6. Agents Targeting the Cell Wall and Membrane Flashcards
amoxicillin, ampicillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, ticarcillin
penicillins
cefazolin, cefaclor, cefdinir, cefixime, cefepime, cefotetan, cefuroxime, cephalexin, ceftaroline, ceftriaxone
cephalosporins
aztreonam
monobactam
vancomycin
glycopeptide
bacitracin
polypeptide
doripenem, ertapenem, imipenem, meropenem
carbapenems
fosfomycin
phosphoenolpyruvate
clavulanic acid, sulbactam, tazobactam
b-lactamase inhibitors
daptomycin
lipopeptides
polymyxin B
detergents
NAM-NAG pentapeptide
basic unit for cell wall synthesis
target for penicillins
penicillin binding proteins
baceriocidal, susceptible to acidic environment which impacts route of adminsitration, susceptible to B-lactamase enzyme. includes penicillins, cephalosporins, monobactams, and carbapenems
B-lactam agents
naturally occuring, varying spectrum of activity, causes hypersensitivity and diarrhea
penicillins
work on gram + and -, B-lactamase sensitive, acid unstable, parenteral adminsitration, renal adminstration requiring dose adjustments, minimal CSF penetration unless inflammation
pencillin G
narrow spectrum, gram + and gram - coverage, B-lactamase sensitive, acid stable, orally adminstered, renal dose adjustments, minimal CSF penetration unless inflammated
pencillin V
very narrow spectrum, gram + staph and strep coverage, B-lactamase resistant, parenteral or orally adminstered, no dose adjustment for elimination, penetrates CSF
methicillin, nafcillin, oxacillin
extended/broad spectrum, ampicillin, gram + and gram - cocci/rods coverage, B-lactamase sensitive, renal dose adjustments necessary, penetrate CSF if inflamed meninges in a newborn
ampicillin
extended/broad spectrum, gram + gram - cocci/rods coverage, B-lactamase sensitive, renal dose adjustements necessary
amoxicillin
extended/broad spectrum, availabile only in combination with beta-lactamase inhibitors, gram + and gram - cocci/rods coverage, B-lactamase sensitive, renal dose adjustments necessary
ticarcillin
extended/broad spectrum, available only in combination with beta-lactamase inhibitors, gram + gram -cocci/rods, B-lactamase sensitive, renal dose adjustments, good CSF penetration but not used for meningitis
piperacillin
inhibit bacterial B-lactamase, clavulanic acid, sulbactam, tazobactam, used in combination with pencillins to increase effectiveness, common combinations of amoxicillin/clavulanic acid (augmentin), ampicillin & sulbactam, or piperacillin & tazobactam, causes adverse effects similar to pencillin adminstered
B-lactamase inhibitors
increases with addition of B-lactamase inhibitors
penicillin spectrum of activity
penicillin, oxacillin/naficillin, cefazolin, cephalexin/cephadine, aztreonam, aminoglycosides, vancomycin, erythromycin, clindamycin, linezolid, quinuprisitin/dalfopristin, daptomycin, metronidazole
narrow spectrum antibiotics
ampicillin, cefotoxin, cefotetan, cefuroxime-axetil, cefaclor, ciprofloxacin, azithromycin, clarithromycin, telithromycin, trimethoprim sulfamethoxazole
moderately broad antibiotics
ampicillin sulbactam, amoxicillin/clavulanate, ceftriazone, cefotaxime, ceftizoxime, ceftazidime, cefixime, cefpodozime protexil, ceftaroline, tetracycline, doxycycline, chloramphenicol, levofloxacin
broad spectrum antibiotics
ticarcillin-clavulanate, piperacillin-tazobactam, cefepime, ceftazidime-avibactam, cefoperazone-sulbactam, ceftolozane-tazobactam, imipenem, meropenem, doripenem, ertapenem, gatifloxacin, moxifloxacin, tigecycline
very broad spectrum antibiotics
used if penicillins are not tolerated, more resistant to B-lactamase than penicillins however resistance on the rise, grouped based on spectrum of activity, bind and inhibit pencillin binding proteins, can cause hypersensitivity and diarrhea, 1st generation covers gram + cocci, second generation covers gram + and some organisms, 3rd generation covers gram +/- cocci and many gram - rods, other generations cover gram +/- & resistant organisms
cephalosporins
1st generation, covers many gram + cocci, resistance by B-lactamase, parenteral administration, long half life, good for intramuscular injection, no CSF penetration
cefazolin
1st generation, covers many gram + cocci, resistance by B-lactamase, oral adminstration, no CSF penetration
cephalexin
2nd generation, covers gram + and some gram -, not used as much as 1st or 3rd generation, less resistance by B-lactamase by first generation, parenteral administration
cefotetan
2nd generation, covers gram + and some gram -, not used as much as 1st or 3rd generation, less resistance by B-lactamase by first generation, oral administration
cefaclor
2nd generation, covers gram + and some gram -, not used as much as 1st or 3rd generation, less resistance by B-lactamase by first generation, parenteral administration, will penetrate CSF
cefuroxime
3rd generation, covers gram + and - cocci, and many gram - rods, not as good as 1st generation for gram +, increases resistance by B-lactamase, parenteral adminsitration with long half life, penetrates CSF
