anti bacterials

Question 1

bactericidal vs bacteriostatic

MIC vs MBC

Answer 1

bactericidal= kills the bacteria
bacteriostatic= stops the active growth of the bacteria but they remain viable

MIC= minimal inhibitory concentration, ie bacteriostatic
MBC= minimal  bactericidal concentration

Question 2

time dependent killing vs concentration dependent killing

Answer 2

time dependent killing: best clinical effect when remain 4-fold above the MIC for >50% of total time, Beta lactams (penicillins, cephalosporins)

Concentration-dependent kiling: maximize the peak concentration (Cmax), Aminoglycosides (gentamicin, tobramycin)

peak conc= Cmax/MIC

Killing dependent of concentrationX time (aka Area under curve dependent killing)

AUC24hr/MIC expressed in hours (quinolones, ma

Question 3

classes of resistance mechanism

Answer 3

Intrinsic resistance- fundamental properties of a given microbe (cell wall structure)

non-inherited resistance- cells not actively replicating

mutations- mutations that alter cell susceptibility to antimicrobial agent

Plasmid-mediated resistance (extrachromosomal genes that encode resistance mechanisms) Can potentially be transferred to other microbes, concept of multiple-resistance (many examples)

Question 4

Beta lactams, genreal information

Answer 4

cell wall agents
most of the time=bactericidal
kill gram positive and gram negative
activity is maximal on actively growing bacteria

MOA: inhibit transpeptidases (penicillin-binding proteins or PBPs) which catalyze cell wall crosslinks (B-lactams covalently bind to PBPs) competitive, irreversible

bacterial resistance to B-lactams: most prevalent is B lactamase (cleaves B lactam ring). S.aureus to ampicillin and penicillin G; B-lactamases also produced by many gram negative

Altered PBP will not bind to B-lactam effectively, methicillin resistance of staphylococci

B-lactam agent cant reach PBPs- problem with many gram negative organisms whose Outer membrane is impermeable to B-lactams)

B- lactams are time-dependent killers: their short T.5 implies the need for shorter dosing intervals. need to keep the drug 4-fold above the MIC for >50% of treatment time

Question 5

Penicillins general

Answer 5

Beta lactams
well distributed to most areas of body (low penetration into CSF but increases during meningitis), oral and IV admin. Short t.5 (30 mins to a few hours, renal elimination- anion transport) all B- lactams are time dependent killers (keep 4 fold above MIC for >50% of time)

all end in cillin

Question 6

penicillin G and V

Answer 6

V is more acid stable than G, for gram pos and gram neg cocci (Non- B lactamase producing) effective against:

gram-pos anaerobes, not Bacteroides fagilis
Streptococcus pneumoniae (20-30% show resistance)
Streptococci (strep throat)
Neisseria meningitidis
Syphilis- IM penicillin G benzathine

good activity against anthrax, listeria, actinomyces

Question 7

oxacillin

Answer 7

for B-lactamase producing staphylococci methicillin-susceptible Staphylococcus aureus (MSSA)

Question 8

ampicillin/amoxicillin

Answer 8

various B-lactamase negative gram positive (listeria, streptococcus) and some gram neg (Haemophilus, Neisseria, Escherichia, Salmonella)

Alternate choice for lyme disease

Question 9

ticarcillin

Answer 9

broad gram neg
Pseudomonas, some enterobacter and proteus

Some anaerobes (when combines with a B-lactamase inhibitor)

often used with B-lactamase inhibitor

Question 10

piperacillin

Answer 10

broad gram neg
Some psuedomonas and klebsiella

often used with B-lactamase inhibitor

Question 11

excretion/metabolism of penicillins

SE of penicillins
Admin of penicillins

Answer 11

Excretion/metabolism of penicillins: 30% hepatic metabolism, mostly renal (20% GF/ 80% tubular anionic excretion)

Some adverse reactions to penicillins: allergic rarely but severe, anaphylaxis, rash, fever
diarrhea, entrocolitis, nausea, vomiting

All antibacterials can cause diarrhea and enterocolitis

elevated liver enzymes, hemolytic anemia, seizures

Admin of penicillins: some IV or IM or oral, generally well distributed, short half lives

Procaine and benzathine penicillin are slow release IM forms that substantially increase the duration over which effective drug levels are maintained
increased CNS distribution with inflamed meninges

Question 12

beta lactamase inhibitors

Answer 12

limit hydrolytic cleavage of B-lactams by some types of B-lactamses

Clavulanic acid, tazobactam: B-lactam analogs that bind irreversibly to B-lactamase

not all b-lactam resistance is due to B-lactamase

Question 13

Cephalosporins

Answer 13

well distributed to most areas of the body, only some reach the CSF

majority require injection, short half lives (at best only a few hours), MOA similar to B-lactam,

resistance mechanism same as penicillins

Start with CEF

Question 14

1st generation cephalosporin

Answer 14

mostly effective against gram positive (MSSA and streptococcus)

