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guidelines for the use of rotavirus vaccine. Pediatrics. 2009;123(5):e764–e769.
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Rep. 2010;59:1074]. MMWR Recomm Rep. 2009;58(RR-2):1.
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MMWR Recomm Rep. 2013;62(R-4):1–34.
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The most common symptoms of meningitis include the triad of fever,
stiff neck, and altered mentalstatus. In neonates and infants, irritability
and poor feeding may be reported along with fever. In the elderly, signs
Adjunctive dexamethasone should be initiated in all patients with
suspected bacterial meningitis either before or concomitant with the first
Intraventricular antibiotics should be considered for patients with
meningitis who have an external drainage device in place. Such therapy
should be used in combination with systemically administered therapy.
Cerebrospinal fluid (CSF) is essential in confirming the diagnosis of
meningitis. The CSF typically contains many white blood cells (WBCs)
with a predominance of neutrophils. Additionally, CSF protein is
typically elevated to greater than 100 mg/dL with a low CSF glucose
concentration (either less than 50 mg/dL or less than 50-60% of a
simultaneously obtained serum glucose value).
Response to therapy should be monitored by resolution of fever, altered
mentalstatus, and stiff neck. A baseline level of mentalstatus should be
evaluated for this reason. Delays in response to therapy may require a
repeat lumbar puncture to re-examine CSF cultures, which are usually
sterile after 18 to 24 hours of therapy. Clinical response should be seen
between 24 and 48 hours of initiation of therapy.
The choice of empiric therapy in patients with meningitis is primarily
driven by age and the presence of predisposing conditions
(postneurosurgical, head trauma, immunocompromised).
Brain abscess is associated with a different spectrum of pathogens,
including oral anaerobes, staphylococci, and aerobic gram-negative
bacilli, depending on the patient. The barrier from the blood to brain
parenchyma differs from that between blood and CSF. Consequently,
the choice of antimicrobial for brain abscess may differ from that
The pharmacotherapy of central nervous system (CNS) infections presents numerous
challenges. Antibiotic penetration often is limited, and host defenses are absent or
inadequate. Thus, morbidity and mortality from infections of the CNS remain high
despite the availability of highly potent, bactericidal antibiotics. In a review of 3,155
episodes of bacterial meningitis between 1998 and 2007, the mortality rate was
1 Although eradication of bacteria is essential, it is only one of the variables that
affect mortality from CNS infections. In an attempt to decrease morbidity and
mortality, the pathophysiologic mechanisms of CNS infections continue to be
A number of infectious processes can occur within the CNS (e.g., meningitis,
encephalitis, meningoencephalitis, brain abscess, subdural empyema, and epidural
abscess). In addition, prosthetic devices placed into the CNS (e.g., CSF shunts for
management of hydrocephalus) often are complicated by infection. Many etiologic
agents are capable of inducing CNS infections, including bacteria, viruses, fungi, and
certain parasites. This chapter focuses primarily on bacterial infections of the CNS,
with an emphasis on the pharmacotherapy of bacterial meningitis and brain abscess.
(Also see Chapter 76, Pharmacotherapy of Human Immunodeficiency Virus Infection,
and Chapter 77, Opportunistic Infection
in HIV-Infected Patients, for presentations pertaining to CNS infections in these
REVIEW OF CENTRAL NERVOUS SYSTEM
Proper therapy of CNS infections requires an understanding of anatomic and
physiologic characteristics. The brain and spinal cord are ensheathed by a protective
covering known as the meninges and suspended in CSF, which acts as a shock
absorber to outside trauma. The meninges consist of three layers of f ibrous tissue:
the pia mater, arachnoid, and dura mater. The pia mater, the innermost layer of the
meninges, is a thin, delicate membrane that closely adheres to the contours of the
brain. Separating the pia mater from the more loosely enclosed arachnoid membrane
is the subarachnoid space, in which the CSF resides. The pia mater and arachnoid,
known collectively as the leptomeninges, lie interior to the dura mater, a tough outer
membrane that adheres to the periosteum and vertebral column. Meningitis is a term
describing inflammation (often the result of infection) of the subarachnoid space.