ceftriaxone
3rd generation, covers gram + and - cocci, and many gram - rods, not as good as 1st generation for gram +, increases resistance by B-lactamase, parenteral adminsitration, penetrates CSF
cefotaxime
3rd generation, covers gram + and - cocci, and many gram - rods, not as good as 1st generation for gram +, increases resistance by B-lactamase, oral administration
cefdinir
3rd generation, covers gram + and - cocci, and many gram - rods, not as good as 1st generation for gram +, increases resistance by B-lactamase, oral administration
cefixime
4th generation, anti-pseudomonal, gram + gram - and multiresistant gram - coverage, very strong resistance by B-lactamase, parenteral adminstration, renal dose adjustments necessary, penetrates CSF
cefepime
anti-MRSA, similar to 3rd generation with extended gram + coverage, parenteral adminstration, renal dose adjustment necessary
ceftaroline
only one is approved in the USA, covers only gram - rods, penetrates CSF, treats serious infections like pneumonia, menigitis, and sepsis, resistance by B-lactamase, binds and inhibits penicillin-binding proteins, causes hypersensitivity reactions and cough
aztreonam
broadest spectrum of all B-lactam antibiotics, includes gram - and gram +, most potent B-lactam antibiotic, resistance by B-lactamase but is also suseceptible to carbapenemase, imipenem inactivated in the kidney so adminstered with cilastatin to prevent inactivation, key effect is to penetrate tissue and fluids very well including CSF, is important for empiric treatment of life threating infections, also used in cancer, nosocomial pneumonia, intra-abdominal infections, UTIs, and skin/soft tissue infections, binds to and inhibits all pencillin binding proteins, causes nausea, vomiting, diarrhea, confusion, tremors, seizures
carbapenems/ doripenem, imipenem, ertapenem, meropenem
natural compound, broad spectrum for gram + bacteria, treats MRSA, enterococci, and c.diff, good tissue penetration except for CNS, due to resistance development oral use is limited to c.diff, delivered by slow IV infusion, prevents elongation of peptidoglycan cell wall structure by binding to D-ala D-ala pentapeptide and acts as steric inhibitor, causes flushing red neck/red man syndrome, abdominal pain, ototoxicity and renal failure
vancomycin
polypeptide, targets a variety of gram + bacteria, use is restricted to topical and opthalmic ointments, combined with other antimicrobial agents like neomycin, polymyxin B, and hydrocortisone, blocks incorporation of amino acids and nucleic acids into the cell wall, causes hypersensitivity reactions but rare
bacitracin
phosphoenolpyruvate, broad spectrum of activity and includes gram - and gram + bacteria, commonly used in the treatment of uncomplicated urinary tract infection in females, safe during pregnancy, blocks early step in cell wall synthesis by preventing synthesis of UOP-N-acetylmuramic acid, causes hypersensitivity reactions but is rare
fosfomycin
targets the membrane, cyclic lipopeptide, useful against gram+ organisms including MRSA, commonly used for treatment of complicated skin and soft tissue infections as well as bacteremia and endocarditis, binds to membrane and causes depolarization of the membrane and is bactericidal, insertion into membrane is Ca++ dependent, causes myopathy and rhabdomyolysis
daptomycin
targets membrane, detergent, used topically to treat skin infections in combination with bactracin, spectrum of activity similar to primarily gram - bacteria, binds to phospholipids in the cell membrane and disrupts structure, specifically LPS, rarely has adverse effects if administered topically
polymyxin B
doxycycline, minocycline, tetracycline, tigecycline
aminoglycosides
amikacin, gentamycin, kanamycin, neomycin, streptocmycin, tobramycin
aminoglycosides
azithromycin, clarithromycin, erythromycin
macrolides
clindamycin, chloramphenicol, linezolid
other protein synthesis inhbitors
include aminoglycosides, macrolides, tetracyline, and some others, some bacteriostatic but can also be bactericidal, disrupt process of translation by targeting molecu.ar machinery ribosomal subunit 50s and 30s needed to translate mRNA to protein
protein synthesis inhibitors
charged tRNA binds to A site > peptidyl tRNA and peptide bond form between growing aminao acid chain and amino acid in A site > newly uncharged tRNA exits > amino acid chain elongates +1 and translocates to P site
prokaryotic translation
generally narrow spectrum with bactericidal effect, uptake is oxygen dependent only working on aerobic organisms, used in combination with B-lactam antibiotics to treat serious gram - infections and are not absorbed well from the gut, binds to 30s and perhaps 50s ribisomes blocking formation of initiation complex disrupting mRNA and 30s binding which would occur prior to step 1 of prokaryotic translation, causes nephortoxicity by renal tubular necrosis and ototoxicity
