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