Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

FLUOROQUINOLONES
EXAMPLES
Ciprofloxacin, danofloxacin, difloxacin, enrofloxacin,
marbofloxacin, norfloxacin, orbifloxacin, sarafloxacin.
Mechanism of action
Fluoroquinolones specifically inhibit topoisomerase II
(also referred to as DNA gyrase), an enzyme that controls
the supercoiling of bacterial DNA by catalyzing
the cleavage/reunion of the two strands in the DNA
molecule. This is the major target of fluoroquinolones
in Gram-negative bacteria. Binding of fluoroquinolones
to DNA gyrase disrupts enzyme activity, resulting in
rapid cell death. The mechanism of action against
Gram-positive bacteria is not well understood but the
primary target may be topoisomerase IV, which also
catalyzes changes in coiling.
The bactericidal action of fluoroquinolones is rapid
and concentration-dependent. The more the concentration
exceeds the MIC, the greater the bactericidal
effect and the less the likelihood of selecting resistant
pathogens. However, activity is inhibited at very high
concentrations through direct inhibition of RNA synthesis
and can be antagonized by protein synthesis
inhibitors (chloramphenicol) and RNA synthesis inhibitors
(rifampicin).
Mechanisms of resistance
Clinically important fluoroquinolone resistance is chromosomally
mediated. There are three mechanisms by
which it can occur: decreased permeability of the bacterial
cell wall, activation of an efflux pump which actively
transports the drug out of the cell and mutation of
DNA topoisomerase II or IV that alters drug-binding
sites. This latter mechanism is the most important.
Cross-resistance between the fluoroquinolones frequently
occurs. In addition, some mutations that alter
permeability or activate the efflux pump also confer
resistance to other antimicrobials such as cephalosporins
and tetracyclines.
Selection of resistant organisms is related to the concentration
of drug at the site of infection; the higher the
concentration, the fewer resistant bacteria. The high
concentrations of fluoroquinolones achieved in urine
and gut following oral dosage tend to prevent the emergence
of low-level resistant mutants but treatment of
infections in other sites may be associated with development
of resistance. Because resistance is chromasomally
mediated, it is stable and not energy dependent. Resistant
bacteria have the potential to persist even after
removal of drug from their environment. Therefore
repeated exposure to sublethal concentrations of drug
can select for high-level, stable resistance. There have
been reports of increasing patterns of resistance to ciprofloxacin
and enrofloxacin amongst several bacteria,
including Staphylococcus aureus, Pseudomonas aeruginosa,
Escherichia and other Gram negatives.
Plasmid-mediated resistance that targets DNA gyrase
has not been clinically demonstrated and may only
become apparent after several decades of intense drug
use. Because fluoroquinolones are important for treating
certain serious Gram-negative infections, it is prudent
to suggest that use of these drugs should ideally be supported
by culture and susceptibility test data whenever
possible.
Antibacterial spectrum (Fig. 8.22)
● Highly active against Gram-negative aerobes.
● Lower, but often useful, activity against Gram-positive
aerobes, though the ‘prudent use’ principle
would argue for choice of a narrower spectrum agent
instead.
● Active against all aerobic enteric Gram-negative
bacilli and all aerobic bacterial gut pathogens.
● Better activity against Pseudomonas than with antipseudomonal
penicillins, cephalosporins or gentamicin;
activity is similar to that of tobramycin.
● Active against 90–100% of bacterial isolates from
urine (where concentrations are 10–20-fold higher
than in plasma) including methicillin-resistant
Staphylococcus.
● Active against Brucella, Chlamydophila, Mycobacterium
and Mycoplasma.
● Penetrate intracellularly, thus potentially effective
against intracellular bacteria. Concentrate in phagolysosomes,
enhancing intracellular killing.
● Variable activity against Streptococcus.
Gram positive
aerobes
Obligate
anaerobes**
Gram negative
aerobes
Penicillinaseproducing
Staphylococcus*
+ Brucella, Mycoplasma, Chlamydophila, Rickettsia,
Mycobacterium spp.
* MRSA may be susceptible
Fig. 8.22 Antibacterial spectrum for fluoroquinolones.
**New fluoroquinolones that have anti-anaerobic
activity may reach the veterinary market in the
future.
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