Week 4 Prunuske - Principles of Chemotherapy Flashcards
Which two drugs are inhibitors of RNA Polymerase?
Rifampin and Fidoxamicin
Which class of drugs inhibits DNA replication?
Fluoroquinolones
Which two classes of drugs are folate antagonists?
Sulfonamides and Trimethoprim
Which two drugs are indirect inhibitors of DNA?
Metronidazole and Nitrofurantoin
Which bactericidal drug binds bacterial polymerase at the active center, consequently blocking the elongation of mRNA?
Rifampin
What drug is used primarily for the treatment of Mycobacteria tuberculosis?
Rifampin
(usually part of a 4 drug cocktail due to a high rate of resistance/mutation)
What happens in the intrinsic resistance of Rifampin?
The drug is unable to bind to the beta subunit of RNA polymerase.
What happens in the acquired resistance of Rifampin?
the strain acquires mutations in rpoB gene preventing drug binding
What drug has adverse side effects such as GI upset, orange/red body fluids?
Rifampin
Deacetylation of Rifampin results in what?
increased excretion of Rifampin in the feces
Impairment of liver function leads to what in the case of Rifampin?
higher blood serum levels
What is the mechanism of action of Fidaxomicin?
inhibits RNA polymerase
Fidaxomicin is a narrow spectrum drug that targets gram positive anaerobes such as what common microbe?
C. difficile
Why does Fidaxomicin have few side effects, if any?
low absorption drug
(spares many of the natural gut flora)
What are the three fluoroquinolones discussed in class?
. . . floxacin:
Ciprofloxacin, Levofloxacin, and Moxifloxacin
Fluoroquinolones inhibit DNA replication by binding to what bacterial DNA machinery?
Topoisomerase II (gyrase)
and
Topoisomerase IV
What two mechanisms of resistance develop in Fluoroquinolones as they are often overprescribed for UTIs, respiratory infections, and acute GI infections?
- Active efflux of the drug
- Mutations in topoisomerases (targe site)
Which drug class treats a very broad spectrum of microbes including gram + and gram -, as well as atypical organisms like Mycoplasma?
Fluoroquinolones
(Ciprofloxacin, Levofloxacin, and Moxifloxacin)
In the event of biological warfare, what drug may be used to treat and prevent dangerous illnesses that are deliberately spread such as plague, tularemia, and anthrax of the skin or mouth?
CIPROFLOXACIN!
(treats GI bugs as well)
Because Fluoroquinolones have a broader spectrum of activity, they also have more adverse side effects, such as:
- GI side effects
- confusion and photosensitivity
- C. diff
- Candida vaginitis (fungal infection)
- arthropathy in pregnancy and children <8
What three important warnings were discussed in the administration of Fluoroquinolones?
- Avoid dairy products or calcium-fortified juice
- Avoid calcium, iron, aluminum, and zinc supplements
- Adjust for renal dysfunction
Antibacterial sulfonamides, such as Sulfamethoxazole, are bacteriostatic drugs that act as competitive inhibitors of what enzyme?
Dihydropteroate synthetase
Sulfa drugs, such as Sulfamethoxazole, act as what kind of analog?
Para-AminoBenzoic Acid Analog
(PABA analog)
What are three ways antibacterial sulfonamides (sulfa drugs) become resistant?
- Change in dihydropteroate synthetase
- Increased efflux
- Increased production of PABA (competes with drug for active site)
What are the adverse side effects of Sulfonamides?
- Hypersensitivity (rash, Stevens-Johnson syndrome)
- Crystalluria (leading to acute renal failure)
- Hemolysis (if G-6-P dehydrogenase deficient)
- Kernicterus (neuro condition in jaundiced newborns)
Sulfonamides can compete for binding to albumin, leading to free bilirubin and complications with drugs like?
Warfarin
Trimethroprim is a bacteriostatic drug that inhibits the conversion of Dihydrofolic acid to Tetrahydrofoic acid by inhibiting what bacterial enzyme?
Dihydrofolate reductase
What are three forms of resistance to Trimethoprim that develop?
- Altered dihydrofolate reductase (change target)
- Increased amounts of dihydrofolate reductase
- Alternative metabolic pathways
What is the only adverse side effect discussed for Trimethoprim?
GI upset
Bactrin is a bactericidal drug that acts by sequential blockade of the folate synthesis pathway, and is made up of what two drugs?
Trimethoprim + Sulfamethoxazole
[TMP-SMX]
Bactrin is used to treat what conditions?
Broad treatment of UTI’s and Pneumocystis
If a patient has a sulfa-allergy, can they use Bactrin?
No, only use trimethoprim alone
(can’t have Sulfamethoxazole)
What does Metronidazole produce when is it is reduced that leads to to DNA strand breaks and cell death (making it bactericidal)?
free radicals
What spectrum of bacteria does Metronidazole target?
Anaerobic bacteria
C.diff
Protozoa
How often is there resistance to Metronidazole?
rarely
What the adverse side effects of Metronidazole?
- nausea
- diarrhea
- headache
- metallic taste
- disulfiram-like reaction with alcohol
*Avoid during pregnancy.
In what conditions is Metronidazole metabolized to its active form?
Anaerobes = reduced to Ferredoxin (active)
(In aerobes, most of the ferredoxin is in the oxidized form)
Metronidazole blocks aldehyde dehydrogenase, inhibiting the oxidation of what?
Acetaldehyde
(causes marked increase in acetaldehyde concentrations after ethanol consumption and leads to the disulfiram-ethanol reaction)
Hangover symptoms such as throbbing headache, nausea, vomiting, sweating, hypotension, and confusion are due to increased serum acetaldehyde and what other reaction when taking Metronidazole?
Disulfiram-ethanol reaction
Nitrofurantoin is bactericidal because it is reduced by bacterial flavoproteins to reactive intermediates that do what?
Inactivate or alter bacterial ribosomal proteins
(thus inhibiting the synthesis of DNA, RNA, cell wall, & protein)
Nitrofurantoin is rapidly excreted in the urine in an active form, and is thus used most commonly for treatment of what condition?
UTIs
(broad spectrum)
What are the forms of resistance to Nitrofurantoin?
No resistance!
Lack of bacterial resistance since the drug interferes with a variety of processes.
What are the two minor adverse side effects from Nitrofurantoin?
Vomiting and rash
Upregulation of para-aminobenzoic (PABA) acid synthesis is associated with the development of drug resistance toward which antibiotic?
Sulfamethoxazole
Which drug is most likely to cuase anemia in individuals with glucose-6-phosphate dehydrogenase deficiency? (Note: von Gierke’s disease)
Sulfisoxazole
A patient’s tears have turned a reddish color. What is the mechanism of action of the antibiotic she is currently taking?
Rifampin: inhibits RNA polymerase
Resistance to which drug occurs following the acquisition of mutations in DNA topoisomerase?
Fluoroquinolones - Ciprofloxacin, Levofloxacin, Moxifloxacin
What is the most likely agen associated with urinary tract infections?
E. coli (gram negative rod)
responsible for 80% of UTIs
(gut → urinary tract)
Considering the treatment of E.coli in UTIs, many enterobacteriaceae have acquired plasmids expressing what?
Extended-spectrum beta-lactamases
When is Nitrofurantoin preferred in the treatment of UTIs?
When resistance patterns of E.coli are prominent to Bactrin and Fluoroquinolones.
What are the five Aminoglycosides?
- Streptomycin
- Neomycin
- Amikacin
- Gentamicin
- Tobramycin
What are the three Tetracyclines?
- Doxycycline
- Minocycline
- Tetracycline
(act on 30S ribosome)
What are the three Macrolides?
- Erythromycin
- Azithromycin
- Clarithromycin
(act on 50S ribosome)
Define selective toxicity in terms of protein synthesis inhibitors.
Bind and inhibit prokaryotic ribosomes without blocking eukaryotic ribosomes.
What protein synthesis inhibitors act on 30S Ribosome?
- Aminoglycosidases
- Streptomycin, Neomycin, Amikacin, Gentamicin, and Tobramycin
- Tetracyclines
- Tetracycline, doxycycline, minocycline
What protein synthesis inhibitors act on 50S ribosomes?
