Gail Itokazu, Pharm.D.
Spring 1998
Central Nervous System Infections
Gail Itokazu, Pharm.D.
Spring 1998
Central Nervous System
Infections
Required Reading
1. Madaras JK, et al. Central Nervous System Infections. In: Pharmacotherapy: A Pathophysiologic Approach. DiPiro JT, et al., eds. Elsevier, NY, 1997 3rd edition. Chapter 99, pp 1971-1994.
Optional Readings
The following readings are not required, but may enhance your understanding of the material in this section.
GOALS:
ANATOMY AND PHYSIOLOGY OF THE CENTRAL NERVOUS SYSTEM (CNS)
MENINGES
The meninges is made up of 3 layers, i.e., dura, arachnoid, and pia.
1. Describe the location of the subarachnoid space.
2. Define meningitis.
Note: Oftentimes you may come across the terms meningitis, encephalitis, and meningoencephalitis. Meningitis is an inflammation of the subarachnoid space; whereas encephalitis is an inflammation of the brain tissue. When meningitis and encephalitis occur together, this is called meningoencephalitis.
Clinically, symptoms of meningitis include a stiff neck, positive Kernig's and Brudzinski's signs. In contrast, encephalitis is characterized by alterations in consciousness, e.g., lethargy, stupor, and coma. Patients with meningoencephalitis have a combination of these clinical findings.
CEREBRAL SPINAL FLUID (CSF)
1. Discuss the differences between a normal and abnormal CSF with respect to glucose, protein, and white blood cell values.
2. Although the clinical presentation may aid in determining the microbiologic etiology of CNS infections, the CSF findings (e.g. WBCs, protein, and glucose) may also be of help. For example, >1000 cells/mm3 with a predominance of polys suggests bacterial meningitis; fewer WBC (<1000 cells/mm3) with a predominance of lymphocytes suggests viral, mycobacterial, or fungal meningitis. However, this may not always hold true since the early stages of viral and mycobacterial meningitis may be characterized by predominantly polys, which is subsequently followed by the more characteristic lymphocytic spinal fluid. Thus, the results of the spinal tap must be used in conjunction with other laboratory and clinical data, as well as patient history when determining the microbiologic etiology of meningitis.
Blood-brain barrier/blood-cerebrospinal fluid barrier
1. List 5 characteristics of antibiotics that affect their penetration into the CSF.
2. Discuss the pros and cons of intraventricular and intrathecal administration of antibiotics.
The first step in the pathogenesis of meningitis is colonization of mucous membranes (e.g. nasopharyngeal, respiratory tract, skin, etc.) of the host, followed by invasion into the bloodstream and entry into the central nervous system. Various aspects of the host’s defense system act to interfere with the steps involved in the pathogenesis of meningitis in order to prevent the development of this infection.
1. State the host defense that acts to prevent colonization.
2. Discuss the role of the polysaccharide capsule of bacteria in resisting the normal host defenses in the bloodstream.
4. Discuss the reason why splenectomized patients and patients with sickle cell disease are predisposed to infection by encapsulated bacteria.
CLINICAL PRESENTATION
1. List 4 clinical manifestations of meningitis.
Since the prognosis of meningitis is significantly influenced by the rapidity with which appropriate antimicrobial therapy is initiated, the capsular antigen-antibody reaction is a valuable test to aid in the early determination of the bacterial etiology of meningitis. This test is also useful in the diagnosis of partially treated meningitis in which the use of antibiotics prior to obtaining CSF for culture may result in a negative bacterial culture.
TREATMENT
Left untreated, bacterial meningitis is a fatal disease. Despite the availability of antimicrobials, mortality can still be as high as 25%. Treatment goals for meningitis are to prevent death and achieve clinical cure without neurologic sequelae such as permanent brain damage, mental retardation, and hearing loss.
Principles of antibiotic therapy for meningitis include the use of drugs which are: 1) rapidly bactericidal, 2) which penetrate the blood-brain barrier, and 3) active in infected CSF (Quagliarello et al. Treatment of bacterial meningitis. N Engl J Med 1997; 336:708).
