Clinical Pharmacy

 Proper therapy of CNS infections first requires an understanding of the anatomic and physiologic characteristics of this region.  The brain and spinal cord are ensheathed by a protective covering known as the meninges and suspended in Cerebrospinal Fluid (CSF), which acts as a “shock absorber” to outside trauma.

 The meninges consist of three layers of fibrous 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, where the CSF resides.

 The 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.

 The blood–brain barrier plays a crucial role in protecting the brain and maintaining homeostasis within the CNS.  Actually, two distinct barriers exist within the brain: the blood– CSF barrier and the blood–brain barrier.  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.

 Meningitis is the most common type of CNS infection. The signs and symptoms associated with bacterial meningitis usually are acute in onset, evolving over 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.

 On occasion, such “aseptic” causes can produce signs and symptoms nearly indistinguishable from those of acute bacterial meningitis.  Drugs that can induce aseptic meningitis include trimethoprim-sulfamethoxazole (TMP-SMX), the antirejection monoclonal antibody muromonab (OKT3), azathioprine, and nonsteroidal anti- inflammatory drugs (NSAID) such as ibuprofen, naproxen, and sulindac.

 Fever  Anorexia  Nuchal rigidity (stiff neck)  Headache  Altered mental status  Photophobia  Seizures  Nausea and vomiting

 Careful examination of the CSF is essential to confirm the diagnosis of meningitis. In acute bacterial meningitis, the CSF is purulent, containing numerous WBC (usually >500 cells/mm 3 ) with a predominance of PMN, and often is turbid. CSF protein nearly always is elevated, usually >100 mg/dL, 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 (<100 cells/mm 3 ), with a mononuclear or lymphocyte predominance.

 Prompt institution of appropriate antimicrobial therapy is essential when treating meningitis.  Delay in antibiotic administration is associated with increased morbidity and mortality.  When choosing antimicrobial therapy, a number of factors must be considered. 1. First, the antibiotics selected must penetrate adequately into the CSF. 2. In addition, the regimen chosen must have potent activity against known or suspected pathogens and exert a bactericidal effect. 3. In general, therapy of meningitis requires the use of high dosages of antimicrobials administered by the IV route.

 Very Good a  Chloramphenicol, metronidazole, TMP-SMX, linezolid  Good b  Penicillins: Penicillin G, ampicillin, nafcillin, piperacillin, ticarcillin  Other β -lactams: Aztreonam, clavulanic acid, imipenem, meropenem, sulbactam  Cephalosporins: Cefepime, cefotaxime, cefazidime, ceftizoxime, ceftriaxone, cefuroxime  Fluoroquinolones: Ciprofloxacin  Other agents: Rifampin  Fair to Poor c  Aminoglycosides: Amikacin, gentamicin, tobramycin  Other agents: Azithromycin, clarithromycin, clindamycin, erythromycin, vancomycin, daptomycin

 Corticosteroids, particularly dexamethasone, can reduce cerebral edema and lower intracranial pressure.  The rationale for steroid therapy in meningitis stems from the fact that steroids reduce the synthesis and release of the proinflammatory cytokines

 The most frequently used regimen to reduce nasopharyngeal carriage of N. meningitidis for children >1 month is rifampin, given once daily in a dosage of 10 mg/kg/day for 2 days.  For adult close contacts, rifampin 600 mg twice a day for 2 days should be administered.  Alternative chemoprophylactic regimens are ceftriaxone 250 mg or 125 mg intramuscularly in adults and children, respectively, and ciprofloxacin 500 mg orally as a single dose in adults.  Because rifampin is not recommended for pregnant women, ceftriaxone would be a viable alternative.

 Epidemiology  Although not nearly as common as meningitis, abscesses of the brain parenchyma (brain abscess) remain an important type of CNS infection.

 Brain abscesses most commonly arise from a contiguous suppurative source of infection (e.g., sinusitis, otitis, mastoiditis, or dental infections).  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).  In children, cyanotic congenital heart disease is a common predisposing factor.  As an infrequent complication of head trauma or neurosurgery.  No identifiable source (cryptogenic abscess) is detected in as many as 30% of cases.

 Surgical Techniques  A combined medical and surgical approach is the best form of therapy for brain abscess.  Antibiotic Therapy  When antibiotic therapy should be instituted depends on the status of the patient and the stage of abscess development.  Adjunctive Corticosteroid Therapy  steroids are indicated only if significant cerebral edema is present, particularly if it is accompanied by rapid neurologic deterioration  Adjunctive Anticonvulsant Therapy