860d DRUGS & medchem

Beta lactams (4)

1) penicillins

2) cephalosporins

3) monobactams

4) carbapenems

what is the MOA of beta lactam inhibition?

inhibit transpeptidase/PBP by irreversible binding to the enzyme active site and prevents the linking for peptidoglycan in the cell wall

- mimics Dala Dala

- suicide inhibitor (forms covalent bond with PBP)

2 natural penicillins

1) penicillin G - procaine, benzethine

2) penicillin V (oral)

2 penicillinase-resistant penicillins -> can be used in MSSA

1) oxacillin

2) nafacillin

aminopenicillins

1. Amoxicillin

2. Ampicillin

3. amoxicillin + clavulanate or sulbactam

extended spectrum penicillin with BLI (has pseudomonas coverage)

piperacillin - tazobactam

cefazolin (IV)

1GC

cephalexin (PO)

1GC

Cefuroxime

2GC

Cefoxitin

2GC

cefdinir (PO)

2GC

What cephalosporin is a "cephamycin" and has activity against gram negative anaerobes & can be used prophylactically in abdominal surgery?

Cefoxitin

Ceftriaxone

3GC

Ceftazidime

3GC

ceftoxamine

3GC

cefpodoxime (PO)

3GC

Cefepime

4GC

Ceftaroline

anti-MRSA cephalosporin

ceftobiprole

anti-MRSA cephalosporin

which 2 cephalosporins have pseudomonas coverage?

Ceftazidime (3GC) & cefepime (4GC)

cefidericol

siderphore reserved B-lactam thats used for MDR pseudomonas

Aztreonam

Monobactam

T/F: Aztreonam has gram positive activity

FALSE

meropenem/imipenem/doripenem

broad spectrum carbapenems

- reserve for resistant organisms (ESBL producing)

- pseudomonas coverage & anaerobic coverage

T/F Ertapenem covers pseudomonas

FALSE

Common ADRs of B-lactam Abx

1) neurotoxicity (seizures, encephalopathy)

2) diarrhea

toxicity of oxacillin/nafacillin

acute interstitial nephritis (AIN) & neutropenia

- monitor Scr and WBC w/ differential

which of the following are non-allergic events to beta lactams?

1) N/V/D

2) headache

3) dizziness

"True" penicillin allergy

IgE mediated/immediate hypersensitivity occuring minutes to hours post exposure

what are low risk penicillin allergies?

1) family history

2) itching w/o rash

3) unknown reaction

4) remote reaction occurring > 5 years ago

What reactions are "high risk" and result in a pt to NEVER receive a beta-lactam again & makes them ineligible for amoxicillin challenge?

1) SJS/TENS/DRESS

2) drug induced hepatitis

3) hemolytic anemia

4) drug induced thrombocytopenia

5) AGER

6) dystonia

vancomycin

Glycopeptide antibiotic effective against Gram-positive bacteria (too large to pass thu the outer membrane of gram negative bacteria)

MOA of vancomycin

binds to the peptidoglycan chain Dala Dala to prevent PBP from binding

ADRS of vancomycin

1) nephrotoxicity

2) rare DRESS allergic rxn

3) late neutropenia

daptomycin

Lipopeptide antibiotic effective against Gram-positive bacteria.

MOA of daptomycin

inserts lipid tail into the cell membrane -> multiple molecules clump together and form a pore channel that causes cell contents to leak from the cell

major ADR of daptomycin

muscle injury & rhabdomyolysis

- no drug interaction with statins (diff mechanism of muscle toxicity)

fosfomycin

Cell wall inhibitor thats used for uncomplicated cystitis

fosfomycin MOA

inhibits the enzyme MurA which is involved in the early synthesis step of lipid I & peptidoglycan synthesis inhibitor

Bacitracin

a mixture of cyclic antimicrobial peptides that inhibits cell wall synthesis

- used topically OTC now (triple abx ointment)

Isoniazid MOA

inhibits mycolic acid synthesis

is Isoniazid a prodrug?

yes - it is converted into active form by KatG (mycobacterial enzyme)

Isoniazid indications (4)

1) prophylaxis of latent TB (usually 6-9 tx duration)

