QUINOLONES

Copyright, Purdue Research Foundation, 1996

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NOTE: Outline (brief) version is more current and has more drugs of veterinary relevance

Nalidixic acid [NegGram[R]] has been used as a primary agent in the treatment of urinary tract infections suspected to be caused by gram negative bacteria. It is not approved for systemic infections and rapid development of resistance is a problem. During the 1980s, fluorinated derivatives of related quinolones were introduced. These fluoroquinolones are useful for treating infections caused by some gram positive organisms as well as the expected gram negative organisms and possess pharmacokinetic characteristics that render them suitable for treating systemic infections. Enrofloxacin [Baytril[R]] is a derivative produced exclusively for veterinary applications. Norfloxacin [Noroxin[R]] and ciprofloxacin [Cipro[R]] are derivatives that have been approved for human applications.

Structure and Chemical Characteristics

The quinolones are carboxylic acids and contain a quinolone ring. Systemically effective, broad spectrum quinolones possess a fluoro group on the main ring. The fluoroquinolones also contain protonatable nitrogens and, therefore, can exist as zwitterions. Simple predictions about effect of pH on ion trapping cannot be made. The activity of the quinolones is reduced by acidic pH, urine(!), bivalent cations (e.g., Mg++), and large inocula. The piperazinyl group confers activity against some Pseudomonas spp. and the Fluorine atom increases activity against gram-positive bacteria.

Mechanism of Action

Manufacturers of fluoroquinolones emphasize the fact that these drugs have very different mechanisms of action from such groups as the beta-lactams and aminoglycosides. Although the exact mechanism is unknown, it is known that the quinolones inhibit the A subunit of DNA gyrase in bacteria. The gyrase, a type II topoisomerase, nicks and seals DNA during replication. Without the gyrase, DNA cannot be replicated, then repacked in daughter cells. The quinolone action also inhibits relaxation of supercoiled (packed) DNA necessary for DNA replication and increases double-stranded DNA breakage.

The gyrase action is required for replication of plasmids. Therefore, the fluoroquinolones may reduce plasmid mediated resistance, even to non-quinolone antimicrobials. Nonetheless, organisms do become resistant to the quinolones.

The quinolones are bactericidal at concentrations only 1 to 4 times the MIC.

Resistance

Rapid development of resistance to nalidixic acid has already been mentioned. The rate of resistance is increased by insufficient dosage as is often caused by lack of patient compliance with drugs that must be given qid.

In contrast, resistance develops slowly to the fluoroquinolones via mutation. The mechanism of resistance is either reduction of gyrase affinity for the quinolone or decreased penetration into the bacterial cell. Certain cell membrane proteins required for penetration are missing in some resistant organisms.

There is cross resistance among the fluoroquinolones, but nalidixic acid resistant strains are usually susceptible to the newer derivatives.

Pharmacokinetics

The quinolones are available in oral dose forms.

Absorption/administration

The quinolones are available in oral dose forms. Absorption from the GI tact is rapid. Bioavailability of the fluoroquinolones is greater than 70% (humans). Enrofloxacin may be greater than 80% in dogs.

Distibution

Nalidixic acid is useful only for urinary tract infections because therapeutic systemic concentrations cannot be achieved.

The fluoroquinolones have low plasma protein binding. Because they are small they can cross cellular membranes. Ciprofloxacin, a zwitterion, has good tissue penetration and accumulates in tissues such as the prostate. In fact, distribution throughout the body is said to be wide. Tissue concentrations of fluoroquinolones are higher than those of plasma. The Vd in humans for Ciprofloxacin is 2 to 3 L/kg, greater than the total body water.

Peak serum concentrations following a standard oral dose of 400 to 500 mg to a human are 1 to 3 mcg/ml for ciprofloxacin and norfloxacin. Concentrations achieved in urine range from 100 to 650 mcg/ml, far exceeding the MIC for most urinary bacterial pathogens.

Serum concentration at 1 hour (peak) for enrofloxacin in dogs after a single oral dose of 2.5 mg/kg (1.13 mg/lb) was approximately 1 mcg/ml (Mobay). Concentration (mcg/ml or mcg/g) at 2 hours in selected dog tissues was as follows: urine (43); eye fluids (0.53); liver (3.02); prostate (1.36); skin (0.66); brain (0.25); and mammary gland (0.45). MICs (mcg/ml) for selected common canine pathogens were reported to be as follows: Bordetella bronchiseptica (0.125-0.5); Clostridium perfringens (0.5); Escherichia coli (<=0.016 to 2.0); Pseudomonas aeruginosa (0.5 to 8); Staphylococcus spp. (coag. +) (0.125 to 0.5); and Streptococcus spp. (alpha hemol.) (0.5 to 8).

