(4/6) Itokazu Lecture: Central Nervous System Infections Central Nervous System infections include inflammation of the meninges and formation of abscesses. Inflammation of the meninges, also known as Meningitis, is far more common and is the topic for this lecture. As with any infection, the goal is to (1) cure infection with antimicrobial therapy and to (2) minimize the risk for complications, or drug-related toxicity. Meningitis: Inflammation of the meninges

- Pathogenesis: Colonial bacteria of the respiratory tract, depending on their virulence, may enter the blood stream and in some cases the CNS. The meninges are the set of tissues layering the brain and spinal cord responsible for maintaining the cerebral spinal fluid (CSF) within the subarachnoid space. The tissue layers are: dura, arachnoid, and pia. The CSF is most common site for infections in the brain.

- Bacterial Causes: The predisposing causes and infective pathogens are heavily reliant on patient age o Age 1-23mo: S. pneumoniae, N. meningitidis, H. influenzae o Age 2-50years: N. meningitidis, S. pneumoniae. With age, H. flu comes off due to vaccination. o à In both cases, the empiric abx choice is Vancomycin + 3rd-generation cephalosporin o Listeria monocytogenes: In the very young, and the very old, Listeria is the major player, thus requiring

alternative empiric therapy. o H. influenzae: 30% produce sufficient beta-lactamases to exhibit ampicillin-resistance o N. meningitidis: Infection very often presents with a ‘petechial rash’

- Clinical Presentation: The prevalent s/sx of meningitis in both adults and infants are fever and seizures. Likely due to a more advanced ability to articulate, adults convey s/sx: headache, visual disturbances, neck stiffness, and confusion. Whereas younger infants present as irritable, vomiting, and have decreased oral intake

o Acute Infection: Bacterial and Viral § Symptoms present within hours to days, progress, and may rapidly become fatal

o Chronic Infection: M. tuberculosis and Fungal § Symptoms occur over a long period of time, sometimes as long as 4 weeks

o There are multiple causes of meningitis, many of which are fatal. Thus, it is critical to accurately diagnose patients to initiate life-saving treatment as soon as possible

- Diagnostics & Labs o CSF Sample: Confirmation of bacterial meningitis consists of:

§ WBCÝ: Represents fighting infection, or inflammatory process § PolysÝ: A ‘left shift’ of PMN suggests ongoing infection to fight § Protein ContentÝ: Due to a break in the BBB, protein can move in § Glucoseß: The WBC quickly consume glucose as energy to battle

o CSF Gram-Stain: Helps with preliminary pathogen identification § G(-) Cocco-bacilli: H. influenzae § G(+) Diplococci: S. pneuomoniae § G(+) Cocci-clusters: Methicillin-resistant S. aureus (MRSA). Looks like a buncha grapes

Supportive Measures of Meningitis - Hydration therapy, replenish electrolytes, facilitate enteral feedings

Pharmacologic Approach for the Treatment of Bacterial Meningitis - Prophylaxis

o Vaccination: Decreases the risk for H. influenzae type b meningitis § Unconjugated-23-valent: For Adults. Includes serotypes to PCN-non-susceptible strains § Conjugated-13-valent: For Adults/Kids ~produces a more robust immune response

o Close Contact Chemoprophylaxis: PCN (S. pneumo), Rifampin (H. inf), Rif/Cipro/Ceft (N. meningitidis) § Eliminates the initial step in meningitis pathophysiology: Nasopharyngeal carriage § Thus, chemoprophylaxis prevents transmission and the development of invasive disease in

colonized persons. Additionally, the CDC recommends limit time & proximity w/ those infected - Role of Steroids: The brain cavity is an enclosed space sensitive to changes in pressure. Given antibiotics,

bacteria will “explode,” releasing their pro-inflammatory contents within the CNS, causing Ýpressure leading to neurologic damage. Therefore, the role of steroids in treating meningitis is to prevent the adverse effects of inflammation. All studies have shown major benefit in reducing unfavorable outcomes by using steroids

