medchem561 exam2

• resistant pathogens (altered pbp, beta-lactamases, etc.)
• allergic reaction
• insufficient drug levels at targeted site/tissue (beta-lactams have poor abscess penetration)

• Nitromidazole antibiotic
• PO, IV, or topical
• antianaerobic activity
• antiprotozoal activity(single-celled eukaryotes)
• acts as prodrug, gets converted to "suicide substrate"

• trichomonas vaginalis
• -trichomoniasis (STD)
• -treat partner also to prevent reinfection
• entamoeba histolytica
• -amebiases (intestinal and liver abscesses, "flask ulcers")
• giardia lamblia
• -giardiasis (infects small intesting-diarrhea)

• bacterial vaginosis (gardnerella vaginalis and many other anaerobes)
• helicobacter pylorii (peptic ulcers, used w/ ppi, bismuth, and other anitbiotics)
• clostridium difficile

• causative organism of antibiotic-associated diarrhea and pseudomembranous colitis (PMC)
• if resistant, use vancomycin (PO)

• intra-abdominal infections(polymicrobial, but commonly involves bacteroides fragilis (gram - anaerobe))
• topical use in acne rosacea(anti-inflammatory)
• CNS infections, often given w/ another antibiotic

• metallic taste-lasts for duration of therapy
• disulfuram reaction-avoid alcohol for at least 3 days after
• rare peripheral neuropathy
• seizures

CYP2C9 inhibitor-interacts with warfarin, tolbutamide, diclofenac, phenytoin, etc.

• rare in anaerobes but:
• 1) reduced drug activation-less reductase activity and reduced uptake
• 2) drug inactivation-nim genes encode and alternate nitroreductase that converts mtz to nontoxic derivative.
• 3) efflux pumps
• 4) increased repair of damaged DNA

• competitive inhibitor for PABA in biosynthesis of folic acid.
• depleting folic acid hinders eventual production of DNA so bacteria cant divide
• often given with trimethoprim (SMX/TMP)
• given PO or IV

• UTI-E.coli, proteus mirablis
• H.influenze
• Salmonella
• Toxoplasma gondii
• Pneumocystis jiroveci-causes pneumocystis pneumonia(PCP) in HIV patients
• CA-MRSA

• UTI
• CA-MRSA

chloroquine resisitant plasmodium falciparum (malaria)

malaria

toxoplasmosis

mycovacterium leprae (causes skin lesions and nerve damage)

• slow acetylators have higher risk of developing toxicity
• G6PD enzyme deficient pts have higher risk of developing hemolytic anemia due to reduced capacity to regenrate glutathione

• kernicterus-brain damage due to excessive jaundice, sulfonamides displace bilirubin from albumin inc bilirubin, dont give to children <2 months
• megaloblastic anemia(folate deficient pts)
• hemolytic anemia
• crystalluria-acetylated sulfonamides are insoluble in urine(take with full glass of water
• rash
• photosensitivity
• stevens-johnson syndrome

SMX is a CYP2C9 inhibitor

• very low risk due to two important stuctural differences.
• N1 nitrogen-containing heterocyclic ring(Type 1 IgE)
• N4 arylamine group associates with non-type 1 hypersensitivity (SJS) and is mediated by hydroxylamine metabolites
• in practice avoid if serious sulfa allergy otherwise not significant

• 1. reduced binding due to mutations in dihydropteroate synthase gene
• 2. some bacteria do not synthesize folic acid therefor "naturally resistant"
• 3. decreased drug permeability
• 4. efflux pumps

• IV, PO, and topical
• binds 50S ribosomal subunit to prevent translocation
• 50S is site shared by other protein synthesis inhibitors(potential for cross resistance)

• gram + cocci, especially strep- may be sensitive although resistance is imp to consider. Enterococcus faecalis and E. faecium are resistant
• Anaerobes- propionibacterium acnes, due to inc B. fragilis ressistance no longer recommended for intra-abdominal infections
• No gram - aerobes

• alt drug for treatment of serious strep and staph infections in penicillin allergic pt(generally not first or second line therapy)
• alternative agent for:
• STDs: gardnerella vaginalis(BV), chlamydia trachomatis (PID)
• parasites: toxoplasma gondii, pneumocystis jiroveci

• necrotizing faeciitis-dec toxin productions (s. pyogenes)
• good penetration into bone
• topical for acne

• metabolized (inactivated) and excreted in urine
• distributes very well into tissues and abscessses but not CNS
• high gut levels even with IV
• extensively excreted in bile and undergoes enterohepatic recycling

