PDA 3 Exam 1: Antibiotics

name

sulfanilamide

• we see this structure in all sulfonamide antibacterials

MOA of sulfonamides

competitive inhibitors of dihydropteroate synthase

• interfere with synthesis of dihydrofolic acid in bacteria (since they need to make theirs)

• bacteriostatic

name

dihydropteridine diphosphate (DHPP)

name

dihydropteroic acid

what enzyme metabolizes DHPP into dihydropteroic acid in bacteria?

dihydropteroate synthase (DHPS)

name

dihydrofolic acid (DHF)

what enzyme metabolizes dihydropteroic acid into DHF in bacteria?

dihydrofolate synthase (DHFS)

name

tetrahydrofolic acid (FH4)

• active coenzyme

what enzyme metabolizes DHF into FH4 in bacteria and humans?

dihydrofolate reductase (DHFR)

name

PABA

• this is what sulfanilamide mimics

• increase in PABA decreases efficacy of sulfonamides (some drugs like local anesthetics are metabolized into PABA)

how can we decrease the incidence of crystalluria with sulfonamides?

• drinks lots of H2O to increase urine flow and volume

• take NaHCO3 which increases urine pH to ~8 (so drug is more ionized and more soluble; less reabsorption)

• decrease pka of sulfonamide N to make it more acidic and more soluble

  • add EWG to sulfonamide N to decrease pka

  • most important modification

name

sulfamethoxazole (SMX)

• oxazole ring is EWG

• no single agent, just in combo with trimethoprim

• 5-methyl on oxazole ring thought to be allergenic moiety

name

sulfadiazine

• would expect incidence of crystals to be increased compared to SMX

• silver sulfadiazine formulation available; used topically for infections of burns; silver though to be eliciting antibacterial activity

name

sulfacetamide sodium

• can be put into soln fairly easily; available as eye soln and oint, lotion, etc

name

sulfasalazine

• prodrug

• used in tx of ulcerative colitis

name

mesalamine

• active metabolite of sulfasalazine

main route of metabolism for sulfonamides

NAT2

• acetylation at N4 creates inactive metab since activity requires unsubstituted N4

• genetically polymorphic; slow acetylators more prone to hypersensitivity rxns

• sulfonamides can also undergo auto-oxidation to reactive nitroso intermediate that can react with thiol groups on proteins and cause toxicity (glutathione can detoxify nitroso compound)

mechanisms of sulfonamide antibacterial drug resistance

• microorganism synthesizes more PABA

• decreased permeability of bacterial cell membrane to drug

• mutations to DHPS such that it has less affinity to drug

name

trimethoprim

• inhibits dihydrofolate reductase (DHFR)

• humans have DHFR too but TMP is like 40,000x more selective for bacteria

Bactrim spectrum of action

• uncomplicated UTI caused by e. coli

• pneumocystis hirovecii pneumonia (PJP)

• community-acquired MRSA

• stenotrophomonas maltophilia pneumonia (skin/skin structure infection)

• Nocardia spp.

why are sulfonamides contraindicated in infants <2mo, pregnant women, and mothers nursing infants <2mo?

sulfonamides displace bilirubin from plasma proteins, causing increased levels of bilirubin that may lead to kernicterus

name

benzylpenicillin (penicillin G) / natural penicillin

• narrow spectrum (gm+ only); rlly good activity against syphilis

• acid-sensitive

• inactivated by beta-lactamases

• can cause allergic rxns (beta-lactam-protein haptem conjugate is allergenic, not drug itself)

• can be formulated with benzathine or procaine counterions that add some lipophilic character; IM inj that basically act as depot form, could be used to treat syphilis

name

penicillin V

• narrow gm(+) spectrum

• hydrolyzed by beta-lactamases

• orally active (bc EWG on acyl side chain)

name

methicillin

• narrow gm(+) spectrum

• beta-lactamase resistant (bc increased bulk in the acyl side chain)

• not orally active

name

oxacillin

• narrow gm(+) spectrum

• beta-lactamase resistant

• orally active (but IV only now)

name

dicloxacillin

• narrow gm(+) spectrum

• beta-lactamase resistant

• orally active

name

nafcillin

• narrow gm(+) spectrum

• beta-lactamase resistant (2,6 substitution)