Elimination

Elimination is primarily via renal excretion of the active drug. The elimination is probenecid sensitive. Elimination half-life of enrofloxacin is greater than 3 hr in the dog. In humans the normal half-life for ciprofloxacin and norfloxacin is 3 to 4 hours. In patients with renal failure the half-life of these 2 drugs increases to 5 to 10 hours.

Adverse effects

The fluoroquinolones are generally very well tolerated. In humans, adverse effects are lower than for trimethoprim - sulfonamide. The most frequent complaints (<=3%) are mild: nausea, upper gastrointestinal discomfort, and dizziness. Rarely are these severe enough to warrant stopping the drug.

Joint toxicity

The drugs accumulate in and damage joint cartilage. This is especially severe in the young during rapid growth. Therefore the drug is contraindicated in humans younger than 18 years old; small and medium dogs between the ages of 2 and 8 months; and in large breeds for up to 18 months. Use during severe exercise may also be hazardous to joints. Company literature claims that enrofloxacin is not contraindicated for kittens, but this claim should be treated with scepticism until more evidence is available. Why should the cat be so different from other species in its handling of cartilaginous development?

[NOTE: Need to check current ages for indications ... seems to be a moving target '95.

According to Dr. David VanSickle (personal communication, April 1995), Fluoroquinolones are not damaging to cartilage in Beagle dogs after 6 months of age. This is after the time that the tide mark which is betwen the underlying calcified cartilage and overlying non-mineralized articular cartilage has disappeared. Once this disappears, drug apparently cannot diffuse easily into the sites where it causes problems.

When Beagle dogs are given 250 mg/kg (5x normal dose), the drug comes from vessels surrounding the joint to the area between the epiphyseal cartilage and the enlage of the articular cartilage. This shreds the cartilage.

There is no information regarding the effect of quinolones on joints of horses, but there is a good chance of harm. The dog is the most sensitive. Primates also have a problem. Biomechanics of the joint drive the drug into the cartilage, therefore, the toxicity is seen in weight bearing joints.

Drug interaction

These drugs may interfere with hepatic biotransformation of theophylline and warfarin.

Indications

These drugs are generally inactive against anaerobes.

Claimed indications for enrofloxacin [Baytril[R]] in dogs are: dermal infections (wounds and abscesses) caused by susceptible strains of E. coli, Klebsiella pneumoniae, Proteus mirabilis, and Staphylococcus aureus, [Pseudomonas aeruginosa if increase dose -- Bowersock'95]; respiratory infections (pneumonia, tonsilitis, rhinitis) caused by susceptible strains of E. coli and Staphylococcus aureus; and urinary cystitis caused by susceptible strains of E. coli, Proteus mirabilis, and Staphylococcus aureus. Swine: Salmonellae.

In humans, norfloxacin is generally regarded as effective for urinary tract infections. Ciprofloxacin is indicated for a wide range of systemic infections including pneumonias, bone infections, diarrhea, skin infections and urinary tract infections.

Norfloxacin has been used in dogs for Enterococcus infections. Norfloxacin is better for enteric Streptococci than enrofloxacin or ciprofloxacin (Bowersock'95)

References

USPDI91: USP Drug Information for the Health Care Professional, 11th edition, 1991. U.S. Pharmacopeial Convention, Inc., Rockville, MD.

Walker, R.C. and A.J. Wright. The Quinolones. Mayo Clin Proc 62:1007-1-12, 1987.

Mobay/Haver promotional material for Baytril[R], December 1988.

Study Questions

1. How does the spectrum of action of nalidixic acid differ from those of the newer fluoroquinolones?

2. How does the tendency for bacteria to develop of resistance to fluroquinolones compare with nalidixic acid?

3. How do the sites of susceptible infections compare for nalidixic acid versus the fluoroquinolones?

4. What tissue is most susceptible to quinolone toxicity? Are they usually very toxic otherwise?

5. Should quinolone derivatives be used in rapidly growing animals and humans?

6. On what is the manufacturer's claim based that fluoroquinolones cannot be cross-resistant with other antiinfective agents?

7. Note: "Outline" version has more questions


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Gordon L. Coppoc, DVM, PhD
Professor of Veterinary Pharmacology
Head, Department of Basic Medical Sciences
School of Veterinary Medicine
Purdue University
West Lafayette, IN 47907-1246
Tel: 317-494-8633Fax: 317-494-0781
Email: coppoc@vet.purdue.edu

Last modified 5:15 PM on 4/16/96 GLC