Antibiotics

Question 1

Beta-lactams

Answer 1

penicillin, cephalosporin, and carbapenems, aztreonam (monocyclic beta-lactam)

bind to penicillin binding proteins (transpeptidases), inhibit bacterial cell wall synth –> leads to autolysis, bactericidal

seizures can result from high doses of beta-lactams

assume cross-allergenicity

renally excreted

Question 2

Penicillin

Answer 2

spectrum: gram pos., few gram neg.
excreted by kidney, short half life (30 min)
-can be increased by simultaneous administration of probenecid (impairs renal secretion of weak acids)

Penicillin V (oral), penicillin G (IV form), benzanthine is longer acting (intramuscular administration, assoc. w/local pain and irritation

hypersensitivity: mild rash-anaphylaxis
side effects: nausea, diarrhea, seizure (drug can enter CNS, cross blood-brain barrier, can use for treating meningitis and other brain infections)

susceptible to penicillinase

Question 3

antistaphylococcal penicillins

Answer 3

narrow spectrum (only used with staph infections)
nafcillin, dicloxacillin (methicillin no longer used)
-large R group, resistant to penicillinases
-methicillin sensitive Staphylococci aureus (MSSA)
-can still result in hypersensitivity reactions

Question 4

penicillinases inhibitors

Answer 4

Clavulanate: combined with penicillin
-binds irreversibly to penicillinase allowing penicillin to be an effective drug

Sulbactam and Tazobactam are add’l beta-lactamase inhibitors

Question 5

aminopenicillins

Answer 5

wider spectrum penicillinase-susceptible drugs (gram pos. and gram neg. bact.)

ampicillin and amoxicillin are more water soluble and can pass through porin channels gram neg. outer membrane

can still result in hypersensitivity runs

ampicillin can be combined with sulbactam
amoxicillin can be combined with clavulanate
(beta-lactamase [penicillinase] inhibitors)

ampicillin is assoc. with pseudomembranous colitis

Question 6

antipseudomonals

Answer 6

wider spectrum penicillinase-susceptible drugs
broad activity against gram-neg. bacilli including Pseudomonas

ticarcillin, piperacillin

combine with penicillinase inhibitor (ticarcillin/clavulanate, piperacillin/tazobactam)

Question 7

aztreonam

Answer 7

monobactam (monocyclic beta-lactam)
use if patient is allergic to penicillin
cell water inhibitor, binds to penicillin binding protein
spectrum: gram negative rods (Klebsiella, Pseudomonas, Serratia)
Inactivated by extended spectrum beta-lactamases (sensitive to penicillinases)

Question 8

cephalosporins

Answer 8

beta-lactams, bactericidal

less susceptible to penicillinases, can e inactivated by extended-spectrum beta-lactamases

may be cross-sensitivity with penicillin (can try to use if patient has had minor penicillin allergy, don’t use if patient has severe penicillin allergy)

some available for oral use without food

excreted by kidney

(1st gen: cephalexin, 2nd gen: cefoxitin, 3rd gen: ceftriaxone, 4th gen: cefepime, 5th gen: ceftaroline)

Question 9

1st gen cephalosporins

Answer 9

cephalexin

spectrum: gram + cocci
use: surgical prophylaxis
don’t use for CNS infections, doesn’t cross blood-brain barrier

Question 10

2nd gen cephalosporins

Answer 10

cefoxitin

spectrum: more gram - activity and weaker gram + activity
use: immediately prior to surgery to prevent infection

• doesn’t cross blood brain barrier well
• can inhibit vitamin K production to prolong bleeding (vit. K promotes clotting)
• can cause a disulfiram-like rxn when coadministered with EtOH (get hangover symptoms)

Question 11

3rd gen cephalosporins

Answer 11

ceftriaxone, cefotaxime, ceftazidime, cefdinir

use: streptococci and more serious gram - infections, resistant to other beta-lactams, meningitis treatment (can cross blood-brain barrier)

ceftriaxone interacts with calcium-containing medications to form crystals that precipitate in lungs and kidneys

Question 12

4th gen cephalosporins

Answer 12

cefepime

broadest spectrum: gram neg, gram pos, including Pseudomonas

Question 13

5th gen cephalosporins

Answer 13

ceftaroline

engineered to bind to penicillin-binding protein 2a present in MRSA that has low affinity for other beta-lactams

use: community acquired bacterial pneumonia (CABP, caused by MRSA) and acute bacterial skin and skin structure infections (ABSSSI)

Question 14

beta-lactamases

Answer 14

many

penicillinases: more common in Staphylococci, prefer penicillin structure
cephalosporinases: prefer cephalosporin structure

extended spectrum beta-lactamases (NDM-1): recognize most beta-lactams and are more common in gram neg. bact.

Question 15

carbapenems

Answer 15

imipenem/cilastatin, meropenem

mech: contain beta-lactam ring, bind to penicillin binding proteins
spectrum: broad, but MRSA is resistant
administration: parenterally (can’t administer orally, also secreted renally)

Toxicity: GI distress, cross allergic, check dose with renal dysfunction to prevent seizures
Imipenem is administered with cilastatin to decrease cleavage of beta-lactam ring by renal dehydropeptidase I and prevent formation of potentially toxic nephrotoxic metabolite

Resistance:
change in penicillin binding protein,
low susceptibility to beta-lactamases, but now Klebsiella pneumoniae carbapenemase which is transmitted through horizontal gene transfer

