Post on 17-Aug-2015
ANTIMICROBIAL FOR
BACTERIAL MENINGITIS
2
NUR FARAH BINTI MUHAMMAD
012013100104
OUTLINES
• Penicillin G• Ampicillin• 3rd generation Cephalosporin• 4th generation cephalosporin• References
PENICILLIN G• have greatest activity against gram-positive
organisms, gram-negative cocci, and non-β-lactamase producing anaerobes
• Have limited activity against gram-negative bacilli, and they are susceptible to hydrolysis by β-lactamases
MOA
Bind to penicillin-binding protein (PBP)
Inhibit transpeptidation reaction
Inhibit bacterial cell wall synthesis
PHARMACOKINETICS
• IV administration• Absorption in the stomach is impaired by food (at
least 1-2 hrs before/after meal)• Half life: 30 minutes• Widely distributed throughout the body• Penetration in CSF is poor but in present of
inflammation(meningitis) adequate amount may reach these site
• Metabolized in the liver & excreted in the urine
ANTIMICROBIAL SPECTRUM
• Narrow spectrum, bactericidal
• Cocci: Streptococci(except group D or enterococci)
• Bacilli: Gram-positive bacilli(majority of B. anthracis, Corynebacterium diphtheriae).
ADVERSE EFFECTS
USES CONTRAINDICATIONS• Streptococcal
infections(pharyngitis).• Pneumococcal infections.• Meningococcal infections.• Gonorrhea.
• History of previous administration and allergic manifestations.• History of asthma, allergic
rhinitis, hay fever will increased risk penicillin allergy.
DRUG INTERACTION
• Penicillin + methotrexate
Mechanism: competitive inhibition of renal tubular secretion of methotrexate
Effect: elevate serum methotrexate concentrations
AMPICILLIN• Extended spectrum of penicillin• Improved activity against Gram-negative
organism
MOABind to penicillin-
binding protein (PBP)
Inhibit transpeptidation reaction
Inhibit bacterial cell wall synthesis
PHARMACOKINETICS
• Oral, i.m, i.v(commonly) administration• Half life: 1 hrs• Penetration in CSF is poor but in present of
inflammation(meningitis) adequate amount may reach these site
• Metabolised in the liver & excreted in the urine
ANTIMICROBIAL SPECTRUM
• Broad spectrum, bactericidal• Gram-positive: Streptococcus spp., Enterococcus spp.,
Listeria monocytogenes • Gram-negative bacilli: H. influenza, E. coli, Proteus,
Salmonella and Shigella• drug of choice for the gram-positive bacillus Listeria
monocytogenes
ADVERSE EFFECT
• Diarrhea, nausea, rash• Headache, and dizziness• Nephritis• Neurotoxicity• Hematologic toxicities
USES CONTRAINDICATIONS• Upper respiratory infections.• Urinary tract infections.• Meningitis
•Allergy to penicillins•Infectious mononucleosis•Allergy to cephalosporins, carbapenems•Adjust dose in renal failure
DRUG INTERACTION
• Ampicillin + probenecid
Mechanism: decrease renal ampicillin excretion
Effect: elevate serum ampicillin concentrations
3rd GENERATION CEPHALOSPORIN
Cefotaxime & Ceftriaxone
MOA:Bind to PBP Inhibit transpeptidation reaction Inhibit cell wall synthesis
PHARMACOKINETICS
• Administered intravenously• Half life: 7-8 hrs• Achieve levels in the CSF sufficient to inhibit
most susceptible pathogens• Metabolized in the liver• Mainly excreted in the feces and others are
excreted in the urine
ANTIMICROBIAL SPECTRUM
• Broad spectrum• active against citrobacter,
Serratia marcescens and beta-lactamase-producing strains of Haemophilus and
Neisseria• generally not active
against Enterobacter species
ADVERSE EFFECTS
Hypersensitivity:-anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, and hemolytic anemia
Toxicity-pain (IM injection), thrombophlebitis (IV injection), renal toxicity
USES CONTRAINDICATION• Meningitis caused by
meningococci and H. influenzae
• Pyelonephritis.• Septicemia.• Community-acquired
pneumonia
• patients with history of penicillin allergy• patients with history of GI
disease, especially colitis• Breastfeeding women
4th GENERATION CEPHALOSPORIN
Cefepime
MOA:Bind to PBP Inhibit transpeptidation reaction Inhibit cell wall synthesis
PHARMACOKINETICS
• must be administered parenterally• Penetrates well into CSF• Half life: 2 hrs• Excreted in the urine
ANTIMICROBIAL SPECTRUM
• Broad spectrum, bectericidal• Good activity against P. aeruginosa,
Enterobacteriaceae, S. aureus and S.pneumoniae
• Highly active against Hemophilus and Neisseria sp.
