fluoroquinolones

QuinolonesQuinolonesA new four‑generation classification of the quinolone drugs

takes into account the expanded antimicrobial spectrum of the more recently introduced fluoroquinolones and their clinical indications.

First‑generation drugs (e.g., nalidixic acid) achieve minimal serum levels.

Second‑generation quinolones (e.g., ciprofloxacin) have increased gram‑negative and systemic activity.

Third‑generation drugs (e.g., levofloxacin) have expanded activity against gram‑positive bacteria and atypical pathogens.

Fourth‑generation quinolone drugs (currently only trovafloxacin) add significant activity against anaerobes

QuinolonesQuinolones

The newer fluoroquinolones have broad‑spectrum bactericidal activity, excellent oral bioavailability, good tissue penetration and favorable safety and tolerability profiles

The quinolones can be differentiated within classes based on their pharmacokinetic properties.

The new classification can help family physicians prescribe these drugs appropriately. (Am Fam Physician 2000;61:2741‑8.)

QuinolonesQuinolonesThe original quinolone antibiotics included nalidixic acid

(NegGram), cinoxacin (Cinobac) and oxolinic acid (no longer available in the United States).

The addition of fluoride to the original quinolone antibiotic compounds yielded a new class of drugs, the fluoroquinolones, which have a broader antimicrobial spectrum and improved pharmacokinetic properties

Enhanced antimicrobial activity has extended the use of the fluoroquinolones beyond the traditional indications for quinolone antibiotics in the treatment of urinary tract infections.

QuinolonesQuinolones

The fluoroquinolones are effective in a wider variety of infectious diseases, including skin and respiratory infections.

Because of their excellent safety and tolerability, fluoroquinolones become popular alternatives to penicillin and cephalosporin derivatives in the treatment of various infections

The most recently released agents have significant antimicrobial activity against gram‑positive streptococci, atypical pathogens and anaerobes

FluoroquinolonesFluoroquinolones

The fluoroquinolones are broad‑spectrum antibiotics with particular activity against gram‑negative organisms,

especially Pseudomonas aeruginosa. These agents are well absorbed when given orally. Tissue and fluid concentrations often exceed the serum

drug concentration, making these antibiotics are particularly useful for certain .infections, such as pneumonia.

Fluoroquinolones are usually well tolerated, with few side effects. However, they can have serious adverse effects

FluoroquinolonesFluoroquinolonesThe most common adverse effects of the fluoroquinolones

are nausea, vomiting and diarrhea, which occur in 3 to 6 percent of recipients.

Other more serious but less common side effects are central nervous system effects (headache, confusion and dizziness), phototoxicity (more common with lomefloxacin [Maxaquin] and sparfloxacin [Zagam]), cardiotoxicity (sparfloxacin) and hepatotoxicity (trovafloxacin [Trovan]).

These drugs are not recommended for use in patients younger than 18 years or in pregnant or lactating

women

FluoroquinolonesFluoroquinolonesMechanism of ActionA. Blocks bacterial DNA synthesis by inhibiting bacterial

topoisomerase II (DNA gyrase) and topoisomerase IV.

B. Inhibition of DNA gyrase II prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication

C. Inhibition of topoisomerase IV interferes with the separation of replicated chromosomal DNA into respective daughter cells during cell division.


DNA Gyrase belongs to the topoisomerases which are involved in the replication, transcription, recombination and repair of bacterial DNA

Type II topoisomerase cleaves sugar-phosphate bonds in both DNA strands thus making possible the supercoiling required for the transition into the lag phase after cellular division.

This compact supercoiled order is necessary for the chromosome to be placed in the cell coat.

FluoroquinolonesFluoroquinolonesType I topoisomerase is needed to despiralize (uncoil) the

DNA in a single strand.

A stepwise decoiling takes place during the metabolic phases (formation of m-RNA.

Type II topoisomerase is required for final coiling.

DNA gyrase is a tetramer consisting of two different subunits ( two A and two B)


DNA gyrase causes an opening of DNA by binding of a hydroxyl group of a tyrosine residue of subunit A to a phosphate group

Supercoiling occurs where part of the DNA strand pulls through the opening. This step requires energy from subunit B, an ATPase.

The incision in the DNA molecule is sealed again by subunit A using energy gained by hydrolysis of a phosphate ester of tyrosine.


DNA gyrase inhibitors interfere with the sealing of DNA strands, leading to a rapid breakdown of metabolism in susceptible bacteria.

