Staphylococcus epidermidis Meningitis/Ventriculitis

Clinical Presentation of CSF Shunt Infections

21. T.A., a 21-year-old woman with a history of congenital hydrocephalus,
is admitted to the neurosurgery unit for worsening
mental status and fever. T.A. has a history of multiple revisions
and placements of intraventricular shunts for control of hydrocephalus.
Currently, she has a ventriculoperitoneal (VP) shunt,
which was placed 1 month ago and previously had been functioning
normally. Over the past few days, T.A. has developed worsening
obtundation, stiff neck, and a temperature of 39.5◦C. A CT
scan performed today reveals enlarged ventricles consistent with
acute hydrocephalus.
T.A.’s medical history is noncontributory except for a seizure
disorder for which she takes phenytoin 400 mg PO QHS. She also
takes Lo-Ovral for birth control. T.A. is allergic to sulfa drugs
(severe skin rash). Her weight on admission is 60 kg.
Laboratory analysiswas significant for aWBCcount of 14,000
cells/mm3 (normal, 3,200–9,800), with a differential of 85% PMN
and 10% lymphocytes; BUN and SrCr values were within the
normal range at 19 mg/dL and 0.9 mg/dL, respectively.
A tap of T.A.’s shunt was performed, and the ventricular fluid
was notable for total protein of 150 mg/dL (normal,<50), glucose
of 40 mg/dL (normal, 60% of serum glucose), and a WBC count
of 200 cells/mm3 (normal, <5 cells/mm3), with 85% PMNs and
10% lymphocytes. Gram stain of the ventricular fluid showed numerous
gram-positive cocci in clusters. What are the subjective
and objective findings of CSF shunt infections, and what manifestations
of this type of infection are present in T.A.?
[SI units: WBC count, 14 × 109 cells/L with 0.85 PMN and 0.1 lymphocytes;
BUN, 6.8 mmol/L urea; SrCr, 80 μmol/L; total protein, 1.0 g/L; glucose, 2.2
mmol/L;WBCcount, 200 ×106 cells/L with 0.85 PMN and 0.1 lymphocytes]
T.A. appears to have meningitis with ventriculitis secondary
to infection of herVPshunt. The most importantway to manage
hydrocephalus involves the use of devices that divert (shunt)
CSF from the cerebral ventricles to other areas of the body such
as the peritoneum (VP shunts) or atrium (VA shunts).8,121,122
This approach alleviates increased CSF pressure and substantially
reduces morbidity and mortality.121,122 Infection of these
devices, however, is a common cause of shunt malfunction, as
seen in T.A. The reported incidence of CSF shunt infections
varies from 2% to 39% (usually between 10% and 11%) and
depends on patient factors, surgical technique, and the type
and duration of the procedure performed (i.e., shunt revision
versus placement of a new device).121,122 T.A., who has been
hydrocephalic since birth and has a history of multiple shunt
procedures, is at high risk for such an infection.
Clinical symptoms associated with infected CSF shunts
vary widely from asymptomatic colonization to fulminant ventriculitis
with meningitis.121−123 Fever is common and, in many
instances, is the only presenting symptom.121 CSF findings also
are slightly different in shunt infection compared with acute
meningitis: the WBC count usually is not as elevated, the decrease
in CSF glucose is less pronounced, and the protein value
may be normal or slightly elevated.121,122 CSF culture is positive
in most patients not receiving concurrent antibiotics.123,124
T.A.’s clinical presentation, CSF findings, and radiographic evidence
of hydrocephalus are highly suggestive of a VP shunt
infection. She is febrile and has altered mental status. The presence
of a stiff neck strongly suggests meningeal involvement.
Evaluation of T.A.’s ventricular fluid reveals a slightly elevated
WBC count, with a predominance of polymorphonuclear neutrophils,
an elevated protein concentration, and a slightly lower
than normal glucose concentration.
Skin microflora are the most common causes for CSF
shunt infections.121−124 Staphylococci account for 75% of all
cases, with two-thirds of these caused by coagulase-negative
staphylococci (usually S. epidermidis) and one-third by S.
aureus.123,124 Other less common pathogens include diphtheroids,
enterococci, and Propionibacterium acnes (an anaerobic
diphtheroid). Enteric gram-negative bacilli are responsible
for a small percentage of cases; these cases usually occur
when the distal end of the shunt is inserted improperly into the
peritoneal cavity.123,124 The gram-positive cocci in clusters on
Gram stain of T.A.’s CSF strongly suggest a staphylococcal
shunt infection. Determining the coagulase status of the isolate
will allowdifferentiation between S. aureus and S. epidermidis.
Treatment of CSF Shunt Infections
22. Culture and sensitivity tests of T.A.’s ventricular fluid are
positive for S. epidermidis. The isolate is resistant to nafcillin but
sensitive to vancomycin, rifampin, and TMP-SMX. How should
T.A.’s CSF shunt infection be treated?
For T.A.’s CSF shunt infection to be optimally treated, a
combined medical and surgical approach is required.117,118,125
Antibiotic therapy directed against the causative organism,
although essential, often is inadequate by itself. On average,
antibiotic therapy by itself produces cure rates of <40%.124 In
contrast, antibiotic therapy plus surgical removal of the infected
device produces clinical cure rates of>80%.124 Because many