ADVERSE EFFECTS
• anaphylaxis, fever, skin rashes• nephritis, granulocytopenia, and hemolytic
anemia• Renal toxicity
USES IS SAME AS 3rd GENERATION
CEPHALOSPORIN
REFERENCES• Basic & Clinical Pharmacology, 12th Edition
Katzung• Lippincott Illustrated Reviews: Pharmacology
Sixth Edition• Essentials of Pharmacology, 6th Edition, KD
Tripathi.• http://www.drugbank.ca/drugs/DB00415• http://www.drugs.com/mtm/ampicillin.html
DRUGS FOR NON-BACTERIAL MENINGITIS
NUR FARAH BINTI MUHAMMAD012013100104
OUTLINERegime of treatment:
Tuberculous meningitis
Parasitic meningitis
Lyme meningitisSyphilitic
meningitis
Drug therapy:Isoniazid RifampinPyrazinamideDexamethasone Amphotericin BMiconazoleDoxycycline
References
Initial Therapy:Isoniazid – 300mg/dRifampicin – 600mg/dPyrazinamide – 30mg/kg/dEthambutol – 15-25 mg/kg/dPyridoxine – 50mg/d
Good Response : Discontinue Pyrazinamide after 2 months continue H & R for 6 – 12 months
Inadequate Resolution : Continue for 9 – 12 months
Corticosteroid (dexamethasone)IV, 60-80 mg/d for 6 weeks
TUBERCULOUS MENINGITIS
PARASITIC MENINGITIS
Amphotericin BMiconazole Rifampin
High -dose IV and intrathecal
LYME MENINGITIS
Ceftriaxone (2 g/day for 14-28 days)Penicillin G (20 million U/day for 14-28 days)Doxycycline (100 mg orally or IV every 12 hours for 14-28 days)
SYPHILITIC MENINGITIS
Aqueous crystalline penicillin G (2-4 million U/day IV every 4 hours for 10-14 days)IM penicillin G benzathine (2.4 million U).
ISONIAZIDMost active drug for treatment of TBBactericidal for actively growing tubercle bacilliPenetrates into macrophages and is active against both extracellular and intracellular organisms.