The effect of gyrase inhibitors is confined to bacteria because of different chromosomal configurations of DNA in higher organisms

FluoroquinolonesFluoroquinolonesThe fluoroquinolones are bactericidal antibiotics that act

by specifically targeting DNA gyrase. In contrast toaminoglycosides and beta‑lactams, some

fluoroquinolones are active against dormant and replicating bacteria.

Fluoroquinolones exhibit a postantibiotic effect following bacterial exposure to inhibitory concentrations. The antibacterial effect continues for approximately two to three hours after bacteria are exposed to these drugs, despite subinhibitory concentrations.

The duration of the postantibiotic effect may be increased with longer bacterial drug exposure and higher drug concentrations.

FluoroquinolonesFluoroquinolonesAntibacterial Activity

Anaerobes are generally resistant to fluoroquinolonesNorfloxacin - least active of fluoroquinolonesOfloxacin and Ciprofloxacin - inhibit gram negative cocci and

bacilli at low concentrations however little activity against streptococci (pneumococcus and enterococci), therefore these are not good for respiratory tract infections.

Levofloxacin (the L isomer of ofloxacin) and Sparfloxacin more active against staph and strep than cipro and ofloxacin.

Fluoroquinolones have activity against intracellular pathogens such as legionella, and chlamydia

fluoroquinolones have activity against some mycobacteria including myco. TB and MI/MA complex


Resistance Resistance appears to be the result of: alterations in the

quinolone enzymatic targets (DNA gyrase), decreased outer membrane permeability or the development of efflux mechanisms.

Resistance may result from one or more point mutations in the quinolone binding region of the target enzyme (topoisomerase II or IV) or from a change in the permeability of the organism (ability of the antibiotic to penetrate the cell membrane)


E. ColiDNA gyrase - primary target enzyme with Single step

mutants exhibiting amino acid substitution in the A subunit of gyrase

Topoisomerase IV - secondary target that is altered in mutants expressing higher levels of resistance

Staphylococci and StreptococciTopoisomerase IV is primary targetDNA gyrase is secondary target

FluoroquinolonesFluoroquinolonesResistance patterns in pneumococci (in Canada)

The prevalence of pneumococci with reduced susceptibility to fluoroquinolones increased significantly from 0% in 1988 and 1993 to 1.7% in 1997 and 1998.*

Among adults, the prevalence increased from 1.5% in 1993 and 1994 combined to 2.9% in 1997 and 1998 combined.

The greatest change in reduced susceptibility was seen in adults aged between 15 and 64 years; the prevalence of pneumococci increased from 0.5% in 1993 and 1994 to 2% in 1997 and 1998.

* Pneumococci with reduced susceptibility to fluoroquinolones were defined as those for which the minimum inhibitory concentration (MIC) of ciprofloxacin was => 4 µg/ml.


The number of fluoroquinolone prescriptions increased from 0.8 per 100 persons per year in 1988 to 5.5 per 100 persons per year in 1997.

Per capita use of fluoroquinolones was greatest among people aged => 65 years and in Ontario.

Resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa have also appeared

FluoroquinolonesFluoroquinolonesResistance to quinolones can also develop because of

alterations in bacterial permeability and the development of efflux pumps.

This resistance mechanism is shared with antimicrobial agents structurally unrelated to the quinolones, such as the beta‑lactams, tetracyclines and chloramphenicol (Chloromycetin).

Cross‑resistance among the quinolones is expected, but the extent to which the minimum inhibitory concentration is affected varies from agent to agent.

FluoroquinolonesFluoroquinolonesIn Vitro Efficacy Study

Isolates are from cancer patients who have been previously treated with antibiotics including beta‑lactams, aminoglycosides, and quinolones.

Clinical trials are needed to determine if differences from this in vitro study correspond to differences in clinical outcomes

Trovafloxacin, ciprofloxacin, levofloxacin, and sparfloxacin have comparable sensitivity profiles against gram‑negative bacteria.

Trovafloxacin appears to be the most active quinolone against gram‑positive bacteria.

FluoroquinolonesFluoroquinolonesAntibiotic Use During Pregnancy

Relatively SafePenicillins, Cephalosporins, Erythromycin base

Caution Advised Trimethoprin/Sulfamethazole, Metronidazole, Aminoglycosides, Chloramphenicol

Relatively Contraindicated Tetracyclines, Erythromycin estolate, Fluoroquinolones


The administration of fluoroquinolone antibiotics (ciprofloxacin, norfloxacin) is considered contraindicated during pregnancy. The fluoroquinolones have been shown to cause permanent lameness in immature animals. There are no reports of fetal defects in humans, but because of the irreversible nature of the lesion, it is prudent to completely avoid fluoroquinolones during pregnancy.

