The New Fluoroquinolones
Special Feature
The New Fluoroquinolones
By Richard A. Harrigan, MD, FAAEM
Pharmacology is a rapidly changing field, with new drugs entering the market seemingly each week. Maintaining an up-to-date working knowledge of antibiotics is especially challenging to the emergency physician. Not only is the antibiotic armamentarium swiftly expanding, but bacterial sensitivity to existing antibiotics also is a dynamic construct. Perhaps one of the most rapidly developing groups of antimicrobials is the fluoroquinolone (FQ) class, with the last 12 months seeing the withdrawal from the market of two relatively new agents (grepafloxacin and trovafloxacin) and FDA approval of a pair of new FQs (moxifloxacin and gatifloxacin). The following review will focus on the newest FQ antibiotics: sparfloxacin; levofloxacin; moxifloxacin; and gatifloxacin. The salient differences with regard to absorption, elimination, drug interactions, adverse effects, and toxicity will be reviewed for these newer agents, highlighting similarities and differences with respect to earlier-generation FQs.
Fluoroquinolones: Background and General Characteristics
Descending from nalidixic acid, the FQs have evolved through several "generations." They share a common bicyclic structural base, with varying side chain substitutions leading to different (and improved) pharmacologic activity and new profiles regarding absorption, elimination, and adverse effects.1 There is some variability in the literature regarding classification of these agents into generations;1,2 awareness of the specific generation is less important than an understanding of the differences between the newer and older agents.
All FQs act by inhibiting the activity of DNA gyrase, which subsequently leads to impaired bacterial replication and rapid cell death.1 They are bactericidal. Interestingly, they exhibit little cross resistance with other antibiotics,1 which may be advantageous, yet can lead to surprising cases of isolated FQ resistance, too.3 (See related story in this issue, p. 6.) Intra-class cross-resistance should not be assumed, either.1 The newer FQs are notable for their enhanced antimicrobial activity, broader clinical indications, longer duration of effect (leading to less frequent administration), and high cost. (See Table 1.) The newer agents feature improved activity against gram-positive, anaerobic, and atypical pathogens.2 Older FQs (e.g., ciprofloxacin, norfloxacin, and ofloxacin) have well-established roles in the treatment of urinary tract nfections, sexually transmitted diseases, and in some cases (e.g., ciprofloxacin) inflammatory diarrhea. The newer agents all feature the FDA-approved indications of acute exacerbation of chronic bronchitis and community-acquired pneumonia. Indications shared by sparfloxacin and moxifloxacin are limited to these, whereas gatifloxacin and levofloxacin have broader indications that include these two syndromes. All new FQs are active against the most common pathogens seen in community-acquired pneumonia: Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Moraxella catarrhalis.4 Indeed, levofloxacin is the first agent to be granted FDA approval for penicillin-resistant pneumococcus in patients with community-acquired pneumonia.5
Table 1 | |
The New Fluoroquinolones: | Cost* |
Sparfloxacin (Zagam) | $76.65 |
Levofloxacin (Levaquin) | $85.34 |
Moxifloxacin (Avelox) | $87.12 |
Gatifloxacin (Tequin) | $72.87 |
* reflects average wholesale price for 10-day course of therapy |
Absorption / Metabolism / Elimination
In general, FQs offer excellent oral absorption and high bioavailability that is only mildly affected by food.6 Some older FQs (ciprofloxacin, enoxacin, norfloxacin) are bound by calcium, and thus should not be co-administered with milk or milk products. This is not a problem with the new FQs.7-10 All FQs are chelated by other divalent cations, however, and the prescribing physician must be aware of interactions with magnesium, aluminum, iron, and zinc. The relevant medications in this regard include magnesium- or aluminum-containing antacids, multivitamins, iron supplements, buffered didanosine (Videx), and sucralfate (Carafate).7-10 Table 2 contains information on the time delay intervals to be observed if these cationic preparations must be co-administered with FQs. (See Table 2.) For the two agents available as intravenous preparations (levofloxacin and gatifloxacin), infusions containing magnesium cannot share the same line. Metabolism and elimination vary among the FQs. Levofloxacin is the best for use in hepatic insufficiency, in that 87% is excreted unchanged in the urine.9 The other new FQs should not be used in moderate-to-severe (moxifloxacin) or severe (sparfloxacin, gatifloxacin) liver dysfunction.7,8,10 All new FQs require a dosage adjustment based on creatinine clearance except moxifloxacin, which can be administered without dose modification.