amingoglycosides/ streptomycin, gentamicin, kanamycin, amikacin, tobramycin, neomycin
aminoglycosides, gram + and gram - aerobic organisms, primarily used for gram - aerobic organisms, used also in pneumonia and UTI, resistance by expression of enzymes altering chemical structure of the drug, adminstered intramuscularly, subq, or topic, poor absorption from the GI tract, eliminated through urine as a parent compound, kidney function affects half life
streptomycin, gentamycin, kanamycin, amikacin, tobramycin, and neomycin
macrocyclic lactone ring structure including natural compounds and semisynthetics, covers mostly gram + and some gram -, overall narrow in spectrum of activity, concentrates in lungs, tonsils, and cervix, spectrum increases as A>C>E, binds to 50s and impairs translocation to the P site, causes stomach cramps, nausea, vomiting, diarrhea due to motilin activity, prolongs QT interval, skin hypersensitivity reactions
erythromycin, clarithomycin, azithromycin
macrolide, narrow spectrum but broadest of all macolides, used in pneumonia, pharyngitis, sinusitis, tonsillitis, STDs, resistance by drug efflux, changes in drug binding to 50s ribosomes, oral and IV administration, concetrations in many tissues like the lungs, tonsils, and cervix, long half life up to 68 hours
azithromycin
macrolide, narrow spectrum but broader than erythromycin, pneumonia, pharyngitis, sinusitis, STDs, resistance by drug efflux and changes in drug binding to the 50s ribosome, oral administration
clarithromycin
macrolides, narrowest spectrum, pneumonia, pharyngitis, tonsillitis, STDs, resistance by drug efflux or changes in drug binding to 50S ribosome, oral adminstration, eliminated by liver metabolism thus hepatic dosing considerations - not renal
erythromycin
four ring structure, broad spectrum with bacteriostatic effect, binds 30S subunit of ribosome and prevents binding of new aminoacyl-tRNA, causes nutrient interactions with calcium which results in disrupted growth of calcified tissue (bone, teeth) particularly during growth with discoloration of the teeth, disrupts normal flora, causes nausea, vomiting, diarrhrea, skin hypersensitivity and photosensitivity, also acts as a chelator preventing absorption of divalent cations
tetracyclines
tetracycline, broad spectrum, used in patients with pencillin allergy, STDS, acne, resistance by drug efflux, adminstered orally, eliminated by the kidney so renal considerations, binds to di and tri valent cations such as calcium and aluminum so food delays absorption
tetracycline
tetracycline, broad spectrum, used in patients with pencillin allergy, STDS, acne, resistance by drug efflux, adminstered orally, IV and topically, eliminated hepatically and renally so impairment considerations, binds di and trivalent cations such as calcium and aluminum so food delays absorption
minocycline
tetracycline, broad spectrum, used in patients with pencillin allergy, STDS, acne, resistance by drug efflux, adminstered IV, severe hepatic insufficiency requires dose adjustements, binds di and trivalent cations such as calcium and aluminum, food delays absorption
tigecycline
tetracycline, broad spectrum, used in patients with pencillin allergy, STDS, acne, resistance by drug efflux, adminstered orally and IV, no hepatic metabolism so there are no hepatic or renal considerations, can bind di and trivalent cations such as calcium and aluminum, however no food restrictions
doxycycline
relatively narrow spectrum, commonly used in treatment of soft tissue infections caused by strep and staph, also used when treating community acquired MRSA of the skin and soft tissue, binds to 50S subunit of the ribosome and prevents formation of initiation complexes and also blocks translocation step, causes nausea, vomiting, diarrhea, and c.diff infection, also causes skin rashes
clindamycin
broad spectrum antibiotic exerting bacteriostatic effect, rarely used except for serious infections such as typhys and rocky mountain spotted fever, also used to treat eye infections, binds to 50S subunit of the ribosome and prevents transpeptidation or peptidyl bone formation, causes suppression of red blood cell production, gray baby syndrome due to lack of glucuonic acid production, nausea, vomiting, diarrhea, and superinfection of oral and vaginal candidiasis
chloramphenicol
effective against most gram + organisms but not very effective for most gram -, effective against penicillin/methicillin/vancomycine resistant strains, inhibits protein synthesis by binding to the P site of the 50S ribosome and inhibits the formation of the ribosomal fMet-tRNA complex blocking first tRNA amino acid binding, causes myelosuppression resulting in anemia, leukopenia, pancytopenia, and thrombocytopenia, inhibits monoamine oxidase so affects these drugs
linezolid
