New Classification and Update on the Quinolone Antibiotics

DANA E. KING, M.D., ROBB MALONE, PHARM.D., and SANDRA H. LILLEY, PHARM.D., East Carolina University School of Medicine, Greenville, North Carolina Am Fam Physician. 2000 May 1;61(9):2741-2748. The newer fluoroquinolones have broad-spectrum bactericidal activity, excellent oral bioavailability, good tissue penetration and favorable safety and tolerability profiles. A new fourgeneration classification of the quinolone drugs takes into account the expanded antimicrobial spectrum of the more recently introduced fluoroquinolones and their clinical indications. Firstgeneration drugs (e.g., nalidixic acid) achieve minimal serum levels. Second-generation quinolones (e.g., ciprofloxacin) have increased gram-negative and systemic activity. Thirdgeneration 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. The quinolones can be differentiated within classes based on their pharmacokinetic properties. The new classification can help family physicians prescribe these drugs appropriately. With the increasing number of available quinolone antibiotics, prescribing these drugs has become a challenge. Compared with older quinolones such as norfloxacin (Noroxin) and ciprofloxacin (Cipro), the newer agents have an expanded antimicrobial spectrum and new indications. The most recently released agents have significant antimicrobial activity against gram-positive streptococci, atypical pathogens and anaerobes. The new classification of quinolone antibiotics by generation can help family physicians prescribe these agents appropriately and evaluate new drugs as they are introduced.1 The 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.2 Enhanced antimicrobial activity has extended the use of the fluoroquinolones beyond the traditional indications for quinolone antibiotics in the treatment of urinary tract infections. The fluoroquinolones are effective in a wider variety of infectious diseases, including skin and respiratory infections.3 Because of their excellent safety and tolerability, they have become popular alternatives to penicillin and cephalosporin derivatives in the treatment of various infections.

Overview of Fluoroquinolones
The fluoroquinolones are broad-spectrum antibiotics with particular activity against gramnegative organisms, especially Pseudomonas aeruginosa. These agents are well absorbed when

given orally. Because tissue and fluid concentrations often exceed the serum drug concentration, these antibiotics are particularly useful for certain infections, such as pneumonia.4-6 Fluoroquinolones are usually well tolerated, with few side effects. However, they can have serious adverse effects.7 SIDE EFFECTS The most common adverse effects of the fluoroquinolones are nausea, vomiting and diarrhea, which occur in 3 to 6 percent of recipients.5 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]). Concern about the adverse effects of quinolones on joints is based primarily on experimental evidence in young animals. These drugs are not recommended for use in patients younger than 18 years or in pregnant or lactating women. In one study, however, no arthropathies were observed in more than 1,000 children who received ciprofloxacin.8 In June 1999, the U.S. Food and Drug Administration (FDA) issued a public health advisory warning about the risk of liver toxicity with trovafloxacin after 14 cases of acute liver failure were associated with its use.9 The advisory recommended that trovafloxacin therapy be reserved for infections judged to be life- or limb-threatening, with treatment initiated only in the inpatient setting and when the benefits of trovafloxacin outweigh the risks. The fluoroquinolones are bactericidal antibiotics that act by specifically targeting DNA gyrase.10 In contrast to aminoglycosides and betalactams, some fluoroquinolones are active against dormant and replicating bacteria.5 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. BACTERIAL RESISTANCE Gram-positive and gram-negative bacteria have been reported to be resistant to quinolones.11,12 This resistance appears to be the result of one of three mechanisms: alterations in the quinolone enzymatic targets (DNA gyrase), decreased outer membrane permeability or the development of efflux mechanisms. The accumulation of several bacterial mutations (DNA gyrase and bacterial permeability) has been associated with the development of very high minimum inhibitory concentrations to ciprofloxacin in isolates of Staphylococcus aureus, Enterobacteriaceae species and P. aeruginosa.11 Resistance 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 betalactams, 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. Therefore, the bacterial susceptibility and pharmacokinetic profiles of each quinolone should be considered in determining the effectiveness of specific agents.2 BROADENED ANTIMICROBIAL ACTIVITY The original fluoroquinolone agents were introduced in the late 1980s. Shortly thereafter, ciprofloxacin became the most frequently used antibiotic throughout the world.7 The first fluoroquinolones were widely used because they were the only orally administered agents available for the treatment of serious infections caused by gram-negative organisms, including Pseudomonas species. Some infectious disease specialists have become concerned about the overuse of fluoroquinolones. Because of the broad spectrum and oral availability of these agents, overuse is quite easy. Family physicians should always follow the principle of using the drug with the narrowest spectrum and the least toxicity. Six new fluoroquinolones have been introduced in the United States during the past five years. Levofloxacin (Levaquin) and sparfloxacin became available in 1996, and 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. Compared 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.6,13 Their expanded gram-positive activity is especially important because it includes significant activity against Streptococcus pneumoniae.1,11 Levofloxacin has enhanced activity against S. pneumoniae, S. aureus and Enterococcus species, as well as good activity against Mycoplasma and Chlamydia species.14,15 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.6,16 CLINICALLY IMPORTANT PHARMACOKINETIC PARAMETERS The newer fluoroquinolone antibiotics also have improved pharmacokinetic parameters compared with the original quinolones. They are rapidly and almost completely absorbed from