Table 2 | |
Cation Dosage | Separation 7-10 |
Sparfloxacin | 4 h/4 h* |
Levofloxacin | 2 h/2 h* |
Moxifloxacin | 4 h/8 h* |
Gatifloxacin | 4 h/4 h* |
* Administer oral dose at least x hours before / y hours after cation-containing agent |
For sparfloxacin and levofloxacin, this adjustment begins when the creatinine clearance is less than 50 mL/min; for gatifloxacin, the threshold is less than 40 mL/min.7,10,11
Drug Interactions
Another advantage of the new FQs is the relative lack of drug-drug interactions. Unlike ciprofloxacin, these agents do not increase theophylline levels. As discussed above, there is the chelation effect when co-administered with divalent cationic preparations (except calcium—again, however, a problem with ciprofloxacin). Sparfloxacin, moxifloxacin, and gatifloxacin all carry warnings regarding prolongation of the QT interval on the electrocardiogram. Thus, they should not be used with type Ia (e.g., quinidine, disopyramide, procainamide) or type III (e.g., sotalol, amiodarone) antiarrhythmics, and should be used with "significant caution" with erythromycin, cisapride, tricyclic antidepressants, or certain antipsychotics. It follows that these agents should not be used in instances of congenital long QT syndromes or metabolically mediated prolongation of the QT interval (e.g., hypokalemia, hypomagnesemia). The issue of QT prolongation and sporadic reports of torsade de pointes led Glaxo Wellcome to voluntarily withdraw grepafloxacin from the market in October 1999. Levofloxacin stands alone as the only new FQ that does not feature QT prolongation precautions.7-11
Toxicity
The new FQs are generally well-tolerated. Their most common side effects are gastrointestinal (e.g., nausea, nemesis, diarrhea), followed by neurologic (headache, dizziness, sleep disturbances, and rare seizures or mental status/psychotic changes).1,12 All FQs carry the risk of phototoxicity, but this appears to be most significant with sparfloxacin, with a reported incidence of 8%. This can be severe, and patients are advised to avoid direct and filtered sunlight while on sparfloxacin and for five days after discontinuation of the drug.1,10,12 Renal insufficiency and abnormal liver function tests have also been reported with the FQs.1,12 Severe hepatotoxicity, including some deaths, led to the recent withdrawal of trovafloxacin from the market. As with the early-generation agents, the newer FQs are not recommended in pregnant or in pediatric/growing adolescent patients. Damage to juvenile articular cartilage in animal models is the basis for this recommendation; reports from children given FQs for compassionate reasons (e.g., infectious complications of cystic fibrosis) seem promising, however.12 FQ tendonopathy has been reported with a number of agents. Characteristically occurring within two weeks of initiation of FQ therapy (but a latency of up to 3 months has been described), the onset is often sudden. Painful swelling along the tendon sheath may be seen, and up to 50% of cases are bilateral. Although any tendon may be involved, there seems to be a predilection for high-stress tendons (e.g., calcaneal, quadriceps). Rupture can occur.
Associated risk factors appear to include age, renal failure, corticosteroid use, and previous FQ tendonopathy. Treatment includes discontinuing the FQ (if still on it), splinting, and rest.13
Summary
The FQ class of antibiotics is rapidly evolving, with four late-generation agents (sparfloxacin, levofloxacin, moxifloxacin, and gatifloxacin) entering the market in recent times, plus two late-generation agents (trovafloxacin and grepafloxacin) having been withdrawn. The new FQs are quite different from early-generation FQs in many respects. Although these new agents share some commonality, they possess variable properties regarding absorption, elimination, drug interactions, and adverse effects. The emergency physician should be familiar with these individual agents, as they are likely to assume a significant role in the treatment of infectious disease.
References
1. Blondeau JM. Expanded activity and utility of the new fluoroquinolones. Clin Therapeutics 1999;21:3-40.
2. Talan DA. New concepts in antimicrobial therapy for emergency department infections. Ann Emerg Med 1999;34:503-516.
3. Kemper CA. Levofloxacin-resistant pneumococci. Infect Dis Alert 2000;19:104.
4. Mandell LA. Antibiotic therapy for community-acquired pneumonia. Clin Chest Med 1999;20:589-598.
5. FDA approves new indication for Levaquin (levofloxacin tablet/injection). http://www.mdconsult.com.
6. Turnidge J. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Drugs 1999;58 (Suppl 2):29-36.
7. Avelox Product Information. Bayer corporation. December 1999.
8. Perry CM, et al. Gatifloxacin. Drugs 1999;58:683-696.
9. Langtry HD, Lamb HM. Levofloxacin. Drugs 1998;56: 487-515.
10. Zagam Product Information. Rhone-Poulenc Rorer. October 1998.
11. Tequin Product Information. Bristol-Myers Squibb. January 2000.
12. Lipsky BA, Baker CA. Fluoroquinolone toxicity profiles: A review focusing on newer agents. Clin Infect Dis 1999;28:352-364.
13. Harrell RM. Fluoroquinolone-induced tendonopathy: What do we know? South Med J 1999;92:622-625.
Which of the following fluoroquinolones has been most significantly linked with phototoxicity?
a. Grepafloxacin
b. Levofloxacin
c. Trovafloxacin
d. Sparfloxacin
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.