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Why do cell wall inhibitors fail?
- resistant pathogens (altered pbp, beta-lactamases, etc.)
- allergic reaction
- insufficient drug levels at targeted site/tissue (beta-lactams have poor abscess penetration)
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Metronidazole, class, ROA, activity, MOA
- Nitromidazole antibiotic
- PO, IV, or topical
- antianaerobic activity
- antiprotozoal activity(single-celled eukaryotes)
- acts as prodrug, gets converted to "suicide substrate"
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metronidazole, spectrum-protozoa?
- 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)
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metronidazole, spectrum-anaerobes?
- bacterial vaginosis (gardnerella vaginalis and many other anaerobes)
- helicobacter pylorii (peptic ulcers, used w/ ppi, bismuth, and other anitbiotics)
- clostridium difficile
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clostridium difficile?
- causative organism of antibiotic-associated diarrhea and pseudomembranous colitis (PMC)
- if resistant, use vancomycin (PO)
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metronidazole-other uses?
- 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
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metronidazole- adverse effects?
- metallic taste-lasts for duration of therapy
- disulfuram reaction-avoid alcohol for at least 3 days after
- rare peripheral neuropathy
- seizures
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metronidazole-drug interactions?
CYP2C9 inhibitor-interacts with warfarin, tolbutamide, diclofenac, phenytoin, etc.
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metronidazole-mechanisms of resistance?
- 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
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sulfonamides moa? and roa?
- 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
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sulfonamides spectrum?
- UTI-E.coli, proteus mirablis
- H.influenze
- Salmonella
- Toxoplasma gondii
- Pneumocystis jiroveci-causes pneumocystis pneumonia(PCP) in HIV patients
- CA-MRSA
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sulfamethoxazole/trimethoprim(SMX-TMP, co-trimoxzaole)
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Sulfadiazine
chloroquine resisitant plasmodium falciparum (malaria)
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sulfadoxine-pyrimethamine
malaria
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sulfadiazine-pyrimethamine
toxoplasmosis
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dapsone
mycovacterium leprae (causes skin lesions and nerve damage)
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sulfonamide metabolism and excretion
- 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
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sulfonamides adverse effects
- 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
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sulfonamides DI?
SMX is a CYP2C9 inhibitor
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sulfonamide and other sulfas cross reactivity?
- 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
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sulfonamides mechanism of resistance
- 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
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clindamycin roa? moa?
- IV, PO, and topical
- binds 50S ribosomal subunit to prevent translocation
- 50S is site shared by other protein synthesis inhibitors(potential for cross resistance)
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clindamycin spectrum
- 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
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clindamycin uses
- 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
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clindamycin metabolism, distribution, excretion
- 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
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clindamycin adverse effects
- 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
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clindamycin mechanisms of resistance
- 1. production of methylated ribosomal binding sites(MRSA resistant)
- 2. Efflux pumps
- 3. Enzymatic drug inactivation
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macrolides?
- erythromycin
- clarithromycin
- azithromycin
- telithromycin
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macrolides chemistry
large macrocytic lactone ring attached to 3 amino sugars
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macrolides moa
- bind 50S to inhibit protein synthesis
- bacteriostatic, but cidal at high doses
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macrolides spectrum
- 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
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macrolides general points
- 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
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erythromycin roa? spectrum? AE? counseling point?
- 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
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erythromycin DI
- p-glycoprotein(pgp) inhibitor=interacts w/ digoxin
- inhibits CYP3A4=interacts w/ carbamazepine and cyclosporine
- inhibits CYP1A2=interacts with theophylline and caffeine
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clarithromycin roa? best for? ae?
- PO only, 2-4x more potent than erythro
- choice for:
- -mycobacterium avium comple (MAC)-common opportunistic infection in AIDS
- -H. pylori
- Metallic taste
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clarithromycin DI
weak inhibitor of CYP3A4 and CYP1A2 but interactions can still be significant
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azithromycin roa? spectrum? best for? ae?
- 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
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azithromycin DI?
- avoid concurrent use with antacids(minor dec in Cmax, but not a chelation interaction)
- minimal CYP3A4 inhibition
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Telithromycin brand? moa? spectrum?
- 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)
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telithromycin ae?
- prolonged qt interval
- muscle weakness
- hepatotoxicity
- blurred or double vision
- exacerbates myasthenia gravis (contraindicated)
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telithromycin di
cyp3a4 inhibitor
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macrolides resistance mechanisms
- 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
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tetracyclines chemistry
- 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
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tetracyclines moa?