Limited gram negative activity
uncomplicated outpatient skin infections
Surgical prophylaxis for skin flora

Cefazolin: best gram positive activity of 1st gen cephalosporins

Cephalexin: oral

Question 15

2nd generation cephalosporins

Answer 15

increased gram negative activity, less active against staphylococci

Cefuroxime: only 2nd generation to penetrate CSF, best of 2nd generation against Haemophilus

Cefoxitin: also good for some anaerobes

Question 16

3rd generation cephalosporins

Answer 16

more active against gram negatives
good for klebsiella, enterobacter, proteus

Ceftriaxone: therapy of choice for gonorrhea with azithromycin or doxycycline) empiric therapy for meningitis long t.5 (6-9 hours)

Ceftazidime: effective againsts many Pseudomonas aeruginosa

Question 17

4th generation cephalosporins

Answer 17

cefepime: IV admin
spectrum like ceftazidime, except more resistant to type 1 B lactamases, empirical treatment of serious inpatient infections

Question 18

excretion/ metabolism SE of cephalosporins

Answer 18

Excretion/metabolism of cephalosporins: renal clearance by glomerular filtation and tubular secretion, some are deacetylated to less potent metabolites

SE: allergic reactions, nausea vomiting, diarrhea, enterocolitis, hepatocellular damage

Question 19

imipenem

Answer 19

B-lactam
administered IV, well distributed
broad spec, not degraded by most B-lactamases including ESBLs), not effective against MRSC

given with cilastatin bc susceptible to hydrolysis by renal dipeptidases

Used for mixed or ill-defined infections
those not responsive to other drugs

SE: hypersensitivity, some cross allergies with penicillin/cephalosporins. Seizures, dizziness, confusion, nausea, vomiting, diarrhea, pseudomembranous colitis, superinfection

Question 20

aztreonam

Answer 20

used against gram neg aerobic rods

not useful against gram positive and anaerobes
not degraded by several B-lactamases, can be used in those with known hypersensitivities to penicillins

not indicated for meningitis

SE: seizures, cramps, nausea, vomiting, enterocolitis, anaphylaxis, transient EKG changes

Question 21

Vancomycin

Answer 21

glycopeptide antibiotic, not a B-lactam

MOA: bactericidal, inhibits cell wall synthesis, binds free carboxyl end of D-Ala-D-Ala of the pentapeptide. interferes with transpeptidation (cross linking) and transglycosylation (elongation)

Used for gram positives only including MRSA, hemolytic streptococcus, S. pneumoniae, Enterococcus, C diff enterocolitis (1st line choice!) empirical meningitis treatment Vancomycin +ceftriaxone

Must be given IV for systemic infections
Oral for C. diff
used in serious infections

SE: red man or red neck syndrome, nephrotoxic, phlebitis, ototoxicity

Question 22

fosfomycin

Answer 22

MOA: inhibits synthesis of peptidoglycan building blocks by by inactivating enolpyruvyl transferase, an early stage cell wall synthesis enzyme

Uses: uncomplicated UTIs caused by E. coli, enterococcus

toxicity: headache, diarrhea, nausea, vaginitis

Question 23

bacitracin

Answer 23

polypeptide, not a b-lactam

MOA: interferes with cell wall synthesis by interfering with lipid carrier that exports early wall components through the cell membrane

Use: topical use only, very nephrotoxic, gram positive cocci and bacilli

toxicity: allergic dermatitis

Question 24

polymyxins general

Answer 24

cell membrane agents

MOA: act as cationic detergents that bind LPS in the outer membrane of gram negatives

uses: polymyxin B: topical use, esp for pseudomonas and other gram negative infections. Systemic use-potential for serious nephrotoxicity and neurotoxicity

Question 25

daptomycin

Answer 25

cell membrane, cyclic lipopeptides MOA: binds to bacterial cytoplasmic membrane, causing rapid membrane depolarization, bactericidal Uses: complicated skin and skin structure infections. Staph aureus (MSSA, MRSA), streptococcus pyogenes and agalactiae, enterococcus, also for staphylococcus bacteremia, NOT FOR PNEUMONIA Iv admin, renal elimination SE: nausea, diarrhea, GI flora alteration, muscle pain and weakness.

