• Combinations of antimicrobials are generally used to broaden the spectrum
of coverage for empiric therapy, achieve synergistic activity against
the infecting organism, and prevent the emergence of resistance.
• Increasing the coverage of antimicrobial therapy is generally necessary in
mixed infections where multiple organisms are likely to be present, such as
intraabdominal and female pelvic infections in which a variety of aerobic and
anaerobic bacteria may produce disease. Another clinical situation in which
increased spectrum of activity is desirable is with nosocomial infection.
Synergism
• The achievement of synergistic antimicrobial activity is advantageous for
infections caused by gram-negative bacilli in immunosuppressed patients.
• Traditionally, combinations of aminoglycosides and β-lactams have been
used since these drugs together generally act synergistically against a wide
variety of bacteria. However, the data supporting superior efficacy of
synergistic over nonsynergistic combinations are weak.
• Synergistic combinations may produce better results in infections caused by
Pseudomonas aeruginosa, in certain infections caused by Enterococcus spp.
• The use of combinations to prevent the emergence of resistance is widely
applied but not often realized. The only circumstance where this has been
clearly effective is in the treatment of tuberculosis.
Disadvantages of Combination Therapy
• Although there are potentially beneficial effects from combining drugs,
there are also potential disadvantages, including increased cost, greater risk
of drug toxicity, and superinfection with even more resistant bacteria.
• Some combinations of antimicrobials are potentially antagonistic. For
example, agents that are capable of inducing β-lactamase production in
bacteria (such as cefoxitin) may antagonize the effects of enzyme-labile
drugs such as penicillins or imipenem.
MONITORING THERAPEUTIC RESPONSE
• After antimicrobial therapy has been instituted, the patient must be
monitored carefully for a therapeutic response. Culture and sensitivity
reports from specimens collected must be reviewed.
• Use of agents with the narrowest spectrum of activity against identified
pathogens is recommended.
• Patient monitoring should include a variety of parameters, including white
blood cell count, temperature, signs and symptoms of infection, appetite,
radiologic studies as appropriate, and determination of antimicrobial
concentrations in body fluids.
• As the patient improves the route of antibiotic administration should be
reevaluated. Switch to oral therapy is an accepted practice for many
infections. Criteria favoring switch to oral therapy include:
✓ Overall clinical improvement
✓ Lack of fever for 8 to 24 hours
✓ Decreased WBC
✓ A functioning GI tract
FAILURE OF ANTIMICROBIAL THERAPY
• A variety of factors may be responsible for apparent lack of response to
therapy. It is possible that the disease is not infectious or nonbacterial in
origin, or there is an undetected pathogen. Other factors include those
directly related to drug selection, the host, or the pathogen. Laboratory
error in identification and/or susceptibility testing errors are rare.
Failures Caused by Drug Selection
• Factors directly related to the drug selection include an inappropriate
selection of drug, dosage, or route of administration. Malabsorption of a
drug product because of GI disease (e.g., short-bowel syndrome) or a drug
interaction (e.g., complexation of fluoroquinolones with multivalent cations
resulting in reduced absorption) may lead to potentially subtherapeutic
serum concentrations.
• Accelerated drug elimination is also a possible reason for failure and may
occur in patients with cystic fibrosis or during pregnancy, when more
rapid clearance or larger volumes of distribution may result in low serum
concentrations, particularly for aminoglycosides.
• A common cause of failure of therapy is poor penetration into the site of
infection. This is especially true for the so-called privileged sites such as the
CNS, the eye, and the prostate gland.
Failures Caused by Host Factors
• Patients who are immunosuppressed (e.g., granulocytopenia from chemotherapy,
acquired immune deficiency syndrome) may respond poorly to
therapy because their own defenses are inadequate to eradicate the infection
despite seemingly adequate drug regimens.
• Other host factors are related to the necessity for surgical drainage of
abscesses or removal of foreign bodies and/or necrotic tissue. If these
situations are not corrected, they result in persistent infection and, occasionally,
bacteremia, despite adequate antimicrobial therapy.
