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UW Pharmacology: Antibiotics
Antibiotics: antibacterials, antivirals, antifungals, etc.
57
Pharmacology
Graduate
11/02/2011

Additional Pharmacology Flashcards

 


 

Cards

Term
Bacteriocidal vs. Bacteriostatic?
Definition

Bacteriocidal:

1. Antibiotics stimulate oxidation of NADH via electron transport chain -->

2. Hyperactivation of electron transport stimulates formation of superoxides -->

3. Damage to iron sulfur clusters making ferrous iron available for oxidation via Fenton reaction -->

4. Fenton reaction leads to hydroxyl radical formation (OH-) -->

5. Damage to DNA, proteins and lipids = cell death

 

Bacteristatic:

1. If drug is removed, then the bacteria can resume growing...

Term

Penicillin G(B/C)

Penicillin V(B/C)

Definition

Classification:

Beta lactam: penicillinase-susceptible penicillin

 

Mechanism of Action:

1. Bind penecillin-binding proteins (PBPs) --> mimics D-ala D-ala structure

2. Inhibition of transpeptidase reaction -->

3. Autolytic enzyme activation in bacterial cell wall -->

 

Clinical Uses:

1. Streptococci

2. Meningococci

3. Gram-positive bacilli

4. Spirochetes (syphilis)

 

Pharmokinetics:

1. Rapid renal elimination

2. Short half-lives

3. Variable CNS

 

Resistance:

1. Beta lactamase production

2. Altered penicillin binding proteins (PBPs) (MRSA)

3. Changes in porin structures (Pseudomonas aeruginosa)

 

Toxicities:

1. Hypersensitivity reactions

2. Ampiciliin (maculopapular rash and GI distress)

Term

Dicloxacillin(B/C)

Methicillin(B/C)

Nafcillin(B/C)

Oxacillin(B/C)

Definition

Classification:

Beta lactam: penicillinase-resistant penicillin

 

Mechanism of Action:

1. Bind penecillin-binding proteins (PBPs) --> mimics D-ala D-ala structure

2. Inhibition of transpeptidase reaction -->

3. Autolytic enzyme activation in bacterial cell wall --> causes lesion in bacterial cell membrane

 

Clinical Uses:

1. Staphyloccocal infections

 

Pharmokinetics:

1. Rapid renal elimination

2. Short half-lives

3. Biliary clearance with nafcillin and oxacillin

4. Variable CNS

 

Resistance:

1. Altered penicillin binding proteins (PBPs) (MRSA)

 

Toxicities:

1. Hypersensitivity reactions

2. Ampiciliin (maculopapular rash and GI distress)

Term

Ampicillin

Amoxicillin(B/C)

Definition

Classification:

Beta lactam: penicillinase-resistant penicillin

 

Mechanism of Action:

1. Bind penecillin-binding proteins (PBPs) --> mimics D-ala D-ala structure

2. Inhibition of transpeptidase reaction -->

3. Autolytic enzyme activation in bacterial cell wall -->

 

Clinical Uses:

1. Staphyloccocal infections

2. Greater activity against Gram-negative organisms

 

Pharmokinetics:

1. Rapid renal elimination

2. Short half-lives

3. Biliary clearance with nafcillin and oxacillin

 

Resistance:

1. Altered penicillin binding proteins (PBPs) (MRSA)

 

Toxicities:

1. Hypersensitivity reactions

2. Ampiciliin (maculopapular rash and GI distress)

Term

Cephalexin

Cefazolin

 

Definition

Classification:

Cephalosporin: 1st generation

 

Mechanism of Action:

1. Bind penecillin-binding proteins (PBPs) --> mimics D-ala D-ala structure

2. Inhibition of transpeptidase reaction -->

3. Autolytic enzyme activation in bacterial cell wall -->

 

Clinical Uses:

1. Gram positive organisms: staphyloccoci and streptococci

2. Gram-negative organisms: E. coli & Klebsiella

 

Pharmokinetics:

1. Rapid renal elimination

2. Short half-lives

3. Biliary clearance with nafcillin and oxacillin

 

Resistance:

1. Altered penicillin binding proteins (PBPs) (MRSA)

2. Changes in membrane permeability

3. Extended spectrum beta lactamases (cephalosporinases)

 

Toxicities:

1. Hypersensitivity reactions

2. Ampiciliin (maculopapular rash and GI distress)

Term

Cefaclor(B/C)

Cefoxitin

Cefotetan

Cefuroxime

Definition

Classification:

Cephalosporin: 2nd generation

 

Mechanism of Action:

1. Bind penecillin-binding proteins (PBPs) --> mimics D-ala D-ala structure

2. Inhibition of transpeptidase reaction -->

3. Autolytic enzyme activation in bacterial cell wall -->

lesions in bacterial cell wall.

 

Clinical Uses:

1. Slightly less Gram negative coverage

2. Extended Gram-negative coverage: Bacteroides fragilis and H. influenzae and M. catarrhalis sinus, ear or respiratory infections.

 

Pharmokinetics:

1. Rapid renal elimination

2. Short half-lives

3. Variable CNS

 

Resistance:

1. Altered penicillin binding proteins (PBPs) (MRSA)

2. Changes in membrane permeability

3. Extended spectrum beta lactamases (cephalosporinases)

 

Toxicities:

1. Hypersensitivity reactions (less than with penicillins)

2. Increase nephrotoxicity of aminoglycosides when used together

Term

Ceftriaxone(B/C)

Cefottaxime

Cefuroxime

Definition

Classification:

Cephalosporin: 3rd generation

 

Mechanism of Action:

1. Bind penecillin-binding proteins (PBPs) --> mimics D-ala D-ala structure

2. Inhibition of transpeptidase reaction -->

3. Autolytic enzyme activation in bacterial cell wall -->

lesions in bacterial cell wall.