MOAIsoniazid (prodrug)
Converted to active form by mycobacterial catalase-
peroxidase (KatG)
Block synthesis of mycolic acids
Disruption of bacterial cell wall
PKreadily absorbed after oral administrationAbsorption is impaired if taken with food (high-fat meals)The drug diffuses into all body fluids, cells, and caseous material. Drug concentrations in the (CSF) are similar to those in the serum.Metabolized in the liver (N -acetyltransferase)Isoniazid metabolites and a small amount of unchanged drug are excreted, mainly in the urine
ADVERSE EFFECTSImmunologic reactionsFever, skin rashesDirect toxicityIsoniazid-induced hepatitis (can be fatal)Clinical hepatitis with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain hepatocellular, damage.Peripheral neuropathyCNSconvulsions, seizures
USES CONTRAINDICATIONSTreating or preventing tuberculosis (TB)
•Liver problem may occur in alcoholic•Hepatitis•Patient receiving certain medicines to treat HIV infection
DRUG INTERACTIONIsoniazid + Phenytoin/ Carbamazepine/ Ethosuximide
Mechanism: Isoniazid inhibits metabolism of above drugs
Effect: Increased effects of above drugs (nystagmus and ataxia)
RIFAMPINhas broader antimicrobial activity than isoniazid, bactericidalactive against gram-positive and gram negative cocci, some enteric bacteria, mycobacteria, and chlamydiae
MOARifampicin binds to β subunit of bacterial DNA-dependent RNA polymerase
Inhibit bacterial DNA-dependent RNA polymerase
Inhibits RNA synthesis
PKAdministered orallyDistribution of rifampin occurs to all body fluids and organs. Concentrations attained in the CSF are variable, often 10% to 20% of blood concentrations.taken up by the liver and undergoes enterohepatic recyclingElimination of rifampin and its metabolites is primarily through the bile and into the feces; a small percentage is cleared in the urine
ADVERSE EFFECTSGenerally well toleratedharmless orange color to urine, sweat, and tears(soft contact lenses may be permanently stained)hepatitisNausea, vomiting, rashes,and nephritisFlulike-syndrome (fever, chills, myalgias, anemia, and thrombocytopenia)
USES CONTRAINDICATIONS•Mycobacterial infections•Bacterial infections (meningococcal carriage)•used as prophylaxis in contacts of children with Haemophilus influenzae type b disease•treatment of serious staphylococcal infections such as osteomyelitis and prosthetic valve endocarditis
•allergic to any ingredient in rifampin or to any rifamycin (eg, rifabutin)•Pregnant women•Breastfeeding women
DRUG INTERACTIONRifampin + OCP
• Mechanism: Rifampicin is an enzyme inducer. It induces metabolism of OCP
• Effect: Contraceptive failure
PYRAZINAMIDEstable and slightly soluble in waterinactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli (bactericidal)drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes
MOA
Pyrazinamide(Pro-drug)
Converted to active form (pyrazinoic
acid)by mycobacterial pyrazinamidase
Pyrazinoic acid disrupts mycobacterial cell membrane
metabolism and transport functions
*EXACT MECHANISM IS UNKNOWN
PKAdministered orallywell absorbed from the gastrointestinal tract and widely distributed in body tissues, including inflamed meningesMetabolized by the liver, but metabolites are renally cleared
ADVERSE EFFECTHepatitisHyperuricemiaGastrointestinal disturbances
USES CONTRAINDICATIONTreating active tuberculosis in combination with other medicines
•Allergic to any ingredient in pyrazinamide•Have gout or severe liver problems•Pregnant & breastfeeding women
Shown to improve overall outcome for patient with certain types of bacterial meningitis, such as H.influenza, tuberculous and pneumococcal meningitisFirst dose should be given prior to starting antibioticsTo decrease cytokine related damage , especially to 8th nerve
DEXAMETHASONE
MOACorticosteroids diffuse across the cell membrane and binds to a cytoplasmic receptor. The receptor forms a dimer.
After dimerizing, the receptor– hormone complex recruits coactivator proteins and translocates into the nucleus, where it attaches to gene promoter elements.
There it acts as a transcription factor to turn genes off (when complexed with corepressors)
Inhibits protein synthesis for immunological response (mediators and leukocytes)
PKCan be administered orally, intravenously and intramuscularly. >90% of absorbed glucocorticoids are bound toplasma proteins, mostly corticosteroid-binding globulin or albumin.Corticosteroids are metabolized by the liver microsomal oxidizingenzymes. The metabolites are conjugated to glucuronic acid or sulfate, and the products are excreted by the kidney.