Failures Caused by Microorganisms
• Factors related to the pathogen include the development of drug resistance
during therapy. Primary resistance refers to the intrinsic resistance of the
pathogens producing the infection. However, acquisition of resistance
during treatment has become a major problem as well.
• The increase in resistance among pathogenic organisms is believed to be
due, in large part, to continued overuse of antimicrobials in the community, as well as in hospitals, and the increasing prevalence of immunosuppressed
patients receiving long-term suppressive antimicrobials for the
prevention of infections.
Central Nervous System Infections
DEFINITION
• CNS infections include a wide variety of clinical conditions and etiologies:
meningitis, meningoencephalitis, encephalitis, brain and meningeal abscesses,
and shunt infections. The focus of this chapter is meningitis.
PATHOPHYSIOLOGY
• Infections are the result of hematogenous spread from a primary infection
site, seeding from a parameningeal focus, reactivation from a latent site,
trauma, or congenital defects in the CNS.
• Passive and active exposure to cigarette smoke and the presence of a
cochlear implant that includes a positioner both increase the risk of
bacterial meningitis.
• CNS infections may be caused by a variety of bacteria, fungi, viruses, and
parasites. The most common causes of bacterial meningitis include Streptococcus
pneumoniae, Neisseria meningitidis, Listeria monocytogenes, and
Haemophilus influenzae.
• The critical first step in the acquisition of acute bacterial meningitis is
nasopharyngeal colonization of the host by the bacterial pathogen. The
bacteria first attach themselves to nasopharyngeal epithelial cells and are
then phagocytized into the host’s bloodstream.
• A common characteristic of most CNS bacterial pathogens (e.g., H.
influenzae, Escherichia coli, and N. meningitidis) is the presence of an
extensive polysaccharide capsule that is resistant to neutrophil phagocytosis
and complement opsonization.
• Bacterial cell death causes the release of cell wall components such as
lipopolysaccharide, lipid A (endotoxin), lipoteichoic acid, teichoic acid,
and peptidoglycan depending on whether the pathogen is gram-positive or
gram-negative. These cell wall components cause capillary endothelial cells
and CNS macrophages to release cytokines (interleukin-1, tumor necrosis
factor, and other inflammatory mediators). Proteolytic products and toxic
oxygen radicals cause an alteration of the blood–brain barrier while
platelet-activating factor activates coagulation and arachidonic acid
metabolites stimulate vasodilation. These events lead to cerebral edema,
elevated intracranial pressure, cerebrospinal fluid (CSF) pleocytosis,
decreased cerebral blood flow, cerebral ischemia, and death.
CLINICAL PRESENTATION
GENERAL
• Meningitis causes CSF fluid changes, and these changes can be used as
diagnostic markers of infection (Table 36-1).
patient, the more atypical and the less pronounced is the clinical picture.
• Up to 50% of patients may receive antibiotics before a diagnosis of
meningitis is made, delaying presentation to the hospital. Prior antibiotic
therapy may cause the Gram stain and CSF culture to be negative, but the
antibiotic therapy rarely affects CSF protein or glucose.
• Classic signs and symptoms include fever, nuchal rigidity, altered mental
status, chills, vomiting, photophobia, and severe headache. Kernig’s and
Brudzinski’s signs may be present but are poorly sensitive and frequently
absent in children. Other signs and symptoms include irritability, delirium,
drowsiness, lethargy, and coma.
• Clinical signs and symptoms in young children may include bulging fontanelle,
apneas, purpuric rash, and convulsions in addition to those just
mentioned.
• Seizures occur more commonly in children (20% to 30%) than in adults
(0% to 12%).
DIFFERENTIAL SIGNS AND SYMPTOMS
• Purpuric and petechial skin lesions typically indicate meningococcal
involvement, although the lesions may be present with
H. influenzae
meningitis. Rashes rarely occur with pneumococcal meningitis.
•
H. influenza
meningitis and meningococcal meningitis both can cause
involvement of the joints during the illness.
• A history of head trauma with or without skull fracture or presence of a
chronically draining ear is associated with pneumococcal involvement.
