Lecture 5: Fluoroquinolones, Novobiocin, and Rifampin

What is the MOA for FQs and how do they affect overall bacterial cell morphology?

inhibit DNA gyrase → bacterial DNA uncoiled and cannoffit within cell → also inhibit topoisomerase → bacteriocidal

Name the MOAs for novobiocin and rifampin and classify each based on bacterial killing versus stasis.

novobiocin: prevents ATP from binding to DNA gyrase, but no effect on topoisomerase - bacteriostatic

rifampin: inhibits RNA polymerase, bactericidal

What “subgroup” of bacteria are unaffected by any of the 5 veterinary FQs?

anaerobes

Why could FQs be considered “designer drugs”?

each chemical addition can broaden or narrow the spectrum:

• to target a specific bug

• kill everything

• circumvent resistance

What is the main method of resistance to fluoroquinolones?

point mutations in DNA gyrase genes → plasma FQ conc. cannot > MIC

Describe the MIC-MPC relationship for FQs.

mutation prevention concentration (MPC) is MIC x 5 or10 → Cmax must exceed the MPC during the dosing interval or else resistance will develop during treatment

Describe 3 side effects of FQs in dogs, 1 in cats, and 1 in horses?

dogs: chondrotoxic in neonates/juveniles (damages mitochondria in immature articular chondrocytes, exacerbates sz in epileptic dogs due to GAB-R antagonism, Herxheimer’s reaction

cats: retinopathies

horses: chondrotoxic in neonates/juveniles

Describe the pharmacokinetics of FQs.

• concentrates in WBCs, brain, and prostate

• well absorbed orally

• low plasma protein binding, high Vd

• excreted mostly unchanged in urine → good vs UTIs and no worries about drug metabolism in patients with hepatopathies

What are the precautions/legal limitations of FQs in food animals?

• never first choice unless potentially fatal malady or antibiogram

• inhibit cP450 enzymes, especially enrofloxacin

• banned in poultry → leads to FQ-R Campylobacter in poultry

• Do not take enrofloxacin → depression and hallucinations

• No extra-label use in food animals

Name 2 drug interactions of FQs.

• antacids → FQs poorly absorbed

• enrofloxacin → depression and hallucinations

What is novobiocin used to treat?

staph aureus, “dry cow” mastitis tx with penicillin

What is rifampin used to treat?

• Rhodococcus equi in horses along with clarithromycin

• deep pyodermas with a cephalosporin

• M. bovis in oryx

What are the toxicity issues associated with rifampin?

• inducer of microsomal enzymes

• immune-mediated hepatitis, dogs on prolonged tx

• causes orange discoloration of body fluids like sweat, urine, and saliva

What FQs are used to treat BRD?

enrofloxacin or danofloxacin or pradofloxacin

What FQs are used to treat feline respiratory disease?

orbifloxacin/marbofloxacin/pradofloxacin

What are the mechanisms of action for sulfonamides and benzylpyrimidines?

• Both inhibit the folate metabolic pathway by mimicking PABA

• BPs inhibit an enzyme downstream

• bacteriostatic alone, bacteriocidal together

Explain why sulfonamides and benzylpyrimidines do not have a significant effect on the analogous pathway in most eukaryotes.

folate metabolic pathway is present in eukaryotes but:

• most folate is ingested 

• sulfas and BPs cannot bind to eukaryotic enzymes

• methotrexate will inhibit DHFR in eukaryotes

Evaluate resistance vs. sensitivity/susceptibility in regards to sulfonamide and benzylpyrimidine combinations.

• If a bacteria is resistant to a sulfa then it will be resistant to the S+BP combination

• if a bacteria is sensitive to a sulfa then it will be sensitive to the S+BP combination

Describe (remember) the “exploitable” pharmacogenetic situation regarding dogs and the pharmacokinetics of benzylpyrimidines.

• eliminated faster in alkaline urine

• trimethoprim 10x concentrates in the dog prostate: used vs prostatitis

Name four side effects of sulfonamides.

• keratoconjunctivitis sicca in dogs

• arthritis in dobermans (especially sulfasalazine)

• decreases sperm counts in male breeding dogs (sulfasalazine)

• growth promotant on rickettsial diseases

What pathogen “group” should NOT be treated with sulfonamides and why?

rickettsial diseases because sulfas act as growth promotants

What is the basis for resistance to sulfonamides and benzylpyrimidines?

• alterations in target enzymes (DHPS and DHFR)

• development of alternate folate synthesis or uptake pathway

Why are sulfonamides and benzylpyrimidines ineffective in abscesses or pus?

abscesses have a lot of free folate and therefore bacteria do not have to synthesize their own folate → hindering the pathway does nothing

Name the two sulfonamides used versus enteric infections and why these drugs are used as such.

• sulfaguanidine because it is not absorbed from the intestines

• sulfasalazine because it is cleaved in the intestines to sulfapyridine + salicylate → net effect is an antibacterial PLUS and anti-inflammatory

Which bacterial (morphologic) “group” is resistant to these sulfonamides?

• mycobacteria and mycoplasma

• spirochetes

How do ionophores work and what species is very sensitive to these drugs?

ionophore inserts into cell wall and binds Na+, K+, and H+ → results in lethal drop in pH → Gm (+) bactericidal and bacteriostatic for coccidia → causes toxic myopathies in horses

Name two non-infectious uses for ionophores.

• growth promotant in cattle

• eliminates lactate- and methane-producing rumen bacteria → more proprionate produced for energy and decreased methane prevents bloat

What is the MOA of polymyxins?

binds to LPS on bacterial cell wall (only works on Gm -) → binding disrupts cell wall = bacteriocidal

When are polymyxins used?

equine endotoxemia slo IV

When is metronidazole used?

• osteomyelitis

• C. difficle diarrhea

• anal saculitis

• IBD

When is ronidazole used?

• feline GI tritrichomonas

What is the MOA of metronidazole?

MNDZ enters pathogen → drug converted to electrophile → binds to DNA → DNA breaks apart = bactericidal

What is included in the spectrum of metronidazole?

• anaerobes

• all protozoa are sensitive

• anthelminthic

What are the potential toxicities of metronidazole?

• peripheral neuropathy: reversible if tx with diazepam

• carcinogenesis