Antibiotics Flashcards
What is chemotherapy?
use of drugs to kill or suppress growth of cells
What is an antibiotic?
chemical produced by one microbe that has the ability to harm other microbes (antimicrobial or anti-infective)
What is selective toxicity?
ability of drug to injure target cells without injury to the host
How is selective toxicity achieved against pathogenic bacteria?
exploits difference between Pro and Eukaryote, targets process unique to path or similar but not identical to host, therapeutic index is an indication of degree of selectivity
What is a bacteriostatic?
at therapeutic doses (MIC) suppresses bacterial proliferation but does not cause cell death, depends on host immune system to clear infection
What is a bactericidal?
at therapeutic doses (MBC) cause direct bacterial cell death; dependent on active bacterial proliferation; effect can be concentration or time dependent or preferred for certain infections
What is innate resistance? Examples
anaerobes more resistant to O2 dependent drugs (aminoglycosides), aerobes resistant to metronidazole (requires enzymatic reduction in absence of O2), non-penetration of lipophilic (PCN) and high MW (Vanco) through outer membrane G-
What is acquired resistance to antibiotics?
loss of antibiotic responsiveness due to change in microbe, individual patient during therapy or general population
What are some examples of acquired resistance?
induction of B drug metabolizing enzyme or efflux tranporter, dec. expression of drug uptake transp., change in microbial receptor enzyme dec. affinity, inc. synth of compounds that anatagonize AB
What are some mechanisms of acquired resistance?
vertical transfer (spontaneous mutation- random, usually to single drug), horizontal transfer (conjugation- plasmid transfer, F + sex pilus, primarily G-, MDR); AB promote resistance via selective pressure
what causes a superinfection?
emergence of drug resistant microbes, loss of normal flora that inhibit growth of invading microbes more likely with broad spectrum, C. diff-
What are the features and causes of C difficile?
pseudomembranous colitis and death, 2 months after infection, 25% recurrence, highest risk with: clindamycin, cephalosporin, PCN, and flouroquinilone, symptoms not controlled by anti-diarrheal, treat with metronidazole or oral vancomycin, fidaxomicin
What accelerates emergence of resistant organisms?
trt B colonization, treat untreatable infection (virus), unknown fever, improper dose and duration of treatment, lack of compliance when symptoms subside, reliance on chemotherapy w/ omission of surgical drainage, using broad when susceptible narrow spectrum ID, using newer AB
What is empiric therapy?
initiation of Trx w/o ID or susceptibility test; when source and susceptibility is “known”- 85% UTI E.Coli can be treated with co-trimoxazole, or delaying therapy would threaten life (B meningitis), sample should be taken before treatment
What is definitive therapy?
match bug and drug; susceptibility tes, MIC usually gives adequate info, generally requires 18-24 hours to complete
What are the various results and what do they mean for susceptibility tests?
susceptible- infection can be treated at standard doses; intermediate- treatment reserved for sites where agent is concentrated (urine) or can be used in higher than std dose w/o adverse effects; resistant- use something else
What host factors must be considered when selecting treatment?
condition of immune system (use bactericidal in immunocomprimised), location of infection (MIC at site, hydrophilic not orally absorbed and poorly penetrate intact BBB; bone, eye, pulm and abscess difficult to penetrate; biofilms on foreign material), renal and hepatic function (most cleared by kidney, impaired and elderly at risk for toxicity, infants immature liver and kidneys), obesity dose for ideal body weight
What antibiotics should be reduced in patients with decreased kidney function?
aminoglycosides, vancomycin, cephalosporins (1st and 2nd gen), sulfonamides / trimethoprim, extended spectrum pcn, carbapenems, ethambutol (a very childish Susan touches every single pricey car emblem)
What antibiotics should be reduced in patients with decreased liver function?
clindamycin, macrolides, chloramphenicol, tetracyclines, metronidazole, isoniazid, rifampin (clean my car to make it rain)
Which antibiotics are not recommended in pregnant women and why?
class D- aminoglycosides(ototoxcicty offspring) and tetracycline (discoloration and poor bone growth) (maternal hepatotoxicity)
Which antibiotics can cause problems when they cross the placenta or enter breast milk?
aminoglycoside (ototoxicity during fetal development) and sulfonamide (induced kernicterus in nursing infants) tetracycline (bones)
Which antibiotics are common allergens?
beta lactams, sulfonamides, trimethoprim, and erythromycin; any can be an allergen; false negatives common on skin testing
When would oral route not be preferred for antibiotics?
poor GI absorption, critically ill, bacterial meningitis or endocarditis, and N/V
What must be considered when dosing an antibiotic to avoid superinfection?
must exceed MIC at site of action, duration must be sufficient to prevent re-infection but not so long as to promote super infection, std- 7-10 days not sure if this is ideal
What are the indications for combination therapy?
mixed B infection (G+ and G-), initial therapy of severe infections with unknown etiology or resistance is suspected, enhance of AB therapy, prevent emergence of resistant microbes (TB!!)
