CONTINUE:
 CEFEPIME
2 GRAMS IV Q 12
VANCOMYCIN 1 GRAM QDAY
Labs: CSF

Gram Stain: Yeast was error, there were no
yeast visualizable on gram stain 2/9/07

Fungal stain: no fungal elements

AFB stain: no organism

Crypto Ag: Negative 2/9/07

Bacterial cultures: No growth
Course:
 3PM,
RN noticed anisocoria and L pupil
non-reactive.
 Neurology
STAT dose mannitol and w/
dilantin.
 Pt
went for stat head Ct:
CT head 2/11/07

A right frontal ventriculostomy catheter

Diffuse sulcal effacement with thickening of the cortex.

Loss of gray-white differentiation and hypodensity in the left parietooccipital region.

There is diffuse hypodensity of the cerebellum and brainstem.

The basilar cisterns are nearly completely effaced.


The lateral ventricles are smaller

Impression:

Worsened diffuse cerebral edema
Course:
 Neurosurgery
saw pt: on exam she had
lost cough, gag reflexes, corneal reflexes,
she had flexed RUE, semipurposeful
with bilateral extended LE.
 Concern
 ICP
for herniation: placed EVD
35-40 10th-11th
Course: 1/11/07
 off
 no
sedation x 1 hr
EO, R 7mm ovular and NR and L 8 mm
ovular , NR
no corneals
 no cough
 no gag
 no motor response to central pain
 no oculocephalic
no oculovestibular (cold calorics)
Labs: CSF
 Bacterial
cultures: No growth
 AFB: no growth
 Fungal culture no growth
 CSF: VDRL negative
 Arbovirus
Panel Serum : Negative EEE,
WEE, St. Louis, Lacrosse, West Nile Virus
Labs: CSF

HSV PCR :NEGATIVE
 VZV PCR: NEGATIVE
 HHV6 PCR: NEGATIVE

CMV PCR QUAL POSITIVE


CMV VIRAL LOAD BLOOD: 140785 copies

EBV VIRAL LD,BLD UNDETECTABLE
Immunology:


1/16/07: TOXOPLASMA IGG NEGATIVE
1/16/07 TOXOPLSMA IGM AB NEGATIVE

1/12/07: CMV IGM NEGATIVE
1/12/07: CMV IGG POSITIVE

EBV SEROLOGIES 1/11/07:






EBV VCAG IGG POSITIVE
EBV VCAG IGM NEGATIVE
EBV NUCLEAR IGG POSITIVE
1/2007 HSV 1 and 1 IgG and IgM negative, prior test 2 years earlier
positive for HSV IgG
CMV: B Herpes Virus

Cytomegalovirus: B herpes virus:

Isolated first from human salivary gland.

Largest virus that infects humans

Linear double stranded DNA encodes 230
nonoverlapping ORFs.
CMV

Transmitted by: blood, tissue exposure, perinatally,
sexual contact, household occupational exposure.

Primary and Secondary Infection:

Like all other herpes viruses CMV can establish latent
infection.

PMN’s, T lymphocytes, endothelial vascular tissue, renal
epithelial cells, salivary glands, can harbor latent virus.

Immunosuppression: HIV infection, immunosuppressive
therapy (ex antilymphocyte antibody (OKT3) infusion.
Illness, can lead to activation from latent state.

CMV: Mononucleosis

CMV in healthy young adult can cause infectious mononucleosis
syndrome (est 21%); fever, lymphadenopathy, lymphocytosis.

Typically “typhoidal” with predominance of fever, lack of sore-throat,
enlarged exudative tonsils found in EBV mono.

No heterophile antibodies in blood. Low level LFT abnormalities.
Jaundice rare

Rare complications: Insterstitial PNA, hepatitis, GB syndrome,
Meningoencephalitis, myocarditis, TTPenia, hemolytic anemia,
rashes

60-70% CMV seroprevalence in US cities, 100% in some parts of
Africa.
CMV: HIV, AIDS pts.

HIV, AIDS: CMV most commone viral opportunistic
infection (21-44% of pts with AIDS in pre HAART):

CMV retinitis

CNS:Polyradiculopathy, Mononeuritis multiplex, painful
neuropathy, Meningoencephalitis (see further)

GI: Esophagitis, Colitis, cholecystitis, acalculous
cholecystitis.
CMV and transplant recipients
 CMV
infection can result in pneumonia,
hepatitis, pancreatitis, and gastrointestinal
side effects, among others, in the
transplant recipient.
See timeline for onset Fig. 26–14 in:
Sabiston. Textbook of Surgery: the Biological Basis of Modern
Surgical Practice. 17th ed.
Book available online via the UNC-CH Libraries
CMV: After Organ Transplant

CMV infections typically occur within first 120 days post transplant
when immunosuppression is greatest.

Antithymocyte infusions, cyclophoshamide, aztothioprine, steroids,
cyclosporine

Degree of immunosuppression correlates with risk for infection with
BMT > renal transplantation.

Symptomatic infection SOT: in 8% kidney, 29% liver, 25% heart,
50% kidney/pancreas, 22% small bowel, 39% heart-lung
CMV: After Organ Transplant

CMV: pneumonitis, hepatitis, esophagitis, colitis,
GB, pancreatitis, epididymitis, retinitis,
meningoencephaltis.

Frequently occurs in transplanted organ.
 Risk dependent on Serological status of
Donor(D) and Recipient

D+/R- (85%)> D+/R+ (69%> D-R+(58)> D-/R-

Primary infection from blood, transplanted organ, or more commonly
reactivation.
CMV: Prophylaxis and Preemptive Rx

Prophylaxis: Universal, Selective (D+/R-, D-/R+)
prophylaxis with acyclovir, valacyclovir, gancyclovir,
valgancyclovir.

