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The New Fluoroquinolones: A Review of Their Properties
The latest generation of agents is the most useful
and potent yet, but with their power and versatility come the danger
of inappropriate use and development of bacterial resistance, making
careful patient selection vital.
By Maryam Behta, PharmD, Kamran M. Khan, MD, and Barry J. Hartman, MD
| Dr. Behta is clinical coordinator of infectious diseases in the department of pharmacy at Weill Cornell Medical Center and Drs. Khan and Hartman are a fellow in the department of medicine and a clinical professor of medicine, respectively, at Cornell University Medical College in New York, New York. |
Since the introduction of ciprofloxacin in 1987, fluoroquinolones have expanded far beyond their early role in the treatment of urinary tract infections. Their ease of administration, favorable pharmacokinetic properties, excellent tolerability, and efficacy give them enormous potential for use and misuse alike. While possessing many of the favorable properties of intravenous agents, most fluoroquinolones offer the convenience of oral administration, thus contributing to decreased health-care costs through increased outpatient therapy and shortened hospital stays. However, because fluoroquinolone resistance has already begun to appear, correct administration of these versatile agents is critical. This article reviews the properties of the newer fluoroquinolones, focusing on their appropriate use in the clinical setting.
MECHANISM OF ACTION AND RESISTANCE
The bactericidal activity generated by fluoroquinolones is caused by their inhibition of bacterial DNA gyrase and topoisomerase IV enzymes. DNA gyrase is essential for the replication, transcription, and repair of bacterial DNA, and topoisomerase IV is involved in the partitioning of chromosomal DNA during cell wall division. By inhibiting those enzymes, fluoroquinolones keep cellular bacterial DNA in a supercoil state, thereby preventing bacterial replication.
Fluoroquinolones are active in both the replicating and nonreplicating regions of the bacterial chromosome. As a result, fluoroquinolone resistance is generally chromosomally mediated and occurs by one of two methods. In some instances, the bacterial DNA gyrase enzyme is altered, leading to decreased fluoroquinolone affinity. In other cases, intracellular drug accumulation is decreased as a result of reduced drug permeability and the development of an enhanced efflux mechanism. Fluoroquinolone resistance has increased considerably in recent years, largely owing to inappropriate dosage and administration in both humans and animals. Resistance to one fluoroquinolone typically, but not always, implies cross-resistance to other fluoroquinolones in the same class.
The bactericidal activity of the fluoroquinolones is dependent on drug concentration. For optimal effectiveness, the plasma concentration of these agents should be two to four times the minimum inhibitory concentration of the bacterium. Fluoroquinolones, like aminoglycosides, demonstrate a postantibiotic effect, whereby bacterial growth continues to be inhibited even after the plasma concentration of the drug has fallen below the minimum inhibitory concentration of the bacterium. This postantibiotic effect generally persists for two to three hours, although under certain circumstances it can last as long as six hours.
SPECTRUM OF ACTIVITY
The fluoroquinolones currently approved by the United States Food and Drug Administration (FDA) are categorized into four generations, each with varying bacterial coverage (see tables below). Compared with their second-generation predecessors, the third- and fourth-generation fluoroquinolones are only slightly less active against gram-negative pathogens and are significantly more active against gram-positive organisms, such as streptococci, atypical pathogens, and, in some cases, anaerobes. Although many of the newer fluoroquinolones demonstrate greater activity against staphylococci and enterococci, considerable resistance to these agents has been noted, particularly among methicillin-resistant Staphylococcus aureus and Enterococcus faecium isolates. In addition to the enhanced coverage mentioned above, newer agents such as moxifloxacin and trovafloxacin are highly active against anaerobes.
