Week 4 - Antibiotics: Inhibitors of Nucleic Acid Synthesis

Question 1

Rifamycins, Fidoxamicin-

Answer 1

inhibitors of RNA polymerase

Question 2

Fluoroquinolones-

Answer 2

inhibitors of DNA replication

Question 3

Sulfonamides, Trimethoprim-

Answer 3

Folate Antagonists

Question 4

Metronidazole, Nitrofurantoin-

Answer 4

Indirect Inhibitor of DNA

Question 5

Rifamycin - **Rifampin **(outside U.S. known as rifampicin)

Mechanism

Sprctrum

Resistance

Answer 5

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

Question 6

What is tuberculosis treated with?

Answer 6

Rifampin

But treat with 4 (additional 3) antibiotics due to hight rate of resistance..

Question 7

Rifampin Spectrum?

Answer 7

Gram + and -

mycobacteria tuberculosis

Question 8

Adverse effects of Rifamycin - **Rifampin **

Answer 8

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

Question 9

What increases Rifampin excrection in feces?

Answer 9

Deacetylation of Rifampin increases its excretion in the feces…

Liver damage will impair excretion*

Impairment of liver function leads to higher blood serum levels

Question 10

Fidaxomicin

Mechanism

Spectrum

Resistance

Side effects

Answer 10

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

Question 11

Spectrum of Fidaxomicin

Answer 11

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*

Question 12

Would you expect rifampin and ficaxomicin to exhibit cross resistance?

Answer 12

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.

Question 13

What are the fluoroquinolones?

Answer 13

Ciprofloxacin, levofloxacin, moxifloxacin

Question 14

Ciprofloxacin, levofloxacin, moxifloxacin

Mechanism

Spectrum

Resistance

Answer 14

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

Question 15

Ciproflaxacin, levofloxacin, moxifloxacin

Spectrum

Answer 15

Spectrum:
Broad spectrum- Gram+, Gram-, and atypical organisms like Mycoplasma

Question 16

What antibiotics will work against atypical organisms like mycoplasmas?

Answer 16

The Fluoroquinolones:

Ciprofloxacin, levofloxacin, moxifloxacin

Question 17

Mycoplasma have no….

Answer 17

Cell wall

Question 18

What is the mechanism of fluoroquinolones?

Answer 18

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 +

Question 19

What do fluoroquinolones cause in double stranded DNA?

Answer 19

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.

Question 20

What are efflux transporters?

Answer 20

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…

Question 21

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

Answer 21

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..

Question 22

Adverse Effects of fluoroquinolones..

Answer 22

Adverse Effects:
GI side effects, confusion and photosensitivity
Tendon Rupture
Contraindicated in pregnant women
Prolongation of the QT interval

Question 23

Important facts on fluoroquinolones

Answer 23

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…

Question 24

What can ciprofoxacin be used for in terms of biologica warfare?

Answer 24

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

Question 25

What is the failure rate of infection impacted by?

Answer 25

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

Question 26

What is mechanism of Sulfonamides and Trimethoprim on Folate?

Answer 26

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.

Question 27

Sulfonamides:

ulfamethoxazole, sulfisoxazole, sulfadiazine

Mechanism

resistance

Answer 27

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

Question 28

Adverse effects of Sulfonamides:

Answer 28

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

Question 29

What is Kernicterus?

Answer 29

Sulfonamides can compete for binding to albumin leading to kernicterus in infants and complications with drugs like warfarin

Question 30

Trimethoprim

Mechanism

Resitance

Adverse Effects

Answer 30

Mechanism: Bacteriostatic- Inhibits bacterial dihydrofolate reductase.

Resistance:
Altered dihydrofolate reductase
Increased amounts of dihydrofolate reductase.
Alternative metabolic pathways

Adverse effects:
Bone marrow suppression
Hyperkalemia

Question 31

Bactrin - Trimethoprim and Sulfamethoxazole mix

mechanism

spectrum

Answer 31

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

Question 32

Use the table to identify, which organism TMP-SMXis least effective against

Staphylococcus aureus
Streptococcus pneumoniae
Haemophilus influenzae
Shigella Sonnei
Proteus vulgaris

Answer 32

Proteus Vulgaris

Question 33

Metrondazole, Tinidazole

Mechanism

Spectrum

Resistence

Adverse Effects

Answer 33

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

Question 34

What is spectrum of Metronidazole (Tinidazole)

Answer 34

Spectrum: Protozoa, Anaerobic bacteria including Clostridium difficle

Question 35

Metronidazole is activated in?

Anaerobes or aerobes?

Answer 35

Anaerobes

Question 36

What is disulfiram-ethanol reaction?

Answer 36

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.

Question 37

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

Answer 37

D. 2nd Generation Cephalosporins

Question 38

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

Answer 38

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.

Question 39

Treatment of E.Coli UTI..

What are they resistant to?

What is the preffered antibiotic?

Answer 39

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)

Question 40

Nitrofurantoin

Mechanism

Spectrum

Resistance

Adverse Effects

Important facts..

Answer 40

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

Question 41

What is Nitrofurantoin used for?

Is there resistance?

Answer 41

UTIs

No resistance, the drug iterferes with a variety of processes

Question 42

Fill out the Summary Table…

Answer 42

w

Question 43

Upregulation of para-aminobenzoic acid synthesis is associated with the development of drug resistance toward which antibiotic

Sulfamethoxazole
Rifamycin
Ciprofloxacin
Metronidazole
Trimethoprim

Answer 43

Sulfamethoxazole

So by increasing para-aminobenzoic acid synthisis you will outcompete the drug

Question 44

Which of the following drugs is most likely to cause anemia in individuals with glucose-6 phosphate dehydrogenase deficiency?

Aztreonam
Nitrofurantoin
Sulfisoxazole
Metronidazole
Vancomycin

Answer 44

Sulfixoxazole

Question 45

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?

Answer 45

Men. It is X-linked..

Women have XX

Men have XY

Question 46

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

Answer 46

Antibiotic is Rifampin

It inhibits RNA polymerase in the bacteria

Question 47

Resistance to which drug occurs following the acquisition of mutations in DNA topoisomerase

A. Rifampin
B. Ciprofloxacin
C. Trimethoprim
D. Nitrofurantoin
E. Metronidazole

Answer 47

B. Ciprofloxacin

The mechanism of fluoroquinolones is to block bacterial DNA synthesis by binding to bacterial topoisomerase II

Question 48

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

Answer 48

A. Nirtrofurantoin

Only effective in urinary tranct.