Abscesses also can form outside the dural space (epidural abscess), often with
CSF is produced and secreted by the choroid plexus in the lateral ventricles and, to a
lesser extent, by the choroid plexuses within the third and fourth ventricles. CSF
flows unidirectionally from the lateral ventricles through the foramina of the third and
fourth ventricles into the subarachnoid space, then over the cerebral hemispheres and
downward into the spinal canal. CSF is absorbed through villous projections
(arachnoid villi) into veins, primarily the cerebral venous sinuses. About 0.35 to 0.4
mL of CSF is secreted per minute, with 50% of the total volume of CSF being
4 The flow of CSF is unidirectional from the ventricles to
the intralumbar space. Therefore, intrathecal injection of antibiotics results in little, if
any, antibiotic reaching the cerebral ventricles.
3 This unidirectional flow of CSF
presents a problem because ventriculitis commonly occurs in conjunction with
bacterial meningitis. Direct intraventricular instillation of antibiotics, usually by
means of a reservoir, is preferable in the setting of ventriculitis (see Case 65-4,
In adults, children, and infants, the volume of CSF is approximately 150 mL, 60 to
100 mL, and 40 to 60 mL, respectively.
6 Knowledge of approximate CSF volume
facilitates estimation of the CSF concentration of a drug subsequent to intrathecal
administration. For example, administration of gentamicin 5 mg (5,000 mcg)
intrathecally should result in a CSF concentration of approximately 33 mcg/mL in an
adult shortly after administration.
The composition of CSF differs from other physiologic fluids. The pH of CSF is
slightly acidic (normal pH, 7.3), and with the exception of chloride ion, electrolyte
concentrations are slightly less than those in serum.
5 Under normal conditions, the
protein concentration in CSF is 15 to 45 mg/dL, CSF glucose values are 50 to 80
mg/dL (approximately 60% those of plasma), and few if any WBCs are present (<5
3 When the meninges become inflamed (i.e., in meningitis), the composition
of the CSF is altered. In particular, the protein concentration in the CSF increases,
and the glucose concentration in the CSF usually declines with meningitis. Therefore,
careful evaluation of CSF chemistries is useful when establishing a diagnosis of
The blood–brain barrier plays a crucial role in protecting the brain and maintaining
4 Actually, two distinct barriers exist within the brain:
the blood–CSF barrier and the blood–brain barrier. The blood–CSF barrier is
characterized morphologically by porous capillaries (Fig. 65-1). This allows
proteins and other molecules (including antibiotics) to pass freely into the immediate
interstitial space. Diffusion of substances into the CSF is restricted by tightly fused
cells lining the ventricular side of the choroid plexus (Fig. 65-1). Cerebral capillary
endothelial cells make up the blood–brain barrier, which separates blood from the
interstitial fluid of the brain. Unlike capillaries in other areas of the body, the
capillary endothelia of the brain are packed closely together, forming tight junctions
that in effect produce a barrier physiologically similar to a continuous lipid bilayer.
The surface area of the blood–brain barrier is more than 5,000 times greater than that
of the blood–CSF barrier; thus, the blood–brain barrier plays a more important role
in protecting the brain and regulating its chemical composition.
traverse the blood–brain barrier with difficulty (see section on Antimicrobial
Penetration Into the Cerebrospinal Fluid below).
Meningitis is the most common type of CNS infection. The signs and symptoms
associated with bacterial meningitis usually are acute in onset, evolving over the
course of a few hours. Prompt recognition and early institution of therapy are
essential to ensuring beneficial outcomes.
In contrast, a diverse group of infectious
(e.g., viruses, fungi, and mycobacteria) and noninfectious (e.g., chemical irritants)
agents produce a meningitic picture often of a less acute or chronic nature.
Generally, meningitis is a disease of the very young and very old: Most cases occur
in children younger than 2 years of age and in elderly adults.
meningitis correlate well with age and underlying conditions (Table 65-1).