|
Examples of Available Fluoroquinolones
|
| Generation |
Generic name |
Brand name (manufacturer) |
Year of FDA
approval |
| First |
Nalidixic acid |
NegGram (Sanofi) |
|
| Second |
Norfloxacin
Ciprofloxacin
Ofloxacin
Enoxacin
Lomefloxacin |
Noroxin (MSD)
Cipro (Bayer)
Floxin (Ortho)
Penetrex (Aventis)
Maxaquin (Searle) |
1986
1987
1990
1991
1992 |
| Third |
Levofloxacin
Sparfloxacin
Gatifloxacin |
Levaquin (Ortho)
Zagam (Aventis)
Tequin (BMS) |
1996
1996
1999 |
| Fourth |
Trovafloxacin
Moxifloxacin |
Trovan (Pfizer)
Avelox (Bayer) |
1997
1999 |
|
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Spectrum of Fluoroquinolone Activity
|
| |
Pathogen
|
| Drug |
Gram-
positive |
Gram-
negative |
Anaerobic* |
Pseudo-
monas species |
Atypical† |
STD
organ-
isms‡ |
| Ofloxacin |
+ |
+++ |
0 |
++ |
+++ |
+++ |
| Ciprofloxacin |
+ |
++++ |
0 |
++++ |
++§ |
++§ |
| Levofloxacin |
++" |
+++ |
+ |
+++ |
+++ |
+++ |
| Sparfloxacin |
++" |
+++ |
+ |
0 |
+++ |
+++ |
| Gatifloxacin |
++" |
+++ |
+ |
++ |
+++ |
+++ |
| Moxifloxacin |
++" |
+++ |
++ |
++ |
+++ |
+++ |
| Trovafloxacin |
++" |
+++ |
+++ |
++ |
+++ |
+++ |
| * |
Only moxifloxacin and trovafloxacin produce reliable anaerobic actvity. |
| † |
Includes Legionella pneumophila, Mycoplasma
pneumoniae and Chlamydia pneumoniae. |
| ‡ |
Includes Neisseria gonorrhea, Mycoplasma
hominis, Chlamydia trachomatis, and Ureaplasma
urealyticum. |
| § |
Not reliably active against Chlamydia trachomatis
or Chlamydia pneumoniae. |
| " |
Activity against streptococci is enhanced; may
be active against some isolates of MRSA
and enterococci. |
|
|
Although the newer agents offer a much broader spectrum of action, ciprofloxacin remains the most effective fluoroquinolone against gram-negative pathogens, including Pseudomonas aeruginosa. It should be noted that sparfloxacin is unusual among the fluoroquinolones in that it is not highly active against P. aeruginosa.
Nearly all of the fluoroquinolones, including the second-generation agents, are highly active against atypical pathogens, such as Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila, and certain sexually transmitted organisms, such as Neisseria gonorrheae, Mycoplasma hominis, Chlamydia trachomatis, and Ureaplasma urealyticum. One exception, however, is ciprofloxacin, which is not reliably active against C. trachomatis and C. pneumoniae.
Although not approved by the FDA for use against mycobacterial infections, several fluoroquinolones are active against Mycobacterium tuberculosis and certain atypical mycobacteria (see table below). Ofloxacin, ciprofloxacin, levofloxacin, and sparfloxacin may be effective against some strains of M. tuberculosis, although none of these agents should be considered for first-line therapy. Atypical or nontuberculous mycobacteria, such as Mycobacterium avium-intracellulare, Mycobacterium fortuitum, Mycobacterium chelonae, and Mycobacterium abscessus, may also be susceptible to agents such as ofloxacin and ciprofloxacin, which are generally given in combination with other drugs.
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FDA-Approved Indications for Fluoroquinolone Therapy
|
Clinical
indications |
Oflox-
acin |
Ciproflox-
acin |
Levoflox-
acin |
Sparflox-
acin |
Gatiflox-
acin |
Moxiflox-
acin |
Trovaflox-
acin* |
| Uncomplicated UTI |
Yes
|
Yes
|
Yes
|
|
Yes
|
|
Yes
|
Complicated UTI and
pyelonephritis |
Yes
|
Yes
|
Yes
|
|
Yes
|
|
|
| Prostatitis |
Yes
|
†
|
|
|
|
|
Yes
|
Uncomplicated urethral, cervical, and rectal
gonorrhea‡ |
Yes
|
Yes
|
|
|
Yes
|
|
Yes
|
| Nongonococcal urethritis and cervicitis |
Yes
|
|
|
|
|
|
Yes
|
| Pelvic inflammatory disease |
§
|
"
|
|
|
|
|
Yes
|
| Infectious diarrhea¶ |
|
Yes
|
|
|
|
|
|
| Intraabdominal and pelvic infections |
|
|
|
|
|
|
Yes
|
| Acute sinusitis |
|
Yes¥
|
Yes
|
†
|
Yes
|
Yes
|
Yes
|
| Acute exacerbations of chronic bronchitis |
|
|
Yes
|
Yes
|
Yes
|
Yes
|
Yes
|
| Community-acquired pneumonia |
|
|
Yes
|
Yes
|
Yes
|
Yes
|
Yes
|
| Nosocomial pneumonia |
|
|
|
|
|
|
Yes
|
| Uncomplicated skin
and soft tissue infection** |
Yes
|
Yes
|
Yes
|
|
|
Yes
|
|
| Complicated skin and soft tissue infection** |
|
|
|
|
|
Yes
|
|
| Gram-negative infection of bone or joint |
|
Yes
|
|
|
|
|
|
| * |
Therapy indicated only for limb- or life-threatening infections in hospitalized patients. |
| † |
Not FDA approved for this indication but clinical experience supports its use. |
| ‡ |
Resistance to fluoroquinolones increasing, especially
in Asia and Cleveland, Ohio; provide treatment
for concomitant Chlamydia infection. |
| § |
May be used in combination with metronidazole. |
| " |
May be used in combination with metronidazole and doxycycline |
| ¶ |
Campylobacter jejuni resistance to fluoroquinolones
increasing in Thailand, North Africa, Mexico,
and Spain. |
| ¥ |
Streptococcus pneumoniae resistance to cirpofloxacin is increasing. |
| ** |
Methicillin-resistant Staphylococci isolates
may be highly resistant to fluoroquinolones |
|
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PHARMACOKINETIC PARAMETERS
Most fluoroquinolones are taken orally, once or twice a day, making them convenient for use in outpatient therapy. After they are absorbed, these agents penetrate well into extravascular spaces and tissues where drug concentrations often exceed the serum levels. They distribute well into ascitic and pleural fluids and to a lesser extent into saliva, bone, and cerebrospinal fluid.