Additionally, norfloxacin has been embryocidal and slightly maternotoxic in cynomolgus monkeys receiving 10 times the equivalent therapeutic dose used in humans

FluoroquinolonesFluoroquinolonesSix new fluoroquinolones have been introduced in the

United States during the past five years. Levofloxacin (Levaquin) and sparfloxacin became

available in 1996. Grepafloxacin (Rexar) and trovafloxacin were introduced

in 1997. Gatifloxacin (Tequin) and moxifloxacin (Avelox) became

available in early 2000. In December 1999, grepafloxacin was voluntarily

withdrawn because of the possibility of torsades de pointes occurring with its use.

FluoroquinolonesFluoroquinolonesCompared with ciprofloxacin (the prototypical agent of

the original fluoroquinolones), the newest fluoroquinolones have enhanced activity against gram‑positive bacteria with only a minimal decrease in activity against gram‑negative bacteria.

Their expanded gram‑positive activity is especially important because it includes significant activity against Streptococcus pneumoniae

Levofloxacin has enhanced activity against S. pneumoniae, S. aureus and Enterococcus species, as well as good activity against Mycoplasma and Chlamydia species


Sparfloxacin has a further expanded spectrum of activity that includes some activity against anaerobes.

Sparfloxacin has even greater activity against Mycoplasma species.

Trovafloxacin is the fluoroquinolone with the most potent anaerobic activity, including activity against Bacteroides species. As a result, this agent has the broadest spectrum of activity of the currently available quinolones, as well as a wide range of indications

FluoroquinolonesFluoroquinolonesNadifloxacin (Acuatim) is a fluoroquinolone for topical

use. No FDA approval for use in USAAdverse effects of the topical 1% cream have included

local erythema and pruritusData regarding systemic absorption/pharmacokinetics are

lackingTopical nadifloxacin may be a useful alternative in acne

vulgaris and bacterial skin infectionsIts structure is similar to that of ofloxacin. Like other

fluoroquinolones, antimicrobial activity is achieved by inhibiting DNA gyrase (topoisomerase II)

FluoroquinolonesFluoroquinolonesThe first‑generation formulation included cinoxacin,

nalidixic acid and oxolinic acid. These early quinolones targeted gram‑negative organisms

including Escherichia coli, and Klebsiella and Proteus species.

Nalidixic acid was once the most commonly used preparation, but poor tissue and serum concentrations now limit its

use to the treatment of simple urinary tract infections. Its utility is also limited by its relatively short half‑life (requiring four doses daily), narrow spectrum of activity and the rapid development of bacterial resistance.

FluoroquinolonesFluoroquinolonesSecond‑generation quinolones have a fluorine substituent in

the main quinolone ring that significantly increases antibacterial activity.

These fluoroquinolones (ciprofloxacin, enoxacin, lomefloxacin, ofloxacin and norfloxacin) exhibit good activity against gram‑negative bacilli and moderate‑to‑good activity against Staphylococcus species.

Ciprofloxacin and ofloxacin have good tissue penetration and reach macrophages and polymorphonuclear leukocytes, making them useful beyond the treatment of urinary tract infections. In addition, their activity against Legionella pneumophila is good; their activity against Chlamydia pneumoniae and Mycoplasma pneumoniae is more variable


NorfloxacinLeast potent fluoroquinoloneNorfloxacin is a "second‑generation" quinoline carboxylic

acid antimicrobial agentNorfloxacin is primarily indicated in urinary tract infections

and gonorrhea. The ophthalmic solution may be used in the treatment of

conjunctivitis.

FluoroquinolonesFluoroquinolonesCiprofloxacin exhibits good activity against Pseudomonas

aeruginosa and strong gram‑negative activity that may be superior to that of ofloxacin.

Coverage against Streptococcus pneumoniae is inadequate, making the use of ciprofloxacin inappropriate in patients with community‑acquired pneumonia.

In summary, ciprofloxacin and ofloxacin are effective in treating (1) urinary tract infections caused by susceptible organisms, (2) respiratory tract infections caused by susceptible gram‑negative organisms, (3) skin and soft‑tissue infections and (4) osteomyelitis (ciprofloxacin only)

FluoroquinolonesFluoroquinolonesThe third‑generation fluoroquinolones (grepafloxacin,

levofloxacin and sparfloxacin) have expanded coverage against streptococci and atypical organisms.

