Week 4 - Antibiotics: Inhibitors of Nucleic Acid Synthesis Flashcards
Rifamycins, Fidoxamicin-
inhibitors of RNA polymerase
Fluoroquinolones-
inhibitors of DNA replication
Sulfonamides, Trimethoprim-
Folate Antagonists
Metronidazole, Nitrofurantoin-
Indirect Inhibitor of DNA
Rifamycin - **Rifampin **(outside U.S. known as rifampicin)
Mechanism
Sprctrum
Resistance
Mechanism:
Bactericidal- Binds bacterial RNA polymerase at the active center, blocking the elongation of the mRNA
Spectrum: Gram + and -, Mycobacteria tuberculosis
Resistance:
Intrinsic resistance- in some bacterial strains the drug is unable to bind to the β subunit of RNA polymerase
Acquired resistance- the strain acquires mutations in rpoB gene preventing drug binding
Treat Mycobacteria tuberculosis with 4 antibiotics due to the high rate of resistance
What is tuberculosis treated with?
Rifampin
But treat with 4 (additional 3) antibiotics due to hight rate of resistance..
Rifampin Spectrum?
Gram + and -
mycobacteria tuberculosis
Adverse effects of Rifamycin - **Rifampin **
Adverse effects:
GI side effects, Hypersensitivity- Fever
Hepatotoxic-
Use caution when administering to patients with chronic liver disease
Induction of cytochrome P450 enzymes can induce the metabolism of other medicines leading to organ rejection and loss of seizure control. Seizure meds will be metabolized much quicker*
Turns body fluids orange-red and can stain contact lens
What increases Rifampin excrection in feces?
Deacetylation of Rifampin increases its excretion in the feces…
Liver damage will impair excretion*
Impairment of liver function leads to higher blood serum levels
Fidaxomicin
Mechanism
Spectrum
Resistance
Side effects
Mechanism: Bactericidal- Inhibits RNA polymerase by binding to sigma subunit of RNA polymerase
Spectrum: narrow spectrum sparing many of the gut flora, Gram positive anaerobes, C. difficile better at preventing recurrent infections
Resistance: Point mutation in RNA polymerase has been observed in vitro.. new drug so haven’t seen much resistence yet
Side effects:
Low absorption
Nausea, vomiting
Spectrum of Fidaxomicin
narrow spectrum sparing many of the gut flora, Gram positive anaerobes, C. difficile better at preventing recurrent infections
It is better than Vancomycin but not as good as fecal transplants*
Would you expect rifampin and ficaxomicin to exhibit cross resistance?
If you have been giving sombody rifampin and the bacteria become resistant.. if try to give fidaxomicin would the bacteria be resistant to fidaxomicin?
No. Drugs are binding to different areas of the enzymes.
What are the fluoroquinolones?
Ciprofloxacin, levofloxacin, moxifloxacin
Ciprofloxacin, levofloxacin, moxifloxacin
Mechanism
Spectrum
Resistance
Mechanism: Bactericidal- Inhibit DNA replication by binding bacterial DNA topoisomerase
Spectrum:
Broad spectrum- Gram+, Gram-, and atypical organisms like Mycoplasma
Resistance: Overprescribed
Active efflux of the drug
Mutations in topoisomerases
Ciproflaxacin, levofloxacin, moxifloxacin
Spectrum
Spectrum:
Broad spectrum- Gram+, Gram-, and atypical organisms like Mycoplasma
What antibiotics will work against atypical organisms like mycoplasmas?
The Fluoroquinolones:
Ciprofloxacin, levofloxacin, moxifloxacin
Mycoplasma have no….
Cell wall
What is the mechanism of fluoroquinolones?
Fluoroquinolones Ciprofloxacin, levofloxacin, moxifloxacin
Block bacterial DNA synthesis by binding to bacterial topoisomerase II (DNA gyrase) and topoisomerase IV.
Inhibition of topoisomerase II prevents relaxation of positively supercoiled DNA that is required for normal transcription and replication. Gram –
Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA (decatenation) into the respective daughter cells during cell division.
Gram +
What do fluoroquinolones cause in double stranded DNA?
Fluoroquinolones cause double-stranded DNA breaks and cell death, which can be prevented through the activation of the DNA stress response (SOS) and DNA repair.
What are efflux transporters?
Multidrug Resistance occurs due to the upregulation of transporters capable of effluxing many types of drugs
This occurs in fluoroquinolones… ***
*Gram negative have 2 membrane layers…
If a strain of pseudomonas aeruginosa has become resistant to lefofloxacin which additional drugs do you expect the bacteria to be resistant to?
Nafcillin
Ciprofloaxin
Aztreonam
All
Cant determine
So… mechanism is to bind DNA topoisomerase inhibiting DNA…
So it could be ALL…
Main take away is that if bacterial become resistant to one drug, they will most likely be resistant to other drugs in the same class..
Adverse Effects of fluoroquinolones..
Adverse Effects:
GI side effects, confusion and photosensitivity
Tendon Rupture
Contraindicated in pregnant women
Prolongation of the QT interval
Important facts on fluoroquinolones
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 for all agents except moxifloxacin, which is not excreted into the urine
Avoid antacids…
What can ciprofoxacin be used for in terms of biologica warfare?
From PubMedHeath…
In the event of biological warfare, ciprofloxacin may be used to treat and prevent dangerous illnesses that are deliberately spread such as plague, tularemia, and anthrax of the skin or mouth. Talk to your doctor about the risks of using this medication for your condition
What is the failure rate of infection impacted by?
Failure reate of infection is impacted by concentration of drug at site of infection…
Levofloxacin- good bioavailability
Ratio Failure rate of therapy Skin tissue/ plasma peak conc. 1.4 16% Epithelial lining/ plasma 2.8 3% Urine/plasma 67 0%
So good for UTI’s
What is mechanism of Sulfonamides and Trimethoprim on Folate?
They are folate antagonists…
…Indirect inhibition of DNA synthesis
Bacteria and fungi that synthesize their own
dihydrofolic acid are sensitive to Sulfonamides.
Mammals obtain dihydrofolic acid in their diets
Bacteria that uptake dihydrofolic acid
are resistant to Sulfonamides as long as there is
enough dihydrofolic acid around.
Sulfonamides:
ulfamethoxazole, sulfisoxazole, sulfadiazine
Mechanism
resistance
Mechanism:
Bacteriostatic- drug is a para-aminobenzoic acid analog and acts as a competitive inhibitor of Dihydropteroate synthetase
Resistance: change in dehydropteroate synthetase, increased efflux
increased production of PABA
Adverse effects of Sulfonamides:
Adverse effects:
Hypersensitivity- Rash, Stevens-Johnson syndrome
Cross reaction to other drugs containing sulfonamide moieties
Crystalluria leading to acute renal failure
Hemolysis if Glucose-6-phosphate dehydrogenase deficient (dont use this drug in pts with deff.)
Kernicterus
What is Kernicterus?
Sulfonamides can compete for binding to albumin leading to kernicterus in infants and complications with drugs like warfarin
Trimethoprim
Mechanism
Resitance
Adverse Effects
Mechanism: Bacteriostatic- Inhibits bacterial dihydrofolate reductase.
Resistance:
Altered dihydrofolate reductase
Increased amounts of dihydrofolate reductase.
Alternative metabolic pathways
Adverse effects:
Bone marrow suppression
Hyperkalemia
Bactrin - Trimethoprim and Sulfamethoxazole mix
mechanism
spectrum
Trimethoprim and sulfamethoxazole [TMP-SMX] (Bactrin)Sequential blockade is bactericidal
Mechanism: Sequential blockage of the folate synthesis pathway
Spectrum: broad treatment of UTIs, Shigella, Salmonella, Pneumocystis
Use the table to identify, which organism TMP-SMXis least effective against
Staphylococcus aureus
Streptococcus pneumoniae
Haemophilus influenzae
Shigella Sonnei
Proteus vulgaris
Proteus Vulgaris
Metrondazole, Tinidazole
Mechanism
Spectrum
Resistence
Adverse Effects
Mechanism: Bactericidal- metronidazole reduced (electron sink). The activated form generates free radicals leading to DNA strand breaks and cell death.
Spectrum: Protozoa, Anaerobic bacteria including Clostridium difficle
Resistance: Rare
Adverse effects:
Nausea, diarrhea, headache, and metallic taste.
Avoid during pregnancy
Disulfiram-like reaction with alcohol
What is spectrum of Metronidazole (Tinidazole)
Spectrum: Protozoa, Anaerobic bacteria including Clostridium difficle
Metronidazole is activated in?