Most of the fluoroquinolones are eliminated primarily through glomerular filtration and tubular secretion in the kidney. For that reason, patients with renal impairment, as evidenced by a creatinine clearance of less than 30 mL/min, should be given lower doses. Although many fluoroquinolones are also significantly metabolized by hepatic glucuronidation or conjugation, only trovafloxacin has the potential to induce hepatic insufficiency and should therefore be administered with caution.
PEDIATRIC ADMINISTRATION
Numerous studies have demonstrated that the fluoroquinolones are generally safe, well tolerated, and effective when administered to adults. Several animal studies, however, have shown that these agents can have adverse effects on joint and cartilage development, a finding that raises concerns about the suitability of these drugs for children. Currently, in view of the potential developmental effects, none of the fluoroquinolones are approved for patients younger than 18 years of age or for pregnant or lactating women.
Accumulating clinical data, however, suggest that the potential effects on joint and cartilage development may not be as significant in humans as they are in animals. Over the past decade, fluoroquinolones have been used increasingly to treat infections in children. Several retrospective studies have documented mild and infrequent joint symptoms, most of which were noted in children and adolescents with cystic fibrosis. The association between cystic fibrosis and hypertrophic pulmonary osteoarthropathy and the so-called cystic fibrosis arthropathy has led to further questioning of the connection between fluoroquinolones and joint disease. Studies involving magnetic resonance imaging have also been performed on children receiving fluoroquinolone therapy and have not demonstrated pathologic changes in the joints or cartilage. As a result, a growing number of physicians believe that for some children, especially those with cystic fibrosis, fluoroquinolone therapy should be considered on a risk-benefit basis, particularly when other antimicrobial agents are either ineffective or unavailable.
ADVERSE EFFECTS
Fluoroquinolones are generally well tolerated. The most common complications affect the gastrointestinal tract and the central nervous system. Gastrointestinal side effects occur in 2% to 13% of patients and include nausea, vomiting, and diarrhea. Central nervous system effects occur in 1% to 8% of patients and include headache, dizziness, agitation, and sleep disturbances. Other, uncommon reactions include rash, hemolytic anemia, and elevated liver enzyme or bilirubin levels. High-dose or prolonged therapy may increase the likelihood of adverse drug reactions.
Two major complications that have recently gained attention are tendinitis and Achilles tendon rupture. These events have been reported with norfloxacin, ciprofloxacin, and ofloxacin; however, it is conceivable that all fluoroquinolones carry the same risk. The pathogenesis of this effect remains unknown; it can occur unilaterally or bilaterally, anywhere from 1 to 90 days after the initiation of therapy. Although fluoroquinolone-related tendinitis generally resolves within one week of discontinuation of therapy, spontaneous ruptures have been reported as long as nine months after cessation of fluoroquinolone use.
Sparfloxacin, and to a lesser extent gatifloxacin and moxifloxacin, can potentially exacerbate QT prolongation. These agents therefore are contraindicated for patients with known QT prolongation or those receiving other drugs that can cause QT prolongation or torsades de pointes. Approximately 6% to 7% of patients taking sparfloxacin suffer other adverse cardiovascular effects, such as hypotension, cardiac insufficiency, vascular embolism, and tachyarrhythmia. Another 2% to 7% of patients taking sparfloxacin may be photosensitive to ultraviolet A light.