 

Clinical Uses:

Many uses:

1. Pneumonia

2. Meningitis

3. Gonorrhea

 

Pharmokinetics:

1. Rapid renal elimination

2. Short half-lives

3. Variable CNS (Book says CNS penetration is good)

4. Ceftriaxone (parenteral)

 

Resistance:

1. Altered penicillin binding proteins (PBPs) (MRSA)

2. Changes in membrane permeability

3. Extended spectrum beta lactamases (cephalosporinases)

 

Toxicities:

1. Hypersensitivity reactions (less than with penicillins)

2. Increase nephrotoxicity of aminoglycosides when used together

 

Term
Cefepime(B)
Definition

Classification:

Cephalosporin: 4th generation

 

Mechanism of Action:

1. Bind penecillin-binding proteins (PBPs) --> mimics D-ala D-ala structure

2. Inhibition of transpeptidase reaction -->

3. Autolytic enzyme activation in bacterial cell wall -->

lesions in bacterial cell wall.

 

Clinical Uses:

More resistant to Gram negative Beta lactamases

*Combination of Gram positive and Gram negative activity


Pharmokinetics:

1. Rapid renal elimination

2. Short half-lives

3. Variable CNS (Book says CNS penetration is good)

4. Ceftriaxone (parenteral)

 

Resistance:

1. Altered penicillin binding proteins (PBPs) (MRSA)

2. Changes in membrane permeability

3. Extended spectrum beta lactamases (cephalosporinases)

 

Toxicities:

1. Hypersensitivity reactions (less than with penicillins)

2. Increase nephrotoxicity of aminoglycosides when used together

 

Term

Piperacillin

Ticarcillin(B/C)

Definition

Classification:

Beta lactam: penicillinase-susceptible penicillin

 

Mechanism of Action:

1. Bind penecillin-binding proteins (PBPs) --> mimics D-ala D-ala structure

2. Inhibition of transpeptidase reaction -->

3. Autolytic enzyme activation in bacterial cell wall -->

 

Clinical Uses:

1. Gram negative rods: Pseudomonas, Klebsiella and Enterobacter

2. Often used with Beta lactamase inhibitor and aminoglycosides (they are susceptible to Beta lactamases

 

Pharmokinetics:

1. Rapid renal elimination

2. Short half-lives

 

Resistance:

1. Altered penicillin binding proteins (PBPs) (MRSA)

2. Beta lactamases (use Beta lactamase inhibitor)

 

Toxicities:

1. Hypersensitivity reactions

2. Ampiciliin (maculopapular rash and GI distress

Term

Clavulanic acid(B/C)

Sulbactam

Tazobactam

Definition

Classification:

Beta lactamase inhibtior

 

Mechanism of Action:

1. Suicide inhibitor of Beta lactamase enzymes

 

Clinical Uses:

1. Active against plasmid-encoded Beta lactamases

2. NOT good at inducible chromosomal Beta lactamases

 

Pharmokinetics:

1. Rapid renal elimination

2. CSF penetration

 

Resistance:


Toxicities:

Term

Meropenem(B/C)

Imipenem

Ertapenem

Definition

Classification:

Carbapenem: low susceptibility to Beta lactamases

 

Mechanism of Action:

1. Bind penecillin-binding proteins (PBPs) --> mimics D-ala D-ala structure

2. Inhibition of transpeptidase reaction -->

3. Autolytic enzyme activation in bacterial cell wall -->

 

Clinical Uses:

1. Gram positive cocci, Gram negative rods, anaerobes

2. NOT MRSA

 

Pharmokinetics:

1. Rapid renal elimination

2. Short half-lives

3. Parenteral administration

4.CNS penetration

*Imipenum is rapidly inactivated by renal dehydropeptidase I (use cilastatin at same time to inhibit enzyme)

 

Resistance:

1. Altered penicillin binding proteins (PBPs) (MRSA)

2. Extended spectrum Beta lactamases

 

Toxicities:

1. Partial cross-hypersensitivity with penicillins

2. GI distress

3. CNS toxicity

4. Rashes

Term

Vancomycin(B/C)

Teicoplanin

Definition

Classification:

Bactericidal glycoprotein cell wall synthesis inhibitor

 

Mechanism of Action:

1. Binds to D-ala-D-ala terminal of nascent pentapeptide side chain -->

2. Inhibits transglycosylation -->

3. Prevents transfer and elongation of peptidoglycan chain

 

Clinical Uses:

1. MRSA

2. Drug resistant Gram positive organisms

3. Backup drug for C. difficile --> *bad oral biovailability, thus high intestinal concentrations are reached

 

Pharmokinetics:

1. Renal elimination unaltered in urine

2. Penetrates most tissues

 

Resistance:

1. VISA: intermediate resistance, probably cell wall thickening

2. VRE/SA: Encoded on Van operon --> leads to replacement of D-ala-D-ala with D-ala-D-lactate --> 1000 fold decreased affinity for vancomycin

 

Toxicities:

1. Diffuse flushing (Red man syndrome) from histamine release

2. Chills, fever, phlebitis, ototoxicity and mild nephrotoxicity (reversible)

 

Term

Daptomycin(B/C)

Polymixin B, E

Definition

Classification:

Cyclic-lipopeptide

 

Mechanism of Action:

1. Disruption of bacterial membrane -->

2. Depolarization of membrane & leakage of ions -->

3. Halting of essential cellular processes

 

Clinical Uses:

Daptomycin: Used in endocarditis and sepsis against MRSA and VRE/VRSA

Polymyxin B/E: Gram-negative organism sepsis

 

Pharmokinetics:

1. Renal elimination

2. Varibale CSF

 

Resistance:

1. Alterations in cell membrane structure (e.g. VISA)

2. Daptomycin does not work in lung as surfactant inactivates it.

 

Toxicities:

1. Myopathy (monitor creatine phosphokinase)

2. Many toxicities with PMB/E

Term
Cycloserine(B)
Definition

Classification:

Antimetabolite

 

Mechanism of Action:

1. Blocks incorporation of D-ala into pentapeptide chain of peptidoglycan (looks like D-ala)

 

Clinical Uses:

1. Tuberculosis that is resistant to first-line therapy

 

Pharmokinetics:

 

Resistance:

 

Toxicities:

1. Potential neurotoxicity (tremors, seizures, psychosis)

 

Term
Bacitracin
Definition

Classification:

Peptide antibiotic

 

Mechanism of Action:

1. Disruption of late-stage bacterial membrane synthesis in Gram positive organisms

 

Clinical Uses:

1. Topical use (component of neosporin)

 

Pharmokinetics:

 

Resistance:

 

Toxicities:

1. nephrotoxic --> topical use only

Term
Fosfomycin(B)
Definition

Classification:

Antimetabolite

 

Mechanism of Action:

Inhibits cytoplasmic enolpyruvate transferase --> prevents formation of N-acteylmuramic acid (necessary for peptidoglycan chain)

 

Clinical Uses:

1. UTI --> excretes in kidney at higher than MIC concentrations

 

Pharmokinetics:

1. Renal clearance --> high concentrations in urine

*Best is a 7-day course of fluorquinolones

 

Resistance:

Fosfomycin enters via non-essential glycerophosphate transporter --> inactivation of transporter = resistance

 

Toxicities:

1. Diarrhea with multiple doses

 

Term
Aztreonam(B)
Definition

Classification:

Monobactam

 

Mechanism of Action:

Binds to specific PBP and inhibits cell wall synthesis

*Syngergistic with aminoglycosides

 

Clinical Uses:

1. Gram-negative rods (resistant to some Beta lactamases)

2. Not active vs. Gram positive organisms

 

Pharmokinetics:

1. Renal tubular secretion elimination

2. Varibale CSF

 

Resistance:

1. Extended spectrum Beta lactamases

 

Toxicities:

1. GI issues

2. Superinfection

3. Vertigo/headache

4. Hepatotoxicity

5. Skin rash (no cross-reactivities with penicillins)

 

Term
Chloramphenicol(B/C)
Definition

Classification:

Broad spectrum protein synthesis inhibitor (bacteriostatic)

 

Mechanism of Action:

1. Reversibly binds 50S subunit --> inhibits translation

 

Clinical Uses:

1. Very few due to toxicity

2. Topical agent

 

Pharmokinetics:

1. Mostly hepatic glucuronidation, some excreted in urine unchanged

2. CSF and placental penetration

 

Resistance:

1. Chloramphenicol acetyl transferase (plasmid)

 

Toxicities:

1. GI disturbances (superinfections, candidiasis)

2. Bone marrow depression (reversible or irreversible aplastic anemia)

3. Gray baby syndrome --> decrease RBCs, cyanosis and CV collapse (neonates are deficient in hepatic glucoronosyltransferase and ares sensitive to doses tolerated in older infants)

*Can also occur in adults with reduced hepatic function!

4. Drug interactions (inhibits hepatic drug metabolizing enzymes) --> increase other drug concentrations

Term

Doxycycline(B/C)

Tetracyclines

Definition

Classification:

Broad-spectrum, bacteriostatic protein synthesis inhibitors

 

Mechanism of Action:

Reversibly binds to 30S ribosomal subunit & interfere with binding of aminoacyl tRNA molecules to bacterial ribosomes

 

Clinical Uses:

1. Many uses

2. Tigecycline for MRSA and VRE

 

Pharmokinetics:

1. Liver elimination

2. Variable CSF

 

Resistance:

1. Efflux pumps

2. Development of ribosomal protection proteins


Toxicities:

1. Can affect growth in children (bone complexes with Ca2+)

2. Permanent discoloration of teeth (complexes with Ca2+)

3. Skin rashes/sensitivity (phototoxicity)

4. GI superinfections with candida, S. aureus or C. difficile

5. Fanconi's anemia (renal tubular acidosis)

6. Vestibular toxicity (dose dependent and reversible)

Term
Chloramphenicol related bone marrow toxicity:
Definition

1. Bone Marrow depression: anemia, leukopenia & thrombocytopenia

*Reversible once treatment is stopped

*Dose related

*Caused by decrease in mitochondrial protein synthesis of ferrochelatase (required for uptake of Fe2+ into heme)

 

2. Aplastic anemia: complete bone marrow depression

*Irreversible and generally fatal or high incidence of leukemia in survivors

*Not dose related and may appear months after treatment

*Rare: 1/25,000 - 1/40,000

Term

Erythromycin(B/C)

Clarithromycin

Azithromycin

Definition

Classification:

Broad-spectrum, bacteriostatic protein synthesis inhibitors of macrolide class

 

Mechanism of Action:

Reversibly binds to 50S ribosomal subunit --> block transpeptidation

 

Clinical Uses:

1. many uses

 

Pharmokinetics:

1. Hepatic elimination & urinary excretion: clarithromycin (2 hr half-life)

2. Biliary excretion: erythromycin (6 hr half-life)

3. Renal excretion: azithromycin (2-4 day half-life)***


Resistance:

1. Efflux pumps

2. Production of ribisomal methylases (Gram +)

3. Drug metabolizing esterases in Enterbacteriaceae


Selective toxicity:

1. Does not penetrate mitochondria

2. Poor binding to mitochondrial and animal ribosomes


Toxicities:

1. GI problems: stimulation of motilin receptor --> epigastric distress, diarrhea, cramps (25% of patients)

2. Erythromycin and clarithromycin inhibit several forms of hepatic cytochrome P450 enzymes

3. cholestatic hepatitis

Term
Clindamycin(B/C)
Definition

Classification:

Broad-spectrum, bacteriostatic protein synthesis inhibitors

 

Mechanism of Action:

Reversibly binds to 50S ribosomal subunit --> block transpeptidation

 

Clinical Uses:

1. Mainly for anaerobes like bacteroides

 

Pharmokinetics:

1. Hepatic metabolism

2. Variable CSF

 

Resistance:

1. Enzymatic inactivation

2. Production of ribisomal methylases

3. Intrinsic resistance in Gram-negative aerobes (membrane thickness)

 

Selective toxicity:

1. Does not penetrate mitochondria

2. Poor binding to mitochondrial and animal ribosomes

 

Toxicities:

1. Superinfection (0.01-10%) with C. difficile with pseudomembranous colitis

Term
Linezolid(B/C)
Definition

Classification:

Broad-spectrum, bacteriostatic protein synthesis inhibitor of oxazolidinone class

 

Mechanism of Action:

Reversibly binds to 23S rRNA of 50S ribosomal subunit --> block transpeptidation

 

Clinical Uses:

1. Many uses

2. MRSA, PRSP and VRE

 

Pharmokinetics:

1. Hepatic elimination

2. Good CSF perfusion

 

Resistance:

1. Rare! Involves decreased affinity for binding site


Selective toxicity:

1. Does not penetrate mitochondria

2. Poor binding to mitochondrial and animal ribosomes


Toxicities:

1. Thrombocytopenia & neutropenia in immunosuppressed

2. Serotonin syndrome when used with patients on SSRIs as it is a slight MAO-inhibitor

 

Term
Quinpristin/Dalfopristin(B/C)
Definition

Classification:

Broad-spectrum, bactericidal protein synthesis inhibitor


Mechanism of Action:

1. Reversibly binds to 50S ribosomal subunit --> constrict the exit channel

2. Inhibition of tRNA synthetase activity

3. Strong post-antibiotic effect

 

Clinical Uses:

1. Many uses

2. MRSA, PRSP, VRSA and VR E. faecium

 

Pharmokinetics:

1. Renal elimination

2. NO CSF!!!

 

Resistance:

1. Efflux: *E. faecalis is intrinsically resistant via efflux transport system


Selective toxicity:

1. Does not penetrate mitochondria

2. Poor binding to mitochondrial and animal ribosomes


Toxicities:

1. Thrombocytopenia & neutropenia in immunosuppressed

2. Potent inhibitors of CYP and increase many drug concentrations

3. Arthralgias or myalgias

Term
Telithromycin(B)
Definition

Classification:

Broad-spectrum, bacteriostatic protein synthesis inhibitors. Similar to macrolide class.


Mechanism of Action:

Reversibly binds to 50S ribosomal subunit --> block transpeptidation


Clinical Uses:

1. many uses

 

Pharmokinetics:

1. Biliary and renal elimination


Resistance:

1. Low, as it binds ribosome more tightly and has less affinity for efflux pumps


Selective toxicity:

1. Does not penetrate mitochondria

2. Poor binding to mitochondrial and animal ribosomes


Toxicities:

1. Hepatic dysfunction

2. Elongation of QTc interval

3. Inhibitor of CYP drug metabolizing system

Term

Amikacin(C)

Gentamycin(B/C)

Tobramycin

Streptomycin

Neomycin

Spectinomycin

Kanamycin

Definition

Classification:

Broad-spectrum, bacteriocidal protein synthesis inhibitors aminoglycosides


Mechanism of Action:

Irreversibly binds to 30S ribosomal subunit -->

1. Block formation of initiation complex

2. Cause misreading of mRNA template

3. Inhibit translocation

4. May also disrupt polysomal structure

*Concentration-dependent action: as plasma level increases above MIC, killing activity increase in rate and proportion

*Can exert a post-antibiotic effect --> killing after [drug] falls below MIC/MBC


Clinical Uses:

1. Many uses, often with Beta lactam which permeabilizes membrane (see #2)

2. Penetration requires O2-dependent transport, thus limited activity vs. anaerobic bacteria.

3. Work best as a single, larger dose --> irreversible binding is bactericidal (post-antibiotic effect) & toxicity is dose- and time-dependant

 

Pharmokinetics:

1. Must be given IM, not absorbed orally.

2. Limited CSF penetration

3. Glomerular filtration is major mode of excretion (directly proportional with creatining clearance), thus dose adjustment in renal insufficiency!


Resistance:

1. Intrinsic: failure to penetrate cell wall

2. Plasmid-mediated transferase enzymes

3. Changes in ribosomal binding


Toxicities:

1. Neurotoxic

2. Nephrotoxic (reversible)

3. Ototoxic (irreversible)

4. Neuromuscular blockade

Term
Aminoglycoside Toxicities
Definition

Mechanisms:

1. Binding of phospholipids

2. Inhibition of mitochondrial protein synthesis (like bacterial)

3. Blockage of ACh release by interfering with Ca2+ binding.


Ototoxicity:

1. Affects both vestibular and auditory; high frequency is first to go.

2. Drug tends to concentrate to high levels in perilymphatic fluid

3. Cochlear hair cells have high ox/phos demands, increased motochondrial translation inhibition? Genetic component enhances toxicity.

 

Nephrotoxicity:

1. Increased [drug] in proximal tubule

2. Altered phospholipid metabolism --> myeloid bodies form

3. Reversible if dose decreased early, permanent damage later


Neurotoxicity:

1. Acute muscular paralysis, apnea and death

2. Non-depolarizing block at NMJ: rare, but increased risk with high dose during surgery with anesthetics or other NMJ blockers, or in myasthenia gravis patients

   - Treatment: Calcium gluconate + edrophonium

3. Blocks ACh release by interfering with Ca2+ binding


Notes:

1. Must adjust dose for patient with renal failure/insufficiency or hepatic disease

2. Genetic component --> mutation in rRNA results in more similarity to bacterial RNA --> confer sensitivity = reduced protein synthesis

3. Best to use single dose, as antibiotic toxicity is dose and time related to threshold of toxicity.

Term

Trimethoprim

pyrimethamine

&

Sulfamethoxazole

sulfadoxine

sulfadiazone


Definition

Classification:

Antifolate drugs in combination are bactericidal --> products are need for DNA, RNA and protein synthesis


Mechanism of Action:

1. Sulfonamides: mimic structure or PABA --> bacteriostatic inhibition of dihydropterate synthase or act as substrate and creat nonfunctional folic acid (dihydrofolic acid is not synthesized)

2. Trimethoprim: inhibits bacterial dihydrofolate reductase (bacterial enzyme is 4-5 orders of magnitude more sensitive than mammalian enzyme)


Clinical Uses:

1. Many including some protozoans like Toxoplasma

 

Pharmokinetics:

1. Oral

2. Kidney

3. CSF penetration


Resistance:

Sulfonamides:

1. Increased PABA production from bacteria

2. Reduced affinity of dihydroperoate synthase

3. Reduced uptake of drug

Trimethoprim:

1. Dihydrofolate reductase with reduced affinity (mutation)


Selective toxicity: mamalian cells don't synthesize folic acid, they get it from diet.


Toxicities:

Sulfonamides:

1. Hypersensitivity, skin rashes

2. GI distress with hepatic dysfunction

**In newborns, may replace serum-bound bilirubin resulting in kernicterus.

3. Hematoxicity: granulocytopenia, thrombocytopenia, aplastic anemia, hemolysis with G6PDH deficiency

 - G6PDH keeps RBC in reduced state, mutations result in oxidiative damage --> hemolysis

4. Precipitate in urine at acidic pH --> crystalluria + hematuria

5. Drug interactions, mostly with competition to bind plasma

6. *Pregnancy: basal ganglia dysfunctions in newborn

Tripmethoprim:

1. Bone marrow depression in patients low in folate: megaloblastic anemia, leukopenia, granulocytopenia

 

Term

Ciprofloxacin

Moxifloxacin

Levofloxacin

etc.

Definition

Classification:

Broad-spectrum, bacteriocidal inhibitors of DNA gyrase in Gram-negative and Topo IV in Gram positive

 

Mechanism of Action:

 1. Binds DNA gyrase Topo II (G-neg) or Topo IV (G-pos) and inhibits DNA replication

2. Strong post-antibiotic effect


Clinical Uses:

1. Urogenital and GI infections with Gram-neg organmisms

2. Many other uses

 

Pharmokinetics:

1. Good oral bioavailability (antacids can interfere with absorption)

2. Good CSF penetration (B. anthracis)

3. Active tubular secretion in kidneys (blocked by probenecid)

4. Moxifloxacin eliminated via hepatic and biliary (do not use for UTIs!)


Resistance:

1. Mutations in DNA gyrase enzyme = reduced affinity


Selective toxicity

Due to selectivity for bacterial enzymes


Toxicities:

1. GI distress

2. Contrindicated for children or pregnant women due to cartilage toxicity

3. Tendon rupture in elderly

4. Prolongation of QTc interval

Term
Drugs getting into CNS?
Definition

Depends on the status of the patient. Often drugs that will not penetrate CNS in a normal patient, will in a patient with infection due to the processes of inflammation.

Term
Isoniazid(B/C)
Definition

Classification:

FAS-II inhibitor --> mycolic acid synthesis inhibitor

*(bactericidal in rapidly dividing and bacteriostatic in slow dividing bacilli)

*Single most important antimycobacterial drug

 

Mechanism of Action:

1. Prodrug is activated by bacterial catalse-peroxidase enzyme (katG)

2. Binds tightly to enoyl-acyl carrier protein reductase (inhA) --> inhibition of fatty synthase II (FAS-II) and mycolic acid.

*Mycolic acid is important component of mycobacterial cell wall.

 

Clinical Uses:

1. In treatment of latent (or prophylaxis for patients in close contacts with active disease), used as sole drug.

2. Used in combination with other antimycobacterial agents to reduce resistance and increase bactericidal activity.

 

Pharmokinetics:

1. Liver inactivation via acylation of drug can vary from slow to fast depending on individual ("fast/slow acylators")

2. CSF penetration

 

Resistance:

1. Deletion, reduced expression or mutations of katG, which activates prodrug, confers high-level resistance (most common).

2. Mutations in inhA confers low-level resistance


Toxicities:

1. Pyridoxine deficiency --> neurotoxicity --> give vitamin B6 pyridoxine to alleviate

2. Hepatotoxicity

 

Note:

Challenges = long treatments, drug toxicity & patient compliance

 

Term

Rifampin(B/C)

Rifabutin

Rifapentine

Definition

Classification:

RNA polymerase II inhibitor

 

Mechanism of Action:

1. Inhibition of RNA polymerase II --> transcriptional inhibition

 

Clinical Uses:

1. In treatment of latent, or prophylaxis (for patients in close contacts with active disease), used as sole drug.

2. Used in combination with other antimycobacterial agents to reduce resistance and increase bactericidal activity.

3. May be used in combination against resistant organisms

 

Pharmokinetics:

1. Liver inactivation --> free drug + metabolites (orange) are eliminated mostly in feces.

2. CSF penetration

 

Resistance:

Resistance from mutations in rpo gene encoding polymerase occur rapidly.


Toxicities/interactions:

1. Strongly induces liver metabolizing enzymes --> enhances elimination rate of many drugs

2. Light-chain proteinuria & impaired antibody response

3. Rashes, thrombocytopenia, nephritis, liver dysfunction, anemia, etc.

4. Oral contraception should not be solely relied on when taking CYP450 inducer like rifampin!!!

*Rifabutin is less likely to cause drug interactions and is as effective as rifampin

 

Note:

Challenges = long treatments, drug toxicity & patient compliance

Term
Pyrazinamide(B/C)
Definition

Classification:

Antimycobacterial translational inhibitor

 

Mechanism of Action:

1. Book says mechanism is unknown

2. Class says binds ribosomes and impairs translation

3. Wikipedia says that it inhibits FAS-I → mycolic acid synthesis

 

*Also inhibits FAS-I and mycolic acid synthesis


Clinical Uses:

3.. Used in combination with other antimycobacterial agents to reduce resistance and increase bactericidal activity.