What are the disadvantages of combination therapy?
drug anatagonism (bacteriostatic w/ bactericidal, or same binding site) exposure of pt to adverse side effects with no therapeutic benefit, broadens the spectrum but increases risk of drug resistant super-infection
When would prophylactic Antibiotic therapy be appropriate?
before potential or after known exposure, surgery (colon, cardiac, transplant, or prosthetic implant), B endocarditis (valvular disease or prosthetic valves undergoing high-risk dental procedures), prevent opportunistic in immunocompromised, recurrent UTIs or STD exposure
What are some features of Gram + cell walls to consider when choosing AB?
thick peptidoglycan wall, maintains osmotic pressure in variable tonicity, hydrophilic and lesser extent hydrophobic can easily diffuse though porous cell wall
What are some features of Gram - cell walls to consider when choosing AB?
thin cell wall, outer membrane- lipid, hinders AB transport, small hydrophilic can cross via porins (loss or mutation can eliminate this, number and size vary amongst organisms), periplasmic space can concentrate enzymes that inactivate AB, transporters can promote drug efflux
What are the classes of AB?
inhibition of cell wall synthesis (transpeptidation, murine precursor synthesis or mycolic acid synthesis), inhibition of protein synthesis (bind 30s or 50s subunit), inhabitation of nucleic acid synthesis (folic acid metabolism, DNA gyrase, RNA polymerase), disrupt plasma membrane structure or function (cationic detergents dissolve membrane, membrane depolarization)
What are the antibiotics belonging to the B-lactam family?
penicillin G (benzathine), penicillin V, nafcillin, amoxicillin, ticarcillin, piperacillin, clavulanic acid, cefazolin, cefoxitin, ceftriaxone, cefepime, ceftaroline, imipenem/cilastatin and aztreonam
What are the different cell wall inhibitors?
B lactams, vancomycin, fosfomycin
What are some general features of penicillins?
B-lactam ring essential for activity,terminal D-ALA-d-ALA residue of NAM/NAG-peptide subunits in peptidoglycan (molecular mimickery), properties of each determined by R group (target affinity, resistance, G- envelope penetration, stability in acid and pharmacokinetics)
What is the mechanism of action of penicillin?
bactericidal, time dependent, disrupts cross linking of cell wall by irreversible inhibition of transpeptidase, targets known collectively as PBPs (penicillin binding proteins, more than transpeptidase), most effective in log phase
What are the consequences of irreversible inhibition of transpeptidase by penicillin?
disinhibition (activation) of autolysins due to accumulation of peptidoglycan precursors, promotes cell wall degradation-> lysis,
What are the mechanisms of resistance to penicillin?
inability of lipophilic to penetrate G- outer membrane, acquired mutations in PBPs (lower affinity), B-lactamase (most important)- cleaves B-lactam ring rendering inactive
What are some important features of B-lactamses?
ring rendered inactive, G+ secrete into surrounding medium, G- retain in periplasmic space (concentrating them), genes on chromosomal and plasmid DNA (horizontal transfer) can be constitutive or inducible, classes with variable specificity (penicillinase, cephalosporinase or broad- extended spectrum B-Lacatmase or carbapenemases)
What are the standard narrow spectrum penicillins? features of each?
Pen G (unstable in stomach) and Pen V (acid stable), both more active against G+ over G-, effective anaerobes, susceptible to B-lactamase inactivation, Pen G repository DOC for syphilis also for RF, still used if bug suceptible
What are the features of Nafcillin?
narrow spectrum anti-staph, penicillinase resistant, (methicillin= interstitial nephritis), used against Pen G resistant staphyloccal endocarditis, skin and soft tissue infection, no G- activity, MRSA due to altered PBPs (PBP2a resists all B-lactams)
What are the features of amoxicillin?
aminopenicillins, broad spectrum, additional gram - due to increased porin penetration, susceptible to B-lacatamase, frequently administered with inhibitors, upper respiratory infections
What are the features of ticarcillin and pipercillin?
antipseudomonal, extended spectrum pncn, give IV, serious hospital acquired G- infections, susceptible to B-lacatamase, used with inhibitor
What are the features of clavulonic acid?