Neonates (infants <1 month) are at an especially high risk of experiencing
meningitis. Meningitis in preterm neonates is most often caused by Escherichia coli
whereas meningitis in term neonates is most often caused by group B streptococci
(Streptococcus agalactiae). These highly virulent pathogens usually are acquired
during passage through the birth canal or from the hospital environment and are
associated with significant morbidity and mortality, particularly in premature
12 Consensus recommendations regarding intra-partum administration of
penicillin to women colonized with group B streptococci have led to an 80%
decrease in early-onset infection due to this pathogen.
another important and often overlooked pathogen in neonates.
monocytogenes is resistant to many antimicrobial agents, including third-generation
cephalosporins, selection of initial (empiric) therapy in neonates must be approached
Microbiology of Bacterial Meningitis
Age Group or Predisposing Condition Most Likely Organisms
Neonates (<1 month) Group B streptococcus (Streptococcus agalactiae), Escherichia
coli, Klebsiella species, Listeria monocytogenes
Infants and children (1–23 months) Streptococcus pneumoniae, Neisseria meningitidis, S. agalactiae,
Children and adults (2–50 years) N. meningitidis, S. pneumoniae
Adults (>50 years) S. pneumoniae, N. meningitidis, L. monocytogenes, E. coli,
Klebsiella species, and other aerobic gram-negative bacilli
Postneurosurgical Staphylococcus aureus, aerobic gram-negative bacilli (e.g., E. coli,
Klebsiella species, Pseudomonas aeruginosa), Staphylococcus
Closed head trauma S. pneumoniae, H. influenzae, group A β-hemolytic streptococci
Penetrating trauma S. aureus, S. epidermidis, aerobic gram-negative bacilli (e.g., E.
coli, Klebsiella species, P. aeruginosa)
CSF shunt Coagulase-negative staphylococci (particularly S. epidermidis), S.
aureus, aerobic gram-negative bacilli (including P. aeruginosa),
aOrganisms listed in descending order of frequency.
bNeed to consider this pathogen only in children not vaccinated with Hib.
cMost commonly seen in association with prosthetic devices (e.g., cerebrospinal fluid shunts).
Infants and children 2 to 23 months old are also at a high risk of meningitis.
Historically, in this age group, the disease was caused predominantly by three
pathogens: Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria
meningitidis. Up to 45% of all cases of meningitis in the United States before 1985
were caused by H. influenzae type b (Hib).
14 From 1991 to 1996, however, Hib
invasive disease incidence in children <5 years of age decreased by >99%. This
reduction in H. influenzae-induced meningitis correlates with the widespread
vaccination of children against invasive H. influenzae disease with the Hib
polysaccharide–protein conjugate vaccines.
N. meningitidis (the meningococcus). Meningococci more commonly are implicated
in individuals aged 2 to 34 years, whereas pneumococci are the predominant
pathogens in adults older than 34 years of age.
1 The incidence of pneumococcal
meningitis has decreased by 26% from 1998 to 2006–2007 with the introduction of
pneumococcal conjugate vaccines, with a decrease of 92% if only serotypes
contained in the seven-valent conjugate vaccine are considered.
of the 13-valent conjugate vaccine has not resulted in further decreases in meningitis
cases in children, with nonvaccine serotypes replacing those contained in the
17 The incidence of meningococcal disease has decreased by 73% from 1996
to 2011. Interestingly, most of this decline in incidence occurred prior to the routine
use of meningococcal conjugate vaccines.
Patients of advanced age and those who undergo neurosurgical procedures or
experience head trauma are also susceptible to meningitis. The most likely causative
pathogens in these patient populations are listed in Table 65-1.
Pathogenesis and Pathophysiology
In general, meningitis can develop from hematogenous spread of organisms, by
contiguous spread from a parameningeal focus (e.g., sinusitis or otitis media), or by
direct bacterial inoculation, as occurs with head trauma or neurosurgery. In
contiguous spread, colonization of mucosal surfaces is a necessary first step in the
pathogenesis of meningitis. Meningeal pathogens then adhere to, and penetrate
through, the epithelial surface and enter the intravascular space. Eventually,
organisms multiply to sufficient numbers that allow invasion of the blood–brain
Once bacteria gain entry into the CSF, host defenses are inadequate to contain the
infection, and bacteria replicate rapidly. Humoral immunity (both complement and
immunoglobulin) essentially is absent within the CSF. In addition, opsonic activity in
CSF is negligible, and although leukocytosis ensues shortly after bacterial invasion,
phagocytosis also is inefficient. Therefore, this relative immunodeficiency state
necessitates the initiation of bactericidal therapy.
Inflammation of the meninges is initiated by contents within the bacterial cell wall.