• not orally active

• sometimes penicillins w/narrow gm(+) spectrum and beta-lactamase resistance are called antistaphylococcal penicillins

name

ampicillin

• broad spectrum (bc hydrophilic group in acyl side chain to get through gm- porin channel)

  • add some gm(-) (enteric gm- rods, H. pylori, H. influenzae)

  • cleaved by beta-lactamases

  • orally active (but usually given IV)

name

amoxicillin

• broad spectrum

• better oral absorption than ampicillin thanks to -OH; so less in GI tract, so less diarrhea than ampicillin

name

piperacillin

• extended-spectrum (deeper gm(-) coverage, including some strains of pseudomonas aeruginosa)

• not beta-lactamase resistant

• not orally active

name

pevmecillinam

• oral prodrug (need CO2H to bind PBP)

• used to treat uncomplicated UTIs (gm(-) e.coli, p.mirabilis, gm(+) s. saphrophitticus)

• nearly exclusively inhibits PBP2

• also forms pivalic acid which can lead to carnitine depletion → hypoglycemia, muscle aches, fatigue, confusion (happens with any drugs that form pivalic acid)

name

mecillinam

• active form of pevmicillinam (refer to pevmicillinam for coverage)

name

clavulanic acid

• irreversible beta-lactamase inhibitor

• activity against class A beta-lactamases excluding KPC

name

sulbactam

• irreversible beta-lactamase inhibitor

• activity against class A beta-lactamases excluding KPC

• has activity against acinetobacter baumannii

name

tazobactam

• irreversible beta-lactamase inhibitor

• activity against class A beta-lactamases excluding KPC

• covers some AmpC and some strains of pseudomonas

name

enmetazobactam

• irreversible beta-lactamase inhibitor

• activity against class A beta-lactamases excluding KPC (also AmpC, oxa-48, ESBLs?)

name

avibactam

• reversible covalent beta-lactamase inhibitor

• inhibits class A and class C ESBLs and KPC

• variable data on class D

name

durlobactam

• reversible covalent beta-lactamase inhibitor

• inhibits class A and class C ESBLs and KPC

• also inhibits class D OXA ?

name

relebactam

• reversible covalent beta-lactamase inhibitor

• inhibits class A and class C ESBLs and KPC

• variable data on class D

name

zidebactam

• reversible covalent beta-lactamase inhibitor

• inhibits class A and class C ESBLs and KPC

• also inhibits PBP2

• recently approved in combo with cefepime (this combo in vivo inh. all 4 classes, even metallo!)

name

vaborbactam

• reversible competitive beta-lactamase inhibitor

• inhibits class A and class C ESBLs and KPC

name

taniborbactam

• reversible competitive beta-lactamase inhibitor under clinical investigation in combo w/cefepime

• activity against all 4 ambler classes (A,B,C,D)

MRSA mechanism

contains mecA gene which encodes for PBP2a, which most PCN antibiotics don’t bind to

name

cephalosporin C

• fungal metabolite from cephalosporium acemonium that has weak antibiotic activity, cephalosporins derived from this compound

• like all beta-lactam antibiotics, they bind to PBP and inhibit correct formation of the bacterial cell wall

general first-gen cephalosporin coverage

• primarily active against gm(+) such as MSSA and streptococci, such as group A, group B, and viridans

• may have moderate activity against some enteric gm(-) rods, such as some strains of e.coli, klebsiella pneumoniae, and proteus mirabilis

• none are beta-lactamase resistant

general second-gen cephalosporin coverage

retain activity against gm(+) species and add gm(-) activity including activity against moraxella catarrhalis and haemophilus influenzae, in addition to some strains of the enterobacterale order

• additionally, the cephamycins are second-gen and they have activity against many anaerobes

• only cefuroxime is beta-lactamase resistant

general third-gen cephalosporin coverage

lose some gm(+) coverage (however, several retain good strep pneumo coverage), but are much more active against gm(-) bacteria than the previous two generations

general fourth-gen cephalosporin coverage

broadest spectrum among the cephalosporins, having good gm(+) coverage and good gm(-) coverage, including pseudomonas