combined with amoxicillin and ticarcillin, B-lacatamase inhibitor, no intrinsic AB activity, doesn’t inhibit all B-lacatamase, no help with MRSA (altered PBP)
What are the pharmacokinetic properties of the penicillin family?
parenterally or orally, wide distributed, poor oral absorption (diarrhea), short half life (30-90 min) give 3-6x a day, exreted unchanged by glomerular filtration (10%) and active secretion (90%), blocked by probenecid (UTIs, concentrated in urine), renal impairment increases half life
What are some adverse reactions to penicillin family?
least toxic, safest during pregnancy, Jarisch -Herxheimer (syphilis, toxin relased as B dies), CNS toxicity (seizures) with high IV dose, repository preps fatal if given IV, amoxicillin macular rash (T cell mediated, not HS IV), ticarcillin large IV -> Na overload->CHF
What are the features of penicillin allergy?
most common drug allergy, non-enzymatic breakdown to penicilloyl and others, forms hapten with proteins, cross-reactivity with other B-lactams except aztreonam, maculopapular uticarial rash, fever, bronchospasm, vasculitis, serum sickness, Steven’s Johnson Syndrom, anaphylaxis; IgE mediated angioedema and anaphylaxis big concern
What is Stevens-Johnson syndrome?
rash on epidermis and mucus membranes, idiosyncratic drug rxn, severe
What are the general fetaures of cephalosporin family?
B-lactam, susceptible to B-lacatamase and altered PBPs, 5 generations, going up in gen: increase in gram - and anaerobe activity, increasing resistance to B-lacatamase, increasing penetration CNS
What are the features of cefazolin?
1st gen cephalosporin, high G+ activity including MSSA and strep but not MRSA, mild penicillin allergy exists, common 1 hour before surgery, prophylaxis for surgical site infection
What are the features of cefoxitin?
2nd gen ceph, more gram - (H, influenza, B. fragilus) due to higher affinity PBP and greater envelope penetration, better B-lacatamase resistance, less active than 1st gen in G+, CNS pen poor, prophylaxis in abdominal surgery (GI anaerobes)
What are the features of ceftriaxone?
3rd gen, higher G- activity, good CNS pen, most widely used, treating meningitis (S. pneumonia, N. meningitides, H. influenziae), impirical for gonorrhea and chlamydia in combo with azithromycin
What are the features of cefepime?
4th gen ceph, highly resistant to B-lactamase, broad spectrum, good CNS penetration, empirical for hospitalized when resistance due to extended spectrum B-lactamase suspected and febrile neutropenia
What are the pharmacokinetic properties of cephalosporin family?
parenterally due to poor absorption, practically all cleared by kidney
What are some adverse reactions to cephalosporin family?
hypersensitivity, low degree cross reactivity with penicillin, diarrhea, potentially nephrotoxic, 2nd gen MTT cef’s inhibit vitamin K->prolonged bleeding (esp w/ anti-coags), disulfiram-like rxn when coadministered with ethanol (antabuse rxn, severe N/V)
What are some cephalosporin generalities?
3rd widely used (1st and 2nd gen rarely used), 4th gen in hospital for drug resistant,
What are the general features of imipenem/cilastatin?
carbapenem, B-lactam antibiotics, broad spectrum, structure similar to penicillin, highly resistant to B-lactamase (except B-Lactamases: A KPC and B-NDM-1); serious nosocomial infections
What are the pharmacokinetic properties of carbapenems?
parenterally, eliminated predominantly by kidneys, imipenem- fixed dose combo with cilastatin (dipeptidase inhibitor) to prevent renal inactivation
What are the therapeutic uses and adverse rxns of carbapenems?
T: MDR infections, anaerobic and mixed infections; A: generally well tolerated, some nausea, diarrhea; hypersensitivity and seizures (imipenem only)
What are the general features of aztreonam?
monobactam, B-lactam not fused with 2nd ring, narrow spectrum against G-aerobic including pseudomonas, resembles aminoglycoside spectrum, highly resistant B-Lacatamase; gen safe for pt with pen allergy and serious gram - pneumonia, meningitis or sepsis
What are the pharmacokinetic properties of aztreonam?
IV, poor oral absorption, excreted unchanged by kidneys
What family does vancomycin belong to? general features and MOA?
tricyclic glycopeptide, reserved for serious G+ infections (S. aureus and S. epidermis), bactericidal, prevents polymerization of cell wall precursors by binding D-ALA-D-ALA of NAM monomer (no NAM-NAG to form chain), can’t penetrate G- envelope due to large size
What are the features of Vancomycin resistance? What drugs are used instead?