• diarrhea-20-30%, risk for PMC but not worse than others, "boxed warning" for PMC, low risk for topical because not absorbed, counsel for prolonged diarrhea
• hepatic toxicity(reversible)-elevation of transaminases, rare jaundice
• hypersensitivity reactions
• hematopoietic abnormalities (neutropenia)
• renal toxicity

• 1. production of methylated ribosomal binding sites(MRSA resistant)
• 2. Efflux pumps
• 3. Enzymatic drug inactivation

• erythromycin
• clarithromycin
• azithromycin
• telithromycin

large macrocytic lactone ring attached to 3 amino sugars

• bind 50S to inhibit protein synthesis
• bacteriostatic, but cidal at high doses

• gram + (s.pneumo, s. pyogenes, mssa but not mrsa)
• gram - (h.flu, m.cat, clarithro and azithro most potent)
• atypicals(not identifiable by gram staining or cultivatable on standard bacteriologic media)
• -mycoplasma pneumoniae(walking pneumonia)
• -legionella pneumonphilia(legionnaires' disease)
• -chlamydia trachomatis(std) and chlamydia pneumoniae

• useful for infections of upper and lower respiratory tract, skin, otitis media, stds, and atypical infections
• excellent tissue penetration (esp azithro & clarithro) but not CNS penetration
• alternative drug in pen-allergic pt unable to take sulfonamides due to staph, strep, and h.flu infections
• risk of PMC

• PO, IV, ophthalmic
• good gram + and - activity
• can cause diarrhea and gi irritation (13-32%)-acts as motilin agonist, activates receptors in small intestine that initiate peristalsis
• unstable in acid environment, take on empty stomach

• p-glycoprotein(pgp) inhibitor=interacts w/ digoxin
• inhibits CYP3A4=interacts w/ carbamazepine and cyclosporine
• inhibits CYP1A2=interacts with theophylline and caffeine

• PO only, 2-4x more potent than erythro
• choice for:
• -mycobacterium avium comple (MAC)-common opportunistic infection in AIDS
• -H. pylori
• Metallic taste

weak inhibitor of CYP3A4 and CYP1A2 but interactions can still be significant

• PO, IV, ophthalmic
• much better gram- (but less gram + )
• choice for:
• -chlamydia trachomatis-1g stat
• -chlamydia pneumoniase, m.cat and h.flu
• -neisseria gonorrhea(for beta-lactam allergic pts)
• -legionella infection
• alternative to clarithro for MAC
• rare hepatotoxicity

• avoid concurrent use with antacids(minor dec in Cmax, but not a chelation interaction)
• minimal CYP3A4 inhibition

• Ketek
• binds 2 sites on 50S and doesn't induce erm
• dose not cover mrsa, but covers prsp
• similar spec to azithro
• long half life (QD for 5-7d)

• prolonged qt interval
• muscle weakness
• hepatotoxicity
• blurred or double vision
• exacerbates myasthenia gravis (contraindicated)

cyp3a4 inhibitor

• 1.erythro ribosomal mehtylase(erm):50s methylation due to erm A,B,C genes
• -erm is inducible, cross resistance with clindamycin
• -leads to resistance to all mecrolides except telithro
• 2.cleavage of lactone ring by esterases
• 3.decreased permeability
• 4.efflux pumps
• not very useful for enterobacteriaceae
• -poor membrane penetration
• -esterase production

• consist of 4 fused rings with substitutions on positions 5,6, and 7
• different pharmacokinetic properties but same spectra
• -short acting-tetracycline
• -long acting-doxycycline, minocycline, tigecycline

• bind 30s to inhibit protein synthesis
• broad spectrum, bacteriostatic

• strep and staph if sensitive, but resistance common
• s.pneumo may be sensitive to doxycycline
• CA-MRSA may be sensitive also

• many are becoming resistant but includes
• -N. gonorrhea
• -many enterobacteriaceae(h.flu, e.coli, klebsiella, shigella, etc)

• rickettsia rickettsii (rocky mountain spotted fever)
• borellia burgdoferi (lyme disease)
• chlamydia trachomatis
• m. pneumoniae
• pasturella multocida(from animal bites)
• brucella, francisella, treponema pallidum(syphilis), actinomyces

PO, short acting (often QID)

• oral or IV
• prolonged half life, convenient BID
• gram + coverage, including mrsa
• h. pylori
• malaria prophylaxis for trips<4 months
• traveler's diarrhea prophylaxis (cipro preferred)
• chlamydia trachomatis (azithro preferred)

• gram + coverage, including mrsa
• used in asymptomatic n. meningitis carriers
• vertigo as possible side effect