ADVERSE EFFECTS
USES CONTRAINDICATIONS•Relief of inflammatory symptoms•Replacement therapy for primary adrenocortical insufficiency (Addison disease)•Diagnosis of Cushing syndrome (supression test)•Replacement therapy for congenital adrenal hyperplasia (CAH)•Treatment of allergies•Acceleration of lung maturation
•Hypersensitivity•Cerebral malaria•Lactating mother •Systemic fungal infection
AMPHOTERICIN BPrototype of polyene antimicrobials used systemically.antifungal antibiotics produced by Streptomyces nodosus.nearly insoluble in water
MOAAmphotericin B binds to ergosterol inthe plasma membranes of sensitive
fungal cells
Forms pores (channels) that require hydrophobic interactions between the
lipophilic segment of the polyene antifungal and the sterol
Pores disrupt membrane function, allowing electrolytes (particularly
potassium) and small molecules to leak from the cell
Resulting in cell death
PKAdministered intravenously with colloidal suspension of amphotericin B and sodium desoxycholateWidely distributed in the body, but poor penetration in CSFBinds to sterols in tissues and lipoproteins in plasma and stays in the body for long period.About 60% of AMB is metabolized in liver.The serum half life is 15 days. Excretion occurs slowly both in urine and bile, but urinary concentration of active drug is low.
ADVERSE EFFECTLow therapeutic indexFever, chills, malaise, weight lossN & V, diarrhea, epigastric painThrombophlebitis Muscle and joint painHeadacheDecreased renal function : azotemia,
hypokalemia, hyposthenuria, renal tubular acidosis, and nephrocalcinosis.
USES CONTRAINIDICATIONS•Antifungal agent with the broadest spectrum of action•Use in treatment for:aspergillosis, cryptococcosis (torulosis), North American blastomycosis, systemic candidiasis, coccidiomycosis, histoplasmosis, zygomycosis including mucormycosis and infections due to related susceptible species of Conidiobolus and Basidiobolus, and Sporotrichosis
Contraindicated in those patients who have shown hypersensitivity to Amphotericin B or any other component in the formulation
DRUG INTERACTIONAntineoplastic agents: enhance the potential for renal toxicity, bronchospasm and hypotension. Antineoplastic agents (e.g., nitrogen mustard, etc.) should be given concomitantly only with caution.Corticosteroids and Corticotropin (ACTH): may potentiate Amphotericin B-induced hypokalemia predisposisng the patient to cardiac dysfunction.Digitalis glycosides: Amphotericin B-induced hypokalemia may potentiate digitalis toxicity. Serum potassium levels and cardiac function should be closely monitored.
MICONAZOLE• Imidazole antifungal agent• commonly applied topically to the skin or to mucous
membrane to cure fungal infections• Prevents fungal organisms from producing vital
substances required for growth and function.
MOA
Miconazole interacts with 14-α demethylase, a
cytochrome P-450 enzyme that is necessary to convert
lanosterol to ergosterol
As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in
increased cellular permeability causing
leakage of cellular contents.
Miconazole may also inhibit endogenous
respiration, interact with membrane phospholipids, inhibit the transformation
of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.
PK• Administered by topically and vaginally.• Minimal systemic absorption following topical
application to skin.• Only small amounts absorbed systemically following
intravaginal administration• Drugs metabolized by hepatic microsomal enzymes.• Systemically absorbed drug excreted in urine and
feces
ADVERSE EFFECTS• Burning, stinging, swelling, irritation, redness,
pimple-like bumps, tenderness, or flaking of the treated skin
USES CONTRAINDICATIONS•Dermatophytoses•Pityriasis (Tinea) Versicolor•Cutaneous Candidiasis•Vulvovaginal Candidiasis
•Known hypersensitivity to miconazole or any ingredient in the formulation
DRUG INTERACTION
• Warfarin + miconazole-may increase the plasma concentrations and hypoprothrombinemic effect of warfarin
-cause to bleed more easily