LABORATORY TESTS
• Several tubes of CSF are collected via lumbar puncture for chemistry,
microbiology, and hematology tests. Theoretically, the first tube has a higher
likelihood of being contaminated with both blood and bacteria during the
puncture, although the total volume is more important in practice than the
tube cultured. CSF should not be refrigerated or stored on ice.
• Analysis of CSF chemistries typically includes measurement of glucose and
total protein concentrations. An elevated CSF protein of 100 mg/dL or greater and a CSF glucose concentration of less than 50% of the simultaneously
obtained peripheral value suggest bacterial meningitis (see Table 36-1).
• The values for CSF glucose, protein, and WBC concentrations found with
bacterial meningitis overlap significantly with those for viral, tuberculous,
and fungal meningitis (see Table 36-1). Therefore, CSF white blood cell
(WBC) counts and CSF glucose and protein concentrations cannot always
distinguish the different etiologies of meningitis.
OTHER DIAGNOSTIC TESTS
• Blood and other specimens should be cultured according to clinical
judgment because meningitis frequently can arise via hematogenous dissemination
or can be associated with infections at other sites. A minimum
of 20 mL of blood in each of two to three separate cultures per each 24-
hour period is necessary for the detection of most bacteremias.
• Gram stain and culture of the CSF are the most important laboratory tests
performed for bacterial meningitis. When performed before antibiotic
therapy is initiated, Gram stain is both rapid and sensitive and can confirm
the diagnosis of bacterial meningitis in 75% to 90% of cases.
• Polymerase chain reaction (PCR) techniques can be used to diagnose
meningitis caused by N. meningitidis, S. pneumoniae, and H. influenzae type
b (Hib). PCR is considered to be highly sensitive and specific. PCR testing
of the CSF is the preferred method of diagnosing most viral meningitis
infections.
• Latex fixation, latex coagglutination, and enzyme immunoassay tests
provide for the rapid identification of several bacterial causes of meningitis,
including S. pneumoniae, N. meningitidis, and Hib. The rapid antigen
tests should be used in situations in which the Gram stain is negative.
• Diagnosis of tuberculosis meningitis employs acid-fast staining, culture,
and PCR of the CSF.
DESIRED OUTCOME
• The goals of treatment include eradication of infection with amelioration
of signs and symptoms, and prevention of neurologic sequelae, such as
seizures, deafness, coma, and death.
TREATMENT
GENERAL PRINCIPLES
• The administration of fluids, electrolytes, antipyretics, analgesia, and other
supportive measures are particularly important for patients presenting
with acute bacterial meningitis.
• Antibiotic dosages for treatment of CNS infections must be maximized to
optimize penetration to the site of infection.
• Meningitis caused by S. pneumoniae is successfully treated with 10 to 14
days of antibiotic therapy. Meningitis caused by N. meningitidis usually can
be treated with a 7-day course. A longer course,
≥21 days, is recommended for patients infected with
L. monocytogenes
. Therapy should be individualized,
and some patients may require longer courses.
PHARMACOLOGIC TREATMENT
• Empiric antimicrobial therapy should be instituted as soon as possible to
eradicate the causative organism (Table 36-2). Antimicrobial therapy should
last at least 48 to 72 hours or until the diagnosis of bacterial meningitis can
be ruled out. Continued therapy should be based on the assessment of
clinical improvement, cultures, and susceptibility testing results. Once a
pathogen is identified, antibiotic therapy should be tailored to the specific
pathogen.
• With increased meningeal inflammation, there will be greater antibiotic
penetration (Table 36-3). Problems of CSF penetration may be overcome
by direct instillation of antibiotics by intrathecal, intracisternal, or intraventricular
routes of administration (Table 36-4).
Dexamethasone as an Adjunctive Treatment for Meningitis
• In addition to antibiotics,
dexamethasone
is a commonly used therapy for
the treatment of pediatric meningitis. Several studies have shown that
dexamethasone causes a significant improvement in CSF concentrations of
proinflammatory cytokines, glucose, protein, and lactate as well as a
significantly lower incidence of neurologic sequelae commonly associated
with bacterial meningitis. However, there are conflicting results.
No comments:
Post a Comment