- bind 30s to inhibit protein synthesis
- broad spectrum, bacteriostatic
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tetracyclines spectrum gram +
- strep and staph if sensitive, but resistance common
- s.pneumo may be sensitive to doxycycline
- CA-MRSA may be sensitive also
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tetracyclines spectrum gram -
- many are becoming resistant but includes
- -N. gonorrhea
- -many enterobacteriaceae(h.flu, e.coli, klebsiella, shigella, etc)
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tetracyclines spectrum unusual
- 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
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tetracycline administration
PO, short acting (often QID)
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Doxycycline administration
- 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)
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minocycline specifics
- gram + coverage, including mrsa
- used in asymptomatic n. meningitis carriers
- vertigo as possible side effect
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tigecycline specific
- Tygacil
- glycylcycline
- iv only
- used agains multiple-drug resistant organisms, includign gram -, but not psudomonas
- also covers mrsa, vre, and bacteroides
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tetracyclines ae?
- 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)
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tetracyclines resistance mechanisms
- tetracycline resistance genes (tet) on plasmids, transposons, and integrons
- -efflux pumps
- -30s ribosomal modifications
- Tigecycline is able to overcome resistance mechanisms
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aminoglycosides?
- tobramycin
- amikacin
- gentamicin
- kanamycin
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aminoglycosides chemistry?
- contain 2 or more sugars linked to aminocyclitol ring.
- very water soluble, but not orally absorbed and are cationic at physiological ph
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why are AG often reserved for serious infections only?
- toxicity concerns
- requires peak and trough monitoring
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AG general points?
- excreted renally, largely unchanged
- PO forms (kanamycin) used for gut sterilization since not well absorbed
- not for CNS infections (dont cross BBB)
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why AG ineffective in anaerobes?
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
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AG MOA
- binds 30s, inhibits protein synthesis
- creates fissures in the outer membrane, leakage of intracellular contents
- concentration-dependent, bactericidal
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AG synergy with cell-wall inhibitors
- 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
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AG spectrum gram -
- -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
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AG spectrum gram +
- -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)
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AG AE renal toxicity?
- -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
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AG AE ototoxicity?
- -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)
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rationale for extended-interval dosing
- 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)
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Gentamicin details
- IV/IM, ophthalmic, topical
- -from micromonospora purpurea
- -all-purpose agent of choice in gram - aerobic infections
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tobramycin details
- IV/IM, ophthalmic
- greater efficacy than gentamicin against p. aeruginosa
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amikacin details
- 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
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kanamycin details
- IV/IM, PO
- can be used PO for gut infections such as intestinal amebiasis
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AG mechanisms of resistance
- 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
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cause of drug-induced photosensitivity
- 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
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flurorquinolones?
- ciprofloxacin, levofloxacin - 3rd gen
- moxifloxacin - 4th gen
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FQ chemistry
- quinolone nucleus with fluorine at position 6 and piperazinyl moiety at position 7
- concentration dep bactericidal
- significant post-antibiotic effect
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FQ MOA?
- 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
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FQ spectrum gram +
- – Organisms vary in sensiGvity
- – The newer agents include Strep. as well as PRSP
- – NOT MRSA or enteroccoci
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FQ gram -
- – AcGvity against most aerobes, even Pseudomonas
- – Excellent against Enterobacteriaceae
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FQ anaerobes
only moxifloxacin
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FQ spectrum other
- – Chlamydia
- – Mycobacterium tuberculosis
- – MAC and certain other
- – Mycoplasma
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cipro roa? spectrum?
- • PO, IV, or ophthalmic
- • Excellent gram (‐) activity but limited gram(+) activity
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cipro indications
- – 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
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cipro DI
ciprofloxacin is a CYP1A2 inhibitor and has beenreported to increase blood levels of theophylline and caffeine
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levofloxacin roa? spectrum?
- • PO, IV, or ophthalmic
- • Has both excellent gram(‐) activity and gram (+) activity
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levofloxacin indications
- – 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
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moxifloxacin roa? spectrum?
- • 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
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moxifloxacin indications
- – 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
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moxifloxacin ae
QT‐interval prolongation (↑risk with concurrent QT‐interval prolonging agents)
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QT-interval prolongation pathophysiology
- • QT interval prolongation
- ‐ delayed cardiac cell repolarization phase
- • Can result in early afterdepolarizations (EADs) torsades depointes sudden cardiac death
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FQ AE
- • 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.
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FA resistance mechanisms
- 1. Altered DNA gyrase and topoisomeraseIV decreased FQ binding
- 2. Efflux pumps
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nitrofurantoin dosage form?
(PO only)– Microcrystalline (Furadantin)– Macrocrystalline (Macrodantin and Macrobid): absorbed moreslowly, less GI distress
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nitrofurantoin uses
- 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
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nitrofurantoin moa?
- • 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
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nitrofurantoin ae?
- • 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)
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