VRSA and VRE, variation in peptide terminus (D-ALA-D-lactate), 1000x decrease in affinity; use linezolid, daptomycin or quinupristin/daflopristin
What are the pharmacokinetic properties of Vancomycin?
IV for systemic and dermal infections, only orally to treat infection within GI tract (minimal absorption), excreted unchanged by kidneys
What are the therapeutic uses of vancomycin?
parenteral- sepsis or endocarditis caused by MRSA or sensitive enterococci, in combo with 3rd gen cephalosporin for meningitis, oral- CDAD if metronidazole ineffective, alternate to penicillin in allergic patients with severe G+ infection
What are the adverse reactions of vancomycin?
ototoxic and nephrotoxic, permanent auditory and vestibular impairment, increases with another oto or nephrotoxic, with rapid infusion- red man syndrome, thrombophlebitis with IV
What is red man syndrome?
flushing, rash, uticaria, tachycardia and hypotension, may result in histamine release
What are the features of Fosfomycin?
bactericidal phosphoenolpyruvate, treat uncomplicated G- UTI, taken orally, only achieves MIC in urine
MOA of Fosfomycin?
inhibit production of murein monomer in cytosol, covalent binding with enzyme enolpyruvate transferase (MUR A)
Resistance of Fosfomycin?
mutation in glycerophosphate transporter prevents entry
What are the general features of aminoglycosides?
highly polar cation, doesn’t cross cell membrane, not absorbed in GI, doesn’t penetrate CNS or Eye, excreted by kidney, attract negatively charged LPS in outer membrane Gram-
What is the mechanism of action of aminoglycosides?
Bactericidal against aeorbic G- (G+ staph w/ B-lactam)activity concentration dependent, passive diffusion through outer membrane porins, active transport (need O2) into cytosol (facultative anaerobes resistant in low O2, abscess), transport enhanced by cell wall inhibitors (inhibited by low pH, lung/bronchi) binds 30s
What is a special feature of aminoglycosides?
long post-antibiotic effect- residual activity several hours after plasma level below MIC
How is B resistant to Aminoglycosides?
plasma encoded tranferases that inactivate drug (bacterial kinase and acetyltransferase
What is the therapeutic use of gentamicin?
narrow spectrum G- aerobes, use in combo with with B-lactam or vancomycin for resistant bacteremia and sepsis, use sparingly to avoid toxicity, monitor blood levels, test hearing before and after; monotherapy tularemia, plague and MDR UTIs
What is the therapeutic use of streptomycin?
main use as second line activeTB
What is the therapeutic use of amikacin?
least susceptible to inactivation, used in hospitals where resistance to gentamicin and tobramycin is common
What is the therapeutic use of neomycin?
combined in OTC topical ointment, Neosporin, with polymixin B and bacitracin
How does aminoglycosides affect protein synthesis?
interfere w/ initation complex formation, misread RNA, block translocation
What are the adverse side effects of aminoglycosides?
ototoxicity (auditory and vestibular, irreversible, drug accumulation in hair cells, elevated trough levels for prolonged period, tinnitus warning) renal impairment (usually worry that it prolongs oto exposure, PT cell damge, reversible, >10d increases risk), and NM block with high doses (respiratory paralysis, reverse with neostigmine or Ca), CI: myasthenia gravis
What are the general features and mechanism of action of doxycycline?
tetracycline, active transport system causes accumulation in bacterial cells (system not in mammalian), binds 30s (inhibit tRNA bind to A site) bacteriostatic
How has resistance to doxycycline (tetracyclines) developed?
increased drug efflux and production of proteins that interfere with 30s binding
What drug in the tetracycline family was developed to combat resistant bugs? How does it do so?
tigecycline, has additional glcyl side chain, resistant to efflux transporters and increased binding affinity to 30s subunit than older tetra’s
What are the pharmacokinetics of tetracyclines?
all except tigecycline are orally effective, form insoluble chelates with multivalent cations decreasing oral absorption (avoid taking with dairy, iron, Mg containing laxative and antacids and Pepto-Bismol, widely distributes in CNS, bone/teeth, placenta and breast milk
What are the therapeutic uses of Tetracyclines?
broad spectrum, aerobic and anaerobic, G+ and G-, use declined due to toxicity, effective with rickettsial infections, chlamydia, lyme disease, anthrax, mycoplasma pneumonia, oral- acne vulgaris and periodontal disease, treat and prophylaxis- malaria; tic borne illnesses
What are the adverse reactions of tetracyclines?
