7. Pharmacotherapy Of Brain Infection.ppt

Setyo Purwono Dept. Pharmacology & Therapy, Faculty of Medicine, UGM

CNS INFECTIONS Overview

 Life-threatening problems with high associated

mortality and morbidity  Presentation may be acute, subacute, or chronic  Clinical findings determined by anatomic site(s) of involvement, infecting pathogen, and host response  Vulnerability of CNS to effects of inflammation & edema mandates prompt diagnosis with appropriate therapy if consequences to be minimized

ACUTE CNS INFECTIONS 1. 2. 3. 4. 5. 6.

Bacterial meningitis*** Meningoencephalitis Brain abscess Subdural empyema Epidural abscess Septic venous sinus thrombophlebitis

THE PATIENT WITH ACUTE CNS INFECTION Overall Goals in Management 1.

To promptly recognize the patient with an acute CNS infection syndrome

2. To rapidly initiate appropriate empiric therapy 3. To rapidly and specifically identify the etiologic agent, adjusting therapies as indicated

4.

To optimize management of complicating features

Meningitis  infection of the meninges (pia and arachnoid) due to

organisms crossing the blood-brain barrier or choroid plexus  wide range of organisms responsible  3500 – 4000 cases per year (UK)  most common – viral meningitis  less common but more severe – bacterial meningitis

Blood Brain Barrier (BBB)  Protects brain from contents of blood  Tight junctions: limit permeability  Astrocyte foot processes induce BBB characteristics

Figure 9-6: The blood-brain barrier

 The blood–brain barrier acts very effectively

to protect the brain from many common bacterial infections.  Thus, infections of the brain are very rare.  However, since antibodies and antibiotics are too large to cross the blood–brain barrier, infections of the brain that do occur are often very serious and difficult to treat.

 However,

the blood–brain barrier becomes more permeable during inflammation, meaning that some antibiotics can get across.  Viruses easily bypass the blood–brain barrier by attaching themselves to circulating immune cells.

APPROACH TO THE PATIENT WITH POSSIBLE CNS INFECTION Crucial and recurring question addressed sequentially over time Points in DecisionMaking Process

Available Data Base For Decision-Making

Within the 1st 30 mins of patient contact

Clinical assessment

After 1-2 hours At 24-48 hours

CSF analysis CSF cultures Thereafter as clinically indicated

APPROACH TO THE PATIENT WITH SUSPECTED MENINGITIS Decision-Making Within the First 30 Minutes

Clinical Assessment Mode of presentation Acute (< 24 hrs) Subacute (< 7 days) Chronic (> 4 wks) Historical/physical exam clues Clinical status of the patient Integrity of host defenses  ANTIBIOTIC EMPIRICAL THERAPY

APPROACH TO THE PATIENT WITH SUSPECTED MENINGITIS Decision-Making at 1-2 Hours

CSF Analysis CSF smears/stains CSF antigen screens CSF “profile”

CSF SMEARS & STAINS  GmS + in 60-90% of pts with untreated

bacterial meningitis  With prior ATB Rx, positivity of GmS decreases to 40-60%  REMEMBER: + GmS = Heavy organism burden & worse prognosis

BACTERIAL VS VIRAL MENINGITIS

Predictors of bacterial etiology:  CSF glucose < 34  CSF: Serum glucose ratio < 0.23  CSF protein > 220  CSF WBC count > 2000  CSF neutrophil count > 1180 [Presence of any ONE of the above findings predicts bacterial etiology with > 99% certainty]

APPROACH TO THE PATIENT WITH SUSPECTED MENINGITIS Decision-Making at 24-48 hours

CSF Culture Results Culture positive  Adjust therapy based upon specific organism and sensitivities Culture negative  Evaluate for “aseptic” meningitis syndrome

BACTERIAL MENINGITIS  Incidence of 3 cases/100,000 population/yr (~25,000 total cases)  Fever, HA, meningismus, & altered mentation

present in > 85% of pts  Other clinical findings  Cranial nerve palsies/focal signs 10-20%  Seizures 25-30%  Papilledema < 1%

Antibiotic Therapy  Therapeutic principle  Good permeability for Blood-brain barrier  Drug combination  Intravenous drip  Full dosage  Full course of treatment

 Therapy is gen’ly IV, high dose, & bolus

 Dosing intervals should be appropriate for drug being administered  Utilize “cidal” therapy whenever possible

 Strive for CSF bactericidal index > 10  Initiate therapy promptly (ie, within 30 mins)

