PHARMACOTHERAPY III PHCY 510 University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY III PHCY 510 Lecture 3 Infectious Diseases “Central Nervous System Infections” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy, CPN University of Nizwa

Course Outcome Upon completion of this lecture the students will be able to explain the most common causes for meningitis and its etiopathogenesis, differential signs and symptoms and diagnosis. individualize the empirical and specific pharmacological treatment for various types of meningitis based on the causative organism.

CNS infections can occur in the membranes The brain is surrounded by membranes (the meninges) and is protected by the skull. CNS infections can occur in the membranes between the skull and the brain (meningitis) or within the brain itself (encephalitis or brain abscesses), or may be associated with an indwelling CNS device (e.g., shunt infections). The focus of this chapter is meningitis.

Meningitis

Etiopathogenesis Predisposing factors for CNS infections include sinusitis, otitis media, head injury, and presence of systemic infections. Infections may be caused by a variety of bacteria, fungi, viruses, and parasites.

Etiopathogenesis The most common causes of bacterial meningitis include Streptococcus pneumoniae Neisseria meningitidis Listeria monocytogenes Haemophilus influenzae Enteroviruses account for 70% of all viral meningitis. Others include herpes virus and HIV. Cryptococcus neoformans causes HIV fungal meningitis.

Critical first step in the getting hold of 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. H. influenzae, Escherichia coli, and N. meningitidis forms an extensive polysaccharide capsule that is resistant to neutrophil phagocytosis.

Presence of bacterial cell wall products triggers production of cytokines, including interleukin-1, tumor necrosis factor, and prostaglandin E, leads to increased blood flow to brain. These cytokines increases BBB permeability causing cerebral edema. Cytotoxins released from neutrophils, and possibly bacteria themselves, also contribute to development of cerebral edema. Intracranial pressure rises secondary to increased blood flow and edema, resulting in decreased cerebral perfusion. The inflammatory process may cause vasculitis and thrombotic events that contribute to overall cerebral ischemia, resulting in neurologic sequelae.

Clinical Presentation Meningitis causes CSF fluid changes, and these changes can be used as diagnostic markers of infection. Clinical presentation varies with age. 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. However, 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. Clinical signs and symptoms in young children may include bulging fontanelle, apneas, purpuric rash, and convulsions in addition. Seizures occur more commonly in children (20% to 30%) than in adults (12%).

Kernig’s sign (Resistance of the leg movement)

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.

Diagnosis Cerebrospinal fluid (CSF) is obtained by lumbar puncture (LP) It contains 0.4 g/L protein and 2.2‐4.4 mmol/L glucose. CSF protein is usually raised above 1 g/L in bacterial, tuberculous and cryptococcal meningitis and above 0.5 g/L in viral meningitis CSF glucose is usually less than 50% of blood glucose in bacterial, tuberculous and cryptococcal meningitis but normal in viral meningitis. This is due to impaired CNS glucose transport and consumption of glucose by microorganisms.

CSF white blood cells are usually raised above 1000 cell/mm3 in bacterial meningitis CSF gram stain; CSF culture; blood culture PCR: microorganism antigen detection. Lumbar puncture

Treatment The administration of fluids, electrolytes, antipyretics, analgesia, and other supportive measures are particularly important for patients presenting with acute bacterial meningitis. 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

To ensure adequate CSF bactericidal activity, therapy must include only those antimicrobials that can penetrate the BBB and achieve adequate levels in the CSF. Bactericidal antibiotics include agents such as penicillins, cephalosporins, vancomycin, quinolones, penems, and aminoglycosides. Agents such as erythromycin, clindamycin, and tetracycline are bacteriostatic and should not be used for the treatment of patients with meningitis. Empiric antimicrobial therapy should be instituted as soon as possible to eradicate the causative organism. Antimicrobial therapy should last at least 48 to 72 hours or until the diagnosis of bacterial meningitis can be ruled out. As in endocarditis and osteomyelitis, the antibiotic chosen for the treatment of patients with CNS infection must be bactericidal. This is an important factor because, compared with blood, the CSF has decreased immunoglobulins, complement, and opsonic activity, which results in impaired phagocytic activity against encapsulated bacteria.

