4/24 Antibacterial Drugs Flashcards
Why are synthesis inhibitors have a broader spectrum compared to ß lactams?
How are our own cells protected from these synthesis inhibitors?
all bacteria need protein synthesis to grow
ribosomes in eukaryotic cells sufficiently different from bacterial to provide selectivity
Difference between Concentration vs. time-dependent killing (CDK vs. TDK)?
CDK - exposure to higher concentration of the drug is more efficient (even if it is short); there is no benefit of longer exposure
TDK - need longer exposure (e.g., frequent dosing)
mnemonic that you should always remember for these synthesis inhibitors
Buy AT 30, CCEL for 50”
can think of “for” as “four” drugs
Of ALL the drugs that we’ve learned, which ones are the only ones that are bactericidal?
Aminoglycosides
- Gentamicin
- Amikacin
- Tobramycin
- Streptomycin
Drugs under the class of aminoglycoside? *ONLY GENERAL CLASS NAME IS USED IN SUBSEQUENT F.C.*
- Gentamicin
- Amikacin
- Tobramycin
- Streptomycin
Aminoglycosides MoA?
binds 30S and inhibits formation of initiation complex, cause misreading of mRNA (blocks translocation), and inhibits recycling of ribosomes
Why are aminoglycosides ineffective against anaerobes?
requires O2 for uptake (ineffective against anaerobes)
What must you consider when giving aminoglycosides to
renal excretion (adjust dose in patients w/ renal dysfunction)
How are aminoglycosides administered?
parenteral administration (poor oral absorption)
Aminoglycosides indications?
GNR
GP - synergistic with ß-lactam antibiotics (??dblck)
Mechanism of resistance in aminoglycosides?
bacterial transferase enzymes inactivate the drug via acetylation, phosphorylation, or adenylation
(also altered membrane permeability, mutation of binding sites, methylation of rRNA)
Side effects of aminoglycosides? must know
Significant post-antibiotic effect (GN aerobes only)
Nephrotoxicity /ATN (esp when used with cephalosporin)
Neuromuscular blockade /muscle weakness
Ototoxicity (esp when used with loop diuretics; drug accumulates in inner ear)
Teratogen / Bone marrow suppression
Drugs under the class of Tetracycline?
Doxycycline
Tetracycline
Minocycline
is tetracycline bacteriostatic or bacteriocidial?
Bacteriostatic
Mechanism of action for tetracycline?
30S – prevents attachment of amino-acyl tRNA (prevents elongation)
What should patients avoid if they’re on tetracyclines?
Divalent cations can inhibits absorption in the gut (avoid milk, antacids, or Fe-preps)
Which tetracycline is the only one that can be used in renal failure patients, and why?
Dox: fecal elimination (only tetracycline that can be used in patients with renal failure)
Indications for tetracycline?
Borrelia burgdorferi Rickettsia (Rocky MTN fever) M. pneumoniae S. pneumoniae Chlamydia Legionella Acne Vulgaris (T = T zone) Anti-parasites malarial
Mechanisms of tetracycline resistance?
Plasma encoded transport pumps result in decr. uptake/incr. efflux
(also reduced binding to ribosomal binding site, enzymatic inactivation)
Why are tetracyclines rarely used in the US?
resistance
Side effect of tetracyclines?
GI distress (N/V/D, hepatotoxicity) Teeth discoloration Inhibition of bone growth in children Photosensitivity Contraindicated in pregnancy, neonates, children – Rx deposits in enamel of teeth and bone
Drugs under the class of Macrolides
Azithromycin
Erythromycin
mechanism of action for Macrolides?
50S – blocks translocation (macro“slides”)
How often should macrolides be dosed? why?
very long t½ = 68 hrs (once-daily dosing)
Indications of Macrolides?
GPC
Atypical pneumonias (Mycoplasma, Chlamydia, Legionella, H influenza)
STD – chlamydia
Pen-allergic patients
S. pneumoniae, S. aureus are often resistant
Mechanisms of resistance in Macrolides?
Methylation of 23S rRNA-binding site prevents binding of drug
(also efflux or reduced permeability, mutation or modification of binding site, production of esterase by enteriobacteriaceae)
Side effect of macrolides?