Question 26

quinolones general

Answer 26

moa: inhibits alpha and beta subunit of DNA gyrase, thereby interfering with control of bacterial DNA winding (replication and repair) bactericidal, killing dependent on AUC/MIC Resistance: altered DNA gyrase, combination of decreased permeability and altered DNA gyrase will result in resistance to the newer fluorinated compounds ``` Uses: nonfluorinated compounds- in urinary tract Fluorinated quinolones (end in floxacin) ```

Question 27

norfloxacin and ciprofloxacin

Answer 27

norfloxacin/ciprofloxacin UTIs: enterobacteriaceae fluoroquinolones not first line for UTIs

Question 28

Ciprofloxacin

Answer 28

UTIs, infectious diarrheam skin infections, bone and joint infections, chlamydia, there are better quinolones for respiratory and gram -pos infections

Question 29

moxifloxacin

Answer 29

better gram positive activity than many quinolones respiratory infections but not for strep throat community acquired pneumonia, bacterial bronchitis

Question 30

excretion and metabolism and side effects of quinolones

Answer 30

excretion/metabolism: GF and active tubular secretion for many, and bile SE: nausea, vomiting, abdominal pain, enterocolitis dizziness, headache, restlessness, depression rare seizures Contraindicated in those with seizures disorders, preganancy, children Rashes EKG irregularities, arrhythmias peripheral neuropathy arthropathy and tendon rupture IV admin, oral, well distributed

Question 31

nitrofurans

Answer 31

MOA: nitroreductase enzyme converts them to reactive compounds (including free radicals) which can damage DNA not common in resistance Uses- inhibit gram positive and negative bacteria Nitrofurantoin for lower UTI (e coli, enterococcus, staphylococcus) Excretion/metabolism: biliary, GF and tubular secretion SE: nausea, vomiting, diarrhea, peripheral neuropathy, hypersensitivity, fever, chills, acute and chronic pulmonary reactions, acute and chronic liver damage, granulocytopenia, leukopenia, megablastic anemia, acute hemolytic anemia Oral admin

Question 32

rifampin

Answer 32

MOA: inhibits bacterial RNA synthesis by binding RNA polymerase B, bactericidal Uses: pulmonary TB, prophylaxis of meningococcal meningitis, prophylaxis of Haemophilus influenza type B meningitis Excretion: liver, biliary Admin: oral and IV SE:serious hepatotoxicity, induction hepatic enzymes (CYPs) that inactivate other drugs, orange color in bodily fluids

Question 33

fidaxomicin

Answer 33

MOA: noncompetitive inhibitor of RNA polymerase, so inhibits RNA synthesis, bactericidal Uses: C. diff infection (1st line choice) Excretion: fecal elim ADmin: oral, poorly absorbed SE: GI upset, GI bleeding, neutropenia

Question 34

Metronidazole

Answer 34

MOA: anaerobes reduce the nitro group of metronidazole, resulting product disrupts DNA and inhibits nuclei acid synthesis, bactericidal Resistance: anaerobes lose ability to reduce Use: some parasites, anaerobes, C diff enterocolitis, therapy for Helicobacter pylori in combination with other antibacterials and acid blocker, Gardnerella vaginalis (bacterial vaginosis) SE: nausea, vomiting, anorexia, diarrhea, transient leukopenia, neutropenia, thrombophlebitis after IV infusion, bacterial and fungal superinfections Admin: oral or IV

Question 35

Bacterial protein synthesis and points where antibacterials act

Answer 35

1) aminoglycosides freeze initiation (premature release of ribosome from mRNA) 2) tetracycline and chloramphenicol prevent tRNA from binding 3) Chloramphenicol blocks peptide bond formation (peptidyl transferase) 4) erythromycin and clindamycin block translocation step 5) aminoglycosides cause misreading of mRNA

Question 36

aminoglycosides

Answer 36

Bactericidal, not absorbed orally (given IV or IM or topically) MOA: penetrate pores of outer membrane of gram negatives or the water filled matrix of the cell wall of gram positive, bind to transport molecule on outer surface of cytoplasmic membrane, transported into bacteria by an energy-requiring aerobic process, binds to several ribosomal sites, stops initiation causes premature release of ribosome from mRNA and mRNA misreading, post-antibiotic effect, concentration-dependent killing Resistance: enzymatic modification of the aminoglycosides Uses: effective against gram negative, poor activity against anaerobes, used for gram neg aerobic bacilli, gram-pos activity requires combination with cell wall inhibitors, uses restricted to serious infections, streptomycin Gentamicin, tobramycin, amikacin Excretion/ metabolism: glomerular filtation SE: narrow therapeutic window, nephrotoxic, ototoxicity, neuromuscular blockade Admin: not absorbed GI, given IV or IM, poor penetration in CSF, often combined with other antibiotics for serious bacterial infection