2) RIPE tx regimen

2 major ADRS with isoniazid

1) hepatotoxicity

2) neuropathy

what is a way to prevent neuropathy with isoniazid?

always give with pyridoxime if >/= 50 mg/day

ethambutol MOA

inhibits EmbA, EmbB, and EmbC

ethambutol indication

part of RIPE tx for active TB infection (usually for a duration < 2 months) & MAC (longer duration)

what is the major concern with long term ethambutol use (> 2 months)

optic neuritis -> major vision changes and changes in color vision

- why usual tx w/ ethambutol in RIPE is < 2 months

cycloserine MOA

structural analog of Dala and is a suicide inhibitor or alanine racemase that add the terminal Dala Dala

major ADRS of cycloserine

neuropsychiatric toxicity (drowsiness, confusion, inability to concentrate)

4 folic acid synthesis inhibitors

1) sulfonamides (sulfamethoxazole)

2) dapsone

3) trimethoprim

4) pyrimethamine

which folic acid synthesis abx inhibit dihydropteroate synthase (DHPS)?

1) sulfonamides (sulfamethoxazole) and 2) dapsone

which folic acid synthesis abx inhibit dihydrofolate reductase (DHFR)?

1) trimethoprim

2) pyrimethamine

5 indications of Bactrim

1) UTI (once organisms is confirmed susceptible)

2) community acquired MRSA (cellulitis w/ abscess)

3) infection caused by stentrophomas maltophilia

4) infection by norcardia (thorn sticks)

5) infection caused by pneumocystitis jerovecii (common in AIDS pts)

indication of pyrimethamine

its a much better anti-parasitic so its good for toxoplasma gondii

- combo with sulfadiazole

ADRS of sulfamethoxazole (3)

1) allergic reactions (DRESS, SJS, TENS)

2) interstitial nephritis

3) hemolytic anemia w/ G6PD deficiency

Trimethoprim ADRs (2)

1) pseudonephrotoxicity (increased Scr due to inhibition of tubular secretion)

2) hyperkalemia

T/F: allergy to sulfonamides transfers to non antibiotic drugs that contain sulfur?

FALSE, cross allergy isn't possible unless with another sulfonamide antibiotic

MOA of fluoroquinolones

inhibits topo II (DNA gyrase) and topo IV

Topo II vs Topo IV

II - introduces negative supercoils into DNA

IV - disentangles newly replicated DNA

what are the "gram negative" fluoroquinolones & can be used for UTI Tx

ciprofloxacin and levofloxacin

what are the "gram positive" fluoroquinolones & can be used for pneumonia

moxifloxacin & levofloxacin

what does "respiratory fluoroquinolones" mean?

That it has S. pneumoniae coverage (most common pathogen in CAP)

which FQ does not cover pseudomonas?

moxifloxacin

what is the anti-MRSA fluoroquinolones

delafloxacin

FQ antibiotics can cause tendinitis and tendon rupture (class effect), what are the 6 major factors that may increase a patients risk for this ADR?

1) age (elderly)

2) corticosteroid use

3) athletes

4) male sex

5) normal BMI

6) CKD

FQ antibiotics can cause aortic aneurysms (AA) and are CI in anyone with AA or history of AA, what are the 5 major factors that may increase a patients risk for this ADR?

1) age (elderly)

2) smoking

3) hypertension

4) diabetes

5) marfan syndrome

what are 7 other ADRs of FQs?

1) peripheral neuropathy

2) CNS toxicity (seizures, encephalopathy)

3) psychiatric events (psychosis, mania, hypomania, anxiety, insomnia)

4) worsening of myasthenia gravis

5) QT prolongation

6) dysglycemia

7) phototoxicity

Torsades de pointe risk factors

1) other drugs that prolong QT (Class III antiarrhytmics, macrolides, azoles)

2) bradycardia

3) hypokalemia & hypermagnesemia

4) prolonged QT at baseline

what are 2 other abx that impair neuromuscular junction transmission and can cause worsening of myasthenia gravis?