C – cholestatic hepatitis R – rash A – arrhythmias/prolonged QT M – motility issues (GI) Eosinophilia or Ototoxicity (in elderly) GI upsets incr. theophyllines and oral anticoagulants bioavailability
mechanism of action of Chloramphenicol?
50S – blocks peptidyltransferase at 50S ribosomal subunit
is chloramphenicol bacteriostatic or bacteriocidial?
bacteriostatic
indications for chloramphenicol?
Meningitis (h. influenza, Neisseria meningitides, Strep. pneumoniae)
Rickettsia (Rocky MTN fever)
mechanism of resistance for Chloramphenicol?
Plasma-encoded acetyltransferase inactivates the drug
side effects of Chloramphenicol?
Anemia
Aplastic anemia
Gray baby syndrome (because they lack liver UDP glucuronyl transferase)
What are some drugs under the class of Lincosamide
Clindamycin
Mechanism of action of Lincosamide?
50s - blocks translocation
is Lincosamide bacteriostatic or bactericidal?
bacteriostatic
Indications for Lincosamide?
Narrow spectrum GPC (Staph, Strep/GAS) Anaerobic infections (Bacteriodes, Clostridium perfringens) in aspiration pneumonia Lung abscess Oral infections (dental prophylaxis)
Mechanism of resistance for Lincosamide
Methylation of 23S rRNA-binding site prevents binding of drug
Can interfere with macrolide action if co-prescribed (binding site partially overlaps with macrolides)
(also efflux or reduced permeability, mutation or modification of binding site, production of esterase by enteriobacteriaceae)
Side effect of Lincosamide?
Pseudomembranous colitis (C. diff) Fever GI intolerance (N/V/D) Bone marrow suppression Hepatotoxic Hypersensitivity: rash
drugs under the class of Oxazolidenone?
Linezolid (synthetic)
Mechanism of action for Oxazolidenone?
50S – blocks formation of the initiation complex
Oral bioavailability for Oxazolidenone? How often should it be dosed?
100% oral bioavailability
t½ = 5hrs (twice daily dosing)
Indications for Oxazolidenone?
GP Bacteriostatic: staph, enterococci Bacteriocidal: strep VRE VRSA MRSA
Mechanism of resistance for Oxazolidenone?
23S rRNA alterations
Side effects of Oxazolidenone
Leukopenia, anemia, thrombocytopenia
GI intolerance (N/V/D)
Hepatitis
Weak drug interaction with MAOi
what’s the difference btwn clindamycin and metronidazole in terms of indications?
clindamycin is used to treat anaerobes ABOVE the diaphragm, metronidazole is used to treat anaerobes BELOW the diaphragm
T/F both eukaryotes and prokaryotes RNA/DNA synthesis need folate synthesis
F. prokaryotes RNA/DNA synthesis does NOT need folate synthesis, while eukaryotes do!
Topoisomerases of eukaryotes?
prokaryotes?
prokaryotic DNA replication requires Topo II/IV
eukaryotic DNA replication requires I/II
Anti-folate drug?
Trimethoprim
Sulfamethoxazole
(TMP/SMX)
MoA for TMP/SMX?
combination therapy causes sequential block of folate synthesis, resulting in decr. synthesis of Thymidine, Methionine, Purines (TMP)
what is SMX?
SMP – analog of PABA; competitively inhibits DHPS (dihydropterorate synthase)
What is TMP
TMP competitively inhibits DHFR (dihydrofolate reductase); 50,000x more active against bacterial DHFR
TMP bacteriostatic or bactericidal?
bacteriostatic
indications for TMP/SMX?
SMX* GP GN Nocardia Chlamdia
TMP/SMX UTI Shigella Salmonella Pneumocystis jirovecii (trmt/prophylaxis) Toxoplasmosis (prophylaxis)
Clinical uses: respiratory tract infections, otitis, UTIs, prostatitis, MRSA skin and soft tissue infections
Mechanism of resistance for TMP? SMX?
TMP - decr. DHFR binding affinity, overexpression of enzyme, reduce bacterial permeability to TMP
SMX – altered enzyme (bacterial dihydropteroate synthase, decr. uptake, or incr. PABA endogenous synthesis
Side effects of TMP?
TMP = Treats Marrow Poorly
Megaloblastic anemia
Leukopenia
Granulocytopenia
Side effects of SMX?