- Antibiotic Selection: Bacterial meningitis can be rapidly fatal or at least produce permanent neurologic damage. Upon identification, it needs to be treated immediatelyà Broad-Spectrum, High-dose, Intravenous, Bactericidal

o Broad-Spectrum: It’s quite deadly, cover everything o High dose: To facilitate passage into the BBB o IV: To enhance bioavailability and produce quicker results o Bactericidal: CNS is an immune-compromised organ set, we cannot rely on a –static drug because the

CNS ‘immune system’ will not be able to deliver the final blow. –cidal for days Treatment Options for Bacterial Meningitis

- Vancomycin: Covers G(+), namely S. pneumoniae ~ Both the PCN-susceptible and PCN-non-susceptible o Distribution: Penetration into the CSF is variable and unpredictable. Sometimes we may have to directly

administer it intrathecally to reach desired concentrations o Redman’s Syndrome: May occur with rapid infusion of IV Vanco, may cause crazy histamine release.

Pruritus and erythema all over. This can be resolved by giving it more slowly. - 3rd-Gen Cephalosporins: Broad, covers H. influenzae, N. meningitidis, S. pneumoniae (PCN-susceptible only)

o Ceftriaxone (q12-24): Has good activity against S. pneuomoniae, poor activity against Pseudomonas § Has significant biliary elimination, may precipitate in there, plug it up, show sx of cholecystitis.

This can potentially be a significant side effect. Sx: Abdominal pain, nausea, vomiting o Cefotaxime (q6-8): Interchangeable with ceftriaxone – same coverage o Ceftazidime: Inadequate activity against S. pnuemoniae. Used frequently for Pseudomonas

- Carbapenems: Used for their coverage of S. pneumoniae o Meropenem: FDA approved for bacterial meningitis in kids, it is preferred over imipenem o Imipenem: Less preferred option, due to increased rate of seizures and adverse effects

§ Requires renal dose adjustment – this will help minimize seizure risk o Doripenem and ertapenem are not well-studied in the treatment of meningitis

- Penicillins o PCN G: Dosage is 6x daily for meningitis. This can be challenging in the hospital setting

Empiric n à Vancomycin + Ceftriaxone/Cefotaxime + Dexamethasone 10mg IV q6º x4days

o Effective empiric therapy for Ages 1-50yo Isolate: Neisseria meningitis n PCN MIC < 0.1 mcg/mL à Penicillin + Dexamethasone 10mg IV q6º x4days n PCN MIC 0.1-1 mcg/mL à Ceftriaxone + Dexamethasone 10mg IV q6º x4days Isolate: Streptococcus pneumoniae n PCN MIC £ 0.06 mcg/mL à PCN G -OR- Ceftriaxone + Dexamethasone 10mg IV q6º x4days n PCN MIC ³ 0.12mcg/mL à Vancomycin + Ceftriaxone + Dexamethasone 10mg IV q6º x4days n Ceftriaxone MIC ³ 1 mcg/mL à Vancomycin + Ceftriaxone + Dexamethasone 10mg IV q6º x4days

With S. pneumoniae, if we do not have any MIC information, will use Ceftriaxone + Vanco Ceftazidime is not effective against S. pneumoniae

Isolate: H. Influenzae n à Ceftriaxone alone + Dexamethasone 10mg IV q6º x4days Hospital-acquired meningitis: Empiric coverage for P. aeruginosa, GNB (E. coli, Klebsiella) n à Vancomycin + Cefepime/Ceftazidime/Meropenem + Dexamethasone 10mg IV q6º x4days

o P. aeruginosa: Ceftazidime, Cefepime, Carbapenems (Meropenem), AG, Aztreonam (PCN-ALL) § Ceftriaxone has inadequate anti-pseudomonal activity § AG: Have poor penetration of the CNS, may require direct instillation into CSF. AG have higher

risks of toxicity, which can be minimized by dosing by weight, renal function, and TDM o Aerobic GNB (E. coli, Klebsiella): Same as above + non-anti-pseudomonal 3rd gen-cephs (ceftriaxone)

§ Polymyxin B can be used for the GNB. FDA approved for intra-thecal use o Risk factors include: Post-neurosurgery, development of meningitis post-admission

Duration of Therapy for Bacterial Meningitis - Ranges from 10-21 days – there is no standard - Determinants

o Pathogen: GNB require longer therapy o Complications secondary to infection o Brain Abscesses: require longer therapy. H. influenzae tends to cause brain abscesses