GI (cramp, nausea, diarrhea), deposition in bones/teeth (Ca2+) causing discoloration (avoid pregnancy and
What are the 3 macrolides discussed? MOA?
erythromycin, azithromycin, clarithromycin; bacteriostatic, (cidal at high concentration with highly susceptible strains), reversibly binds with 50s subunit (inhibit translocation, no elongation), selective toxicity (no mammalian 50s, wont enter mitochondria) (same binding site as clindamycin and chloramphenicol)
How has resistance developed to macrolides?
express efflux transporters, plasmid-encoded methylation of 50s decreasing affinity (ERM gene, confers MDR phenotype MSLb- macrolide-clindamycin-streptogramin B)
What are the pharmacokinetic properties of macrolides?
orally or parentereally; ester form increase bioavailability (erythromycin inactivated by gastric H), Eryth- eliminated primarily hepatic CYP3A4 (warfarin, theophylline, cyclosporine) azithromycin least inhibitory; good distribution
What are the therapeutic uses of macrolides?
substitute for penicillin, atypical pneumonias (legionnaire’s, mycoplasma p, chlamydia (in pregnancy) and upper resp., bordetella pertussis and diphtheria; atypical orgnisms (MAC), H.pylori and GI infections
What are the adverse reactions to macrolides?
GI irritation (increase motility), cholestatic hepatitis (erithromycin, rare), prolonged Q-T with high plasma levels due to other CYP3A4 substrates (rare, inc risk arrhythmia and SCD)
What is the MOA of clindamycin?
similar to macrolide, binding site overlap at 50s, block peptide bond formation btwn A and P sites
What are the therapeutic uses of clindamycin?
most anaerobes and G+ aerobes, usually bacteriostatic (cidal depending on dose and sensitivity), alt. PNCN, not in combination with macrolide or chloramphenicol (antagonism), severe group A strep and gas gangrene (Cl. Perfringens), Abd and Pelvic inf. B. Fragilis, topical- acne and bacterial vaginosis; seriour staph (MRSA) and strep
What are the adverse reactions of clindamycin?
diarrhea (~20%) CDAD major concern (3-5%) even wks after withdrawal
what is the mechanism of action of Chloramphenicol?
binds to peptidyl transferase center of 50s subunit, prevents attachment of incoming tRNA to A-site
What are the general features of Chloramphenicol?
broad spectrum bacteriostatic, G+ (MRSA, VRE), G- and anaerobes, orally, widely distributes in tissues (CNS), metabolized by liver (glucuronide)
What is the reason for resistance to Chloramphenicol?
acetyltransferase that acetylates (inactivates) the drug
What are the adverse reaction of Chloramphenicol?
gray baby syndrome, bone marrow suppression, aplastic anemia
What is gray baby syndrome?
gray skin, vomiting, abdominal distention, usually in neonates, drug accumulation due to insufficient liver and kidneys; don’t give to infants or nursing moms
What are the features of bone marrow suppression with Chloramphenicol?
dose-related, anemia, leucopenia, thrombocytopenia, inhibition of protein synthesis in host mitochondria
What are the features of aplastic anemia from Chloramphenicol?
rare and fatal pancytopenia and bone marrow aplasia, not dose related, can be weeks/months after termination of therapy; unknown mechanism
What is the MOA of linezolid?
an oxizolidinone, binds unique site 23s of 50s subunit, blocks formation of intiation complex, bacteriostatic,
What is the therapeutic use of linezolid?
MDR G+ pathogens, VRE, MRSA, should not be used when other agentsare likely effective
What are the adverse reactions and drug interactions of linezolid?
reversible myelosupression (anemia, leucopenia, thrombocytopenia- weekly blood counts), peripheral and optic neuropathy possibly permanent; DI: MAOIs and SSRIs (potentially fatal serotonin syndrome)
What is the mechanism of action of quinupristin-dalfopristin?
synergistic bactericidal, D- directly inhibits peptidyl transferase center of 23s, Quinupristin binds same site as macrolides
What are the general properties of quinupristin-dalfopristin?
active against many G+, G- limited, approved FDA for serious infections by VRE, fixed dose combo
What are the adverse reactions of quinupristin-dalfopristin?
hyperbilirubinemia and arthralgia/myalgia, phlebitis; inhibits CYP3A4
What is the prototype fluoroquinolone?
ciprofloxacin; fluorinated derivative of quinilone
What if the MOA of fluoroquinolone?