Choosing the Right Antibiotic Crossing the Blood Brain Barrier

 Factors Influencing antibiotic concentrations in CSF Factor

Example

Effect

Drug Lipophilicity

Fluoroquinolones Rifampin

Rapid entry into CSF, Relatively good CSF conc Half life similar to serum

High degree of ionization

Beta-lactams

Low lipid solubility with poor BBB penetration

High serum protein binding

Ceftriaxone

Delayed entry into CSF Long CSF and serum half-life

Active Transport system

Penicillin

Relatively rapid entry into CSF Short duration of effective CSF levels

Inflammation

Meningitis

Increased penetration of hydrophilic agents Minimal effect on lipophilic agents

Infecting organism

Listeria, Haemophilus E coli, Strep pneumoniae

Greater antibiotic penetration Lesser antibiotic penetration (CID

1998;27:1117-29)

Choosing the Right Antibiotic Pharmacodynamics of Antibiotics in CSF  Pharmacodynamics: concerned with the time course of antimicrobial activity at the site of infection  The CSF has poor immune response because there are very low concentrations

of pathogen-specific antibodies and complement factors even during meninigitis. Therefore antibiotics should have rapid bactericidal activity for successful treatment (J Antimicrobial Chemo. 1993; 31, Suppl D, 61-70)

 Concentration-dependent killing: efficacy depends on high peak concentrations and prolonged recovery period after drug levels fall below MIC. The recovery period is characterized by postantibiotic effect, in which there is delayed regrowth of bacteria after exposure and removal of an antibiotic (examples:Aminoglycosides/Fluoroquinolones)

 Time-dependent killing: efficacy depends on the time their concentration exceeds the MIC (T>MIC) (examples: Beta-lactams, macrolides, clindamycin) Inf Dis North Am. 1999 Sep; 13(3):595-618

THE THERAPY OF MENINGITIS CNS Penetration Good Diffusion Penicillins 3rd Gen Cephalosporines (ceftriaxone; cefotaxime; ceftazidime)

4th

Gen Cephalosporines

(cefepime)

Chloramphenicol Rifampin Meropenem

Poor Diffusion Early Gen Cephalosporins (Cephalothin, Cephapirin) Clindamycin AMGs Tetracyclines Macrolides

Antibiotic Therapy

 Course of treatment

 7 days for meningococcal infection  10～14 days for H influenzae or S pneumoniae

infection  More than 21 days for S aureus or E coli infection

 14～21 days for other organisms

Antibiotic Therapy  Selection of antibiotic  No Certainly Bacterium 

Community-acquired bacterial infection



Nosocomial infection acquired in a hospital Broad-spectrum antibiotic coverage as noted below 



Children under age 3 months 

Cefotaxime and ampicillin



Ceftriaxone and ampicillin (children over age 1months)

Children over 3 months 

Cefotaxime or Ceftriaxone or ampicillin and chloramphenicol

Antibiotic Therapy  Certainly Bacterium  Once the pathogen has been identified and the antibiotic sensitivities determined, the most appropriate drugs should selected.     

N meningitidis : penicillin, tert- cephalosporin S pneumoniae: penicillin, tert- cephalosporin, vancomycin H influenzae: ampicillin, tert- cephalosporin S aureus: penicillin, nefcillin, vancomycin E coli: ampicillin, chloramphenicol, tert- cephalosporin

COMMON BACTERIAL PATHOGENS BASED ON PREDISPOSING FACTOR IN PATIENTS WITH MENINGITIS Predisposing Factor Age 0-4 wk

4-12 wk

3 mo to 18 yr 18-50 yr >50 yr

Common Bacterial Pathogens Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes, Klebsiella pneumoniae, Enterococcus spp., Salmonella spp. S. agalactiae, E. coli, L. monocytogenes, Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis H. influenzae, N. meningitidis, S. pneumoniae S. pneumoniae, N. meningitidis S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli

COMMON BACTERIAL PATHOGENS BASED ON PREDISPOSING FACTOR IN PATIENTS WITH MENINGITIS Predisposing Factor Immunocompromised state

Basilar skull fracture Head trauma; postneurosurgery

Cerebrospinal fluid shunt

Common Bacterial Pathogens S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli (including P. aeruginosa) S. pneumoniae, H. influenzae, group A βhemolytic streptococci Staphylococcus aureus, Staphylococcus epidermidis, aerobic gram-negative bacilli (including P. aeruginosa) S. epidermidis, S. aureus, aerobic gramnegative bacilli (including P. aeruginosa), P. acnes