• Tygacil
• glycylcycline
• iv only
• used agains multiple-drug resistant organisms, includign gram -, but not psudomonas
• also covers mrsa, vre, and bacteroides

• accumulates in growing bones and teeth in children therefore not recommended for children under 8yr or during pregancy(category D)
• chelates with divalent cations-avoid dairy, iron, or antacid products for 2hrs
• avoid taking with meals (doxy ok with)
• esophagitis-take with lots of water and remain upright for at least 30 mins
• photosensitivity
• do not use outdated products dur to higher renal toxicity(Fanconi syndrome)
• superinfection risk due to impact on normal flors(candida and c.diff)

• tetracycline resistance genes (tet) on plasmids, transposons, and integrons
• -efflux pumps
• -30s ribosomal modifications
• Tigecycline is able to overcome resistance mechanisms

• tobramycin
• amikacin
• gentamicin
• kanamycin

• contain 2 or more sugars linked to aminocyclitol ring.
• very water soluble, but not orally absorbed and are cationic at physiological ph

• toxicity concerns
• requires peak and trough monitoring

• excreted renally, largely unchanged
• PO forms (kanamycin) used for gut sterilization since not well absorbed
• not for CNS infections (dont cross BBB)

diffuse through porin channels in outer membrane but need active transport to cross inner membrane. transport doesn't occur in anaerobes isnce it require oxygen

• binds 30s, inhibits protein synthesis
• creates fissures in the outer membrane, leakage of intracellular contents
• concentration-dependent, bactericidal

• gram + activity of ag limited w/o beta-lactam or vanco
• disrupts peptidoglycan layer to allow more rapid entry of AGs into cell
• some beta-lactams inactivate AGs when mixed so administer seperately

• -enterobacteriaceae-enterobacter, klebsiella, proteus, providencia, morganella, serratia
• -p. aeruginosa-use is being replaced by less toxic cephs and fluoroguinolones. 2 drug regimens for serious infections still useful

• -E. faecalis and E.faecium (combined with vanco or possibly pen g or ampicillin) use alone has 40-60% resistance
• -staph infections (MRSA) as an alternate to other antibiotics (combined with vanco)

• -accumulate in proximal tubules of renal cortex
• -characterized by dec in CrCl, gradual inc in SrCr, oliguria, proteinuria or evidence of nitrogen retention
• -usually reversible
• -occurs in 5-10% of treated

• -results from destruction of cochlear hair cells, less common than nephrotoxicity
• -vestibular toxicity: imbalance, tinnitus, vertigo, or nystagmus; more predominant with gentamicin
• -auditory toxicity; high tone hearing loss; mroe common with kanamycin, and amikacin
• -trobramycin affects both vestibular and auditory toxicity equally
• -irreversible(cochlear hair cells cannot regenerate)
• -can be potentiated by loop diuretics (i.e. furosemide)

• 1. concentration-dependent bactericidal action
• 2. significan post antibiotic effect
• 3. rate of ag uptake in inner ear and renal cortex is saturable (risk of nephro/ototoxicity is equal or less)
• 4. avoid adaptive post-exposure resistance by bacteria(initial exposure down-regulates subsequent uptake of AGs)

• IV/IM, ophthalmic, topical
• -from micromonospora purpurea
• -all-purpose agent of choice in gram - aerobic infections

• IV/IM, ophthalmic
• greater efficacy than gentamicin against p. aeruginosa

• IV/IM
• fewer sites available to enzymatic modification
• reserved for infection resistant to gentamicin and tobramycin
• if pathogen resistant to amikaciin, resistant to all AGs

• IV/IM, PO
• can be used PO for gut infections such as intestinal amebiasis

• 1. production of plasmid mediated ag modifying enzymes (most common mech)
• -acetylation, adenylation, and phosphorylation
• -presence of the substituent amide at position 1 w/ amikacin confers resistance to enzymatic derivatization at all positions except 6'
• 2. impaired transport into cell via cation pump in inner membrane. (gram - and anaerobes have this resistance, possibly pseugomonas)
• 3. altered ribosomal binding site

• 1.phototoxicity
• -direct cellular damage
• -photodegeneration of drug by UV light, formation oxidative radicals, attack cellular lippid membranes, inflammatory processes and eventual DNA damage
• 2. photoallergy
• -photoallergen(hapten) formation
• -immediate or delayed hypersensitivity

• ciprofloxacin, levofloxacin - 3rd gen
• moxifloxacin - 4th gen

• quinolone nucleus with fluorine at position 6 and piperazinyl moiety at position 7
• concentration dep bactericidal
• significant post-antibiotic effect