bactericidal, inhibit on of two DNA gyrase, occurs after DNa strand is nicked by enzyme, high concentration causes dissociation, double knicked can’t be replicated, cell dies
What is the mechanism of resistance to fluoroquinolone?
mutated DNA gyrase, reduced ability to cross bacterial membranes, increased efflux, plasmid mediated Qnr proteins that protect DNA gyrase
What are the therapeutic uses of fluoroquinolone?
broad spectrum, widely used for UTI, respiratory and GI infections (overused) by aerobic G- (E.Coli, K. Pneumoniae, P. aerugenosa, N. Gonorrhea, enterobacter, salmonella, shigella), prophylaxis for anthrax if spores inhaled
What are the adverse side effects of fluoroquinolone?
tendon rupture (Achilles, disrupt ECM collagen, reversible early on, rare) avoid under 18, confusion, somnolence, visual disturbances (esp. elderly), some prolong QT interval (watch with class IA and III antiarryhtmics), CDAD with cipro; Peripheral neuropathy may be permanent, hepatotoxicity, photosensitivity, hypoglycemia esp elderly diabetics and after insulin dose, CI: myasthenia gravis
What are the drug interactions with fluoroquinolone?
increase plasma level theophylline and warfarin, oral absorption reduced if taken with multivalent cations
What is the MOA of metronidazole?
bactericidal in anaerobes, microaeropihilic, and sensitive protozoa, prodrug- inactive til reduced in anaerobes by PFOR (pyruvate-ferredoxin oxidoreductase) or nitroreductase (mammals lack both), reduction produces cytotoxic intermediate causing DNA strands to break, loss of helical structure;
Therapeutic uses of metronidazole?
anaerobic B infections (intra-abdominal, B. vaginosis), resistance rare, drug of choice for CDAD (vaco 2nd), combo with tetracycline and Pepto-Bismol to eradicate H.Pylori, antiparasitic (amebiasis, giardiasis, trichomoniasis)
Adverse reactions with metronidazole? drug interactions?
headache, GI disturbances, metallic taste, dark red-brown urine; CYP3A4 substrate-> disulfiram-liek reaction with ethanol, inhibits metabolism of warfarin-> bleeding; Carcinogenic in animals, neuropathy with prolonged use
What class and what is the MOA of sulfamethoxazole (SMX)?
sulfonamide; bacteriostatic, structural analog to PABA, competitive inhibitor of dihydropteroate synthase, blocks formation of dihydropteric acid->DNA, mammals lack this enzyme
What is the mechanism of resistance to sulfamethoxazole (SMX)?
sytnehsis of sufficient PABA to overcome inhibition, mutation of dihydropteroate synthase active site reducing drug affinity, decrease drug uptake
What are the therapeutic uses of sulfamethoxazole (SMX)?
broad spectrum G+/G-, use diminished due to resistance and safer alternatives, UTIs (E.Coli) with trimethoprim
What are the adverse reactions of sulfamethoxazole (SMX)?
kernicterus (brain damage in newborns, compete with bilirubin to bind with albumin), hypersensitivity- 2nd most common allergy, Stevens-Johnson syndrome (rare), hemolytic anemia (geneitc G6PD deficiency)
What is the MOA for trimethoprim (TMP)?
competitive inhibitor of dihydrofolate reductase; prevent reduction of dihydrofolate to tetrahydrofolate, blocks formation of A, G, T. Bacterial DHFR 40Kx higher affinity
What is the mechanism of resistance with trimethoprim (TMP)?
increased synthesis of DHFR, production of mutated DHFR with lower drug affinity, reduced drug uptake
Therapeutic use of trimethoprim (TMP)?
most enteric G-, some G+ bacilli, some pathogenic protozoa, alone initial therapy for uncomplicated UTI and otitis media
Adverse reactions of trimethoprim (TMP)?
in folate deficient (pregnant, alcoholic and malnourished) bone marrow suppression (megaloblastic anemia, thrombocytopenia, neutropenia); high dose- fetal malformations in experiment animals; Hyperkalemia – blocks sodium channels in renal collecting ducts to promote excess retention of potassium
What are the general features of co-trimoxazole?
fixed dose combo of TMP/SMX; bactericidal synergistic- inhibition of sequential steps of folate biosynthesis, broad spectrum (G+ and G-), resistance less than each alone
What is the therapeutic use of co-trimoxazole?
