Lecture 1: Pharmacology of Neurological Infections Flashcards
What is the standard emperic antibiotic regimen for acute pyogenic meningitis?
- [Cefotaxime or ceftriaxone] + vancomycin
- Ampicillin added in older patients (>50 years)
What’s the standard treatment for infantile meningitis caused by H. influenzae type B?
- Hib vaccine
- Cefotaxime or ceftriaxone
What’s the empiric treatment for acute pyogenic meningitis in patients with a beta-lactam allergy?
Beta-lactam allergy in patients age >50?
- Standard = Vancomycin + moxifloxacin
- >50 y/o = Vancomycin + moxifloxacin + TMP/SMX
What’s the empiric treatment for acute pyogenic meningitis in immunocompromised patients?
Vancomycin + ampicillin + [cefepime or meropenem]
Which virus family and viruses in this family are the major cause of acute aseptic meningitis?
- Enteroviruses
- Coxsackievirus, echovirus
CSF findings (immune cells, protein, glucose, and opening pressure) seen with acute aseptic meningitis?
- Lymphocytic pleocytosis
- Moderate protein elevation
- Normal glucose
- Opening pressure can be normal or elevated
What is the standard of care if you begin antibiotics after a lumbar puncture for suspected meningits, but the bacterial cultures are negative?
Discontinue antibiotics
What are the two 3rd gen. Cephalosporins used for meningitis?
- Cefotaxime
- Ceftriaxone
What is the 4th gen. Cephalosporin used in the treatment of meningitis?
Cefepime
What is the Glycopeptide used in the treatment of meningitis/brain abscesses/subdural empyema?
Vancomycin
What is the Carbapenem used in the treatment of meningitis/brain abscesses/subdural empyema?
Meropenem
What is the Aminopenicillin used in the treatment of meningitis?
Ampicillin
What is the Fluoroquinolone used in the treatment of meningitis?
Moxifloxacin
What are the Benzylpyrimidine/Sulfonamide used in the treatment of meningitis?
Trimethoprim/Sulfamethoxazole (TMP/SMX)
What is the CSF content (immune cells, glucose, and protein) seen with a brain abscess?
- High white cell count
- Increased protein concentration
- Normal glucose content
What are the most common pathogens that cause brain abscesses?
- Viridans streptococci
- S. aureus
Which group of pathogens is the most likely culprit for a brain abscess in an immunocompetent vs. immunocompromised patient?
- Immunocompetent = bacteria
- Immunocompromised = fungi (can be bacterial too)
What is the standard of care for a brain abscess?
- Surgery + antibiotic reduces otherwise high mortality rate to 10%
- Aspiration
- Craniotomy to drain abscess or to totally remove it
What is the empiric therapy of brain abscess with unknown source?
Vancomycin + [ceftriaxone or cefotaxime] + metronidazole
Which antibiotic is used to cover aerobic and anaerobic streptococci (mouth flora) involved in a brain abscess?
Penicillin G
Which antibiotic can readily penetrate a brain abscess and is often combined with other agents during treatment of brain abscesses?
Metronidazole
Which antibiotic can be used as a substitue for Penicillin G while treating a brain abscess?
Ceftriaxone or Cefotaxime
Which organisms are covered by Ceftriaxone and Cefotaxime?
- Most aerobic and microaerophilic streptococci
- Many enterobacteriaceae
Which antibiotics are used if a brain abscess complicates a neurosurgical procedure or cases in which the abscess culture grows P. aeruginosa?
Ceftazidime, cefepime, or meropenem
What is the standard for the use of Vancomycin in the treatment of brain abscesses?
When would you stop using?
Which antibiotics will be substituted for the Vancomycin?
- Included in tx regimen until culture and susceptibility results are available
- No MRSA = NO vancomycin
- Naficillin or oxacillin should be substituted for vancomycin
What are the three Cephalosporin: 3rd gen. used in the treatment of brain abscesses/subdural empyema?
- Cefotaxime
- Ceftriaxone
- Ceftazidime
What’s a Subdural empyema?
Produced by bacteria (and rarely fungal) infections of the skull bones or air sinuses that spread to the subdural space
What are the common pathogens that cause subdural empyemas?
Following neurosurgical procedures or head trauma?
- Aerobic and anaerobic Streptococci,Staphylococci, Enterobacteriaceae, andanaerobic bacteria
- Following neuro procedure/trauma: Staphylococci (MRSA) and gram-negative bacilli (P. aeruginosa)
What is the immediate treatment for a subdural empyema?
- Medical emergency!
- Surgery to evacuate the empyema
- Antibiotic therapy
What is the empiric antibiotic therapy for subdural empyema that is community acquired?
[Cefotaxime or ceftriaxone] + vancomycin + metronidazole
What is the empiric antibiotic therapy for subdural empyema that is hospital acquired (P. aeruginosa or MRSA)?
Meropenem + vancomycin
What are 4 types of Viral Meningoencephalitis?
1) Parenchymal infection of the brain: associated w/ meningoencephalitis and encephalomyelitis
2) Arthropod borne viral encephalitis
3) Subacute sclerosis panencephalitis (SSPE): measles
4) Poliomyelitis
SSPE caused by measles is characterized by?