narrow spectrum with gram + coverage, used in skin and soft tissue infections including CA-MRSA, cross resistance with macrolides because of similar mechanism of action, administered IV IM and topically, eliminated primarily hepatically, good tissue penetration particularly in abscesses, but no good CSF penetration
clindamycin
broad spectrum, good against anaerobic bacteria, resistance by expression of inactivating enzymes, administered oral, IV, and topically, eliminated by the liver and excreted by the kidneys, well absorbed orally and widely distributed, penetrates CSF
choramphenicol
mostly gram + coverage, has some resistant organisms, adminstered orally and IV, no dosage adjustments necessary, 100% bio-availability after oral administration so oral and IV dose are the same
linezolid
sulfur containing compounds, broad spectrum covering gram + and gram - bacteria, not frequently used as a single agent, do not effect mammalian cells because they depend upon exogenous folate and do not synthesize folate, resistance in bacteria can occur if excess PABA is produced, sulfonamide uptake is altered, or sulfonamide binding to dihydropteroate synthase is altered, works by competing with PABA for dihydropteroate synthase and blocks dihydrofolic acid synthesis and this DNA synthase, causes skin hypersensitivity, photosensitivity, steven-johnson syndrome presenting as serious/fatal skin and mucous membrane eruption, also nausea, vomiting, diarrhea, and urine preciptates causing crystalluria, hematuria, and obstruction
sulfonamides - sulfadiazine/sulfamethoxazole/sulfamethizole
pyrimidine compunds including trimethoprim and primethamien, covers gram - bacteria, resistance in bacteria may occur if there is change in drug uptake or reduced reductase binding, inhibitor of bacterial dihydrofolate reductase in impaired DNA synthesis, causes bone marrow suppression, megaloblastic anemia, leukopenia, and granulocytopenia, also nausea, vomiting, and diarrhea
trimethoprim/pyrimethamine - antifolates
combination, commonly used to treat urinary tract infection and prostatitis, in addition at lower doses used prophylactially to treat recurrent urinary tract infection, in addition is effective in treating pneumonia, shigellosis, and systemic salmonella infections, works by synergistic effect of combining trimethoprim-sulfamethoxazole, causes same adverse effect of each of the individual agents
trimethoprim sulfamethoxazole - TMP/SMX
synthetic flourinated compounds, broad spectrum antibiotics covering gram + and gram - bacteria, used in the treatment of urinary, gastrointestinal and respiratory infections as well as some sexually transmitted diseases like gonorrhea, effective against anthrax, works by disrupting the winding of DNA and the separation of DNA strands during transcription and replication specifically inhibiting topoisomerase II (DNA gyrase) and topoisomerase IV, causes nausea, vomiting, diarrhea, drug-nutrient interactions by binding divalent cations and preventing absorption, prolongs QT interval, causes rash, itching, photosensitivity, also causes tendinopathy in adults and arthropathy due to growing cartilage
fluoroquinolones/ ciprofloxacin and levofloxacin
least active fluoroquinolone
norfloxacin
fluoroquinolone working well against gram - with some activity against gram +
ciprofloxacin, levofloxacin, ofloxacin
best activity against gram +
gatifloxacin, gemifloxacin, moxifloxacin
unknown mechanism of action which is antibacterial and antiprotozoal, coverage limited to anaerobic bacteria, good tissue penetration and distribution, used in the treatment of abdominal infections, vaginitis, c. diff colitis, and brain abscess, works as a prodrug inactive until taken up by the organism and undergoes chemical reduction, reaction metabolites bind to DNA and disrupt function and cause damage, causes nausea, vomiting, diarrhea, affects metabolism with disulfiram effect so avoid alcohol, also causes neuropathy
metronidazole - DNA damaging agent
antifolate with broad spectrum coverage, used for UTI, resistance by changes in folate synthesis pathway or drug uptake, adminstered orally, renal impairment increases half life so renal considerations necessary, although renal clearance decreases, can still be used to treat kidney infection,
sulfamethoxazole
antifolate with gram - coverage, used in UTI, resistance by changes in folate synthesis pathway or drug uptake, administered orally, half life increases with renal impairment
trimethoprim
fluoroquinolone with broad spectrum activity, used in UTI, abdominal, respiratory, skin and soft tissue infections, and anthrax, resistance is by changes in drug targets or drug efflux pumps, administered orally or IV, no hepatic elimination adjustments necesssary, but minor change to half life with renal impairment, is absorbed well and avoids first pass metabolism
ciprofloxacin
covers anaerobic organisms and c. diff infection, resistance is by mutations in the rdxA gene, adminstered orally, IV and topically, no elimination dose adjustments necessary
metronidazole