EMPIRIC THERAPY OF MENINGITIS IN THE ADULT Clinical Setting

Likely Pathogens

Therapy

Community-acquired

S. pneumoniae N. meningitidis [Listeria] [H. influenzae]

Ceftriaxone 2 gm q12h + Vancomycin 1-2 gm 12h +/Ampicillin 2 gm q4h

Closed head trauma

S. pneumoniae Streptococci

Pen G 3-4 mu q4h + Vancomycin 1-2 gm q12h

EMPIRIC THERAPY OF MENINGITIS IN THE ADULT Clinical Setting

Likely Pathogens

High risk patients Compromised hosts Neurosurgical Open head injury Nosocomial Elderly

S. aureus Gram negative bacilli Listeria

Therapy Vancomycin 2-3 gm/d + Ceftazidime 2 gm q8h or Cefepime 2 gm q8h [Ceftriaxone 2 gm q12h] [Cefotaxime 2 gm q4h] +/Ampicillin 2 gm q4h

SPECIFIC THERAPY FOR KNOWN PATHOGENS Pathogen S. pneumoniae* N. meningitidis Streptococci

Recommended Therapy Pen G 18-24 mu/d or Ampicillin 12 gm/d [Chloro 75-100 mg/kg/d] [Ceftriaxone 2-4 gm/d]

H. influenzae

Cefotaxime 12 gm/d [Ceftriaxone 2-4 gm/d] Pen G 18-24 mu/d or Ampicillin 12 gm/d [plus aminoglycoside]

Group B strep

SPECIFIC THERAPY FOR KNOWN PATHOGENS S. aureus

Nafcillin 12 gm/d [Vancomycin 2-3 gm/d] Listeria Ampicillin 12 gm/d or Pen G 18-24 mu/d [plus aminoglycoside] Gram negative Cefotaxime 12 gm/d bacilli [Ceftriaxone 2-4 gm/d] Pseudomonas Ceftazidime 6-8 gm/d or Cefepime 6 gm/d [plus aminoglycoside] *Penicillin-susceptible (i.e. PCN MIC < 0.06).

CORTICOSTEROIDS AND MENINGITIS  Role of steroids still somewhat uncertain  Recent European study in adults suggested that Rx with dexa associated with ↓ in risk of unfavorable outcome (25%→15%, RR 0.59) & in mortality

(15%→7%, RR for death 0.48)  Dose of dex was 10mg IV q6h X 4d; per protocol, dex given concurrent with or 15-20 mins before 1st

dose of ATBs

CORTICOSTEROIDS AND MENINGITIS (Cont)  Only pts with cloudy CSF, + CSF GmS, or CSF WBC count >1000 were enrolled  Practically speaking, almost all pts with presumed

bacterial meningitis are candidates for at least 1 dose of dexa NEJM 2002;347:1549

PREDICTORS OF ADVERSE CLINICAL OUTCOMES IN PTS WITH COMMUNITY-ACQUIRED BACTERIAL MENINGITIS  Retrospecitve study; 269 pts (84% culture +)

 Adverse clinical outcome in 36% of pts (Death 27%, neuro

deficit 9%)  ↓BP, altered MS, and seizures on presentation all independently associated with adverse clinical outcome  Adverse outcomes in 5% of low risk pts (0 features), 37% of intermediate risk pts (1 feature), and 63% of high risk pts (2-3 features)  Delay in administration of appropriate ATB Rx also associated with adverse clinical outcome Aronin et al, AIM1998;129:862

BACTERIAL MENINGITIS Duration of ATB Rx Pathogen Duration of Rx (d) H. influenzae 7 N. meningitidis 7 S. pneumoniae 10-14 L. monocytogenes 14-21 Group B strep 14-21 GNRs 21 NEJM 1997;336:708

VIRAL MENINGITIS/ENCEPHALITIS Herpesviruses Herpes simplex Varicella-zoster Epstein Barr Cytomegalovirus Myxo/paramyxoviruses Influenza/parainfluenzae Mumps Measles Miscellaneous Adenoviruses LCM Rabies HIV

Enteroviruses Polioviruses Coxsackieviruses Echoviruses Togaviruses Eastern equine Western equine Venezuelan equine St. Louis Powasson California West Nile

NONVIRAL CAUSES OF ENCEPHALOMYELITIS Rocky Mountain spotted fever Typhus Mycoplasma Brucellosis Subacute bacterial endocarditis Syphilis (meningovascular) Relapsing fever Lyme disease Leptospirosis Tuberculosis Cryptococcus Histoplasma Naegleria

Acanthamoeba Toxoplasma Plasmodium falciparum Trypanosomiasis Whipple’s disease Behcet’s disease Vasculitis

