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...

Penicillin G^(B/C)

Penicillin V^(B/C)

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)

Dicloxacillin^(B/C)

Methicillin^(B/C)

Nafcillin^(B/C)

Oxacillin^(B/C)

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)

Ampicillin

Amoxicillin^(B/C)

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)

Cephalexin

Cefazolin

Classification:

Cephalosporin: 1^st 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)

Cefaclor^(B/C)

Cefoxitin

Cefotetan

Cefuroxime

Classification:

Cephalosporin: 2^nd 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

Ceftriaxone^(B/C)

Cefottaxime

Cefuroxime

Classification:

Cephalosporin: 3^rd 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

Classification:

Cephalosporin: 4^th 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

Piperacillin

Ticarcillin^(B/C)

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

Clavulanic acid^(B/C)

Sulbactam

Tazobactam

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:

Meropenem^(B/C)

Imipenem

Ertapenem

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

Vancomycin^(B/C)

Teicoplanin

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)

Daptomycin^(B/C)

Polymixin B, E

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

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)

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

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

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)

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

Doxycycline^(B/C)

Tetracyclines

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)

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

Erythromycin^(B/C)

Clarithromycin

Azithromycin

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

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

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

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

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

Amikacin^(C)

Gentamycin^(B/C)

Tobramycin

Streptomycin

Neomycin

Spectinomycin

Kanamycin

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

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.

Trimethoprim

pyrimethamine

&

Sulfamethoxazole

sulfadoxine

sulfadiazone

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

Ciprofloxacin

Moxifloxacin

Levofloxacin

etc.

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

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.

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

Rifampin^(B/C)

Rifabutin

Rifapentine

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

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

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

First line:

INH + pyrazinamide + ethambutol + rifampin

Second line:

Streptomycin + fluoroquinolones

Dapsone^(B)

Acedapsone

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

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)

Amphotericin B^(B/C)

Nystatin

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

Fluconazole^(B/C)

Itraconazole

Voriconazole

Posaconazole

Ketoconazole

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

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

Caspofungin^(B/C)

Anidulafungin

Micafungin

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

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

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

Metronidazole^(B/C)

Tinidazole

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

Acyclovir^(B/C)

Valacyclovir

Penciclovir

Famciclovir

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. 1^o 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

Ganciclovir^(B/C)

Valganciclovir (prodrug)

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

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%

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

Oseltamavir^(B/C)

Zanamavir

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

Amantadine^(B)

Rimantidine

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

Zidovudine^(B/C)

Lamivudine (3TC)

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

Efavirenz^(B/C)

Nevirapine

Delaviridine

Etravirine

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

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

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:

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

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:

Telaprevir^(B/C)

Boceprevir

Classification:

Protease inhibitor (Hep C)

Mechanism of Action:

1. Inhibition of Hep C protease

Resistance:

Clinical Uses:

Hepatitis C

Pharmokinetics:

Toxicities/interactions: