Lecture 5: Fluoroquinolones, Novobiocin, and Rifampin

What is the mechanism of action of fluoroquinolones?

Inhibit DNA gyrase and topoisomerase IV → disrupt DNA supercoiling → bactericidal

What is the spectrum of veterinary fluoroquinolones?

Gm(+) and Gm(−) aerobes; not anaerobes

Why are fluoroquinolones considered "designer drugs"?

Their chemical structure can be modified at four sites to tailor spectrum, potency, and resistance profile

What is the major resistance mechanism for fluoroquinolones?

Point mutations in DNA gyrase/topoisomerase genes → reduced drug binding

What is the mutation prevention concentration (MPC)?

MPC = MIC × 5 (Gm+) or ×10 (Gm−); Cmax must exceed MPC to prevent resistance

What is the post-antibiotic effect of fluoroquinolones?

Momentary exposure suppresses bacterial growth for up to 48 hours

What are three side effects of fluoroquinolones in dogs?

Chondrotoxicity in juveniles, seizures (GABA-R antagonism), Herxheimer's reaction with S. canis

What is a side effect of fluoroquinolones in cats?

Retinopathies (especially enrofloxacin)

What is a side effect of fluoroquinolones in horses?

Chondrotoxicity (less common)

What are two drug interactions of fluoroquinolones?

Chelation with divalent cations; inhibition of cytochrome P450 enzymes

What are legal limitations of fluoroquinolones in food animals?

Extra-label use prohibited; banned in poultry due to resistance risk

Which fluoroquinolone is safest in cats?

Pradofloxacin — non-retinotoxic

Which fluoroquinolone has best peritoneal distribution?

Difloxacin

Which fluoroquinolone is approved for BRD and SRD?

Enrofloxacin, danofloxacin, pradofloxacin

Which fluoroquinolone is used for feline respiratory disease?

Orbifloxacin, marbofloxacin, pradofloxacin

What is the mechanism of action of novobiocin?

Prevents ATP binding to DNA gyrase → bacteriostatic

What is the clinical use of novobiocin?

Staph aureus mastitis in dry cows (combined with penicillin)

What is the mechanism of action of rifampin?

Inhibits RNA polymerase → blocks transcription → bactericidal

What is the spectrum of rifampin?

Mycobacteria and Gm(+) bacteria

What are side effects of rifampin?

Immune-mediated hepatitis, orange discoloration of body fluids, hemolysis

Why is rifampin used with another drug?

Resistance develops rapidly when used alone

What is the mechanism of action of sulfonamides?

Inhibit dihydropteroate synthetase → block folate synthesis → bacteriostatic

What is the mechanism of action of benzylpyrimidines?

Inhibit dihydrofolate reductase → block folate synthesis → bacteriostatic

Why are sulfonamides and BPs safe in eukaryotes?

Eukaryotes ingest folate and have different enzyme structures

What is the effect of combining sulfonamides and BPs?

Synergistic → bactericidal

What is the spectrum of sulfa + BP combinations?

Broad: Gm(+), Gm(−), aerobes, anaerobes, protozoa (except Enterococcus and Pseudomonas)

What is the resistance mechanism for sulfonamides and BPs?

Mutations in DHPS and DHFR; alternate folate pathways

Why are sulfonamides ineffective in abscesses?

Abscesses contain free folate → bacteria bypass folate synthesis

What are four side effects of sulfonamides?

Keratoconjunctivitis sicca, arthritis in Dobermans, decreased sperm count, pseudohypothyroidism

Which pathogens should not be treated with sulfonamides?

Rickettsia — sulfas promote growth via folate regulation

Which sulfonamides are used for enteric infections?

Sulfaguanidine (non-absorbed), sulfasalazine (anti-inflammatory + antibacterial)

Which bacterial groups are resistant to sulfonamides?

Mycobacteria, Mycoplasma, spirochetes

What is a pharmacogenetic advantage of trimethoprim in dogs?

Concentrates 10× in the prostate → ideal for prostatitis

What is the mechanism of action of ionophores?

Insert into Gm(+) membranes → bind Na⁺, K⁺, H⁺ → disrupt pH → bactericidal

What is the spectrum of ionophores?

Gm(+) bacteria (cidal) and coccidia (static)

Which species is highly sensitive to ionophores?

Horses — risk of fatal myopathy

What are two non-infectious uses of ionophores?

Growth promotion in cattle; prevention of bloat and fog fever

What is the mechanism of action of polymyxins?

Bind LPS in Gm(−) outer membrane → disrupt membrane → bactericidal

What are clinical uses of polymyxins?

Topical for GI infections; slow IV for equine endotoxemia

What is the mechanism of action of metronidazole?

Converted to electrophile → binds and breaks DNA → bactericidal

What is the spectrum of metronidazole?

Anaerobes, protozoa, some helminths

What are non-antimicrobial effects of metronidazole?

Anti-inflammatory: inhibits WBC-endothelial adhesion

What are toxicities of metronidazole?

Peripheral neuropathy, carcinogenesis (banned in food animals)

Why is ronidazole preferred for feline Tritrichomonas?

It is converted to an electrophile in feline gut; metronidazole is not

What are clinical uses of metronidazole?

Osteomyelitis, C. difficile diarrhea, anal sacculitis, IBD

What is Baytril® Otic composed of?

Enrofloxacin (antibacterial) + silver sulfadiazine (antifungal)

What are the safest antibiotics for guinea pigs?

Enrofloxacin, SMZ-TMP, doxycycline