• currently there’s only 1 - cefepime

general fifth-gen cephalosporin coverage

characterized by having anti-MRSA activity

• currently there’s only 2 - ceftaroline and ceftobiprole

• no pseudomonas activity (broad gm(-) spectrum but no activity against non-fermentated like pseudomonas and acinetobacter)

name

cephalexin

• 1st gen

• orally active (ampicillin-like group and acid-stable group at C3)

name

cefaclor

• 2nd gen

• orally active (ampicillin-like group and acid-stable group at C3)

name

cefadroxil

• 1st gen

• orally active (amoxicillin-like group and acid-stable group at C3)

name

cefprozil

• 2nd gen

• orally active (amoxicillin-like group and acid-stable group at C3)

name

cefixime

• 3rd gen

• orally active (vinyl group at C3)

• conveys more pronounced beta-lactamase inhibition

  • covers pseudomonas?? (more complex oxime structure)

name

cefdinir

• 3rd gen

• orally active (vinyl group at C3)

• maintains strep pneumo coverage

name

cefuroxime

• 2nd gen

• not orally active; soln for inj

• beta-lactamase resistant (oxime group)

name

cefuroxime axetil

• oral prodrug of cefuroxime

• orally active (lipid soluble prodrug ester)

name

cefpodoxime proxetil

• 3rd gen

• oral prodrug

• maintains strep pneumo coverage

name

cefotaxime

• 3rd gen

• beta-lactamase resistant (3rd gen and on all resistant → oxime group)

• syn isomer is active, anti-isomer of oxime is inactive in terms of beta-lactamase inhibition

• acetoxymethyl group at C3 susceptible to metabolic inactivation by esterases in vivo (CO2H converted to inactive lactone)

• maintains strep pneumo coverage

name

ceftazidime

• 3rd gen

• not orally active, IV only

• more pronounced beta-lactamase inhibition, covers pseudomonas

  • formulated with avibactam to cover some ESBLs, enhances gm(-) coverage

• good leaving group at C3 activates beta-lactam ring toward rxn with PBP and inhibition of cell wall transpeptidases (also enhances pseudomonas activity

• by expanding gm(-), lose some gm(+)

name

cephamycin C

• 2nd gen

• 7-alpha-methoxy group increases steric bulk and provides resistance to beta-lactamases

• activity against anaerobes

• cephamycins sometimes used for prophylaxis for abdominal surgeries

name

cefoxitin

• 2nd gen cephamycin

  • activity against anaerobes

name

NMTT group

• group added to C3 of cephalosporins to enhance potency

  • found in cefotetan

• group assoc with hypoprothrombinemia and bleeding tendency (inhibits vit. K epoxide reductase); also assoc. w/ disulfiram-like rxn (vomiting when drinking alcohol)

name

cefepime

• 4th gen

• has spectrum of 1st gen (cefazolin) + 3rd gen (ceftazidime) (preserves full gm(+) and has expanded gm(-) all the way to pseudomonas

• more activity against enterobacter than ceftazidime since can rapidly reach PBP

• permanently positive NMP group is a good leaving group and confers anti-pseudomonal activity

• in formulation with enmetazobactam and with zidebactam to extend spectrum against gm(-) beta-lactamases

name

ceftriaxone

• 3rd gen

• popular IM cephalosporin

• longest half-life of the cephalosporins (6-9 hours) which enables once daily dosing

• highly protein bound, so kinda acts as depot form

• has an activating thiotriazindione group at C3

• contraindicated in neonates, can cause kernicterus same as Bactrim

• don’t administer with Ca2+ containing solns, chelates that can precipitate in lungs and kidneys → fatal

• maintains strep pneumo coverage

name

ceftaroline fosamil

• prodrug (5th gen) to give excellent H2O solubility to form soln for inj

• this specific oxime group has the highest affinity to PBP2a; group at C3 also anti-MRSA

• effective against gm(+) MRSA (PBP2a), PCN + ceph-resistant strep pneumo (PBP2x)

