Antibiotics 2

Question 1

Rifampin MOA, Spectrum & Resistance

Answer 1

Mechanism:
BacteriCIDAL- Binds bacterial RNA polymerase at the active center, blocking the elongation of the mRNA
Spectrum: WIDE - 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 2

Rifampin AE’s

Answer 2

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. Important to monitor liver enzymes for int’x w/ anticonvuslants.

Turns body fluids orange-red and can stain contact lens

Question 3

______ of Rifampin increases its excretion in the feces leading to what?

Answer 3

Impairment of liver function leads to higher blood serum levels

Question 4

Fidoxamicin Mechanism & Spectrum

Answer 4

Mechanism: BacteriCIDAL- Inhibits RNA polymerase by binding to sigma subunit of RNA polymerase. – diff subunit than rifampin; cross resistance from rifampin-resistant strains is NOT very likely.

Spectrum: narrow spectrum sparing many of the gut flora, Gram positive anaerobes, C. difficile - better at preventing recurrent infections.

Question 5

Fidoxamicin Resistance & AE’s

Answer 5

Resistance: Point mutation in RNA polymerase has been observed in vitro

Side effects:
Low absorption
Nausea, vomiting

Question 6

Fluoroquinolones Mechanism & Spectrum

Answer 6

Mechanism: BacteriCIDAL- Inhibit DNA replication by binding bacterial DNA topoisomerases. topoisomerase II (gyrase): Gram -‘s, topoisomerase IV: Gram +

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

Question 7

Flouroquinalones Resistance, AE’s and Special Facts

Answer 7

Resistance:

*Overprescribed
*Active efflux of the drug
*Mutations in topoisomerases

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

Important Facts:
*Chelate cations so don’t take with calcium, iron, aluminum, and zinc
*avoid dairy products or calcium-fortified juice - decrease absorption
*Adjust for renal dysfunction for all agents except moxifloxacin, which is not excreted into the urine

Question 8

____ ____ of infection is impacted by concentration of drug at site of infection. Levofloxacin as good _____ making it extremely affective in tx UTI’s.

Answer 8

Failure rate; bioavailability

Question 9

Folate antagonists: _____ & _____ Indirectly inhibit DNA synthesis by inhibiting

Answer 9

Sulfamethoxazole & trimethiprim indirectly inhibit DNA synthesis by inhibiting dyhydropterase synthetase (SMX) and dyhydrofolate reductase (TMP) in folate synthesis. Remember folate cofactors are vital in NT 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 10

Sulfonamides Mechanism & Resistance

Answer 10

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 11

Sulfonamides AE’s

Answer 11

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

*Kernicterus (bilirubin-induced brain dysfunction) Hyperbilirubinemia may cause bilirubin to accumulate in the gray matter of the CNS, potentially causing irreversible neurological damage

Question 12

Sulfonamides can compete for binding to _____leading to ______ in infants and complications with drugs like _____.

Answer 12

Albumin, kernicterus, warfarin

Question 13

Trimethoprim MOA, Spectrum, Resistance & AE’s

Answer 13

Mechanism: BacterioSTATIC- Inhibits bacterial dihydrofolate reductase. Bactericidal w/ sulfa

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

Adverse effects:
Bone marrow suppression
Hyperkalemia

Question 14

Trimethoprim and sulfamethoxazole [TMP-SMX] (Bactrin)Sequential blockade is _______.

Answer 14

BacteriCIDAL

Mechanism: Sequential blockage of the folate synthesis pathway

Spectrum: broad treatment of UTIs, Shigella, Salmonella, Pneumocystis – a weird fungi.

Question 15

Low/High MIC (minimum inhibitory concentration) of antibiotics lead to more affective treatment.

Answer 15

LOW MIC’s mean less drug is needed to kill a certain amount of bacteria.

Question 16

Metronidazole, Tinidazole MOA, Spectrum, Resistance & AE’s

Answer 16

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 & giardia
Resistance: Rare

Adverse effects:
Nausea, diarrhea, headache, and metallic taste.
*Avoid during pregnancy *
Disulfiram-like reaction with alcohol

Question 17

Unique limiting factor re: Metronidizole:

Answer 17

Metronidazole is only metabolized to the active form in anaerobes and not in aerobes

In aerobes, most of the ferredoxin is in the oxidized form.
Don’t have enough reduced form to activate metro.

Question 18

The disulfiram-ethanol reaction

Answer 18

Metro acts here

I

I

Hangover from acetaldehyde

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.

*Sx of the disulfiram reaction include throbbing headache, nausea, vomiting, sweating, hypotension, confusion.

Question 19

What other antibiotic class did we discuss that can cause disulfiram
   reaction and should not be consumed with alcohol?

Answer 19

2nd-generation Cephalosporins

Question 20

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.

Answer 20

E. coli accounts for as much as 95% of UTI’s

Resistance patterns of E. coli to TMP-SMX and fluoroquinolones is variable and clinicians should understand resistance patterns in their community.

Nitrofurantoin is preferred

Question 21

Nitrofurantoin (aka macrobid, macrodantin) MOA & Spectrum

Answer 21

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 – generally non-specific MOA.

Spectrum: Broad Spectrum, Rapidly excreted in the urine in an active form
***Only reach high concentrations in the urine

Question 22

Nitrofurantoin Resistance, AE’s and Important facts

Answer 22

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 23

Nucleic Acid Inhibitor Summary

Answer 23

Rifampin – Beta subunit of RNA Polymerase – WIDE - Gram + and -, Mycobacteria tuberculosis

Fluoroquinolones – Topo II & Topo IV involved w/ DNA synthesis – recurrent RTI’s, UTI’s

Trimethoprim/Sulfamethoxazole –inhibition of folate synthesis in bacteria that don’t consume folate –> Indirect inhibition of DNA snythesis – UTI’s, Shigella, Salmonella, Pneumocystis – a weird fungi.

Metronidiazole – Metabolite formation of free radicals that lead to DNA strand breaks & cell death – Anaerobes, C. diff

Nitrofurantoin – Many MOA involving DNA, RNA & protein synthesis due to crx of free radicals – ONLY UTI’s; High urine conc/poor tissue levels

Question 24

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

Answer 24

Sulfamethoxazole

Question 25

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

Answer 25

Sulfisoxizole

Question 26

Alex’s tears have turned a reddish color. What is the mechanism of action of the antibiotic she is currently taking?

Answer 26

Inhibits RNA polymerase – from rifampin

Question 27

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

Answer 27

any of the flouroquinalones

Question 28

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?

Answer 28

Nitrofurantoin