Anaerobes or aerobes?
Anaerobes
What is disulfiram-ethanol reaction?
The disulfiram-ethanol reaction is due to increased serum acetaldehyde Metronidazole blocks aldehyde dehydrogenase, inhibiting the oxidation of acetaldehyde and causing a marked increase in acetaldehyde concentrations after ethanol consumption.
Symptoms of the disulfiram reaction include throbbing headache,
nausea, vomiting, sweating, hypotension, confusion.
What other antibiotic class did we discuss that can cause disulfiram reaction and should not be consumed with alcohol?
A. Penicillin
B. Carbapenems
C. Daptomycin
D. 2nd Generation Cephalosporins
E. Polymyxin B
D. 2nd Generation Cephalosporins
A 21 year old woman presents with a 3-day duration of discomfort with urination and increased urinary frequency. Microscopic examination of the sediment of a centrifuged urine sample reveals 10-15 white blood cells per high power field and numerous Gram negative bacteria.
Which of the following organisms is most likely?
Escherichia coli
Pseudomonas aeruginosa
Enterococcus
Group B streptococci
Mycoplasma
So A and B are gram -
Streptococci and Enteroccoc are all gram +
A. E. Coli is the answer
Even though e coli is usually in the gut… there are more virulence forms that can cause endotoxins? outside of body and cause disease.
Treatment of E.Coli UTI..
What are they resistant to?
What is the preffered antibiotic?
E.Coli is the bacteria in 75-95% or UTIs
Most E. coli are resistant to beta-lactam antibiotics
Resistance patterns of E. coli to TMP-SMX and fluoroquinolones is variable and clinicians should understand resistance patterns in their community.
Nitrofurantoin is preferred (if pts uncomplicated first UTI)
Nitrofurantoin
Mechanism
Spectrum
Resistance
Adverse Effects
Important facts..
Really only used in urinary tract….Not effective ouside of urinary tract
Mechanism: Bactericidal- Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates, which inactivate or alter bacterial ribosomal proteins and other macromolecules. Leading to an inhibition of the synthesis of DNA, RNA, cell wall, and protein
Spectrum: Broad Spectrum, Rapidly excreted in the urine in an active form
Only reach high concentrations in the urine
Resistance: Lack of bacterial resistance since the drug interferes with a variety of processes.
Adverse effects: Vomiting and Pulmonary Toxicity
Important facts: Ineffective for infections outside of lower urinary tract
What is Nitrofurantoin used for?
Is there resistance?
UTIs
No resistance, the drug iterferes with a variety of processes
Fill out the Summary Table…
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Upregulation of para-aminobenzoic acid synthesis is associated with the development of drug resistance toward which antibiotic
Sulfamethoxazole
Rifamycin
Ciprofloxacin
Metronidazole
Trimethoprim
Sulfamethoxazole
So by increasing para-aminobenzoic acid synthisis you will outcompete the drug
Which of the following drugs is most likely to cause anemia in individuals with glucose-6 phosphate dehydrogenase deficiency?
Aztreonam
Nitrofurantoin
Sulfisoxazole
Metronidazole
Vancomycin
Sulfixoxazole
Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease.
Would you expect this deficiency to be more common in men or women?
Men. It is X-linked..
Women have XX
Men have XY
Alex’s tears have turned a reddish color. What is the mechanism of action of the antibiotic she is currently taking?
Inhibits DNA polymerase
Inhibits glucose-6-phosphate dehydrogenase
Inhibits RNA polymerase
Inhibits dihydrofolate reductase
Inhibits DNA topoisomerase
Antibiotic is Rifampin
It inhibits RNA polymerase in the bacteria
Resistance to which drug occurs following the acquisition of mutations in DNA topoisomerase
A. Rifampin
B. Ciprofloxacin
C. Trimethoprim
D. Nitrofurantoin
E. Metronidazole
B. Ciprofloxacin
The mechanism of fluoroquinolones is to block bacterial DNA synthesis by binding to bacterial topoisomerase II
Which of the following antibiotics would you use for empiric therapy in a patient with signs and symptoms of a urinary tract infection with a positive urinalysis
A. Nitrofurantoin
B. Nafcillin
C. Metronidazole
D. Penicillin G
E. Rifampin
A. Nirtrofurantoin
Only effective in urinary tranct.