Release of these contents (lipopolysaccharide for gram negatives and teichoic acid
for gram positives) induces the production and secretion of inflammatory cytokines,
which promote the adherence of leukocytes to cerebral capillary endothelial cells
and facilitate the migration of leukocytes into the CSF. This results in the
characteristic CSF leukocytosis as well as an eventual increase in blood–brain
Inflammation of the blood–brain barrier may lead to brain edema, which,
combined with obstruction of CSF outflow, increases intracranial pressure and alters
cerebral blood flow. Resultant hyperperfusion or hypoperfusion of the brain may
ultimately result in neuronal injury, cerebral ischemia, and irreversible brain
damage. The inflammatory response in meningitis also can be aggravated by some
antibiotics, notably the penicillins and cephalosporins.
antibiotics lyse bacterial cell walls, large amounts of cell wall products are
liberated, and these products amplify the inflammatory response. The long-term
benefits of β-lactam therapy far outweigh such detrimental effects, and the use of
adjunctive corticosteroids in certain patient populations can substantially reduce
inflammation and the subsequent neurologic sequelae of meningitis.
In a systemic review of approximately three decades of data surrounding
neurologic sequelae, the median risk of developing at least one major or minor
sequela was 19.9% (12.3%–35.3%).
21 The type and severity of neurologic
complications vary with the specific infecting organism, the severity of the infection,
and the susceptibility of the host. In a long-term prospective study of 185 children
with acute bacterial meningitis, permanent hearing loss occurred in 6%, 10.5%, and
31% of children with meningitis caused by H. influenzae, N. meningitidis, and S.
pneumoniae, respectively. Although seizures are fairly common on initial
presentation, long-term epilepsy occurs in approximately 7% of patients. Other
important long-term complications include spastic paraparesis, behavioral disorders,
Diagnosis and Clinical Features
CLINICAL AND LABORATORY FEATURES OF BACTERIAL MENINGITIS
is unknown. S.C. and his brother currently attend a community day-care center.
mm Hg, and a respiratory rate of 32 breaths/minute. His weight on admission was 20 kg. Neurologic
Blood drawn for laboratory tests revealed the following results:
Blood urea nitrogen (BUN), 16 mg/dL
Serum creatinine (SCr), 0.6 mg/dL
The WBC count was 18,000 cells/μL with 95% polymorphonuclear (PMN) cells; the hemoglobin (Hgb),
S.C. display that are suggestive of meningitis?
Signs and Symptoms of Acute Bacterial Meningitis
Nuchal rigidity (stiff neck) Headache
Altered mentalstatus Photophobia
aSee text for description of sign.
bSymptoms seen in infants with meningitis.
The clinical features of bacterial meningitis are summarized in Table 65-2. The
most common symptoms include the triad of fever, stiff neck (nuchal rigidity), and
altered mental status. When all three of these features are present, as is S.C.’s case,
meningitis should be strongly suspected. Other less common signs and symptoms
include headache, photophobia (unusual intolerance to light), and focal neurologic
deficits, including cranial nerve palsies.
23 A positive Brudzinski sign (reflex flexion
of the hips and knees produced on flexion of the neck when lying in the recumbent
position) and Kernig sign (pain on extension of the hamstrings when lying supine with
the thighs perpendicular to the trunk) provide physical evidence of meningeal
24 Brudzinski and Kernig signs both were positive in S.C. Seizures occur on
initial presentation in up to 60% of patients and may be focal or generalized.
presence of seizures or a severely depressed mental status (i.e., obtundation or coma)
generally is associated with a poorer prognosis.
25 According to the most recent
practice guidelines for the management of bacterial meningitis, a computed
tomographic (CT) scan should be obtained before lumbar puncture in patients with
specific criteria. These include immunocompromised state, history of CNS disease,
new-onset seizure, papilledema, abnormal level of consciousness, and focal
neurologic deficit. Although controversial, brain herniation can occur when lumbar
puncture is performed in patients with elevated intracranial pressure because of the
pressure changes induced within the cranial vault.
S.C. has many of the clinical features associated with acute bacterial meningitis.
Furthermore, the low blood pressure (hypotension) and increased respiratory rate are
characteristic findings in severe, life-threatening types of bacterial infection (e.g.,
septic shock, meningitis) and are likely the result of endotoxin release.