the gastrointestinal tract. Peak serum concentrations obtained after oral administration are very near those achieved with intravenous administration.3 Consequently, the oral route is generally preferred in most situations, and hospitalized patients should be switched from intravenous to oral formulations as soon as oral medications can be tolerated. Absorption of orally administered fluoroquinolones is significantly decreased when these agents are coadministered with aluminum, magnesium, calcium, iron or zinc, because of the formation of insoluble drugcationic chelate complexes in the gastrointestinal tract.3,10 The problem can be overcome largely by administering products containing these metal ions at least four hours before or two hours after oral administration of a fluoroquinolone. Because sucralfate (Carafate) contains aluminum, it can also reduce absorption of the quinolones. Adequate spacing of administration times has not been determined, and coadministration of quinolones and sucralfate should be avoided. Because the fluoroquinolones have a large volume of distribution, they concentrate in tissues at levels that often exceed serum drug concentrations. Penetration is particularly high in renal, lung, prostate, bronchial, nasal, gall bladder, bile and genital tract tissues.4-6 Urine drug concentrations of some fluoroquinolones, such as ciprofloxacin and ofloxacin (Floxin), may be as much as 25 times higher than serum drug concentrations. Consequently, these agents are especially useful in treating urinary tract infections.5 Distribution of the fluoroquinolones into respiratory tract tissues and fluids is of particular interest because of the activity of these agents against common respiratory pathogens. Trovafloxacin penetrates noninflamed meninges and may have a future role in the treatment of bacterial meningitis. 4,17 The long half-lives of the newer fluoroquinolones allow once- or twice-daily dosing. The quinolones vary with respect to the relative contribution of renal and nonrenal pathways for their elimination. Only ofloxacin and levofloxacin are exclusively eliminated by the kidney.2,5,6 Renal and nonrenal (gastrointestinal or hepatic) mechanisms are responsible for the elimination of nalidixic acid, cinoxacin, norfloxacin, ciprofloxacin, enoxacin (Penetrex), lomefloxacin, gatifloxacin, moxifloxacin and sparfloxacin. Dosage adjustments based on estimated creatinine clearance values must be made for the agents with significant renal elimination. In most instances, administering the usual dose at an extended interval is recommended. Trovafloxacin is eliminated primarily by hepatic mechanisms.18 Approximately 50 percent of a trovafloxacin dose is conjugated in the liver; 43 percent is excreted unchanged in the feces.17 Significant hepatic disease may increase the elimination half-life of trovafloxacin. Dosage adjustments are required in patients with mild to moderate cirrhosis. No data are available on patients with severe liver disease.18 Increased serum fluoroquinolone concentrations have been noted in the elderly. The usual cause is the somewhat decreased volume of distribution and decreased renal function in older persons. However, dosage adjustment based on age alone is not recommended.