UTI (E.Coli, Klebsiella)- chronic and recurrent, pneumocystis jirovicii pneumonia- opportunistic infection in immunocoprimised, otitis media (H. influenza, S. Aureus); skin and soft tissue staph inf. (incl. MRSA)
What are the adverse reactions to co-trimoxazole?
same as individual, AIDS patients 55% incidence of fever, rash, leucopenia
What are the general features and MOA of fidaxomicin?
new actually macrolide, inhibits bacterial RNA polymerase, bactericidal in G+
What are the pharmacokinetic properties therapeutic uses, and adverse reactions with fidaxomicin?
give orally but not absorbed from GI; CDAD, alternative to metronidazole and vancomycin, minimally disruptive to normal flora, lowers recurrence; nausea, hypersensitivity reactions
What is the prototype and general features of cyclic lipopeptides?
daptomycin; bactericidal, only G+, cant penetrate G- outer membrane, inactivated by surfactant so not effective against pneumonia
What is the MOA of daptomycin? and pharmacokinetics?
Ca2+ dependent insertion of lipophilic tail into plasma membrane forms ion-permeable channel that permits efflux of intracellular K+, membrane depolarization, inhibit DNA, RNA and protein synthesis; bactericidal (G+); distribution mostly vascular space, cleared by kidneys, inactivated by surfactant
What are the therapeutic uses and adverse reactions to daptomycin?
IV only, do not give IM, complicated skin and skin structure infections by MRSA and VRSA, complicated bacteremia and right sided endocarditis MRSA; AR- eosinophilic penumoniamyopathy (measure CPK)
What is the MOA of polymixins? Examples in this family.
binds to negatively charged LPS in outer membrane of G-, hydrophobic tail detergent effect that disruptsouter and plasma membrane, increase membrane permeability; colistin, polymixin B
What are the different formulations and use of polymixins?
colistin sulfate- cationic, for topical and oral (GI) use, colistimethate- anionic, parenteral only, prodrug of colistin
What is the therapeutic use of colistimethate?
last resort for serious MDR G-, P Aeruginosa, acinobacter baumannii and Klebsiella pneumonia
What is the therapeutic use of colistin sulfate/ polymixin B?
topical (ophthalmic, dermal) for infections of skin, mucous membranes, eye and ear (external otitis)
What are the adverse side effects of polymixins?
associated only with parenteral treatment, not absorbed topically, reversible nephrotoxicity and neurotoxicity (NMJ- weakness, apnea), must monitor renal function
What are the intrisinc features of resistance in mycobacterium?
highly complex and relatively impermeable cell wall, efflux tranporters(ATP binding cassette) in plasma membrane, intracellular location of infection (Macs), slow proliferation (wks to determine susceptibility)
What are the features of acquired resistance?
due to spontaneous mutations, likely because therapy long term, each mutation confers resistence to one drug; esp if patients not adherent to meds during treatment
Why use multidrug therapy with mycobacterium?
reduces incidence of relapse (some against active other dormant), does not broaden spectrum of AB and lead to superinfection because standard drugs selective for TB
What resistance is being seen with TB?
MDR- to isoniazid and rifampin (mosty inadequate therapy and compliance); XDR (extensive)- MDR + fluoroquinolone and aminoglycosides
What is the mechanism of action of isoniazid (INH)?
inhibit synthesis of mycolic acid- passive diffuse into mycobacterium, prodrug activated by MB catalase/peroxidase (KatG) to free radical which covalently binds NAD+ and NADP+ forming adducts that inhibit enzymes in synthesis of mycolic acid
What are the general features of isoniazid?
bactericidal to active bacilli, bacteriostatic to quiescent bacilli, active against extracellular and intracellular organisms
What is the mechanism of resistance to isoniazid?
mutation or deletion of katG gene
How is isoniazid metabolized?
acetylation in liver, N-acetyl-INH excreted by kidneys, half-life 1 hr in rapid acetylators, 3 in slow, acetylator status does not usually affect dosing or therapeutic outcome; more likely to reach toxic levels of prodrug in slow acetylators
What are the therapeutic uses of isoniazid?
indicated for active and latent TB, used alone for latent and in combo with rifampin for active TB
What are the adverse reactions and drug interactions of isoniazid?
peripheral neuropathy (20%) hepatitis (potentially fatal necrosis, toxic metabolite, 8% in >65 yrs, 0 in
What are the features of peripheral neuropathy in isoniazid?
dose related paresthesias in extremities, from drug induced deficiency of pyridoxine (reversed by B6), more common in slow acetylators
What is the method of action of rifampin?
a rifamycin, inhibits DNA-dependent RNA polymerase (rpoB), binds B subunit B RNA polymerase, inhibiting RNA synthesis; bactericidal
What is the mechanism of resistance to rifampin?