- Variable inflammation of white and grey matter
- Neurofibrillary tangles
What are the initial signs of Poliomyelitis?
Mild gastroenteritis
Which immunoglobulins are produced with a live vaccine?
Killed vaccine?
Live = IgA and IgG
Killed = IgG
Is there cell-mediated immunity produced with a live vaccine and killed vaccine?
- Live vaccine = yes
- Killed vaccine = weakly or none
What type of vaccine is the MMR?
Live attenuated
What are the 2 types of poliomyelitis vaccine and which is safer?
1) Inactivated poliovirus vaccine (IPV): killed virus vaccine; does NOT cause vaccine-associated paralytic poliomyelitis
2) Live attenuated oral poliovirus vaccine (OPC): can cause polio in a small % of pts
Which fungi is a common cause of fungal meningoencephalitis?
Who is particularly at risk?
CSF finding?
- Cryptococcal meningitis
- Common opportunistic infection in setting of AIDS
- CSF contents = likely high protein concentration
How does fungal meningoencephalitis manifest; appearance of brain sections?
- Manifests as chronic meningitis affecting the basal leptomeninges
- Appears of “soap bubbles” on whole-brain sections
What is the common clinical presentation for Fungal meningoencephalitis?
- Stiff neck, photophobia, and vomiting
- Lethargy and confusion
Which infection should you hav a high suspicion of with advanced HIV patients that have a CD4 count <100 cells/uL and presenting with stiff neck, photophobia, and vomiting?
Cryptococcal meningitis
Which antibiotics are used for the induction phase and then consolidation phase of therapy for funal meningoencephalitis?
- Induction phase: Amphotericin B + Flucytosine (5-FC)
- Consolidation: Fluconazole
What is Ergosterol?
- Vital part of cell membranes of fungi (not found in human cell membranes)
- Most anti-fungal agents bind ergosterol w/ a higher affinity than cholesterol
What is the MOA of the anti-fungal, Amphotericin B?
- Forms complex w/ ergosterol and disrupts the fungal cell membrane
- Leads to cytoplasmic leakage and fungal cell death
How is the anti-fungal, Amphotericin B administered?
Adverse effects?
- Given IV and directly into the CSF (not absorbed orally)
- Adverse effects:
- Renal toxicity
- Acute febrile rxn: chills and fever, common
- Anemia
*Often nicknamed in the clinic: AWFUL-tericin or Ampho-TERRIBLE
What is the MOA of the anti-fungal, Flucytosine (5-FC)?
Why should it not be used alone?
- Antimetabolite
- Converted to 5-fluorouracil (5-FU) inside fungal cells
- Inhibits DNA and RNA synthesis (similar structure to uracil so can integrate itself into DNA and RNA causing cell death
- Rapid resistance develops if used alone
What are the possible adverse effects of the anti-fungal, Flucytosine (5-FC)?
- Conversion of 5-FC to 5-FU OUTSIDE of the fungal cells
- Bone marrow depression, nausea, vomiting, and diarrhea
*Logically, will affect the rapidly proliferating cells of your body, like within the bone marrow and GI mucosa!!!
What is the MOA of the anti-fungals, Fluconazole, Azole, and Triazole?
How easy do they get into CSF?
- Inhibit ergosterol synthesis by inhibiting fungal P450 enzymes
- Very good CSF penetration
What are the adverse effects of Fluconazole?
Limited, widest therapeutic index of all the azoles
Which 4 antibiotic classes + one drug not belonging to a class should NOT be used to treat neuroinfections?
1) Cephalosporins: 1st gen –> Cefazolin
2) Aminoglycosides: (-mysin and -micin)
3) Tetracyclines: (-cyclines)
4) Macrolides: (-mysin and -micin)
5) No class: Clindamycin
How is Metronidazole activated?
- Anaerobic pathogens contain an electron transport system w/ a high negative redox potential, which donates electrons to Metronidazole
- When electron is donated, a highly reactive nitro radical anion is formed; allows for the killing of organisms by means of radical-mediated DNA damage
What is one major way of resisting Metronidazole?
- Increasing intracellular levels of O2
- Resistance correlates w/ impaired O2 scavenging, which leads to increased intracellular O2 levels
Metronidazole is active against which pathogens?
- Flagellated protozoa: T. vaginalis and G. lamblia
- E. histolytica (protozoan)
- Anaerobic cocci and Anaerobic gram-negative bacilli
- Helicobacter and Campylobacter spp. (gram-negative)
- Clostridium spp. (gram-positive bacilli)
What are adverse effects that are unique to Metronidazole?
- Metallic taste in pt’s mouth
- Disulfiram-like effect: induces vomiting if alcohol consumed during or within 3 days of treatment; also flushing, abdominal discomfort, or headache
CSF content associated with acute pyogenic meningits?
- Increased neutrophils
- Increased protein
- Decreased glucose
Which class does Metronidazole belong to?
5-nitroimidazoles
What are the concerns with the use of live vaccines?
- Attenuated viral mutants revert to virulence either during vaccine production or in the immunized person: Polio, not measles and is pathogenic in immunocompromised pts
- Excretion of live virus to infect other: Herd immunity and Double edged sword