*Short course therapy


Pharmokinetics:

1. Partial liver inactivation --> free drug + metabolites are excreted mostly in urine

2. CSF penetration

*plasma half-life increased in hepatic or renal failure.

 

Resistance:

1. Prodrug is activated by pyrazinimidases encoded by pncA gene, thus mutations in pncA result in resistance

2. Increased expression of drug efflux systems


Toxicities/interactions:

1. 40% of patients develop nongoutry polyarthralgia

2. Asymptomatic hyperuricemia

3. Serious hepatic injury


Note:

Challenges = long treatments, drug toxicity & patient compliance

 

Term
Ethambutol(B/C)
Definition

Classification:

Antimycobacterial arbinosyl transferase inhibitor

 

Mechanism of Action:

1. Inhibitor of arabinosyl transferases (embCAB operon) -->

2. Inhibition of arabinogalactan synthesis

*Arabinogalactan is an important component of mycobacterial cell walls

 

Clinical Uses:

1. Always used in combination against tuberculosis with other antimycobacterial agents to reduce resistance and increase bactericidal activity.


Pharmokinetics:

1. Renal elimination unchanged in urine

2. CSF penetration

 

Resistance:

1. Resistance from mutations in embCAB operon occurs rapidly if drug is used alone.


Toxicities/interactions:

1. Dose-dependen visual disturbances (decreased acuity, RG colorblindness, optic neuritis and possible retinal damage)

 

Note:

Challenges = long treatments, drug toxicity & patient compliance

 

Term
Antimycobacterial strategies?
Definition

First line:

INH + pyrazinamide + ethambutol + rifampin

 

Second line:

Streptomycin + fluoroquinolones

Term

Dapsone(B)

Acedapsone

Definition

Classification:

Antimycobacterial (M. leprae)

 

Mechanism of Action:

1. May involve inhibition of folic acid synthesis

*Due to resistance, used in combination with colfazimine and/or rifampin.

 

Clinical Uses:

1. Treatment of Mycobacterium leprae & alternative drug for treatment of Pneumocystis jiroveci

2. Acedapsone = repository form that provides inhibitory plasma concentrations for many months

 

Pharmokinetics:

1. Mostly renal excretion + some acylation

2. CSF penetration

 

Resistance:

Resistance is increasingly reported


Toxicities/interactions:

1. Hemolysis in G6PDH deficiency

2. Methemoglobinemia

 

Term
Clofazamine(B)
Definition

Classification:

Antimycobacterial (M. leprae)

 

Mechanism of Action:

1. Phenazine dye that may interact with DNA

 

Clinical Uses:

1. Treatment of Mycobacterium leprae 


Pharmokinetics:

 

Toxicities/interactions:

1. GI distress

2. Skin discoloration (red-brown to black)

Term

Amphotericin B(B/C)

Nystatin

Definition

Classification:

Polyene antifungal

 

Mechanism of Action:

1. Preferentially binds ergosterol in fungal membrane -->

2. Trans-membrane pore formation -->

3. Leakage of monovalent ions


Resistance:

1. Uncommon, but from either structural changes or decreased levels of ergosterol


Clinical Uses:

1. Severe fungal infections

2. Synergistic with flucytosine

3. Antagonistic with fluconazole

4. Nystatin only used as topical (toxicity)


Pharmokinetics:

1. Parenteral

2. Not very good penetration into CNS

3. Long half-life (weeks as it binds to membranes --> not dialyzable)

4. Lipid formulation decreases nephrotoxicity --> more likely to induce chills/hypoxia


Toxicities/interactions:

1. Nephrotoxicity

2. Fever

3. Chills

4. Chronic use --> nephrotoxicity 40-80% of patients

- Disrupts K+/H+ exchange --> hypokalemia + acidosis

- reverisble unless dosage is too high

Term

Fluconazole(B/C)

Itraconazole

Voriconazole

Posaconazole

Ketoconazole

Definition

Classification:

Triazole antifungal agent (except ketoconazole is imidazole)

 

Mechanism of Action:

1. Inhibition of fungal CYP450 14-alpha-demethylase -->

2. Lanosterol demethylation inhibition -->

3. Inhibition of ergosterol synthesis

*antagonistic with Ampho-B, which binds ergosterol

 

Resistance:

1. 85% due to MDR efflux pumps

2. Mutations/overproduction of 14-alpha demethylase


Clinical Uses:

1.Systemic mycoses

 

Pharmokinetics:

1. Oral, Kidney, CSF = Fluconazole

2. Oral, Liver, NO CSF= Itraconazole


Toxicities/interactions:

1. Vomiting, diarrhea and rash

2. Inhibitor of CYP450 enzymes in liver and adrenals --> increases other [drug] and interferes with testosterone synthesis → gynecomastia

(Ketoconazole is most potent inhibitor, fluconazole is least)

3. Voriconazole causes transitent visual disturbances

 

 

Term
Flucytosine(B/C)
Definition

Classification:

Pyrimidine antimetabolite antifungal


Mechanism of Action:

1. Membrane fungal permease takes up drug -->

2. Drug concentrates in fungal cells -->

3. Fungal cytodine deaminase converst to 5-fluorouracil -->

4. UMP-pyrophosphorylase converts to 5-FU mono-P

5. Inhibition of thymidylate synthesis -->

5. Purine (nucleic acid) synthesis is blocked -->

6. Defective RNA and disrupted DNA synthesis

*Selective toxicity due to low levels of permease and deaminase enzymes in mammalian cells

 

Resistance:

1. Decreased activity of fungal permease

2. Decreased activity of fungal deaminase

3. UMP-Pyrophosphorylase mutation


Clinical Uses:

1. Systemic mycoses

2. Synergistic with azole or Ampho-B


Pharmokinetics:

1. Oral, Kidney, CSF


Toxicities/interactions:

1. Reverisble bone marrow depression

 

Term

Caspofungin(B/C)

Anidulafungin

Micafungin

Definition

Classification:

Echinocandin antifungal


Mechanism of Action:

1. Inhibition of B(1-2)glucan synthase -->

(B(1-2)glycan is component of cell wall)

2. Inhibition of cell wall synthesis -->

*may increase exposure of glucan on fungal surface stimulating immune system clearance...


