Goals and Objectives.

By the end of the lecture the student should be able to discuss the following about quinolone antibiotics:

1. Describe their mechanism of action and pharmacologic properties.

2. Describe their spectrum of activity.

3. Describe their major side effects and drug interactions.

4. Discuss their use in the clinical setting.

I. BACKGROUND

Nalidixic acid was the first member of the quinolone class of antimicrobials described in 1962. However, its limited spectrum of activity and the rapid development of resistance limited its usefulness. In the 1980's, modification of the quinolone ring including addition of a fluorine at position 6 (hence the name fluoroquinolone) led to agents with: 1) an increased antibacterial spectrum, and 2) improved pharmacokinetic properties. The terms fluoroquinolone and quinolone will be used interchangeably.

II. MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES

1. Inhibits bacterial DNA synthesis by interfering with DNA gyrase (bacterial topoisomerase II), which is an enzyme necessary for DNA replication.

2. Rapidly bactericidal.

3. Concentration-dependent bactericidal activity, which means that the extent of bacterial killing increases as drug concentrations increase.

4. Post-antibiotic effect is seen for some aerobic gram-positive and negative bacteria; the clinical significance of this finding is unknown.

1. Absorption.
   Well absorbed after oral administration (50% to >95%). Absorption of ciprofloxacin and ofloxcin result in blood levels comparable to their intravenous preparations. Thus, oral dosage formulations (and not the parenteral formulations) should be used if the patient is able to take oral medications.

2. Distribution.
   Urine, kidney, prostate tissue, lung, bone, stool, neutrophils, macrophages.

   Given this tissue distribution, the fluoroquinolones are very useful for the management of infections in these areas of the body.

3. Elimination.
   The kidneys are an important route of elimination; however the extent of elimination by the kidneys varies between agents. Appropriate references should be consulted for specific dosage reductions for various degrees of renal dysfunction.

Fluoroquinolone(a)	Dose(b)	F(c)	Renal	Effect of Food on Oral Absorption
Norfloxacin	400mg po Q12	35-70%	27%	may decrease(f)
Ciprofloxacin	250-750mg po Q12 200-400mg IV Q12(e)	70%	29%	---(g)
Ofloxacin	200-400mg po Q12 200-400mg IV Q12	98%	70%	slight decrease(h)
Enoxacin	200-400mg po Q12	88%	44%	decreased
Lomefloxacin	400mg po Q24	>95%	66%

a=quinolones available in the United States. b=when dosage range is given, the dose will depend in part, on the type and severity of infection. c=bioavailability. d=renal elimination. e=AUCs of the 400mg IV dose and 500mg oral dose are similar. AUCs of 200mg IV dose and 250mg oral dose are similar. f = recommended to take 1 hr before or 2 hr after meals. g=may take without regard to meals, however the manufacturer recommends the ideal time is 2 hrs after meals. h=manufacturer does not recommend taking with food, but since the rate and extent of absorption is only slightly decreased, can usually be taken without regard to meals.

V. SPECTRUM OF ACTIVITY

Fluoroquinolones are useful for infections caused by gram-negative bacilli. However currently marketed drugs in this county have only moderate activity against gram-positive bacteria and are therefore not the drugs of choice for infections caused by these bacteria. The currently available quinolones in the United States have no clinically useful anaerobic activity.

1. Gram-positive bacteria. Moderate activity against Streptococci and Staphylococci including some methicillin-resistant Staphylococci, although resistance to methicillin-resistant Staphylococci is now more frequent to quinolones.

2. Gram-negative bacilli. Excellent activity against pathogens seen in hospital-acquired infections such as the Enterobacteriaceae (Escherichia coli, Klebsiella species, Enterobacter species); community-acquired respiratory infections (Hemophilus influenzae and Moraxella catarrhalis); gastrointestinal infections (Salmonella, Shigella, Campylobacter, and Vibrio species) and sexually transmitted diseases (Neisseria gonorrhea and Chlamydia trachomatis). Ciprofloxacin is the most active quinolone against Pseudomonas aeruginosa. Other differences between quinolones for specific organisms exist and will be discussed under the individual agents.

3. Other. Some quinolones are used in combination with other antimycobacterial drugs for the treatment of Mycobacterium tuberculosis and Mycobacterium-avium-intracellulare.

Clinically significant resistance to Fluoroquinolones is an increasing problem worldwide. Overuse and exposure to quinolones are important risk factors for the emergence of resistance. Pseudomonas aeruginosa and Staphylococci are pathogens where resistance is becoming more commonplace.

1. Mechanisms of resistance

a. alterations in DNA gyrase
b. decreased permeability.

SIDE EFFECTS/PRECAUTIONS

1. Safety and efficacy in children <18 years has not been established and animal studies have demonstrated destruction to cartilage tissue. Specific literature should be consulted when the benefit of using quinolones in children outweighs the risk of using these agents.

2. Should not be used in pregnant or nursing women.

3. Tendon rupture, particularly the Achilles tendon has been reported. Quinolones should be discontinued at the first sign of possible tendon rupture (eg: pain, inflammation) and to refrain from exercise until the diagnosis of tendinitis is excluded.

4. Intravenous ciprofloxacin may cause irritation at the infusion site if the drug is infused over less than 60 minutes or a small peripheral vein is used.

