Download Highly lipophilic Β-lactams ~ 10-30% of serum

Pharm 9- Pharmacology of CNS Infections
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Bacterial Meningitis
Meningitis is the most common type of CNS infection
In the U.S., the 3 most likely pathogens are Streptococcus pneumoniae, Neisseria meningiditis, and Hemophilus
influenzae
The incidence of H. influenzae infections has declined by more than 90% since the introduction of the Hib
vaccine in 1985
The pneumococcal vaccine, introduced in 2000, decreased rates of meningitis in children less than 5 years old
nearly 60%
Important anatomical considerations for drug therapy
 Barriers to exchange of drugs: blood-brain-barrier (BBB) and blood-CSF barrier (BCSFB)
 BBB – tightly joined capillary endothelial cells; drugs enter by direct passage and penetrate the glial cells that
envelop the capillary structure
 BCSFB – tightly fused ependymal cells of the choroid plexus create a barrier to diffusion of substances
 The surface of the BBB is > 5000 times that of the BCSFB
Treatment Principles
 Prompt institution of appropriate antimicrobial therapy; delay is associated increased morbidity and mortality
 Antibiotics must penetrate adequately into the CSF
 Regimen must have potent activity against the known or suspected pathogen(s) AND exert a bactericidal effect
Antimicrobial penetration into CSF
 Amount of bacteria in the CSF is often much higher than the standard inoculum used for susceptibility testing
(105 CFUs/mL)
 Inoculum effect: increase in MIC with increase in inoculum size
 Purulent CSF is acidic; may reduce bactericidal activity
 Lipid solubility, molecular weight, protein binding, active transport systems of the choroid plexus also affect
penetration
 Good news – penetration of most antibiotics into the CSF is increased when the meninges are inflamed
Pharm 9- Pharmacology of CNS Infections
Treatment by Organism
S. pneumonia (Pneumonococcus): gram+ aerobe
 3rd generation cephalosporins: cefotaxime or ceftriaxone
PLUS
 Vancomycin, in case of highly resistant isolates
 Monitor culture & sensitivity results and adjust accordingly
 Duration of therapy: 10-14 days
3rd Generation cephalosporins
o Cefotaxime and ceftriaxone
o Good activity against pneumococcus
o MOA: Cell wall synthesis inhibitors
o P’kinetics: given IV
o Cefotaxime metabolized by the kidney & liver; active metabolite; 20-36% excreted unchanged
via urine; t ½ ≈ 1 h; adjust dose if ClCr < 20 mL/min
o Ceftriaxone metabolized & excreted by the kidney and bile/feces (33-67% unchanged); t ½ ≈6-9h
o AEs: Well-tolerated; ~ 5% “cross-sensitivity” with pcns; diarrhea w/high doses ceftriaxone; “biliary
sludging”
o CI: ceftriaxone - neonates with hyperbilirubinemia
Vancomycin
o Active against gram+ cocci (aerobes), some strains of MRSA
o MOA: bacterial cell wall synthesis inhibitor
o P’kinetics: not absorbed orally; not metabolized; eliminated via the kidney; t ½ ≈ 4-6 h
o AEs:
o “Red man syndrome” – hypotension and erythematous rash on the face if infused too quickly
o Oto- and possibly nephrotoxicity w/high concentrations
Pharm 9- Pharmacology of CNS Infections
N. meningiditis (Meningococcus): gram- aerobe
 Aggressive, early, high-dose penicillin G IV q4h
 OR
 3rd generation cephalosporin (cefotaxime or ceftriaxone)
 Alternative: chloramphenicol
 Monitor culture & sensitivity results and adjust accordingly
 Duration of therapy: 7 days
 Spread by direct person-to-person contact including respiratory droplets & pharyngeal secretions
 Prophylaxis for close contacts (day care center, household): rifampin PO every 12 h for 2 days
Penicillin
o Active against gram+ cocci, N. meningiditis & spirochetes
o MOA: bacterial cell wall synthesis inhibitors
o P’kinetics: metabolized & eliminated via the kidneys; t ½ ≈ 20-30 min
o AEs: immediate hypersensitivity (IgE), i.e., urticaria or anaphylactic shock, serum sickness, interstitial
nephritis, rash
o CI: penicillin allergy
Chloramphenicol
o Active against gram+ cocci, meningococci, H. influenzae in meningitis
o MOA: binds to the 50S ribosomal subunit and inhibits bacterial protein synthesis
o P’kinetics: lipophilic -  concentrations in CNS; metabolized by the liver; excreted via the kidney; t ½ ≈
1.5 – 4 h
o AEs: “Gray baby” syndrome – weakness, respiratory depression, hypotension, shock & ashen gray
cyanosis; aplastic anemia
o DIs: CYP 3A4 inhibitor
o Rarely used due to unpredictable metabolism in infants and DIs
Rifampin
o Broad spectrum, active against gram+, gram- and acid-fast bacilli including M. tuberculosis & M. aviumintracellulare
o MOA: binds to the β-subunit of RNA polymerase; inhibits protein synthesis
o P’kinetics: rapidly absorbed; widely distributed including lung, saliva, peritoneal and pleural fluids;
metabolized in the liver to desacetylrifampin (active metabolite); excreted primarily in the feces via
biliary elimination; t ½ ≈ 3-5 h; 2-3h with repeated dosing
o AEs: hepatitis – monitor LFTs; hypersensitivity reaction – flu-like; reddish-brown saliva, tears & urine
o Drug interactions
Inducer of CYP450 1A2, 2C9, and 3A4- increases metabolism of macrolides, calcium channel
blockers, digoxin, estrogens, warfarin and others
P-gp inducer
H. influenzae
 3rd generation cephalosporins – active against β-lactamase-producing and non- β-lactamase-producing H.