- Linezolid
- Macrolides
- Chloramphenicol
- Clindamycin
- Quinupristin/dalfopristin
Linezolid
- Oxazolidinones
- Bacteriostatic
- acts on 50S ribosome (prevents formation of initiation complex, binds to P-site)
- Gram + (MRSA & Vancomycin resistant Enterococci)
- Resistance: Change target (23S rRNA on 50S)
- Bone marrow supression, hallucinations, increased heart rate, agitation, nausea, Serotonin Syndrome (if on SSRI)
Gentamicin
- Aminoglycosides
- Bacteriocidal
- Act on 30S ribosome (prevent formation of initiation complex, misread RNA, early termination)
- Gram (-) aerobic (require energy to enter cell)
- Intrinsic resistance: failure to enter cell (anaerobic), Acquired resistance: enzymes change drug through acetylation, phosphorylation, or adenylation
- Tubular necrosis, Nephrotoxicity, Ototoxicity, Pregnancy Class D (hearing loss in fetus)
- Important facts: Usually IV (poor gut absorption), excluded from CSF (polar)
Tobramycin
- Aminoglycosides
- Bacteriocidal
- Act on 30S ribosome (prevent formation of initiation complex, misread RNA, early termination)
- Gram (-) aerobic, (require energy to enter cell)
- Intrinsic resistance: failure to enter cell (anaerobic), Acquired resistance: enzymes change drug through acetylation, phosphorylation, or adenylation
- Tubular necrosis, Nephrotoxicity, Ototoxicity, Pregnancy Class D (hearing loss in fetus)
Important facts: Usually IV (poor gut absorption), excluded from CSF (polar)
Amikacin
- Aminoglycosides
- Bacteriocidal
- Act on 30S ribosome (prevent formation of initiation complex, misread RNA, early termination)
- Gram (-) aerobic (require energy to enter cell), broader including Pseudomonas
- Intrinsic resistance: failure to enter cell (anaerobic), less susceptible to enzyme inactivation
- Tubular necrosis, Nephrotoxicity, Ototoxicity, Pregnancy Class D (hearing loss in fetus)
Important facts: Usually IV (poor gut absorption), excluded from CSF (polar)
Neomycin
- Aminoglycosides
- Bacteriocidal
- Act on 30S ribosome (prevent formation of initiation complex, misread RNA, early termination)
- Gram (-) aerobic (require energy to enter cell)
- Intrinsic resistance: failure to enter cell (anaerobic), Acquired resistance: enzymes change drug through acetylation, phosphorylation, or adenylation
- Tubular necrosis, Nephrotoxicity, Ototoxicity, Pregnancy Class D (hearing loss in fetus)
Important facts: Usually IV (poor gut absorption), excluded from CSF (polar)
Streptomycin
- Aminoglycosides
- Bacteriocidal
- Act on 30S ribosome (prevent formation of initiation complex, misread RNA, early termination)
- Gram (-) aerobic (require energy to enter cell)
- Intrinsic resistance: failure to enter cell (anaerobic), Acquired resistance: enzymes change drug through acetylation, phosphorylation, or adenylation
- Tubular necrosis, Nephrotoxicity, Ototoxicity, Pregnancy Class D (hearing loss in fetus)
Important facts: Usually IV (poor gut absorption), excluded from CSF (polar)
What are the three Mechanisms of Action of Aminoglycosides?
- Block initiation of protein synthesis
- Incorporation of incorrect amino acid/causes misreading of mRNA
- Induces early termination
Act on 30S Ribosome!
Bactericidal!
What is concentration-dependent killing?
Achieve more killing at a higher concentration.
- Peak concentration is greater than 10 times over minimum inhibitory concentration (MIC)
- 1 or 2 high daily doses
What are two types of drugs that demonstrate concentration-dependent killing?
Aminoglycosides & Fluoroquinolones
What is time-dependent killing?
Time is greater than the minimun inhibitory concentration depending on the half life of the antibiotic. May need to dose multiple times per day, or may not.
What are two types of drugs that demonstrate time-dependent killing?
Beta-lactams and Vancomycin
Tetracycline
- Tetracyclines
- Bacteriostatic
- bind 30S, preventing attatchment of aminoacyl-tRNA
- Broad spectrum initially (B. burgdorferi, H.pylori, Mycoplasma pneumonia)
- Intrinsic: decreased uptake, Acquired: increased efflux, altered ribosomal target, rarely enzymatic inactivation of drug.
- chelates with metal ions, GI upset, photosensitivity, discoloration of teeth
- Inhibits bone growth in children, Pregnancy Class D
Doxycycline
- Tetracyclines
- Bacteriostatic
- bind 30S, preventing attatchment of aminoacyl-tRNA
- Broad spectrum initially (B. burgdorferi, H.pylori, Mycoplasma pneumonia)
- Intrinsic: decreased uptake, Acquired: increased efflux, altered ribosomal target, rarely enzymatic inactivation of drug.
- chelates with metal ions, GI upset, photosensitivity, discoloration of teeth
- Inhibits bone growth in children, Pregnancy Class D
Minocycline
- Tetracyclines
- Bacteriostatic
- bind 30S, preventing attatchment of aminoacyl-tRNA
- Broad spectrum initially (B. burgdorferi, H.pylori, Mycoplasma pneumonia)
- Intrinsic: decreased uptake, Acquired: increased efflux, altered ribosomal target, rarely enzymatic inactivation of drug.
- chelates with metal ions, GI upset, photosensitivity, discoloration of teeth
- Inhibits bone growth in children, Pregnancy Class D
Chloramphenicol
- Bacteriostatic
- binds 50S ribosome, preventing peptide bond formation (peptidyltransferase can’t associat with amino acid substrate)
- Extended spectrum
- Acetyltransferase modifies drug to prevent binding to the ribosome
- TOXIC, bone marrow depression, aplastic anemia, Gray baby syndrome
Use limited due to severe side effects.