Maximal doses of bactericidal drugs are necessary because infection is in an area where there is impairment of local host defenses (e.g., low concentrations of complement and antibodies), thus resulting in inefficient phagocytosis and rapid bacterial multiplication. For this reason, bacteriostatic drugs are not effective because they will only inhibit the growth of bacteria.
As mentioned above, rapid bactericidal activity is desired in the treatment of meningitis. Consistent with this principle is the finding of more neurologic deficits in children treated with cefuroxime versus ceftriaxone; a finding attributed to delayed sterilization of the CSF with cefuroxime (N Engl J Med 1990; 322:141). However, paradoxically, more rapid killing of bacteria from the CSF may also adversely influence the outcome of meningitis by increasing the release of inflammatory mediators which are responsible for complications associated with this infection (see figure 94.3, pg 1528 of Dipiros). The use of dexamethasone to prevent this inflammatory response will be discussed later.
CAUSATIVE AGENTS
The bacterial etiology of meningitis is influenced by the age of the patient, time of the year, and clinical findings.
a. Neisseria meningitides (Meningococcus)
1. List the patient populations in whom the meningococcus is a likely pathogen.
2. State the cutaneous manifestation associated with meningitis caused by the meningococcus.
3. State the antibiotic of first choice for the treatment of meningococcal meningitis.
Note that resistance of meningococci to penicillin has been reported. This resistance has been termed relative resistance, though the clinical significance of this is unknown since most patients have been successfully treated with penicillin. The second type of resistance is termed absolute resistance to penicillin and is due to inactivation of the beta-lactam structure of the penicillin molecule by beta-lactamase enzymes. Treatment of beta-lactamase producing meningococci requires the use of beta-lactamase stable cephalosporins (Clin Infect Dis 1993; 17:603).
4. Discuss why prophylaxis of close contacts of patients with meningococcal meningitis is necessary.
5. List 3 drugs that have been used for the prophylaxis of meningococcal meningitis.
b. Streptococcus pneumoniae (Pneumococcus or Diplococcus)
1. List the age groups likely to acquire pneumococcal meningitis.
2. The appropriate therapy for meningitis due to S. pneumoniae is dependent on the penicillin MIC of the isolate. Penicillin-susceptible S. pneumoniae are defined as isolates with a penicillin MIC <0.1mcg/ml. Be familiar with what is meant by S. pneumoniae that are relatively resistant to penicillin and that are highly resistant to penicillin.
3. The mechanism of S. pneumoniae resistance to penicillin is a decreased affinity for the target site of the organism; i.e., penicillin-binding proteins (PBPs).
4. List treatment options for S. pneumoniae meningitis.
Empiric Therapy for Meningitis Due to S. pneumoniae
Antimicrobial Susceptibility to Penicillin Unknown Gram-positive cocci on gram stain
S. pneumoniae on culture
Vancomycin + cefotaxime or ceftriaxone Penicillin MIC < 0.06 mcg/ml & Ceftriaxone MIC < 0.5mcg/ml
Penicillin or ceftriaxone or cefotaxime Penicillin MIC 0.1-1.0 mcg/ml & Ceftriaxone MIC <0.5mcg/ml
Ceftriaxone or cefotaxime Penicillin MIC > 0.1 mcg/ml & Ceftriaxone MIC >0.5mcg/ml
Vancomycin + cefotaxime (or ceftriaxone) or rifampin* *Children – if steroids are used in conjunction with antimicrobials, vancomycin + cefotaxime (or ceftriaxone). Adults – if steroids are used in conjunction with antimicrobials, the recommended regimen is ceftriaxone plus rifampin (Quagliarello et al. Treatment of bacterial meningitis. N Engl J Med 1997; 336:708). See below for further discussion.
As seen in the Table above, treatment options are based on the susceptibility of the isolate to both penicillin and cefotaxime (or ceftriaxone).