Question 37

tetracyclines

Answer 37

MOA: modern ones minocycline, doxycycline have longer t.5 and are more lipophilic. Transported into the cells, bind to 30S ribosomal subunits, prevent attachment of aminoacyl-tRNA to the acceptor site on the mRNA-ribosomal complex, AAs cannot be added to the protein being synthesized, bacteriostatic Resistance: most common- increased transport of the drugs out of the bacterial cells, resistance to one tetracycline often implies resistance to them all Uses: resistance has increased, preferred agents for (rickettsial diseases, chlamydia, mycoplasma, ureaplasma, borrelia lyme disease) admin: oral admin, Ca binds to tetracyclines inhibiting their absorption (antacids and Ca and Mg decrease absorption), can also be given parenternally SE: GI disturbances, pseudomembranous enterocolitis, Candida superinfection in colon, photosensitization with rash, teeth discoloration in kids, CX in pregnancy

Question 38

tigecycline

Answer 38

MOA: bacteriostatic, binds 30 S ribosomal subunit and blocks aminoacyl-tRNA entry, also binds additional unique sites in the ribosomes Resistance: no cross-resistance with other antibacterials including tetracyclines Uses: skin/skin structure infection, complicated intraabdominal infections, community acquired pneumonia (CAP). By pathogen: e. coli, citrobacter, klebsiella, enterobacter, staphylococcus (MSSA and MRSA), bacteroides, C. perfringens, S pneumoniae, Haemophilus SE: nausea, vomiting, enterocolitis, others similar to tetracyclines including calcium binding, higher death rate than with other antibacterials

Question 39

chloramphenicol

Answer 39

MOA: interferes with binding of aminoacyl-tRNA to 50S subunit and inhibits peptide bond formation, usually bacteriostatic Uses: originally had broad spectrum, very serious side effects so use as alternate agent for treatment of meningitis and brain abscesses SE: bone marrow depression, can progress to a fatal aplastic anemia, grey baby syndrome, optic neuritis and blindness, GI effects

Question 40

Macrolides general

Answer 40

Erythromycin, Clarithromycin, Azithromycin MOA: all bind to the 50S ribosomal subunit, blocking protein synthesis by blocking the translocation step, bacteriostatic resistance: common

Question 41

erythromycin

Answer 41

uses: oral/IV, primarily against gram positive, used as alternative in B-lactam allergic patients also effective against: chlamydia, mycoplasma, legionella, bordetella, campylobacter Toxicity: nausea/vomiting, inhibits CYP3A4 metabolism/excretion of many drugs, increases risk of arrhythmias and cardiac arrest

Question 42

Clarithromycin

Answer 42

mechanims: similar to erythromycin Uses: alternative to erythromycin for treatment of: pharyngitis, respiratory infections, same as erythromycin plus expanded spectrum (haemophilus, moraxella, penicillin-resistant strep pneumonia) Helicobacter pylori (in combination with other antibacterials and an acid suppressant) treatment of atypical mycobacterial infections SE: Cv risk prolonged QT interval, GI distrubances, hearing loss

Question 43

Azithromycin

Answer 43

MOA: similar to erythromycin Uses: respiratory infections, GI pathogens, genital (chlamydia, with ceftriaxone for N. gonorrhoeae) SE: fewer GI disturbances, few drug interactions, cardiac QT prolongation)

Question 44

Clindamycin

Answer 44

macrolide-like, binds to 50s ribosomal subunit, blocks translocation along ribosomes uses: most gram positive cocci and many anaerobes including bacteroides fragilis, cause of C. diff, can suppress bacterial toxin production SE: antibiotic-associated enterocolitis, GI ittitation, diarrhea, hepatotoxicity, neuromuscular transmission

Question 45

linezolid

Answer 45

interferes with protein synthesis, binds to 50 S ribosomal subunit, interfering with formation of 70 S initiation complex, bacteriostatic uses: Vancomycin resistant enterococcus faecium, Staphylococcus aureus, MRSA and MSSA, streptococcus group A and B, streptococcus pneumoniae Admin: iv, oral SE: non selective inhibitor of MAO (drug and foods with tyramine interactions), CX: SSRI tricyclics, triptans, buspirone, GIT stuff, bone marrow suppression

Question 46

Sulfonamides

Answer 46

antifolate, bacteriostatic MOA: folate is needed and produced by the bacteria sulfonamides: inhibit folate synthesis in bacteria by competitive inhibition of dihydropteroate synthase. Uses: UTI, sulfamethoxazole f]given with trimethoprim, UTI, nocardiosis, ulcerative colitis Silver sulfadiazine used topically for burn patients SE: hypersensitivity, rashes, serum sickness, GI disturbances, renal damage from crystalluria, inhibit CYP2C9: potentiates action of various other drugs

Question 47

trimethoprim

Answer 47

MOA: inhibits folate synthesis in bacteria by competitvely inhibiting dihydrofolate reductase Uses: in conjuction with sulfamethoxazole, the synergistisic effects are bactericidal, urinary infections, upper respiratory and ear infections, also for pneumocystis jiroveci carinii, Some adverse reactions: nausea, vomiting diarrhea, rashes, eosinophils, neutropenia, bone marrow suppression