1. Cation-containing compounds. Co-administration of fluoroquinolones with cation-containing compounds (eg: aluminum, magnesium, calcium, zinc, iron, sucralfate, the buffer in DDI ) results in the formation of cation-quinolone complexes which are poorly absorbed. Concurrent administration of nutritional supplements have also been found to decrease the absorption of quinolones because they may contain the divalent cations zinc and iron. Therapeutic failure may result from this significant drug interaction.

   *DDI or dideoxyinosine is used to treat HIV infection.

   Management of Interaction: Separate administration of quinolone and cation-containing compound. Use alternative therapies such as histamine blockers instead of antacids when appropriate.

2. Theophylline/Caffeine. By inhibiting the microsomal P450 enzymes involved in the metabolism of theophylline, increased concentrations of theophylline may occur. The effect on theophylline metabolism varies with the quinolone, enoxacin having the greatest effect (40-65% reduction in theophylline clearance), followed by ciprofloxacin (30% reduction in theophylline clearance), and norfloxacin, ofloxacin, lomefloxacin having the least effect (2-11% increase in theophylline levels).

   Management of Interaction. Monitor for clinical signs and symptoms of theophylline toxicity (nausea, vomiting, headache, insomnia, restlessness) and measure theophylline levels in patients receiving enoxacin or ciprofloxacin. No adjustment should be necessary in patients receiving norfloxacin, ofloxacin, or lomefloxacin.

3. Non-steroids anti-inflammatory drugs (NSAID). Concurrent use of the NSAID fenprofen has resulted in stimulation of the central nervous system (ie: seizures). The mechanism of this interaction may be displacement of the inhibitory neurotransmitter GABA from their receptors in the brain.

   Management of Interaction: Warn patients of the potential for stimulation of the central nervous system.

4. Warfarin. It is not clear if there is an interaction between warfarin (increase in prothrombin time) or cyclosporine (increase in cyclosporine levels). Close monitoring of prothrombin time and cyclosporine levels should be employed until more conclusive data are available.

Fluoroquinolones are effective agents for a variety of infections, including those listed below. However, because of the concern over resistance with indiscriminate use of these agents, in general, fluoroquinolones should be reserved for infections due to bacteria that are resistant to other less expensive antimicrobials or for use in patients unable to tolerate these other antimicrobials.

1. Urinary tract infections. Uncomplicated, complicated urinary tract infections, prostatitis. Only ofloxacin and ciprofloxacin are approved for prostatitis.

2. Sexually transmitted diseases.
   Neisseria gonorrhea. single doses of ciprofloxacin and ofloxacin can be used for uncomplicated urethritis, cervicitis, or rectal infections. Reports of fluoroquinolone-resistant gonococci are emerging.

   Chlamydia trachomatis. Ofloxacin is the only approved quinolone.

   Chancroid. Ciprofloxacin approved.

3. Gastrointestinal.

4. Respiratory tract.
   Community-acquired (eg: pneumonia, bronchitis, otitis). Should not be used alone as empiric therapy because of their inadequate activity against Streptococcus pneumoniae, one of the common pathogens in these infections. Quinolones would be effective alternatives when infections are caused by gram-negative bacteria such as Hemophilus influenzae, and Moraxella catarrhalis that are resistant to agents such as amoxicillin, trimethoprim/sulfamethoxazole.

   Hospital-acquired (eg:pneumonia). Have been effective for gram-negative pneumonia.

   Aspiration pneumonia. Should not be used because of their lack of activity against anaerobes.

   Atypical pneumonia (eg: Mycoplasma, Chlamydia, Legionella). Further studies are needed to determine the role of quinolones in these infections.

5. Bone and Joint. Gram-positive bacteria. Although data exists to demonstrate their effectiveness, quinolones are not the drugs of choice because of their moderate activity against Staphylococci, and tendency for resistance to develop.

   Gram-negative bacteria. Convenient alternative for long-term, outpatient therapy.

6. Skin and soft tissue. Not the drugs of choice because of moderate activity against gram-positive bacteria. For mixed infections with gram-positive and gram-negative bacteria, a quinolone can be combined with an agent such as clindamycin. Clindamycin is active against gram-positive bacteria and anaerobes.

1. Norfloxacin (NoroxinR). Poorly absorbed, and should not be used for infections outside the urinary tract.

2. Ciprofloxacin (CiproR). Most potent quinolone against Pseudomonas aeruginosa, a common cause of hospital-acquired infections. May be used as part of a combination regimen for Mycobacterium-avium-intracellularae infections in HIV patients. An ophthalmic preparation (Ciloxan(R)) for bacterial keratitis and conjunctivitis is available.

3. Ofloxacin (FloxinR). Similar spectrum of activity to ciprofloxacin, but is at least 4-fold less potent than ciprofloxacin against Pseudomonas aeruginosa. Ofloxacin is the most potent quinolone against Chlamydia trachomatis, a pathogen causing sexually transmitted diseases. An ophthalmic preparation of ofloxacin has been recently marketed.

4. Enoxacin (PenetrexR). Overall is less active against gram-negative aerobes than is ciprofloxacin and ofloxacin.

   Absorption is decreased in an alkaline environment as may occur with simultaneous administration of drugs that lower gastric acidity. Has the most potential to reduce theophylline clearance.

5. Lomefloxacin (MaxaquinR). Long half-life permits once daily dosing. Postmarketing surveillance has found this quinolone to be a more frequent cause of photosensitivity than was initially suspected.