Metronidazole, septra, fosfomycin and nitrofurantoin

Question 1

What is the MOA of metronidazole?

Answer 1

Metronidazole is a nitroimidazole and works by passive diffusion into the cytoplasm of anaerobic bacteria where transport proteins such ferredoxin transfer electrons to the nitro group of metronidazole forming a nitroso free radical.

This creates a concentration gradient for intracellular transport of metronidazole where the free radical of metronidazole interacts with intracellular DNA resulting in the inhibition of DNA synthesis and degradation and ultimately bacterial death

Question 2

What are common toxicities of metronidazole?

Answer 2

Disulfiram-like reaction when taken with alcohol: nausea, vomiting, abdominal cramps, headache

• Abdominal discomfort, metallic taste, diarrhea and nausea
• Jarisch Herxheimer reaction (sepsis like reaction)
• Dizziness and headache
• Serious side effects can include, SJS, TEN, leukopenia, and neuropathies.

Question 3

Describe the PK of metronidazole?

Answer 3

available orally and parenterally
* very good absorption (100%); may be taken with food * hepatically metabolized and renally eliminated

Question 4

What is the spectrum of activity of Metronidazole?

Answer 4

Only active against **anaerobic bacteria: **

• Bacteroides fragilis
• Clostridium species (including C. difficile) Effective against H. pylori.

Some anti-parasitic activity: * Entamoeba histolytica * Giardia lamblia * Trichomonas vaginalis

Question 5

What is the MOA of sulfa/trim?

Answer 5

Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competition with para-amino benzoic acid. * Trimethoprim, a trimethoxybenzylpyrimidine, blocks the production of tetrahydrofolic acid from dihydrofolic acid by reversibly inhibiting the required enzyme, dihydrofolate reductase, bacterial dihydrofolic reductase. acid

Both given together produces sequential blocking in this metabolic sequence (blocks with 2 different MOAs), resulting in marked enhancement (synergism) of the activity of both drugs * The combination often is bactericidal, compared to the bacteriostatic activity of a sulfonamide alone.

Question 6

What are common toxicities of Sulfa/trim?

Answer 6

• Mild GI symptoms: nausea, diarrhea, cramps
• Skin rashes are common: diffuse maculopapular rash or mild toxic erythema exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis occur rarely o increased incidence of rashes in patients with HIV/AIDS
• Bone marrow toxicity o more common in HIV/AIDS patients and those with bone marrow transplants o thrombocytopenia and neutropenia have been reported o folinic acid administration may reduce bone marrow toxicity
• possible teratogenicity and increased risk for kernicterus in newborn if used near term; avoid in pregnancy

Question 7

Describe the PK of Sulfatrim?

Answer 7

• Available for oral and parenteral administration
• Well absorbed (90-100%)
• Excreted primarily by kidneys; dosage adjustment in renal failure is necessary

Question 8

What is the spectrum of activity for Sulfatrim?

Answer 8

Spectrum of Activity: Synergistic activity results in bactericidal effect

Gram +ve
Gram positive bacteria including Staph and Strep species (not great against , S. pneumoniae) including some strains of MRSA

Gram -ve
E.coli (check susceptibilities) ,
Salmonella and
Shigella species,
H. influenza (check susceptibilities) and
Moraxella catarrhalis are susceptible
Burkholdaria cepacia and Stenotrophomonas maltophilia
Others Listeria monocytogenes and Legionella species are susceptible Many nocardia species are susceptible

Question 9

What is the MOA of nitrofurantoin?

Answer 9

• Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates, which inactivate or alter bacterial ribosomal proteins and other macromolecules.
• These inactivations or alterations of bacterial ribosomal proteins and macromolecules cause the inhibition of vital biochemical processes of aerobic energy metabolism and the syntheses of bacterial deoxyribonucleic acid (DNA), ribonucleic acid (RNA), cell wall, and protein.
• Therapeutic concentrations are only achieved in urine and is generally bactericidal

Question 10

What are the toxicities of nitrofurantoin?

Answer 10

• Loss of appetite, nauseas and vomiting
• Hemolytic anemia
• Hepatic toxicity
• Peripheral neuropathy
• Pulmonary toxicity (pulmonary fibrosis, interstitial pneumonia)

Question 11

What is the PK of nitrofurantoin?

Answer 11

• Absorbed well which increases with food
• Renally and biliary eliminated (30-40% unchanged

Question 12

What is the spectrum of activity of nitrofurantoin?

Answer 12

Spectrum of Activity: Only in urine!
Gram +ve
Gram positive bacteria including Staph (including MRSA), Strep and both Enterococcus species

Gram -ve
E.coli (sometimes ESBL E. coli), Salmonella and Shigella

Question 13

How does fosfomycin work?

Answer 13

• Fosfomycin inactivates enolpyruvyl transferase, ultimately inhibits bacterial cell wall synthesis .
• Fosfomycin also decreases the adherence of bacteria to epithelial cells of the urinary tract.

Question 14

What are toxicities of fosfomycin?

Answer 14

• Diarrhea, nausea * Headache,
  back ache

Question 15

What is the PK of Fosfomycin?

Answer 15

PK: * Absorbed well which increases with food * Only used for UTIs

Question 16

What is the spectrum of activity of fosfomycin?

Answer 16

Spectrum of Activity: Only in urine!

Gram +ve
Gram positive bacteria including Staph (including MRSA), Strep pneumonia and Enterococcus faecalis

Gram -ve
E.coli (including ESBL and KPC) and Klebsiella (including ESBl and KPC) , Salmonella and Enterobacter