mutation of rpoB gene-> decreased binding affinity (mammals RNA pol wont bind this), effective against intracellular organisms
What are the therapeutic uses of rifampin?
combo with isoniazid for TB; monotherapy for latent TB prophylaxis, leprosy, broad spectrum against Neisseria meningitides, H. influenza, S. Aureus (serious infections), MAC, Legionella
What are the adverse reactions of rifampin?
hepatotoxicity (cholestatic jaundice, hepatitis, rare, not additive to INH), discoloration body fluids, strong induction of CYP isoforms, increase elimination of other drugs (OC, warfarin, HIV drugs)
What is the MOA of ethambutol? mechanism of resistance?
disrupts assembly of mycobacterial cell wall: inhibit MB arabinosyl transferase III (add arabinose to growing chain), bacteriostatic; resistance due to mutation of embAB gene
What is the therapeutic use and adverse reaction of ethambutol?
combo treatment of TB; optic neuritis (loss of visual acuity and red-green color blindness) baseline visual acuity testing
What is the MOA of Pyrazinamide?
prodrug converted to pyrazinoic acid (POA) by mycobacterial pyrazinamidase,, POA is active under acidic conditions, bactericidal, target unknown
What use the therapeutic use and adverse effects of pyrazinamide?
combo treatment for TB, sterilizing agent against residual organisms that may cause relapse; hepatotoxicity (1-5%) and hyperuricemia (gout)
When would you use a second line antimycobaterial agent?
if primary ineffective due to resistance or is contraindicated, less effective and more toxic than first line
What are some examples of second-line antimycobaterial agents? What do they work against?
streptomycin (IV)- severe life threatening TB, extracellular bacilli
What is the therapy for prophylaxis in TB?
high-risk with latent infection to prevent active disease; daily or twice weekly monotherapy for 6 mo with Isoniazid (INF) or rifampin
When would you use definitive combination therapy?
active TB confirmed by culture and drug susceptibility tested; induction phase- eliminate actively dividing EC MB, renders sputum non-infectious; Continuation phase (4 mo)- eliminate IC MB, inc duration for MDR
What does definitive combination therapy look like?
induction phase- (1st 2 mo) - INH, rifampin, pyrazinamide, and ethambutol, followed by intermittent INH plus rifampin (4 mo), Ethambutol or Streptomycin if INH resistant; Continuation phase intermittent INH plus rifampin
What is MIC?
Minimum inhibitory concentration (MIC) – lowest concentration of an agent that prevents visible bacterial growth in 24 hrs
What is MBC?
Minimum bactericidal concentration (MBC) – lowest concentration that kills a particular bacterium; determined from broth-dilution (MIC) tests by sub-culturing to agar plates that do not contain the test agent
What is the difference between high-level and low-level resistance?
high level cannot be overcome by increasing AB dose but low level can.
Which AB/AB categories are bacteriostatic?
COSTEM CT (chloramphenicol, oxazolidinones, sulfonamides, tetracyclines, ethambutol, macrolides, clindamycin, and trimethoprim
Which AB/AB categories are bactericidal?
A black dog fell in my pretty pink rose vines ( Aminoglycosides, B-lactams, Daptomycin, Flouroquinolones, Isoniazid, Metronidazle, polymixins, pyrazinamide, rifampin, vancomycin)
What are the important features of ceftaroline
5th gen, MRSA activity
What are the therapeutic uses for tigecycline?
IV, highly resistant gram -, only when alternatives are not effective; resistant gram + like VRE
What adverse effects are specific for tigecycline and not other tetracyclines?
increased mortality
What is the mechanism of resistance to clindamycin?
50S subunit methylation (MLSB); gram-negative organisms are innately resistant due to poor drug penetration across outer membrane
What are the pharmacokinetic properties of clindamycin?
orally well-absorbed; penetrates well into bone and abscessed tissue
What are the therapeutic uses of Chloramphenicol?
broad spectrum agent used mainly outside US due to toxicity (MRSA, VRE, gram -, & anaerobes); Used (rarely) in US for meningitis in children with severe beta lactam allergy
What are the pharmacokinetic properties of linezolid?
orally well-absorbed; distributes well into tissues
Which protein synthesis inhibitors bind the 30s unit?
Almost To 30(s) (aminoglycosides, tetracyclines)
Which protein synthesis inhibitors bind the 50s subunit?
dairy queen likes every customers cash (50$) dalfopristin/quinupristin, linezolid, erythromycin, chloramphenicol, clindamycin
What are the pharmacokinetic effects of flouroquinolones?
oral absorption reduced by multivalent cations; cleared by the kidneys