SMX
Hypersensitivity
Hemolysis (if GCPD deficient)
Nephrotoxicity (tubulointerstitial nephritis)
Photosensitivity
Kernicterus in infants
Displaces drugs from albumin (ie warfarin)
Side effect of TMP/SMX?
Erythema Multiforme Hepatitis Hyperkalemia Bone marrow suppression GI upsets (N/V) Avoid in the 1st trimester of pregnancy
Drugs under the class of Fluoroquinolones?
Ciprofloxacin
Levofloxacin
Moxifloxacin
MoA of Fluoroquinolones?
inhibits DNA Gyrase (Topo II) and DNA Topo IV (impt in alleviating supercoiling that occurs during DNA replication)
Fluoroquinolones bacteriostatic or bactericidal?
bactericidal
distribution of Fluoroquinolones?
wide distribution, high concentration in tissues and CSF
cipro – hepatic + renal clearance
moxi/levo – mostly hepatically cleared
what should you avoid if you’re on Fluoroquinolones?
antacids
indications for ciprofloxacin?
GN (Pseudomonas, E. coli, etc)
Legionella, MAC
Poor BP activity
Chlamydia
Clinical uses:
Ciprofloxacin: UTI, STD
indications for Levofloxacin/Moxifloxacin?
GP
GN
Chlamydia
Clinical uses:
Moxi/Levo-: pneumonia
Levo: UTI
MoA for Fluoroquinolones?
Mutation in DNA gyrase
efflux pumps
plasma-mediated resistance via Qnr proteins
Side effects of Fluoroquinolones?
GI upset (N/V/D)
Superinfections
Skin rashes
CNS: HA, dizziness, seizures
Less common: tendon inflammation, rupture (esp. in elderly >60 and those on prednisone Rx), leg cramps, myalgias
“-lones” hurt attachments to your bones
Arthralgia, joint swelling in children
CI in pregnant patients due to possible damage to cartilage
Ciprofloxacin - inhibits hepatic CYP450 (Moxi/Levo do not)
rare: bone marrow failure, hemolytic anemia, nephrotoxicity, arthropathy in CF patients
DNA Alkylator
Metronidazole
Mechanism of action of Metronidazole?
forms a reactive nitro-anion and free radical toxic metabolites that damage DNA, mainly at the AT base pairs (may also damage proteins, lipids)
Metronidazole - bacteriostatic or bactericidal?
bactericidal and anti-protozoal
Metronidazole absorption and distribution?
well absorbed in the GI tract, but food delays its absorption
widely distributes; enters CSF well
Indications for Metronidazole?
Protozoa
(Giardia Lamblia, Entamoeba Histolytica, Trichomonas,)
Gardnerella vaginalis
Anaerobes (Bacteroides , C. difficile)
Pylori (use with PPI and clarithromycin, “triple therapy”)
Side effects of Metronidazole?
Inhibits CYP3A4 and aldehyde dehydrogenase (-> acetaldehyde accumulates), resulting in a disulfram-like rxn (flushing, tachycardia, hypotension with OH intake “instant hangover”)
HA
GI upsets
Metallic taste
CNS effects: ataxia, vertigo
Neutropenia
Dark urine
Teratogenic
Drugs under the class of Rifamycins?
Rifampin (semi-synthetic derivative of rifamycin B)
MoA of Rifamycins?
RNA Polymerase Inhibitors (does not inhibit mammalian nuclear RNA polymerase but does inhibit mammalian mitochondrial RNA polymerase at high concentrations)
Rifamycins - bacteriostatic or bactericidal?
bacteriostatic and bactericidal
absorption and distribution of Rifamycins?
good oral absorption, but impaired by food
enters CSF well
indications of Rifamycins?
Myoplasma Tuberculosis and other mycobacteria
Most GP, many GN (broad spectrum)
Staph Aureus
Legionella
Neisseria meningitides prophylaxis in children with H. influenza type B
Mechanism of reaction for rifamycin?
Mutations in RNA polymerase (rpoB)
Never use alone due to increasing problems with Mycoplasma TB therapy
side effects of Rifamycins?
Red orange body fluids Rapid resistance if used alone Ramps up cytochrome P450, creating multiple drug interactions (rifabutin does not and is preferred in HIV patients) GI intolerance: N/V Hepatitis