Resistance:

1. Mutations in B(1-2)glycan synthase (rare)

 

Clinical Uses:

1. Disseminated infections that fail to respond to Ampho-B


Pharmokinetics:

1. Parenteral

2. Liver metabolism

3. CSF


Toxicities/interactions:

1. Headache

2. GI distress

3. Histamine release --> flushing

 

Term
Griseofulvin(B)
Definition

Classification:

Antifungal (fungistatic)

 

Mechanism of Action:

1.Drug taken up by energy dependent mechanism

2. Interferes with microtubule function in dermatophytes --> mitotic inhibitor

3. May also inhibit synthesis and polymerization of nucleic acids

 

Resistance:

1. Decrease in energy dependent transport of drug


Clinical Uses:

1. Dermatophytoses

 

Pharmokinetics:

1. Oral

2. Binds keratin in stratum corneum

3. Biliary excretion is responsible for elimination


Toxicities/interactions:

1. headaches, confusion, GI distress, photosensitivity

2. Changes in liver function --> decreases bioavailability of drugs

 

Term
Terbinafine(B)
Definition

Classification:

 

Antifungal (fungicidal)


Mechanism of Action:

 

1. Inhibits fungal squalene epoxidase -->

2. Prevents conversion of squalene to ianosterol -->

3. Accumulation of toxic levels of squalene -->

4. Inhibition of ergosterol synthesis

*Accumulates on keratin like griseofulvin

 

 

 

Resistance:

 

 

 

Clinical Uses:

 

1. Dermatophytoses

2. More effective in onychomycosis

 

 

 

Pharmokinetics:

 

1. Oral or topical

 

2. Binds keratin in stratum corneum

 

 


 

Toxicities/interactions:

 

1. Headaches, GI distress, taste disturbances

 

Term

Metronidazole(B/C)

Tinidazole

Definition

Classification:

Antiprotazoal and antibacterial imidazole derivative


Mechanism of Action:

1. Drug undergoes reductive bioactivation by ferredoxin (anaerobic parasites) -->

2. Formation of reactive cytotoxic products that interfere with nucleic acid synthesis

 

Resistance:

1. Unknown --> inhibition of drug reduction


Clinical Uses:

1. Anaerobic bacteria and/or parasites

2. Bacteroides & Clostridium species


Pharmokinetics:

1. Oral

2. Liver

3. CSF


Toxicities/interactions:

1. headaches

2. Peripheral neuropathy

3. Alcohol sensitivity

Term

Acyclovir(B/C)

Valacyclovir

Penciclovir

Famciclovir

Definition

Classification:

Antiviral: deoxyguanosine structural analog

 

Mechanism of Action:

1. Taken up into cell -->

2. Preferentially phosphorylated by viral thymidine kinase -->

3. Preferentially incorporated by viral polymerase -->

4. Results in chain termination of viral DNA (penciclovir does not, only DNA polymerase inhibition)

*Activated and concentrated in HSV infected cells

**Valacyclovir is prodrug converted to acyclovir by hepatic metabolism

**Famciclovir is prodrug converted to penciclovir by hepatic metabolism

 

Resistance:

1. Mutations in viral TK gene (complete inactivation or reduced affinity)

2. Polymerase mutations (reduced recognition of substrate) --> leads to cross resistance of other chain terminators (gancyclovir, famciclovir, valacyclovir)


Clinical Uses:

1. 1o herpes infections: genital, encephalitis, neonatal

2. Chronic infections

 

Pharmokinetics:

1. 20% oral bioavailability (valacyclovir 3-5x better)

2. Kidney

3. CSF


Toxicities/interactions:

1. Gi distress, headaches

Term

Ganciclovir(B/C)

Valganciclovir (prodrug)

Definition

Classification:

Guanine deriviative antiviral


Mechanism of Action:

1. Triphsophorylated by virus-specific enzymes in infected cell -->

2. Preferentially used by viral DNA polymerse -->

3. Inhibtion of viral DNA polymerase & chain termination


Resistance:

1. CMV = mutations in enzymes that encode phosphotransferase & DNA polymerase

2. HSV = Deletion of TK gene


Clinical Uses:

1. CMV

2. Varicella-Zoster

3. HSV


Pharmokinetics:

1. Poor oral availability (6-9%)

2. Kidney

3. CSF penetration


Toxicities/interactions:

1. Bone Marrow Depression

2. CNS = headaches, convulsions, psychosis

*Some sort of toxic effect in 40% of patients

Term
Foscarnet(B/C)
Definition

Classification:

Antiviral (DNA-synthesis inhibitor)

 

Mechanism of Action:

1. Taken into cell (does not require phosphorylation for activity)

2. Binds pyrophosphate site of viral polymerases

3. Inhibits viral DNA, RNA polymerases and reverse transcriptase

*100 fold greater selectivity for viral polymerases over human.