In June 1999, the FDA issued an advisory about the possibility of fulminant hepatotoxicity being caused by the use of trovafloxacin. The warning came after 14 cases of acute liver failure, some of which led to liver transplantation or death, were linked to the drug. Since that time, the FDA has recommended limiting trovafloxacin therapy to inpatients with serious limb- or life-threatening infections, for whom the potential benefits clearly outweigh the risks. Whenever trovafloxacin is given, liver enzyme levels must be closely monitored for hepatitis or liver failure, and the regimen should be limited to no more than 14 days.
The FDA has assigned fluoroquinolones to pregnancy risk category C, indicating that these drugs have the potential to cause teratogenic or embryocidal effects. Giving fluoroquinolones during pregnancy is not recommended unless the benefits justify the potential risks to the fetus. These agents are also excreted in breast milk and should be avoided during breast-feeding if at all possible.
DRUG INTERACTIONS
Most clinically significant drug interactions with the fluoroquinolones occur in the gastrointestinal tract and cause the latter to be inadequately absorbed (see table, below). This interaction usually occurs as a result of chelation between the active ingredients of the fluoroquinolone with cationic elements, such as calcium, magnesium, iron, or zinc. Fluoroquinolones therefore should not be administered simultaneously with any other medications or products containing high concentrations of those elements.
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Interactions Between Fluroquinolones and Other Drugs
|
| Medication |
Interaction |
Comments |
| Antacids containing magnesium or aluminum
Products containing calcium, magnesium, iron, and zinc |
All fluroquinolones: decreased absorption caused by chelation |
Separate doses by at
least 2 hrs. Also consider supplemental nutrients (e.g.,
Ensure products) that may contain high concentrations
of these elements. |
| Sucralfate |
All fluroquinolones: decreased absorption |
Avoid during therapy. If absolutely necessary,
separate doses by 2 hrs. |
| Didanosine (ddl) |
All fluroquinolones: decreased absorption |
Interaction involves
binding of the fluroquinolone to aluminum and magnesium
cations used as buffers in didanosine formulation. Separate
doses by 2 hrs. |
| Warfarin |
All fluroquinolones: unknown mechanism, possible decrease of warfarin metabolism |
Monitor PT and INR levels for possible
elevation. |
| Theophylline |
Ciprofloxacin:decreases theophylline metabolism |
Monitor theophylline
levels for possible elevation. |
| Caffeine |
Ciprofloxacin and trovafloxacin:decrease
caffeine metabolism |
Caffeine levels may be elevated. |
| Phenytoin |
All fluroquinolones: unknown mechanism, may alter phenytoin levels |
Monitor phenytoin levels for possible
elevation or depression. |
| Erythromycin and azithromycin
Tricyclic antidepressants and phenotiazines
Class I and III antiarrhythmics
Cisapride, terfenadine and pentamidine |
Sparfloxacin |
To avoid adverse effects on QTc interval,
do not administer sparfloxacin concurrently with these
agents or to patients who have prolonged QTc interval
or hypokalemia. |
| Morphine |
Trovafloxacin (oral administration only): mechanism unknown |
Morphine decreases oral absorption of
trovafloxacin |
|
Other drug interactions may result from fluoroquinolone-induced alterations of hepatic pathways with subsequent impairment of drug metabolism. In addition, the central nervous system stimulation seen with fluoroquinolones may be enhanced by nonsteroidal antiinflammatory drugs through displacement of gamma-aminobutyric acid from its receptors.
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Suggested Reading
Blondeau JM: Expanded activity and utility of the new fluoroquinolones: a review. Clin Ther 21:3, 1999.
Cambau E, et al.: Mechanisms of resistance to quinolones. Drugs 45(Suppl 3):15, 1993.
Casparian JM, et al.: Quinolones and tendon ruptures. South Med J 93(5):488-91, 2000.
Dagan R: Fluoroquinolones in pediatrics-1995. Drugs 49(Suppl 2): 92, 1995.
Giamarellou H: Activity of quinolones against gram-positive cocci: Clinical features. Drugs 49(Suppl 2):58, 1995.
Harrel RM: Fluoroquinolone-induced tendinopathy: What do we know? South Med J 92(6):622, 1999.
Hooper DC: New uses for new and old fluoroquinolones and the challenge of resistance. Clin Infect Dis 30:243, 2000.
Lipsky BA, et al.: Fluoroquinolone toxicity profiles: A review focusing on newer agents. Clin Infect Dis 28:352, 1999.
Stein GE: Pharmacokinetics and pharmacodynamics of newer fluoroquinolones. Clin Infect Dis 23(Suppl 1):S19, 1996.
Walker RC: The fluoroquinolones. Mayo Clin Proc 74:1030, 1999. |
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