patients cannot tolerate the complete removal of their shunt for

long, externalization of the distal end of the shunt, or shunt removal

and placement of an external drainage device, often is

necessary during systemic antibiotic therapy. The presence of

an externalized device permits sequential sampling of ventricular

fluid and also provides a convenient way to administer

antibiotic intraventricularly (see the following discussion).

GLYCOCALYX

Although S. epidermidis is not as virulent a pathogen as

S. aureus, it is extremely difficult to eradicate this organism

from prosthetic devices such as CSF shunts. This is because

many strains of S. epidermidis produce a mucous film or slime

layer known as glycocalyx, which allows the staphylococci to

adhere tightly to the Silastic shunt material, protecting them

against phagocytosis.126,127 As expected, antibiotic failures are

much more likely with slime-producing strains of S. epidermidis.

Vancomycin is the drug of choice for treatment of shunt

infections caused by S. epidermidis and should be instituted

immediately in T.A.8,121,127 This is because a high percentage

(>60%) of coagulase-negative staphylococci are resistant

to methicillin (e.g., methicillin-resistant S. epidermidis

[MRSE]). Furthermore, methicillin-resistant staphylococci

(both methicillin-resistant S. aureus [MRSA] and MRSE) also

are resistant to cephalosporins. T.A.’s isolate also is sensitive

to TMP-SMX, as is the case with many strains of MRSE (and

also MRSA),8 and it must be avoided because T.A. is allergic

to this drug combination. Although many staphylococcal

isolates (both S. epidermidis and S. aureus) are susceptible to

rifampin, monotherapy with this drug is not recommended because

of rapid emergence of resistance. Combination therapy

with vancomycin and rifampin may be synergistic and sometimes

is used.

VANCOMYCIN THERAPY

23. What would be an appropriate dosage of vancomycin therapy

in T.A.? What subjective or objective data should be monitored

to evaluate the efficacy and toxicity of the treatment?

Vancomycin therapy for T.A.’s CSF shunt infection requires

the use of higher than usual doses, which is true for

the treatment of other types of staphylococcal CNS infections

as well.8,56,128 For adults such as T.A., vancomycin dosages

of 20 to 30 mg/kg/day to a maximum of 2 g/day have been

suggested. Even higher dosages, however, may be required

in patients with fulminant disease (Table 58-6).8,56,96,128 For

children with meningitis or infected shunts, the recommended

dosage of vancomycin is 40 to 60 mg/kg/day, given IV in two to

four divided doses (Table 58-6).8,56 Although specific recommendations

are lacking, it is reasonable to target serum trough

concentrations of vancomycin toward the higher end of the target

range (i.e., ∼15 to 20 mcg/mL). With an every-12-hour

dosing schedule, peak serum levels will approach or possibly

exceed 40 mcg/mL. It is unlikely, however, that peak serum

concentrations of >60 mcg/mL will be observed. Although

the potential for toxicity may be greater, higher than usual

vancomycin serum concentrations are warranted to ensure adequate

penetration into the CSF.96,128

T.A., who weighs 60 kg, should be started on a vancomycin

regimen of 1 g IV Q 12 h (∼30 mg/kg/day) because her renal

function is normal. Alternatively, the dose could be calculated

using population estimates of vancomycin pharmacokinetic

parameters to achieve a trough serum concentration of 15

mcg/mL. In either case, trough serum concentrations should

be obtained at steady-state to assess whether the initial dosing

regimen is adequate.