What is Gray Baby Syndrome?
Adverse effect of Chloramphenicol in fetus or premature infants.
- Premature infants lack the enzyme UDP-glucuronyl transferase and have decreased renal function so high levels of the drug accumulate, which can lead to cardiovascular and respiratory collapse
Erythromycin
- Macrolides
- Bacteriostatic
- Inhibits translocation by binding 23S rRNA of the 50S subunit
- Broad coverage of respiratory pathogens, Chlamydia
- Resistance by methylation of 23S rRNA (target binding site), increased efflux, and hydrolysis of drug
- GI upset, hepatic failure, prolonged QT interval, cross rxn with cytochrome p450 inhibitors
Azithromycin
- Macrolides
- Bacteriostatic
- Inhibits translocation by binding 23S rRNA of the 50S subunit
- Broad coverage of respiratory pathogens, Chlamydia
- Resistance by methylation of 23S rRNA (target binding site), increased efflux, and hydrolysis of drug
- GI upset, hepatic failure, prolonged QT interval, cross rxn with cytochrome p450 inhibitors
Clarithromycin
- Macrolides
- Bacteriostatic
- Inhibits translocation by binding 23S rRNA of the 50S subunit
- Broad coverage of respiratory pathogens, Chlamydia
- Resistance by methylation of 23S rRNA (target binding site), increased efflux, and hydrolysis of drug
- GI upset, hepatic failure, prolonged QT interval, cross rxn with cytochrome p450 inhibitors
***Not safe during pregnancy!
What drugs are used to treat atypcial pneumonia caused by Mycoplasma pneumonia?
- Doxycycline (Tetracyline)
- Azithromycin (Macrolide)
- Levofloxacin (Fluoroquinolone)
- Beta-lactams are not effective
Clindamycin
- Lincosamides
- Bacteriostatic
- blocks translocation at 50S ribosome
- Gram + , including anaerobic, treat acne
- Resistance formed by mutation of ribosome, methylation of rRNA, inactivate drug by adenylation, cross resistance with macrolides and streptogramins
- Hypersensitivity (rash/fever), GI upset, mucous and blood in stool, C.diff
Quinupristin/Dalfopristin
- Streptogramins
- Bacteriostatic (bactericidal for some organisms)
- Binds to 50S to inhibit translocation
- Reserved for infections caused by multiple drug-resistant Gram + bactera
- Resistance by methylation of ribosome, enzymatic inactivation of the drug, increased efflux, cross resistance with macrolides and clindamycin
- Arthralgias, myalgias, inhibits cytochrome p450 enzyme (likely to have significant drug interactions)
What drugs are reserved for infections due to hard to treat drug resistant bacteria like MRSA and VRE?
- 5th generation cephalosporin (Ceftaroline)
- Vancomycin
- Daptomycin
- Quinupristin/Dalfopristin
- Linezolid
Which two drugs/drug classes are not to be used with newborns?
Chloramphenicol
Sulfonamides
Which two drugs/drug classes are not to be used in children?
Tetracyclines
Fluoroquinolones
What drugs/drug classes are not to be used during pregnancy?
- Tetracycline
- Aminoglycosides
- Clarithromycin
- Fluoroquinolones
- Chloramphenicol
- Sulfonamides
Which drugs/drug classes have to be adjusted for reduced renal function in the elderly?
- Beta-lactams
- Aminoglycosides
- Fluoroquinolones
***Half-life is increased with poor renal function.
What drug agents may cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency?
Sulfonamides (Trimethoprim/Sulfamethoxazole)
What drugs/drug classes demonstrate the Disulfiram-reaction when taken with alcohol?
Metronidazole
2nd generation Cephalosporin (with methylthiotetrazole groups)
Which of the beta-lactams is least likely to cause an allergic reaction?
Aztreonam
What drug induces drug metabolizing p450 enzymes?
Rifampin
Which two drugs inhibit hepatic metabolism?
Clarithromycin
Erythromycin
Why is it beneficial in some cases to treat with combination drug therapy?
- Enhancement of antibacterial activity (synergism)
- Treatment of mixed bacterial infections caused by two or more microbes.
- Therapy of severe infection in which a specific etiology is unknown.
- Prevention of the emergence of resistant organisms (Tb)
- Addition of inhibitors to prevent degradation or excretion of the enzyme.
What are some drawback of using drugs in combination?
- Risk of toxicity from two agents.
- Antagonism
- Selection of microorganisms resistant to antibiotics
- Superinfection
- Extra cost $$$