The role of steroids in S. pneumoniae meningitis is controversial. In animal models, concomitant use of steroids decreased the CSF penetration of vancomycin, resulting in delayed sterilization of CSF. However, the combination of ceftriaxone and rifampin was effective in sterilizing the CSF of highly resistant strains of S. pneumoniae (Paris et al. Effect of dexamethasone on therapy of experimental penicillin and cephalosporin-resistant pneumococcal meningitis. Antimicrob Agents Chemother 194; 38:1320).
Clinically, steroids have not decreased the CSF penetration of vancomycin in children, thus the combination of vancomycin plus ceftriaxone can be given; in adults given steroids, the preferred regimen is ceftriaxone plus rifampin.
Penicillin-resistant S. pneumoniae is now a worldwide concern. Treatment options are still evolving. Until recently, relatively resistant pneumococci were treated with selected third generation cephalosporins (e.g., ceftriaxone, cefotaxime); however, resistance to these agents and treatment failures have been reported. (Note: although ceftizoxime, ceftazidime, and cefoperazone are also 3rd generation cephalosporins, they are not appropriate treatment options for meningitis due to S. pneumoniae).
Treatment options for penicillin-resistant S. Pneumoniae include the use of vancomycin + rifampin. (Clin Infect Dis 1993; 17:603). Carbapenems are active against penicillin-resistant S. pneumoniae though the use of imipenem is tempered by its propensity to cause seizures. A recently released carbapenem, meropenem appears to be less likely to cause seizures, and could also be a treatment option. Limited data suggests that the use of dexamethasone in adults with pneumococcal meningitis who are comatose may reduce morbidity and mortality, thus some experts recommend its use (Pediatr Infect Dis J 1989; 8:848, Antimicrob Agents Chemother 1995; 39:2171).
If steroids are administered, they should be give before the first dose of antibiotic in order to prevent the release of inflammatory mediators that are responsible for the adverse neurological events.
Discuss the role of intra-ventricular vancomycin for S. pneumoniae meningitis.
Discuss the importance of immunization with the currently available 23-valent pneumococcal vaccine.
Although the pneumococcal vaccine is available, it is estimated that only 28-30% of adults over the age of 65 years has received it (MMWR 1996; 45:853). Thus, increasing the rate of vaccination could further reduce meningitis in this population.
c. Gram-Negative Meningitis
1. List the 2 most common organisms causing gram-negative meningitis in the post-neonatal period.
2. Discuss the antimicrobial treatment options for meningitis caused by Pseudomonas aeruginosa.
3. Know why intraventricular administration of antimicrobials is more likely than intrathecal administration of antimicrobials to produce therapeutic concentrations throughout the CSF.
d. Haemophilus influenzae
1.List the age groups most likely to acquire H. influenzae meningitis.
Prior to the availability of the conjugate vaccine of H. influenzae type b, this organism accounted for 70% of the cases of bacterial meningitis in children < 5 years of age. A recent survey has found that since the introduction of this vaccine, the median age of patients with meningitis has dramatically increased from 15 months in 1986 to 25 years in 1995. Thus, meningitis is now a disease primarily of adults versus infants and children (Schuchat et al. Bacterial meningitis in the united states in 1995. N Engl J Med 1997; 337:970).
2. Discuss the antimicrobial treatment option for meningitis caused by beta-lactamase-positive and beta-lactamase negative H. influenzae.
3. State the goal of prophylaxis of close contacts of patients with H. influenzae meningitis.
4. For close contacts exposed to patients with H. influenzae meningitis, list 2 drugs which may be used for the prophylaxis of H. influenzae meningitis.
5. Discuss the rationale for using dexamethasone as an adjunct to the management of bacterial meningitis.
6. Discuss the effect of dexamethasone on the CSF (e.g. with respect to CSF glucose and protein).
7. Discuss the benefit of dexamethasone on hearing.
The clinical benefit of dexamethasone as an adjunctive therapy in the management of meningitis has been primarily demonstrated in children with meningitis due to H. influenzae type b. There is controversy with regard to the value of dexamethasone in other patient populations (e.g. children with meningitis due to other pathogens) and no definitive recommendations exist.