The signs and symptoms of meningitis in the very young and very old differ from
those in older children and adults. In neonates, signs of meningeal irritation may be
absent; fever, irritability, and
poor feeding are often the only symptoms manifested.
age, accurate assessment of his mental status is challenging. Irritability (crying), as
was manifested by S.C., is an important finding that suggests an altered mental status.
In elderly patients, many of the classic signs of meningeal irritation are absent as
well, and the disease presentation can be subtler.
consequences of a misdiagnosis, clinicians caring for infants and elderly patients
must have a particularly high index of suspicion for meningitis.
Laboratory evaluation of meningitis should include serum chemistries and a
hemogram as well as a detailed examination of the CSF.
often is markedly elevated in acute bacterial meningitis, usually with a left shift
evident on the differential. This finding, however, is nonspecific and occurs in many
acute inflammatory and infectious diseases. S.C. has a marked leukocytosis with a
predominance of PMN cells on the differential.
The abrupt onset of S.C.’s clinical symptoms is consistent with an acute bacterial
process rather than a fungal or viral etiology. Given his age (5 years) and the
community-acquired nature of the infection, the most likely pathogens for his
meningitis are H. influenzae, N. meningitidis, and S. pneumoniae. The presence of
maculopapular lesions argues for N. meningitidis as the causative pathogen because
this is a common finding in cases of meningococcemia or meningococcal
20 To make an accurate clinical and microbiologic diagnosis in S.C., it is
necessary to obtain CSF for analysis. Thus, a lumbar puncture is required as soon as
CEREBROSPINAL FLUID EXAMINATION
Opening pressure, 300 mm Hg (normal, <20)
CSF glucose, 20 mg/dL (normal, 50-60% of plasma glucose)
Protein, 250 mg/dL (normal, <50 mg/dL)
WBC count, 1,200 cells/μL, with 90% PMN, 4% monohistiocytes, and 6% lymphocytes
The CSF red blood cell (RBC) count was 50/μL. A stat Gram stain of CSF revealed numerous WBCs but no
organisms. CSF, blood, and urine cultures are pending. Provide an assessment of the CSF results.
Careful examination of the CSF is essential to confirm the diagnosis of meningitis.
Table 65-3 compares the typical findings in CSF obtained from patients with acute
bacterial meningitis with those seen with fungal or viral causes.
bacterial meningitis, the CSF is often purulent, containing numerous WBCs with a
predominance of PMNs, and often is turbid. CSF protein nearly always is elevated,
and the CSF glucose concentration is low.
In contrast, CSF obtained in viral and
fungal cases of meningitis usually is clear and characterized by a much lower WBC
count with a mononuclear or lymphocyte predominance. Although the CSF protein
concentration often is elevated, it may be normal. A variable effect is observed with
Microbiologic evaluation should include examination of CSF by Gram stain and
culture as well as cultures obtained from other potential sites of infection (e.g.,
blood, sputum, urine). The presence of organisms on smear is indicative of a high
bacterial inoculum (i.e., inoculum >10
5 colony-forming units/mL) and is associated
22 The absence of organisms on Gram stain by no means
rules out infection, but does make selection of empiric therapy more difficult.
Although a positive Gram stain should prompt a re-evaluation of empiric therapy to
ensure appropriate coverage, Gram stain results should not, by themselves, prompt a
narrowing of appropriate empiric therapy.
Cerebrospinal Fluid (CSF) Findings in Various Types of Meningitis
Bacterial >500 PMN Elevated Low
Fungal 10–500 MN Elevated Variable
Viral 10–200 PMN or MN Variable Normal
MN, mononuclear cells; PMN, polymorphonuclear neutrophils; WBC, white blood cell.
S.C. has a negative Gram stain, which may be the result of previous antibiotic
therapy or the early detection of disease. Given the negative CSF Gram stain result,
S.C. must receive antibacterial therapy sufficiently broad to cover all pathogens
associated with meningitis in his age group until the results from his CSF culture are
available (usually within 24–48 hours). The CSF culture nearly always is positive in
purulent meningitis, although CSF cultures can be negative in a patient who clearly
has meningitis, particularly with antecedent receipt of antibiotic therapy.
results from cultures of other sites, such as the blood, urine, and sputum (when
appropriate), can yield useful microbiologic information.