influenzae
 Switch to ampicillin if pcn-susceptible
 Duration of therapy: 7 days
 Prophylaxis with rifampin for close contacts
 Exposed unvaccinated children should receive the vaccine
Pharm 9- Pharmacology of CNS Infections
L. monocytogenes: gram+ aerobe/ facultative anaerobe
Neonates, alcoholics, immunocompromised adults and elderly
 Penicillin G or ampicillin +/- gentamicin
 Alternative: TMP/SMX
 Duration of therapy: ≥ 21 days; combination for 10-day minimum; complete with pcn or ampicillin alone
Gentamicin
o Active against aerobic gram-negative bacilli; synergistic against L. monocytogenes
o MOA: binds to the 30S ribosomal subunit, inhibiting protein synthesis
o P’kinetics: poor absorption; eliminated via the kidneys; t ½ ≈ 2.5 h
o AEs: renal toxicity, ototoxicity
TMP-SMX
o Active against gram- aerobes, MRSA
o MOA: bacterial dihydrofolate synthesis inhibitor
o P’kinetics: well absorbed; widely distributed (CSF); excreted via urine; t ½ ≈ 6-10 h
o AEs: skin hypersensitivity reactions (Stevens-Johnson Syndrome), hemolytic anemia w/G6PD deficiency,
hyperkalemia
o DIs: warfarin, phenytoin
Adjunctive treatment
Dexamethasone
o MOA: inhibits the production of cytokines TNF and IL-1
o Possible protection against hearing loss
o Recommendations: give dexamethasone for pneumococcal or H. influenzae meningitis in adults and
children for 2-4 days
o 1st dose should be administered prior to the 1st dose of antibiotics
Prevention= VACCINATION
Pharm 9- Pharmacology of CNS Infections
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Brain Abscess
Bacterial - Streptococci (aerobic, anaerobic, and microaerophilic) 70%; Staphylococcus aureus 10% - 20%;
Bacteroides species, gram- bacilli
Protozoal - Toxoplasma gondii is most common
Fungal - Candida spp. is most prevalent
Treatment Principles
 Antimicrobial therapy with high-dose intravenous agents has traditionally been administered for 6 to 8 weeks in
patients with bacterial brain abscesses
o Shorter courses (3 - 4 weeks) of antimicrobial therapy may be adequate for patients who have
undergone surgical excision of the abscess
 Optimal therapy for brain abscesses usually requires a combined medical and surgical approach
 There is no role for monotherapy for toxoplasmosis
Metronidazole
o Active against: anaerobic bacteria; some parasites
o Nitroimidazole compound, chemically reduced in anaerobic bacteria
o MOA: reactive reduction products (free nitro-radicals) appear to exert antimicrobial activity
o P’kinetics: well absorbed; good penetration into brain abscess cavities; extensively metabolized; renally
excreted
o AEs: anorexia, N/V, metallic taste; take w/food
o DIs: 2C9 inhibitor; warfarin. Disulfiram-like reaction w/EtOH: nausea, vomiting, sweating, flushing,
palpitations & dyspnea
Toxoplasmosis (T. gondii)
Pyrimethamine – most effective anti-Toxoplasma agent
o MOA: folic acid antagonist (inhibits dihydrofolate reductase)
o P’kinetics: excreted via urine t½ ≈ 96 h
o AEs: bone marrow suppression (most common), which may be decreased by concomitant administration of
folinic acid; GI distress, rash, headaches, a bad taste in the mouth
o DIs: other myelosuppressive drugs
AND
Sulfadiazine – synergistic with pyrimethamine
o AEs: skin rashes (which may be life-threatening) and crystal-induced nephrotoxicity
Alternative: Clindamycin
o AEs: diarrhea, Clostridium difficile colitis (diarrhea, abdominal pain and fever)
Pharm 9- Pharmacology of CNS Infections