VIRAL MENINGITIS
1. List two drugs that may be used to treat herpes simplex encephalitis.
SHUNT INFECTIONS
1. Discuss the purpose of surgical shunting procedures.
2. Know the difference between a ventriculoatrial (VA) and ventriculoperitoneal (VP) shunt.
3. List the 2 most common organisms associated with VA and VP shunt infections.
4. Describe the 2 postulated etiologies for the pathogenesis of shunt infections.
5. Discuss the reason why "slime" production by S. epidermidis aids in the development of shunt infections.
TREATMENT
1. Strong consideration should be given to the possibility that methicillin-resistant staphylococci may be organisms responsible for shunt infections. Knowing this, discuss the antimicrobial regimen that should be considered for the treatment of this infection.
2. When direct instillation of antibiotics into the CNS is planned, discuss 3 factors to consider when deciding what dose of antibiotic to use.
BRAIN ABSCESS
CLINICAL PRESENTATION
1. List the most common organisms associated with brain abscesses.
TREATMENT
1. List 2 factors to consider in the selection of antimicrobials for the treatment of brain abscesses.
2. List 4 factors which may adversely affect the efficacy of antibiotics when used for the treatment of brain abscesses.
3. Discuss why metronidazole is a drug that is useful for the treatment of anaerobic brain abscesses.
4. Know why metronidazole and cefotaxime (or ceftriaxone) are used in the treatment of brain abscesses (i.e., know which pathogens these antibiotics are active against).
CC: fever, stiff neck, seizures, headache, and decreased mental status
HPI: TM is a 25 year old male admitted with the above complaints which began about 3 days ago. The only medication he took was acetaminophen which provided temporary relief of the fever and headache.
PMH: chronic sinusitis, sickle cell disease
PE: temp 102 degrees Fahrenheit, HR 100, RR 20, B/P within normal limits
HEENT: stiffness of the neck, positive Brudzinski's sign, and positive Kernig's sign.
LABS: WBC 30,000 60% segs, 25% bands, 10% lymphs, 5% others
BUN 10mg/100ml , serum creatinine 1.0mg/100ml
CSF: RBC 950, WBC 3000 (predominance of polys), protein 300mg/100ml, gram stain with gram-positive diplococci, latex fixation test positive for Streptococcus pneumoniae.
1. What is your recommendation for empiric antibiotics? Why?
The data points to the diagnosis of meningitis due to Streptococcus pneumoniae (gram-positive diplococci, positive latex fixation test). The patient has risk factors for infection with Streptococcus pneumoniae (sinusitis, sickle cell disease), and the spinal tap is consistent with bacterial meningitis. However, since the susceptibility to penicillin is still pending, and because penicillin resistant S. pneumoniae has been identified in many parts of the United States, some experts recommend the use of a 3rd generation cephalosporin (cefotaxime or ceftriaxone) plus vancomycin until the susceptibility to penicillin is available (refer to Table in handout, "Empiric Therapy for Meningitis due to S. Pneumoniae). Clinicians should be aware of the incidence of penicillin resistant S. pneumoniae in their hospital.
2. The following data is reported: MIC to penicillin <0.06 mcg/ml, MIC to ceftriaxone <0.5mcg/ml. What antimicrobial therapy would you suggest?
This isolate is sensitive to penicillin and ceftriaxone, therefore penicillin G 4 million units IV Q4 is appropriate. Ceftriaxone 2 grams IV Q12 hours or cefotaxime 2 grams IV Q4 could also be used.
3. What are your goals of therapy?
Review "Treatment Section" of handout for goals of therapy.
4. How might further episodes of S. pneumoniae be prevented?
Administer oral penicillin prophylaxis or pneumococcal vaccine.
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