  • gm(-) not used for pseudomonas, limited to respiratory like moraxella catarrhalis and influenzae

name

ceftaroline

• 5th gen, active compound

• indicated for acute bacterial skin and skin structure infections, and community-acquired MRSA

name

ceftobiprole

• 5th gen (anti-MRSA)

• made as water soluble prodrug since zwitterion is poorly soluble

• C3 group has affinity to PBP2a and PBP2x

• has gm(-) activity but we’re really focusing on the anti-MRSA and multidrug resistant strep

name

ceftobiprole medocaril

• 5th gen prodrug

name

cefiderocol

• siderophore cephalosporin (C3 group) (kinda it’s own gen)

  • enhances gm(-) activity and resistance to beta-lactamases

  • smuggles drug thru gm(-) outer membrane (iron transport) like trojan horse (bc of catechol group binding Fe)

  • ceftazidime-like oxime group enhances beta-lactamase resistance

    • resistant against all 4 ambler classes

  • exclusive gm(-) spectrum

name

ceftolozane

• 3rd gen

• antipseudomonal activity (ceftazidime-like group)

• kinda a better ceftazidime due to activity against strep pneumo

• used for complicated intraabdominal infections and complicated UTIs (so rlly used for its gm(-) spectrum

  • doesn’t cover anaerobes, so give w/metronidazole if you need that coverage for like an intraabdominal inf

• commonly formulated with tazobactam

• only 3rd gen with thiadiazole ring, like the 5th gen, instead of thiazole ring …. some places call this 5th gen but no anti mrsa activity??

what differentiates the cephamycins?

7alpha-methoxy group (cefoxitin and cefotetan)

• this group adds beta-lactamase resistance to many

which 3rd gen cephalosporins maintain strep pneumo coverage?

• cefotaxime

• ceftriaxone

• cefdinir

• cefpodoxime

• ceftolozane/tazobactam (reported to have coverage but clinically used for gm(-) infections)

• also 4th gen cefepime but that’s kinda in the def of 4th gen

name

imipenem

• carbapenem

• pretty broad spectrum (covers MSSA/streptococci → gm(-) entero rods, ESBL anaerobes, pseudomonas, acinetobacter)

• not orally active

• beta-lactamase resistant thanks to group on left

• used to treat severe/resistant infection, especially nosocomial

  • but rarely first choice since it can cause allergic rxn and is a beta-lactamase inducer

• binds differently to PBP than penicillins and cephalosporins; has affinity to most bacterial PBP but NOT MRSA and NOT penicillin-resistant strep

• often combined with cilastatin and relebactam

why is imipenem combined with cilastatin?

cilastatin is a renal dehydropeptidase inhibitor that prevents imipenem from being hydrolyzed by dehydropeptidase-1 in the renal brush border (this destroys drug and releases nephrotoxic degradation products)

name

meropenem

• carbapenem

• beta-lactamase resistant

• IV

• formulated with vaborbactam

• spectrum similar to imipenem but has lots of anti-pseudomonal activity

name

ertapenem

• carbapenem

• beta-lactamase resistant

• used in home infusion therapy for susceptible infection

• broad spectrum but not like pseudo

• very high protein binding (95%)

• increased DOA allows once a day dosing

name

sulopenem etzadroxil

• oral thiopenem prodrug

• indicated for tx of uncomplicated UTI caused by e. coli, K. pneumoniae, or P. mirabilis

• beta-lactamase resistant

• broad spectrum, no activity against pseudomonas

• formulated with probenecid

name

probenecid

• combined with sulopenem, inhibits the tubular secretion of weak acids/inhibits OAT3, which sulopenem is a substrate for

name

tebipenem pivoxil hydrobromide

• oral carbapenem prodrug

• indicated for tx of complicated UTI, including pyelonephritis, caused by several susceptible microorganisms in adults who have limited or no alternative oral tx options

• broad spectrum, does not cover pseudomonas

• beta-lactamase resistant

name

aztreonam

• monobactam

• exclusive gm(-) spectrum, including nonfermentated bacteria like pseudomonas

• used for severe gm(-) infections acquired in hospital

• safe to administer in pts with beta-lactam allergy unless they had specific rxn to ceftazidime or ceftolozane or cefiderocol