Anecdotal evidence suggests that very high dosages of vancomycin

(≥3 g/day in adults with normal renal function) are

associated with an increased risk of ototoxicity.96,129 This observation

is difficult to verify because hearing loss also is a

potential sequelae of meningitis. High-dose vancomycin therapy

also has a greater likelihood of inducing the “red man

syndrome.”130,131 This adverse effect, manifested by flushing

and pruritus, with or without hypotension, is related directly

to the amount of drug infused over a given period of

time.130 It usually can be avoided or minimized by infusing

vancomycin doses of 1,000 mg in ≥250 mL of solution (either

D5W or normal saline) over at least 1 hour. If red man

syndrome is observed, slowing the infusion rate often ameliorates

symptoms.130 Pretreatment with antihistamines (diphenhydramine

or hydroxyzine) may also minimize the reaction

because the proposed mechanism partially involves histamine

release.131

Another consideration for T.A. is the addition of rifampin

to her vancomycin regimen. This is based on the excellent

staphylococcal activity of rifampin, its good CSF penetration,

and the potential for synergy between these two agents.8,121

Whether rifampin plus vancomycin is superior to vancomycin

alone has not been determined. For T.A., it is best to avoid

rifampin because evidence supporting its efficacy is weak, and

she currently is taking phenytoin and birth control pills. Rifampin

is a potent inducer of hepatic microsomal enzymes,

which can lower serum phenytoin concentrations (possibly resulting

in seizure activity) and increase the possibility of an

unplanned pregnancy (from reduced effectiveness of the birth

control pill).

Intraventricular and Intravenous Dosing of Vancomycin

24. Should T.A. receive intraventricular vancomycin? If so,

what would be an appropriate dosage?

T.A. has a long history of hydrocephalus and will require

placement of an external drainage device after removal of

her VP shunt. This makes intraventricular administration of

vancomycin possible, and such treatment should be instituted

promptly. The dosages used in the literature vary from 5 to

20 mg/day. Experts recommend 20 mg/day of intraventricular

vancomycin; therefore, an intraventricular vancomycin dosage

of 20 mg/day is recommended for T.A. Also, serial (daily)

cultures of CSF are recommended to monitor her response to

therapy. Some authors suggest adjusting intraventricular vancomycin

doses to achieve trough CSF vancomycin concentrations

of at least 5 mcg/mL orCSFbactericidal activity of at least

1:8 against the infecting strain.8,121 Until more information is

available, monitoring serial CSF trough concentrations is more

appropriate thanCSFbactericidal titers, and serial trough levels

should be obtained in T.A. To summarize, T.A. should receive

combined IV and intraventricular vancomycin therapy as described

previously. Therapy should be continued for at least 10

days after sterilization of her ventricular fluid is documented,

at which time a new VP shunt can be placed.121,124,132

In contrast to T.A.’s situation, vancomycin therapy for patients

with staphylococcal meningitis not associated with a

CSF shunt or indwelling ventricular catheter is more problematic.

Because of this, therapy often is instituted with IV vancomycin

alone.96,128 Intrathecal vancomycin, although preferable,

requires either daily lumbar puncture (for intralumbar

therapy) or surgical placement of an intraventricular reservoir.

If the response to therapy is inadequate within the first 24 to

48 hours, the addition of intrathecal vancomycin therapy (5

to 20 mg/day) is recommended.96,128 In fulminant cases of

staphylococcal meningitis, however, intrathecal vancomycin

should be instituted as quickly as possible (i.e., with the first

lumbar puncture) to optimize the response to therapy.

BRAIN ABSCESS

Epidemiology

Although not nearly as common as meningitis, abscesses of the

brain parenchyma (brain abscess) remain an important type of

CNS infection. The incidence of brain abscess has not varied

since the preantibiotic era and is estimated to account for 1 in

10,000 hospital admissions.133 On a busy neurosurgical service,

4 to 10 cases a year typically are seen.133,134 For reasons

that are not entirely clear, men are more likely to develop abscesses

within the brain than women.133,135 Brain abscess can

occur at any age, but the median age is 30 to 40 years, with

approximately 25% of cases occurring in children.133,136,137

Despite advances in antimicrobial therapy over the past several

decades, mortality rates from brain abscess has remained

above 40% until just recently. Developments in imaging techniques

(e.g., CT and MRI scanning), which allow early recognition

of abscesses and the ability to serially monitor the radiographic

response to antimicrobial therapy, have had the most

profound impact on reducing morbidity and mortality from

brain abscess.133,134,138 In a review of 102 cases of bacterial

abscesses occurring over a 17-year period, mortality was 41%

in the period before 1975 (pre-CT scan era), compared with

6% during 1975 to 1986, when CT scanning became routinely

available.134With the combined medical and surgical approach

currently recommended, mortality rates continue to average

<10%.133,134,138
Predisposing Factors

Brain abscesses most commonly arise from a contiguous

suppurative source of infection (e.g., sinusitis, otitis, mastoiditis,

or dental infections).133,135,139 In the United States,

abscesses occurring as a complication of sinusitis are more

common than abscesses arising from otitic or dental sources.133

The formation of a single abscess cavity usually is found

when infection develops from a contiguous source. In addition,

the abscess nearly always is formed in close proximity

to the primary focus of infection (Table 58-10).133,139 For example,

abscesses of sinusitic origin more commonly involve

the frontal lobe, whereas otitic infections often lead to temporal

lobe abscess formation.139 Brain abscess also occurs as a

consequence of metastatic spread of organisms from a primary

site of infection (e.g., lung abscess, endocarditis, osteomyelitis,

pelvic, and intra-abdominal infections).129,131 In children,

cyanotic congenital heart disease is a common predisposing

factor for brain abscess.136,137 Multiple abscesses suggest a

metastatic source of infection.133 As with meningitis, brain

abscess occurs as an infrequent complication of head trauma

or neurosurgery.11,133,139 No identifiable source (cryptogenic

abscess) is detected in as many as 30% of cases.133,139

Staging

Once an intracranial focus of infection is established, the evolution

of brain abscess involves two distinct stages: cerebritis and

capsule formation.136,138 The cerebritis stage evolves gradually

over the first 9 to 10 days of infection and is characterized by an

area of marked inflammatory infiltrate that contains a necrotic

center surrounded by an area of cerebral edema.136,138 Capsule

formation occurs about 10 to 14 days after the initiation of infection,

and once formed, the capsule continues to thicken over

a period of weeks.136,138 The stage of abscess development has

important implications for therapy. Although it is best to wait

until the capsule is fully formed before attempting any type of

surgical intervention, antimicrobial therapy alone may resolve

the infection if discovered in the early cerebritis stage.138

Microbiology

The microbiology of brain abscess is distinctly different from

that of meningitis. Streptococci are implicated in 60% to 70%

of cases and include anaerobic aswell as microaerophilic streptococci

of the S. milleri group.133,139,140 Other anaerobes, particularly

Bacteroides species (including B. fragilis) and Prevotella

species, are found in up to 40% of cases, usually in

mixed culture.133,139 In recent years, staphylococci appear to

be decreasing and enteric gram-negative bacteria increasing as

etiologic agents of bacterial brain abscess.123 Although somewhat

imprecise, a reasonable correlation exists between the

various predisposing conditions and the microbiologic etiology

of brain abscess (Table 58-10).133,135,137,138

In the immunocompromised patient, a diverse group of microorganisms

can induce abscesses within the brain. In patients

with AIDS, Toxoplasma gondii is by far the most common infectious

cause of focal brain lesions.141 Transplant recipients

and those receiving immunosuppressive therapy are susceptible

to infection from Nocardia species.142 In Mexico and other

Central American countries, cysticercosis

Table 58-10 Predisposing Conditions, Microbiology, and

Recommended Therapy for Bacterial Brain Abscess

Predisposing Condition Usual Location of Abscess Most Likely Organisms

Recommended Therapy

Contiguous Site
Otitic infection Temporal lobe or cerebellum Streptococci (anaerobic and
aerobic), Bacteroides
fragilis, gram-negative bacilli
Penicillin G + metronidazole +
cefotaxime or ceftriaxone
Sinusitis Frontal lobe Streptococci (predominantly), Bacteroides species,
gram-negative bacilli, Staphylococcus aureus,
Haemophilus species
Penicillin G + metronidazole +
cefotaxime or ceftriaxone
Dental infection Frontal lobe Fusobacteria species, Bacteroides species, and
streptococci
Penicillin G + metronidazole

Primary Infection
Head trauma or
neurosurgery
Related to site of wound Gram-negative bacilli, staphylococci, streptococci,
diphtheroids
Vancomycin + ceftazidime