1) aminoglycosides

2) ketolides (telithromycin)

Collateral damage with FQ abx

disbiosis in the gut biome by transient suppression of enterobacterales may lead to infection from other bacteria

- could promote MRSA (not MSSA) & C. diff infections

metronidazole

nitroimidazole abx with amazing anaerobic coverage

metronidazole MOA

reduces a toxic metabolite under anaerobic conditions to produce nitro radical anions that form adducts with DNA and cause DNA damage

ADRs of metronidazole

1) encephalopathy & peripheral neuropathy associated with long duration or high dose tx (> 4 week; > 44g)

2) metallic taste

3) GI

4) NO evidence for disulfiram like rxn with alcohol

which antibiotics cause inhibition of bacterial transcription through bacterial DNA dependent RNA polymerase inhibition?

rifampin & rifamycins

which 3 antibiotic classes inhibit the 30s ribosome to inhibit bacterial protein synthesis?

1) aminoglycosides

2) tetracyclines

3) oxazolidinone (linezolid)

which 4 antibiotic classes inhibit the 50S ribosome to inhibit bacterial protein synthesis?

1) lincosamides (clindamycin)

2) macrolides (erythromycin; azithromycin) & ketolides

3) streptogramins

4) chloramphenicol

which rifamycin abx is not absorbed in the gut & therefore cannot be used systemically?

rifaximin

rifaximin indications

1) IBS-D

2) travelers diarrhea

3) hepatic encephalopathy

4) E. coli

5) SIBO

rifampin indications

1) latent TB tx (shorter duration than isoniazid tx)

2) RIPE regimen for active TB

3) S. aureus in combo for prosthetic implant infections

4) prophylaxis after potential exposure to Neisseria meningitidis

T/F: rifampin is a very potent metabolic inducer of hepatic enzymes and transporters and has a lot of DDIs

TRUE

T/F: resistance to aminiglycosides happens due to mutations in the 30s ribosome

FALSE since this area is highly conserved, resistance commonly occurs due to amino glycoside modifying enzymes or efflux/porin loss

are aminoglycosides absorbed when given orally?

NO

what are common ADRs of aminoglycosides?

1) nephrotoxicity (tubular necrosis)

2) ototoxicity (high frequency most susceptible)

7 uses for tetracyclines

1) purulent cellulitis

2) RTI (CAP)

3) Lymes disease

4) RMSF (tick infection)

5) acne/rosacea

6) maleria prevention

7) STIs (chlamydia)

ADRs of tetracyclines (4)

1) GI (N/V/D, loss of appetite)

2) esophageal injury (oral)

3) phototoxicity

4) teeth staining

what two patient populations should tetracylines be avoided in?

1) pregnancy

2) children (< 8)

counseling points with tetracyclines

1) forms chelation complex with metal cations (Mg, Al, Ca, Fe, Zn) which will impair oral absorption

2) remain upright for 15 min and take with lots of water to prevent esophageal injury

3) cover up & avoid sun exposure

what is an indication that you would give doxycycline to a kid?

if the child has RMSF (tick borne infection)

linezolid

oxazolidinones

linezolids ADEs are most commonly caused by _____

mitochondrial toxicity -> causing blood toxicity, peripheral neuropathy, optic neuropathy, lactic acidosis, serotonin syndrome

macrolides

Azithromycin

Clarithromycin

Erythromycin

indications of macrolides

1) CAP (covers atypical organisms)

2) URI (2nd line)

3) STI

4) MAC

5) travelers diarrhea

clindamycin (lincosamide) indications

1) necrotizing fasciitis from Streptococcus progenes

2) toxin related infections such as toxic shock syndrome from S. aureus TSST-1 toxin production

T/F: clindamycin is often used with B-lactam & inhibits the toxin production in the bacteria since it inhibits protein synthesis

TRUE

T/F: clindamycin is associated with one of the highest rates for C. diff infection

TRUE

Quinupristin & dalfopristin

streptogramin; gram + spectrum

what is the structural feature that makes penicillin V orally available?

electron withdrawing R group (phenoxymethyl) at the acylamido side

- reduces the nucleophilicity of the carbonyl making the amide a weaker nucleophile

what is present in methicillin making it resistance to beta latamase?

the presence of the ortho-dimethoxyphenyl group attached to the side chain carbonyl group of the penicillin nucleus

what functional groups present in dicloxacillin make this drug resistant to acidic degradation & beta lactamase?

the 2 chlorine groups attached the the benzene side chain (bulky & EWG)