Question 16

vancomycin

Answer 16

NOT beta-lactam

mech: binds w/high affinity to amino terminus of cell wall precursor, inhibits transglycosylase reaction of bact. cell wall (bactericidal)
spectrum: narrow; gram pos., esp. MRSA, C. difficile

added to empiric treatment

oral vanco is poorly absorbed (if treating C. diff, will administer orally b/c infection is in the gut)

side effects:
red man syndrome -hypersensitivity
nephrotoxicity -excreted by kidney
dosage adjusted in renal insufficiency

resistance in enterococci (replaces D-alanyl-D-alanine w/ D-alanyl-D-lactate or D-alanyl-D-serine to prevent vancomycin binding)
some staphylococci have learned vancomycin-resistance from enterococci

Question 17

bacitracin

Answer 17

mech: prevents dephosphorylation of bactoprenol carrier needed for elongation of peptidoglycan cell wall (NOT a beta-lactam)
usage: poor bioavailability if taken orally,topical ophthalmic and dermatologic preparations, though weak evidence of benefit

side effect: nephrotoxic when given IM

resistance: rare

Question 18

polymyxin B

Answer 18

mech: bind to LPS in membrane, creates holes, leads to release of cellular contents

spectrum: multidrug resistant gram neg. bacilli including Pseudomonas aeruginosa and Klebsiella pneumoniae
used in combination with other antibiotics to help facilitate entry

side effects: severe nephrotoxicity

resistance: infrequent and slow to develop, cross resistance doesn’t develop with any other presently used antibiotics

Question 19

daptomycin

Answer 19

mech: binds to cell membrane, aggregates leading to depolarization of membrane (b/c drug is positively charged) and cell death, bactericidal
spectrum: only gram-pos. organisms (vanco-resistant, MRSA)

side effects: reversibile organizing pneumonia binds pulmonary surfactant accumulating in pulmonary spaces

resistance: add’n of positively charged lysine to cell surface which repels the positively charged drug

Question 20

rifampin

Answer 20

(rifamycin)
mech: bactericidal- binds bact. RNA pol. at active center, blocking elongation of mRNA

spectrum: Myobacteria tuberculosis (treat w/4 antibiotics)

resistance:
intrinsic resistance- drug isn’t able to bind to the beta subunit of RNA pol
acquired resistance- strain requires mutations in rpoB gene preventing drug binding

adverse effects:
harmless metabolite turns body fluids orange-red and can stain contact lens

hepatitis, induction of cytochrome P450 enzyme CYP3A4 can induce metabolism of other medicines leading to organ rejection, loss of seizure control, and risk of pregnancy if on birth control

Question 21

fidaxomicin

Answer 21

mech: bactericidal: inhibits RNA pol

spectrum: narrow, sparing many of gut flora
gram pos. anaerobes -treatment of C. diff

side effects: few due to low absorption, 92% of drug excreted in feces

resistance: pt mutation in RNA pol has been observed in vitro

Question 22

fluoroquinolone

Answer 22

ciprofloxacin, levofloxacin, moxifloxacin

mech: bactericidal- inhibit DNA repl. by binding bact DNA topo II (gyrase, gram neg.) and topo IV (gram pos.)
spectrum: broad; gram +, gram -, atypical organisms like mycoplasma hospital acquired pneumonia and UTI

resistance: overprescribed
- active efflux of drug
- mutations in topoisomerases

adverse effects:
GI side effects
confusion (penetrates CNS)
clostridium difficile colitis, candida vaginitis
contraindicated in pregnant and breastfeeding women and children due to arthropathy

Important facts: chelate cations so don’t take with Calcium, iron, aluminum, and zinc, avoid dairy products or calcium-fortified juice
adjust for renal dysfunction

Question 23

sulfanomides

Answer 23

sulfamethoxazole, sulfisoxazole

folate antagonists, indirect inhibition of DNA synth.

mech: bacteriostatic- drug is a para-aminobenzoic acid (PABA) analog, acts as competitive inhibitor of dihydropteroate synthetase (combine with trimethoprim –> bactericidal)
resistance: change in dihydropteroate synthetase, increased drug efflux, increased production of PABA

adverse effects:
hypersensitivity- rash, cross rxn w/other drugs containing sulfonamide moieties
crystalluria leading to acute renal failure
hemolysis if G-6-P dehydrogenase deficient
kernicterus- neurologic condition occuring in severely jaundiced newborns (compete for binding to albumin leading to free bilirubin that can build up in the brain, neonates high risk b/c no blood brain barrier)

Question 24

trimethoprim

Answer 24

folate antagonist, combine with sulfamethoxazole

mech: bacteriostatic, inhibits bacterial dihydrofolate reductase, low affinity for mammalian enzyme
resistance: altered dihydrofolate reductase, increased amts of dihydrofolate reductase, alternative metabolic pathways

adverse effects: GI upset

Question 25

bactrin

Answer 25

trimethoprim + sulfamethoxazole

mech: sequential blockage of folate synth pathway, but if sulfa allergy, can use trimethoprim alone
spectrum: broad treatment of UTIs, Pneumocystis

Question 26

5-nitroimidazoles

Answer 26

metronidazole, tinidazole

mech: bactericidal- when metronidazole is reduced (e- sink) it generates free radicals leading to DNA strand breaks and cell death
spectrum: anaerobic bacteria including C. diff, protazoa- giardia and trichomonas
resistance: down-regulation of enzyme pyruvate:ferredoxin oxidoreductase that activates drug to its toxic radical state

adverse effects: nausea, diarrhea, headache, and metallic taste; avoid during pregnancy; disulfiram-like rxn w/alcohol (hangover symptoms)

Question 27

nitrofurantoin

Answer 27

mech: bactericidal- reduced by bact. flavoproteins to reactive intermediates, which inactivate or alter bacterial ribosomal proteins to inhibit the synthesis of DNA, RNA, cell wall, and protein
spectrum: broad, rapidly excreted in urine in active form -used for UTIs
resistance: none b/c interferes w/ a variety of processes

adverse effects: vomiting and rash