The CSF findings in S.C. also strongly support the diagnosis of bacterial
meningitis. He has a markedly elevated opening CSF pressure, CSF leukocytosis
(with a predominance of PMNs), an elevated CSF protein concentration, and a
depressed CSF glucose value. A few RBCs are present in the CSF, which suggests
contamination with peripheral blood caused by the traumatic nature of the lumbar
puncture. Precise identification of the offending organism is not possible until CSF
culture results are available.
Prompt institution of appropriate antimicrobial therapy is essential when treating
meningitis. Delay in antibiotic administration is associated with increased morbidity
8 When choosing antimicrobial therapy, a number of factors must be
considered. First, the antibiotics selected must penetrate adequately into the CSF. In
addition, the regimen chosen must have potent activity against known or suspected
pathogens and exert a bactericidal effect.
ANTIMICROBIAL PENETRATION INTO THE CEREBROSPINAL FLUID
The ability of antimicrobials to penetrate into CSF is affected by lipid solubility,
degree of ionization, molecular weight, protein binding, and susceptibility to active
transport systems operative within the choroid plexus. In general, the penetration of
most antibiotics into the CSF is increased when the meninges are inflamed.
Antimicrobial penetration into CSF is most commonly reported as a ratio of CSF to
serum antimicrobial levels. Table 65-4 summarizes the CSF penetration
characteristics of various antimicrobials during acute bacterial meningitis.
Metronidazole, sulfamethoxazole, and trimethoprim are small, highly lipophilic
compounds and penetrate into the CSF well, achieving adequate concentrations even
when meningeal inflammation is absent. Rifampin is lipophilic but is a larger
compound with a high degree of protein binding. Thus, it achieves satisfactory CSF
penetration and may be combined with vancomycin to treat coagulase-negative
staphylococcal infections in the CNS. Because β-lactams usually are ionized at
inflamed, most penicillins and the third- and fourth-generation cephalosporins
achieve CSF concentrations sufficient to treat meningitis (~10%–30% of
simultaneously obtained serum concentrations). First- and second-generation
cephalosporins are not recommended in the treatment of meningitis due to inadequate
penetration and/or inferior efficacy.
31 Ceftriaxone achieves sustained, reliable
bactericidal activity within the CSF despite its high protein binding and has been
used successfully to treat meningitis in both children and adults. An additional factor
working against maintenance of therapeutic concentrations of β-lactams in the CSF is
the active transport system of the choroid plexus, which pumps these organic acids
out of the CSF. Meropenem achieves CSF levels 10% to 40% of serum levels.
the present time, data are too limited to draw conclusions on the utility of the newer
agents ceftaroline, ceftolozane/tazobactam, or doripenem in the treatment of CNS
Cerebrospinal Fluid Penetration Characteristics of Various Antimicrobials
Uncommonly utilized; reserve use for specific scenarios
: linezolid, rifampin, fluoroquinolones (ciprofloxacin,
Penicillins: penicillin G, ampicillin, piperacillin, nafcillin
Other β-lactams: aztreonam, clavulanate, imipenem, meropenem, sulbactam, tazobactam
- and 4th-generation cephalosporins
: cefotaxime, ceftazidime, ceftriaxone, cefepime
Other agents: vancomycin, doxycycline
Aminoglycosides: amikacin, gentamicin, tobramycin
Polymyxins: colistin, Polymyxin B
1st-generation cephalosporins: Cefazolin
Other agents: macrolides (azithromycin, clarithromycin, erythromycin), clindamycin, daptomycin
dCefuroxime has similar CNS penetration, but is not recommended due to inferior efficacy.
ePenetration often inadequate even when the meninges are inflamed.
CSF, cerebrospinal fluid; TMP-SMX, trimethoprim–sulfamethoxazole.
The aminoglycosides have a low therapeutic index, and adequate CSF
concentrations are difficult to achieve with IV dosing alone without risking
significant toxicity. Thus, when aminoglycoside therapy is initiated for adults with
CNS infections, concomitant intrathecal therapy is usually required. Similarly, the
polymyxins are large hydrophilic compounds with substantial toxicity, and thus
intrathecal administration is preferred.
Vancomycin is a large hydrophilic compound with moderate protein binding
(50%) and as such does not diffuse well across the blood–CSF barrier. Therapeutic
concentrations in the CSF (up to 30% of serum concentrations) may be attained with
systemic vancomycin therapy when the meninges are inflamed. Other studies have
found much lower penetration, however, and as such, concomitant intraventricular
therapy also may be necessary in selected circumstances.
recommend aggressive dosing (troughs 15–20 μg/mL) when treating meningitis.