New Classification of Quinolones

The new classification of quinolone antibiotics takes into account the expanded antimicrobial spectrum of the newer fluoroquinolones and their clinical indications (Tables 11,57,9,1113,19 and 220). Introduced in 1997, this classification is a useful tool for physicians to use when empirically prescribing these drugs or evaluating new agents introduced to the market.1 Drugs in each group are similar in antimicrobial activity. With each successive generation, a significant new group of pathogens is added to the coverage. TABLE 1 Classification of Quinolone Antibiotics Classification Agents First Nalidixic acid generation (NegGram) Cinoxacin (Cinobac) Second Norfloxacin generation (Noroxin) Lomefloxacin (Maxaquin) Enoxacin (Penetrex) Ofloxacin (Floxin) Ciprofloxacin (Cipro) Third Levofloxacin generation (Levaquin) Sparfloxacin (Zagam) Gatifloxacin (Tequin) Moxifloxacin (Avelox) Fourth Trovafloxacin generation (Trovan) Antimicrobial spectrum Gram-negative organisms (but not Pseudomonas species) General clinical indications* Uncomplicated urinary tract infections

Gram-negative organisms (including Pseudomonas species), some gram-positive organisms (including Staphylococcus aureus but not Streptococcus pneumoniae) and some atypical pathogens

Uncomplicated and complicated urinary tract infections and pyelonephritis, sexually transmitted diseases, prostatitis, skin and soft tissue infections

Same as for second-generation Acute exacerbations of chronic agents plus expanded grambronchitis, community-acquired positive coverage (penicillinpneumonia sensitive and penicillin-resistant S. pneumoniae) and expanded activity against atypical pathogens Same as for third-generation agents plus broad anaerobic coverage Same as for first-, second- and third-generation agents (excluding complicated urinary tract infections and pyelonephritis) plus intraabdominal infections, nosocomial pneumonia, pelvic infections

*These indications may not correlate with those labeled by the U.S. Food and Drug Administration.

Information from references 1,5 through 7,9,11 through 13 and 19. TABLE 2 Indications for Quinolone Antibiotics Labeled by the U.S. Food and Drug Administration Indications Uncomplicated urinary tract infections Agents Nalidixic acid (NegGram), cinoxacin (Cinobac), norfloxacin (Noroxin), lomefloxacin (Maxaquin), enoxacin (Penetrex), ofloxacin (Floxin), ciprofloxacin (Cipro), levofloxacin (Levaquin), gatifloxacin (Tequin), trovafloxacin (Trovan)* Complicated urinary tract Norfloxacin, lomefloxacin, enoxacin, ofloxacin, ciprofloxacin, infections and levofloxacin, gatifloxacin pyelonephritis Lower respiratory tract Lomefloxacin, ofloxacin, ciprofloxacin, trovafloxacin* infections (limited) Skin and skin-structure Ofloxacin, ciprofloxacin, levofloxacin, trovafloxacin* infections Urethral and cervical Norfloxacin, enoxacin, ofloxacin, ciprofloxacin, gatifloxacin, gonococcal infections trovafloxacin* Urethral and cervical Ofloxacin, trovafloxacin* chlamydial and gonnococcal infections Bone and joint infections, Ciprofloxacin gram-negative bacterial infections Infectious diarrhea Ciprofloxacin Typhoid fever Ciprofloxacin Prostatitis Norfloxacin, ofloxacin, trovafloxacin* Acute sinusitis Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin (Avelox), trovafloxacin* Acute exacerbations of Levofloxacin, sparfloxacin (Zagam), gatifloxacin, moxifloxacin, chronic bronchitis trovafloxacin* Community-acquired Levofloxacin, sparfloxacin, gatifloxacin, Moxifloxacin, pneumonia trovafloxacin* Intra-abdominal infections Trovafloxacin* Gynecologic and pelvic Trovafloxacin* infections Nosocomial pneumonia Trovafloxacin*

*Treatment with trovafloxacin is reserved for life- or limb-threatening infections.9 Information from Drug facts and comparisons: loose-leaf information service. St. Louis: Facts and Comparisons, Wolters Kluwer Company, 2000:128093.