 

Resistance:

1. Point mutations in polymerases that affect affinity

 

Clinical Uses:

1. Alternative for acyclovir/ganciclovir-resistant CMV and HSV strains

 

Pharmokinetics:

1. Parenteral

2. Kidney

3. CSF penetration

 

Toxicities/interactions:

1. Nephrotoxicity is high (~ 50%), but reversible

2. CNS effects (headache, hallucinations and seizures) 25%

3. Electrolyte disturbances (hypocalcemia) 25%

 

Term
Interferon(B/C)
Definition

Classification:

Glycoproteins that are natural part of immune system

Alpha: leukocytes (response to viral infection - IL1, 2, TNF)

Beta: fibroblasts (response to viral infection - IL1, 2, TNF)

Gamma: activated T-cells --> immune response


Mechanism of Action:

1. Binds receptors on cell --> 

2. Regulates Jak/Stat pathway -->

3. Results in:

- mRNA degradation (2-5A pathway --> RNase L activation

- inhibition of protein synthesis (PKR pathway --> phosphorylation of eIF-2)

- Transcriptional inhibition (Mx proteins)

 

Resistance:

 

Clinical Uses:

1. Genital warts (papillomavirus)

2. Hep B & C

3. HSV VIII (Kaposi's sarcoma)


Pharmokinetics:

1. Parenteral

 

Toxicities/interactions:

1. Fever and fatigue

2. Marrow suppression, depression

3. Acute influenza-like symptoms

*10-20% discontinue due to symptoms

Term

Oseltamavir(B/C)

Zanamavir

Definition

Classification:

Neuraminidase inhibitor

 

Mechanism of Action:

1. Inhibition of viral neuraminidase

2. Neuraminidase can't cleave terminal sialic acid residues recognized by hemagglutinin -->

3. Virus remains trapped on cell surface and cannot release infectious particles

 

Resistance:

1. Rare, but due to mutations in viral neuraminidase

 

Clinical Uses:

1. Active against both Influenza A and B

 

Pharmokinetics:

1. Oral

2. Liver

3. Poor CSF

*Most effective within 24 hours of onset.

 

Toxicities/interactions:

1. No major limiting toxicity issues

Term

Amantadine(B)

Rimantidine

Definition

Classification:

Anti-influenza

 

Mechanism of Action:

1. Blocks M2 ion channel on endosomes -->

2. Prevents H+ entry -->

3. No acidification = virus cannot uncoat

 

Resistance:

1. M2 protein mutations that allow acidification (drug still binds)

*Amantadine resistant mutants are now common

 

Clinical Uses:

1. Only active against Influenza A


Pharmokinetics:

 

Toxicities/interactions:

1. Mild CNS effects

Term

Zidovudine(B/C)

Lamivudine (3TC)

Definition

Classification:

Reverse-transcriptase inhibitors

 

Mechanism of Action:

1. Inhibition of viral RT & chain termination

*1000 fold more selective for viral RT than human polymerase

 

Resistance:

1. Mutations in RT

2. Lamivudine = met184val mutation occurs rapidly

 

Clinical Uses:

1. HAART

2. Lamivudine also for Hep B

 

Pharmokinetics:

 

Toxicities/interactions:

1. Marrow depression

2. Headache, nasea, myopathy, anorexia, fatigue, etc.

3. Lamivudine + zidovudine combination is synergystic

*Met184val mutation seems to slow development of resistance to zidovudine

Term

Efavirenz(B/C)

Nevirapine

Delaviridine

Etravirine

 

Definition

Classification:

Non-nucleoside RT inhibitor

 

Mechanism of Action:

1. Bind to distinct site on RT than NRTIs

*Do not require phosphorylation and do not compete with nucleoside triphosphates

*No cross-resistance with NRTIs


Resistance:

1. Mutations in pol gene occur rapidly if used alone

 

Clinical Uses:

1. HIV HAART

 

Pharmokinetics:

1. Oral

2. Liver

3. CSF

 

Toxicities/interactions:

1. CNS toxicity

2. Rashes

3. Drug interactions

 

Term
Ritonavir(B/C)
Definition

Classification:

HIV protease inhibitor

 

Mechanism of Action:

1. Viral protease inhibitor -->

2. Inhibition of polyprotein cleavage -->

3. Inhibition of viral assembly

 

Resistance:

1. Multiple point mutations in pol gene

2. Extent of cross resistance is variable

 

Clinical Uses:

1. HIV HAART component

 

Pharmokinetics:

1. Oral

2. Liver

3. CSF

 

Toxicities/interactions:

1. Inhibits CYP3A4 --> increased levels of toher compounds

2. *inhibits other protease inhibitor metabolism by CYP3A4 at sub-therapeutic levels

Term
Enfuvirtide(B/C)
Definition

Classification:

1. Viral entry inhibitor

 

Mechanism of Action:

1. Peptide that binds gp41 -->

2. Prevents formation of entry pore -->

3. Virus cannot enter cell

 

Resistance:

1. Mutations in env gene

 

Clinical Uses:

1. HIV-1

 

Pharmokinetics:

1. Parenteral

2. No CSF

 

Toxicities/interactions:

Term
Fosamprenavir(C)
Definition

Classification:

HIV protease inhibitor (prodrug of amprenavir)


Mechanism of Action:

1.Prodrug hydrolyzed in GI tract

2. Viral protease inhibitor -->

3. Inhibition of polyprotein cleavage -->

4. Inhibition of viral assembly

 

Resistance:

1. Multiple point mutations in pol gene

2. Extent of cross resistance is variable

 

Clinical Uses:

1. HIV HAART component

 

Pharmokinetics:

1. Oral

2. Liver

3. CSF

 

Toxicities/interactions:

1. Inhibits CYP3A4 --> increased levels of other compounds

2. Includes propylene glycol --> no pregnancy or women

 

Term
Raltegravir(B/C)
Definition

Classification:

HIV integrase inhibitor

 

Mechanism of Action:

1. Targets and inhibits enzyme integrase

2. Viral genome cannot integrate into host genome and be expressed

 

Resistance:


Clinical Uses:

1. HIV


Pharmokinetics:

1. Oral


Toxicities/interactions:

Term

Telaprevir(B/C)

Boceprevir

Definition

Classification:

Protease inhibitor (Hep C)

 

Mechanism of Action:

1. Inhibition of Hep C protease

 

Resistance:


Clinical Uses:

Hepatitis C

 

Pharmokinetics:

Toxicities/interactions:

 

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