Fluoroquinolones are moderately lipophilic, have a molecular weight of ~300 Da,
and are not protein bound to a large extent. As would be expected, they penetrate
reasonably well into the CSF on a percentage basis (~40%–60% or higher).
Despite this, clinical data supporting the use of fluoroquinolones for bacterial CNS
infections are lacking, although some hypotheses may be made. First, given its potent
activity against S. pneumoniae, moxifloxacin may be an option for pneumococcal
33 Second, CSF concentrations attained are likely
inadequate for infection caused by bacteria with higher MICs (≥0.125–0.5 mcg/mL,
depending on the specific organism and drug).
34 This is especially relevant because
concerns regarding CNS toxicity have generally limited the study and practice of
nonstandard, increased fluoroquinolone dosages for bacterial CNS infections.
Finally, given the high rates of gram-negative resistance to fluoroquinolones, these
agents should not be considered reliable as empiric therapy options in patients
considered at risk for infections caused by such organisms.
fluoroquinolones are rarely utilized for the treatment of bacterial CNS infections.
Macrolides such as erythromycin and clarithromycin have a relatively high
molecular weight and are substrates for a transporter that is abundant at the blood–
brain barrier, P-glycoprotein. As such, they do not reach adequate concentrations
when meningeal inflammation is lacking, and their lack of bactericidal activity
further limits their utility in the treatment of bacterial meningitis. Bacteriostatic
activity against S. pneumoniae also limits the utility of the tetracyclines and
tigecycline. Clindamycin penetrates the CSF poorly and should not be used in the
treatment of meningitis. Linezolid is also generally bacteriostatic, but as it often
retains activity against multiresistant gram-positive pathogens and achieves CSF
levels comparable to those in plasma, it may be considered an option for infections
caused by gram-positive infections that are resistant or refractory to frontline options.
Daptomycin is generally bactericidal and active against multiresistant gram-positive
pathogens, but it is a large, highly protein-bound compound, and thus, CSF
penetration is low (≤10% of plasma levels). Use of higher doses and intrathecal
administration are being actively explored, but current utility is limited.
EMPIRIC THERAPY FOR CHILDHOOD MENINGITIS
of administration should be used?
Because results from culture and sensitivity testing of CSF will not be available
for >24 hours, empiric therapy must be instituted promptly. The regimen should take
into consideration the patient’s age, any predisposing conditions, results from the
CSF Gram stain, history of allergy, and the presence of organ dysfunction. Table 65-
5 gives recommendations for empiric antimicrobial therapy for acute bacterial
S.C. is 5 years of age and has a negative CSF Gram stain. Therefore, therapy with
a third-generation cephalosporin, such as ceftriaxone or cefotaxime, is preferred.
Either of these two agents will provide excellent coverage of the most likely
pathogens in this age group (S. pneumoniae and N. meningitidis).
pathogens, S.C.’s rash suggests that N. meningitidis is likely.
very likely because he was vaccinated against Hib. Thus, initiation of ceftriaxone
plus vancomycin would be appropriate for S.C. at this time.
Empiric Therapy for Bacterial Meningitis
Condition Recommended Therapy Alternative Therapy
Neonates (<1 month) Ampicillin + cefotaxime Ampicillin + gentamicin
Infants and children (1–23 months) Cefotaxime or ceftriaxone +
Older children and adults (2–50
Elderly (>50 years) Ampicillin, cefotaxime, or
Postneurosurgical Vancomycin +
Closed head trauma Cefotaxime or ceftriaxone +
Penetrating head trauma Vancomycin +
Immunocompromised Vancomycin + cefepime +
Use of a cephalosporin in this case is appropriate despite the allergic history with
amoxicillin (history of skin rash). Patients with a documented penicillin allergy carry
a 5% to 11% risk of cross-reactivity when cephalosporins are prescribed, depending
upon the agent. In this setting, the type of reaction to penicillin is important to
consider. Patients with a history of accelerated hypersensitivity reactions (e.g., hives,
shortness of breath [SOB], or anaphylaxis) to penicillins should not be given
cephalosporins in most instances. Conversely, a benign skin rash would not
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