BRAIN ABSCESS  Infrequent but not uncommon; pathogenesis diverse with    

 

contiguous spread & blood-borne seeding most common Clinical features include HA (90%), fever (57%), MS changes (67%), hemiparesis (61%), & papilledema (56%) Dx often suggested by neuroimaging (CCT or MRI) LP is contraindicated due to risk of herniation Infxns often polymicrobial (strep, enteric GNRs, &/or anaerobes); S. aureus may cause abscesses in association with IE Other less common etiologies include Nocardia, fungi, M. tuberculosis, T. gondii, & neurocysticercosis Drainage often a necessary component of management

BRAIN ABSCESS Empiric Therapy Penicillin G Metronidazole

18-24 mu IV qd 500 mg IV q6h

 Add nafcillin 12 gm/d if staph suspected

(use vanc if MRSA a concern)  Add cefotaxime, ceftriaxone, or ceftazidime if GNRs suspected  Substitute vanc 2-4 gm IV/d for pen G if DRSP suspected

Some Helminths Affecting the CNS Disease

Agent

Taenia solium (pork tape worm) Echinococcus Hydatid Disease species Schistosoma Schistosomiasis species Paragonimiasis Paragonimus Angiostrongylus cantonensis Eosinophilic (rat lung worm) Meningitis Gnathostoma spinigerum

Cysticercosis

Predominant Tissues Muscle and brain Liver (75%) and lungs (15%) Liver or bladder Lungs Lungs Various organs

Treatment 

symptomatic treatment (eg, antiepileptic drugs) 



praziquantel and albendazole kill the cysts faster  



spontaneous cures noted especially in children limited clinical benefit administer with corticosteroids (antiinflammatory)

surgical excision of cysts was previous treatment

ANTHELMINTIC DRUGS ALBENDAZOLE  Broad spectrum oral anthelmintic  Drug of choice for treatment of hydatid disease and

cysticercosis,it is also used for the treatment of ascariasis ,tricurasis and strongyloidiasis, pinworm, hookworm

Mechanism Of Action

 Inhibits microtubule synthesis by binding to β –tubulin.  Inhibits mitochondrial reductase causing reduced glucose transport.. Intestinal parasites are immobilized and die slowly.  larvicidal in hydatid ,cysticercosis , ascariasis and hook worm infections.  Ovicidal in ascariasis ,hookworm , trichuriasis

Albendazole 

Neurocysticercosis: Used with corticosteroid to decrease the inflammation caused by dying organism and it also reduces the duration of course for 21 days



Other infections: Drug of choice in cutaneous and visceral larva migrans , intestinal capillariasis, giardiasis & taeniasis.

PRAZIQUANTEL

Introduction Praziquantel is effective in the treatment of schistosome infections of all species and most other trematode and cestode infections, including cysticercosis. Praziquantel is not effective against Fasciola hepatica or in hydatid disease. it is the drug of choice (as an investigational drug) for many other cestode and trematode infections. Chemistry & Pharmacokinetics Praziquantel is a synthetic isoquinoline-pyrazine derivative

Anthelmintic Actions The (-) isomer is responsible for most of the drug's anthelmintic activity Praziquantel's in vitro action on all platyhelminths appears to be the same뾲he drug increases cell membrane permeability to calcium, resulting in vacuolization, marked contraction, paralysis, dislodgement, and death. In schistosome infections of experimental animals, praziquantel is effective against adult worms and immature stages; adult worms are rapidly immobilized and then passively shift to the liver. In addition, when a single high dose of praziquantel is given concurrently with an infecting dose of cercariae, all immature forms are killed; thus, praziquantel has a prophylactic effect. Clinical Uses A. Schistosomiasis B. Clonorchiasis and Opisthorchiasis C. Paragonimiasis D. Taeniasis and Diphyllobothriasis E. Neurocysticercosis F. H nana G. Hydatid Disease H. Other Parasites: fasciolopsiasis, metagonimiasis, heterophyiasis.

Cryptococcosis: Treatment • The recommended initial treatment is amphotericin B

deoxycholate, at a dose of 0.7 mg/kg daily, combined with flucytosine, at a dose of 100 mg/kg daily in four divided doses, for ≥2 weeks for those with normal renal function. • The combination of amphotericin B deoxycholate with fluconazole, 400 mg daily (BII), is inferior to amphotericin B combined with flucytosine in terms of clearing Cryptococcus from the CSF but is better than amphotericin B alone 52

Cryptococcosis: Treatment • After at least a 2-week period of successful induction

therapy, defined as significant clinical improvement and a negative CSF culture after repeat lumbar puncture, amphotericin B and flucytosine may be discontinued and follow-up therapy initiated with fluconazole 400 mg daily. • This should continue for 8 weeks • Itraconazole is an acceptable though less effective alternative

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