Prophylaxis: rifampicin, ciprofloxacin, vaccines (pneumovax, Hibvax). 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. Direct intraventricular administration of antibiotics in meningitis is important for drugs that penetrate CSF poorly e,g, vancomycin and aminoglycosides. The most common situation is in shunt associated meningitis where there is a resistant coagulase‐negative staphylococcus. Prophylaxis: rifampicin, ciprofloxacin, vaccines (pneumovax, Hibvax). Due to meningeal inflammation, CSF penetration problems may be overcome by direct instillation of antibiotics by intrathecal, intracisternal, or intraventricular routes of administration.

Intra‐ventricular Catheter

Dexamethasone as an Adjunctive Treatment for pediatric meningitis. Dexamethasone for infants and children aged 2 months or older with pneumococcal meningitis and H. influenzae meningitis. The commonly used IV dexamethasone dose is 0.15 mg/kg every 6 hours for 4 days. Dexamethasone should be administered prior to the first antibiotic dose and not after antibiotics have already been started.

Neisseria meningitidis (Meningococcus) N. meningitidis meningitis is the leading cause of bacterial meningitis in children and young adults usually occur in the winter or spring. Aggressive, early intervention with high-dose IV crystalline penicillin G, 50,000 units/kg every 4 hours, is recommended. Several third generation cephalosporins (e.g., cefotaxime, ceftizoxime, ceftriaxone, and Cefuroxime ) are acceptable alternatives to penicillin G. Meropenem and fluoroquinolones are suitable alternatives for treatment of penicillin-non susceptible meningococci. Adult patients should receive 600 mg of rifampin orally every 12 hours for four doses. Close contacts of patients contracting N. meningitidis meningitis are at an increased risk of developing meningitis.

Streptococcus pneumoniae (Pneumococcus or Diplococcus) leading cause of meningitis in adults and neurologic complications, such as coma and seizures, are common. treatment of choice until susceptibility of the organism is known as the combination of vancomycin plus ceftriaxone. Penicillin may be used for drug-susceptible isolates. For intermediate isolates, ceftriaxone is used For highly drug-resistant isolates a combination of ceftriaxone and vancomycin should be used.

Haemophilus influenzae Most common cause of meningitis in children 6 months to 3 years of age. 30% to 40% of H. influenzae are ampicillin resistant and hence many clinicians use a third-generation cephalosporin (cefotaxime or ceftriaxone) for initial antimicrobial therapy. Cefepime and fluoroquinolones are suitable alternatives regardless of b-lactamase activity. Vaccination with Hib conjugate vaccines is usually begun in children at 2 months. The vaccine should be considered in patients older than 5 years with sickle cell disease, asplenia (absence of normal spleen function), or immunocompromising diseases.

Listeria monocytogenes A gram-positive, diphtheroid-like organism that is responsible for 8% cases neonates, alcoholics, immunocompromised patients, and the elderly. Combination of penicillin G or ampicillin with an aminoglycoside results in a bactericidal effect. Gram-Negative Bacillary Meningitis Meningitis caused by Pseudomonas aeruginosa is initially treated with ceftazidime or cefepime, piperacillin + tazobactam, or meropenem plus an aminoglycoside, usually tobramycin.

Mycobacterium Tuberculosis Meningitis regimen should consist of isoniazid, rifampin, pyrazinamide, and ethambutol, for the first 2 months generally followed by isoniazid plus rifampin for the duration of therapy. Pyridoxine hydrochloride (vitamin B6), 50 mg/ day, are recommended to prevent the peripheral neuropathy associated with isoniazid. Cryptococcus Neoformans Meningitis Most common form of fungal meningitis in immunosuppressed patients Fever and a history of headaches are the most common symptoms. Amphotericin B is the drug of choice for treatment of acute C. neoformans meningitis.