• inhibit type II topoisomerases
• -DNA gyrase (primary target in gram -) negatively supercoils bacterial DNA and repairs nicks in single stranded DNA
• -Topoisomerase IV(primary target in gram +) ensures proper segregation of daughter chromosomes

• – Organisms vary in sensiGvity
• – The newer agents include Strep. as well as PRSP
• – NOT MRSA or enteroccoci

• – AcGvity against most aerobes, even Pseudomonas
• – Excellent against Enterobacteriaceae

only moxifloxacin

• – Chlamydia
• – Mycobacterium tuberculosis
• – MAC and certain other
• – Mycoplasma

• • PO, IV, or ophthalmic
• • Excellent gram (‐) activity but limited gram(+) activity

• – Respiratory: Acute sinusiGs, LRI, nosocomial pneumoniae (IV)
• – Skin or skin structure
• – Bone/joint
• – UTI
• – Uncomplicated cysGGs (bladder infecGon
• )– Chronic bacterial prostaGGs
• – InfecGous diarrhea
• – Gonorrhea (500 mg stat), but resistance is increasing

ciprofloxacin is a CYP1A2 inhibitor and has beenreported to increase blood levels of theophylline and caffeine

• • PO, IV, or ophthalmic
• • Has both excellent gram(‐) activity and gram (+) activity

• – Respiratory: acute sinusitis, acute exacerbation of chronic bronchitis,nosocomial pneumonia, community acquired pneumonia
• – Complicated and uncomplicated skin and skin structure
• – Complicated and uncomplicated UTI
• – Acute pyelonephitis
• – Prostatitis

• • PO, IV, or ophthalmic• C‐8‐methoxy group: believed to confer dual targeting activity
• – binds to BOTH DNAgyrase and topoisomerase IV in gram(+), whereas other FQs bind to just one
• • Has the best gram (+) activity, but limited gram(‐) activity– Best FQ for respiratory infections by S. pneumoniae, including PRSP

• – Respiratory: acute sinusitis, acute exacerbation of chronic bronchitis, nosocomialpneumonia, community acquired pneumonia
• – Complicated and uncomplicated skin and skin structure
• – Complicated and uncomplicated UTI
• – Acute pyelonephitis
• – Prostatitis
• • Not exclusively eliminated by kidney, so not a good drug for UTI

QT‐interval prolongation (↑risk with concurrent QT‐interval prolonging agents)

• • QT interval prolongation
• ‐ delayed cardiac cell repolarization phase
• • Can result in early afterdepolarizations (EADs)  torsades depointes  sudden cardiac death

• • Chelates with divalent cations  avoid dairy, iron, or antacidproducts for at least 2 hours
• • Prolonged diarrhea (for C. difficile overgrowth)
• • Photosensitivity (mostly ciprofloxacin)
• • Potential risk of tendonitis or tendon rupture
• – 0.14% to 0.4% incidence
• – Ischemic vascular process (narrowed vasculature of the tendon)
• – Direct toxicity to the collagen (tendon necrosis)– Risk factors: concurrent steroid use (i.e., prednisone), renal disease, organtransplant, advanced age (>60 y.o.)
• – FQs are contraindicated in <18 y.o. and pregnancy (risk of carGlagedamage). Also not recommended during breastfeeding.

• 1. Altered DNA gyrase and topoisomeraseIV  decreased FQ binding
• 2. Efflux pumps

(PO only)– Microcrystalline (Furadantin)– Macrocrystalline (Macrodantin and Macrobid): absorbed moreslowly, less GI distress

• Used for UTIs, not for systemic infections
• – One of the few non‐penicillins active against enteroccoci (includingVRE) and S. aureus
• – Also active against many gram(‐) aerobes, especially E.coli
• – Little to no acGvity against Proteus, Serratia, Klebsiella, Enterobacterspp. or Pseudomonas

• • Bactericida
• l• Multiple complex mechanisms
• – Reduction by bacterial flavoprotein systems (i.e.,nitroreductase) to form reactive intermediates binds ribosomes, DNA, and enzymes involved incellular respiration
• – Parent drug also has activity
• – Resistance from already susceptible organisms has not yet developed, no cross resistance to MTZ

• • GI effects (dose related): nausea, vomiting
• • Rare but serious adverse effects (<<1%)
• – Peripheral neuropathy
• – Hepatotoxicity
• – Pulmonary toxicity (bronchitis, asthma)
• – Hemolytic anemia, especially in G6PD deficient patients
• • Renally cleared, so contraindicated in renal insufficiency
• • Also contraindicated in pregnancy (38‐42 weeks gestation)