Preemptive Rx: Monitor peripheral blood viral load,
evidence of end-organ disease and then treat.
CMV CNS Disease:
 CMV:
hematogenous spread in
monocytes, macrophages from blood to
CNS.
 Possibly
 Can
through direct infection of CNS
infect: astrocytes, neurons,
oligodendroglia, capillary endothelia
CMV CNS Disease: Most Data
from HIV, AIDS
Reported cases of cytomegalovirus of the
brain, 1965 to 1995

See table in:

Arribas et al, Cytomegalovirus Encephalitis, Annals of Internal
Medicine, 1996, Vol 125, Issue 7
CMV CNS Disease: Polyradiculopathy

Symptoms:


Initial lower extremity weakness
Sacral pain, paresthesias
 Urinary retention
 Ascending flaccid paralysis




Labs:
CSF:
Polymorphonuclear pleocytosis, Low Glucose (<40)
+CMV by PCR in CSF

Peripheral Blood: CMV viremia

MRI: may see transverse hyperintense lesions on T2WI, gad enhancement
of myelin, meninges, roots of spinal cord.

Treatment: Critical early diagnosis, IV gancyclovir, (if exp to gancylovir) add
foscarnet, (50% respond, CI1995)
CMV encephalitis lesions
Pathologic lesions associated with
cytomegalovirus encephalitis

See images in:

Arribas et al, Cytomegalovirus Encephalitis, Annals of Internal
Medicine, 1996, Vol 125, Issue 7
CMV: Encephalitis
 The
microglial form: first described in renal
transplant patient. Several glial nodules
predominantly in grey matter.
CMV: Ventriculoencephalitis

Clinical: Can have abrupt presentation of confusion,
apathy, impaired memory, withdrawal, nystagmus, motor
weakness, cranial nerve deficits, ataxia, seizures, coma.
Can rapidly progress.

Labs:
CSF: Monocytic Pleocytosis, Low Glucose
CMV PCR Positive in CSF:
(Sensitivity, Specifity 80, 90%, PPV, NPV, 86-92, 9598%)
Serum CMV viremia





MRI: Subependymal enhancement, diffuse hyperintense
T2WI, ventriculomegaly.
MRI of CMV patient
Magnetic resonance images of a patient with
cytomegalovirus ventriculitis

Ependymal enhancement after injection of gadoliniumDPTA seen on coronal T1-weighted image.
 Highly abnormal ependmal signal on proton densityweighted image of the brain in axial section.

See images in:

Arribas et al, Cytomegalovirus Encephalitis, Annals of Internal
Medicine, 1996, Vol 125, Issue 7
CMV Encephalitis in Transplant Patients

Miller et al, 2005, reviewed 4 prior documented
cases (+one probable case) with new case of
CNS infection in Peripheral Blood Stem Cell
Transplant Patients.

3 of 4 documented cases clinically had evidence
of ventriculoencephalitis.

Rapid progression of cognitive dysfunction,
confusion.
CMV Encephalitis in Transplant Patients

2 of patients including their case report had high CSF
viral loads (ex > one million) with relatively low viremia,
2K range

4 of 5 had CSF DNA genotypes performed.

One had UL97 (gancyclovir R) and one had UL54 (R to
gancylovir and cidofovir)

Despite failing antiviral therapy, 2 of patients had no
resistance mutations in DNA derived from CSF.


Compartamentalization of CMV disease to CNS?
Problems with CNS levels of Drugs?
Autopsy of Brain
See Figure 1 in:
Miller,G et al, Cytomegalovirus Ventriculoencephalitis in Peripheral
Blood Stem Cell Transplant Recipient, CID 2006: 42: e26-9.
CMV Encephalitis: Treatment
 Appropriate
treatment is not defined
 Anduze-Faries,et
al (2000) published
nonblinded pilot, multicenter study
with HIV infected patients with myelitis
(14), encephalitis (17) of patients who
received gancyclovir 5mg/kg iv bid,
foscarnet 90mg/kg bid for median of 41
days followed by maintenance therapy
with once daily gancyclovir and foscarnet.
CMV Encephalitis: Treatment
 23
(74%) showed clinical improvement or
stabilization, 8 did not respond.
 Median
survival for all of the patients was
3 months.
 Many
experts recommend dual
gancyclovir, foscarnet bid, followed by
lifelong once daily dose of combination
therapy
CMV Encephalitis: Treatment
 Other
drugs:
 Cidofovir
(cytosine analog with probenecid
 Leflunomide:
assembly
interferes with late stage viral
References:

Arribas et al, Cytomegalovirus Encephalitis, Annals of Internal Medicine,
1996, Vol 125, Issue 7

Boivin, Guy. Diagnosis of Herpesvirus Infection of the Central Nervous
System, HERPES

Crumpacker and Wadwa, chapter 134 Cytomegalovirus, Mandell and
Bennett’s Textbook of Infectious Disease, p 1786-, 2005

Book available online via the UNC-CH Libraries

Griffiths, Paul, Cytomegalovirus Infection in the Central Nervous System,
HERPES,

Maschke, M et al, CNS Manifestations of Cytomegalovirus Infections:
Diagnosis and Treatment, CNS Drugs 2002: 16(5) 203-315.

Miller,G et al, Cytomegalovirus Ventriculoencephalitis in Peripheral Blood
Stem Cell Transplant Recipient, CID 2006: 42: e26-9.

Trulock, F, Cytomegalovirus infection in lung transplant recipients, UptoDate
2006.
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