This attribute has improved the usefulness of fluoroquinolones in treating patients with community‑acquired pneumonia acute sinusitis and acute exacerbations of chronic bronchitis, which are their primary FDA‑labeled indications.

Activity against Haemophilus influenzae and Moraxella catarrhalis is high,

Activity against other gram‑negative bacteria, especially P. aeruginosa, is less than that of ciprofloxacin


All third‑generation fluoroquinolones are taken once daily. In patients with renal disease, dose adjustment for

levofloxacin and sparfloxacin is necessary. In summary, this generation of fluoroquinolones is useful in

treating patients with the following conditions: (1) - community‑acquired pneumonia and bacterial

exacerbations of acute bronchitis, (2) - urinary tract infections and (3) - skin or skin‑structure infections.

FluoroquinolonesFluoroquinolonesLevofloxacin does not affect the QT interval.The fluoroquinolone ofloxacin exists as 2 optically‑active

isomers due to its asymmetric center at C3 of the oxazine ring.

Levofloxacin is the S(‑)‑enantiomer of ofloxacin, and is considered primarily responsible for the clinical antibacterial efficacy of the racemate .

It is reportedly 8 to 128 times more potent than R(+)‑ofloxacin (DR‑3354), and twice as potent as racemic ofloxacin.

Results of some animal studies suggest that levofloxacin may have a lower propensity for adverse central nervous system effects than ofloxacin

FluoroquinolonesFluoroquinolonesFourth‑generation fluoroquinolones (clinafloxacin, gatifloxacin,

moxifloxacin and trovafloxacin) add significant anaerobic coverage.

A long half‑life allows once‑daily dosage, and extensive hepatic metabolism makes dose adjustment unnecessary in patients with renal disease.

Indications for use include nosocomial pneumonia, intra‑abdominal infections and serious penicillin‑ or cephalosporin‑resistant S. pneumoniae infections.

Gatifloxacin has FDA‑labeled indications for urinary tract infections and gonorrhea.

FluoroquinolonesFluoroquinolonesBecause of reports of rare but serious liver injuries, the U.S.

Food and Drug Administration issued an advisory notice (June 1999) that trovafloxacin should be reserved for use in patients meeting all of the following criteria: (1) management of a life‑ or limb‑threatening disease, (2) treatment should be initiated in an inpatient setting and (3) the physician believes that the benefit of the product for the patient outweighs the potential risk.

Dosage duration should be no longer than 14 days, and therapy should be discontinued if clinical symptoms of liver dysfunction are present.

FluoroquinolonesFluoroquinolonesSparfloxacin carries a significant risk of phototoxicity.Grepafloxacin, sparfloxacin and moxifloxacin have been

reported to cause prolongation of the QT interval; Gatifloxacin has not been reported to cause QT prolongation. The FDA recommends that all of these drugs should be

avoided in patients who are taking drugs that are known to prolong the QT interval, such as tricyclic antidepressants, phenothiazines and class I antiarrhythmics.

Levofloxacin does not affect the QT interval.Rapid bolus intravenous injection may cause hypotension;

administer over a period of not less than 60 minutes

Cost of Fluoroquinolone Therapy

Agent Usual Dose Cost in DollarsNorfloxacin (Noroxin) 400 mg twice daily orally 68Lomefloxacin (Maxaquin) 400 mg per day orally 66Enoxacin (Penetrex) 200 to 400 mg b.i.d. orally 62 to 65Ofloxin (Floxin) 200 to 400 mg b.i.d. orally 75 to 94

400 mg every 12 hours I.V. 158Ciprofloxacin (Cipro) 250 to 750 mg b.i.d. orally 68 to 80

400 mg every 12 hours I.V. 69 to 81Levofloxacin (Levaquin) 250 to 500 mg per day orally 69 to 81

500 mg every 24 hours I.V. 119

Cost of Fluoroquinolone Therapy

Agent Usual dose Cost in DollarsSparfloxacin(Zagam) 200 mg per day orally 67Gatifloxacin (Tequin) 400 mg per day orally 70

400 mg every 24 hours I.V. 119Moxifloxacin (Avelox) 400 mg per day orally 87Trovafloxacin (Trovan) 100 to 200 mg per day orally 59 to 72Alatrofloxacin (Trovan) 200 mg every 24 hours I.V. 111

‑Estimated cost to the pharmacist (rounded to the nearest dollar) for 10 days of oral therapy or three days of intravenous treatment, based on average wholesale prices in Red book. Montvale, N.J.: Medical Economics Data, 2000. Cost to the patient will be higher, depending on prescription filling fee.

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fluoroquinolones