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Viral Encephalitis
Prolonged hospitalizations, a multitude of expensive diagnostic tests, and frequently poor outcomes including
disability and death
Worldwide – mumps and poliomyelitis
U.S. – coxsackieviruses A & B and enteroviruses 70 & 71 account for 85%
Pathogens are not usually identified; 1/3 to 2/3 of encephalitis cases remain of unknown, thus, treatment is
supportive
Herpes simplex virus is treated with IV acyclovir; decreases mortality to 20%
Alternative for acyclovir-resistant HSV: foscarnet
Acyclovir
 MOA: Nucleoside analogue that competitively inhibits DNA polymerases & terminates DNA elongation 
inhibits viral DNA & RNA synthesis
 P’kinetics: bioavailability 22%; distributes into CSF, vesicular fluid, vaginal secretions and tissues; excreted
renally; t ½ ≈ 3 h
 AEs: phlebitis (15%), crystalline nephropathy
 DIs: probenecid
Foscarnet
 MOA: inhibits DNA & RNA polymerases & reverse transcriptases
 Used primarily for CMV retinitis; alternative for acyclovir-resistant HSV
 P’kinetics: low bioavailability, given IV; binds to divalent cations and accumulates in bone; excreted unchanged
in urine; t ½ ≈ 3-4h
 AEs: hypocalcemia, hypomagnesemia, seizures, cardiac arrhythmias, renal insufficiency (monitor SCr)
 DIs: other nephrotoxic drugs (aminoglycosides, acyclovir)
Pharm 9- Pharmacology of CNS Infections
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Fungal Meningitis
Cryptococcus neoformans is the most common cause of fungal meningitis
Major cause of morbidity and mortality, especially in immunosuppressed patients
85% of cases in HIV-infected patients
DOC – amphotericin B +/- flucytosine
Alternative: azole antifungals – fluconazole, posaconazole
Amphotericin B
 Polyene antifungal active against a wide variety of fungi
 MOA: Binds to ergosterol in fungal membranes,  permeability; K+ & Mg++ leaks out  metabolism is
disrupted (also bind to cholesterol in mammalian cells)
 P’kinetics: not absorbed orally; hepatic metabolism; excreted in the urine; t ½ ≈ 24h; 15 d
 AEs:”Amphoterrible” – renal toxicity in 80% of patients; hypokalemia & hypomagnesemia; acute liver failure,
arrhythmias, anemia, leukopenia, thrombocytopenia, chills, fever, headache
 N/V: pre-treatment with corticosteroids, acetaminophen and antihistamines may help
 Note: lipid formulations cause less renal toxicity
 DIs: other nephrotoxic drugs (aminoglycosides, etc.)
Flucytosine
 Pyrimidine antimetabolite
 MOA: inhibits protein synthesis; only antifungal that affects nucleic acid
 Drug resistance develops rapidly; used in combination w/amphotericin B
 P’kinetics: well absorbed; excreted unchanged in urine; t ½ ≈ 3-6 h
 AEs: well-tolerated; myelosuppression
 DIs: other nephrotoxic drugs (aminoglycosides, etc.)
Azole antifungals (fluconazole, et al)
 Active against a wide variety of fungi
 MOA: inhibit 14-α-demethylase and block ergosterol synthesis
 P’kinetics: well absorbed; widely distributed to tissues and body fluids; only fluconazole, voriconazole &
posaconazole achieve significant concentrations in the CSF; hepatic metabolism; renal excretion; t ½ ≈ 35h
 AEs: hepatotoxicity
 DIs: 2C9/19, 3A4 inhibitor; HMG-CoA-reductase inhibitors (“statins”), warfarin, some benzodiazepines
Pharm 9- Pharmacology of CNS Infections
Bottom Line…
 Treat immediately…or faster!
 Do appropriate lab/diagnostic tests
 Empiric coverage for the most common pathogens
 Use drugs that penetrate the BBB, at a high enough dose for a sufficient length of time