With some exceptions, agents in the four fluoroquinolone classes can also be grouped by their clinical indications. The drugs can be further differentiated based on available formulations, required dosage adjustments in renal or hepatic disease, significant adverse effects and significant drug interactions (Table 3).26,8,10,14,15,17,19 TABLE 3 Distinguishing Characteristics of Quinolone Antibiotics Dosage Class and Half- Route of adjustment agent life* administration required First generation Nalidixic acid 60 to 90Oral Renal (NegGram) minutes impairment Cinoxacin 1.1 to Oral Renal (Cinobac) 2.7 impairment hours Second generation Norfloxacin 2.3 to Oral (Noroxin) 5.5 hours Lomefloxacin 7 to 8.5 Oral (Maxaquin) hours

Significant adverse effects

Significant drug interactions Warfarin (Coumadin)

Hypersensitivity (fewer than 3 percent of recipients) Warfarin, cyclosporine (Sandimmune)

Renal impairment Renal impairment

Enoxacin (Penetrex)

3.3 to 7 Oral hours

Ofloxacin (Floxin)

5 to 8 hours

Oral, intravenous

Ciprofloxacin 3 to 5.4 Oral, (Cipro) hours intravenous

Phototoxicity, headache (3 to 44 percent of recipients), abdominal pain (11 percent), nausea (5.6 percent) Renal or Phototoxicity Warfarin, ranitidine hepatic (mild) (Zantac), bismuth impairment subsalicylate, (patients with theophylline, caffeine advanced cirrhosis) Renal or Insomnia (13 Warfarin hepatic percent of impairment recipients) (patients with severe disease) Renal Nausea, vomiting, Warfarin, impairment abdominal pain theophylline, caffeine, cyclosporine, glyburide (Micronase)

Third generation

Class and agent Levofloxacin (Levaquin) Sparfloxacin (Zagam)

Dosage Half- Route of adjustment life* administration required 6 hours Oral, Renal intravenous impairment 21 hours Oral Renal impairment

Gatifloxacin 7 hours (Tequin) Moxifloxacin 12 (Avelox) hours Fourth generation Trovafloxacin 7.8 (Trovan) hours Alatrofloxacin (Trovan IV)

Oral, intravenous Oral

Renal impairment Hepatic impairment

Significant Significant drug adverse effects interactions Headache, nausea (6.6 percent of recipients), diarrhea Phototoxicity (8 Drugs that prolong the percent of QT interval, including recipients), QTclass I interval antiarrhythmics, prolongation, tricyclic torsades des pointes antidepressants, phenothiazines, cisapride (Propulsid), pentamidine (Pentam) and erythromycin Same as for sparfloxacin QT-interval Same as for prolongation sparfloxacin

Oral Intravenous

Hepatic Dizziness (2.4 to 11 Morphine, citric acid impairment percent of sodium citrate (patients with recipients), severe (Bicitra) mild to hepatotoxicity moderate (rare), candidal cirrhosis) vaginitis (1 to 10 percent)

*Half-lives are significantly increased for renally eliminated compounds. All quinolones cause nausea, insomnia, headache and dizziness (3 percent or more of recipients); tendon rupture and cartilage damage are considered a possible effect of any quinolone. All quinolones interact with sucralfate (Carafate), antacids containing aluminum or magnesium, iron, calcium and zinc. As of July 14, 2000, cisapride will be available only to patients who meet specific clinical eligibility criteria for a limited-access protocol. Information from references 2 through 6,8,10,14,15,17 and 19. FIRST GENERATION

The first-generation agents include cinoxacin and nalidixic acid, which are the oldest and least often used quinolones. Because minimal serum levels are achieved, use of these drugs has been restricted to the treatment of uncomplicated urinary tract infections. Cinoxacin and nalidixic acid require more frequent dosing than the newer quinolones, and they are more susceptible to the development of bacterial resistance. These agents are not recommended for use in patients with poor renal function because of significantly decreased urine concentrations.2,10 SECOND GENERATION The second-generation quinolones have increased gram-negative activity, as well as some grampositive and atypical pathogen coverage. Compared with first-generation drugs and considered as a group, these agents have broader clinical applications in the treatment of complicated urinary tract infections and pyelonephritis, sexually transmitted diseases, selected pneumonias and skin infections. Second-generation agents include ciprofloxacin, enoxacin, lomefloxacin, norfloxacin and ofloxacin. Ciprofloxacin is the most potent fluoroquinolone against P. aeruginosa.21,22 Because of its good penetration into bone, orally administered ciprofloxacin is a useful alternative to parenterally administered antibiotics for the treatment of osteomyelitis caused by susceptible organisms. Although the FDA has labeled some second-generation quinolones for the treatment of lower respiratory tract infections and acute sinusitis, it should be stressed that S. pneumoniae is frequently resistant to agents in this class. Consequently, second-generation quinolones are not the drugs of first choice for lower respiratory tract infections and acute sinusitis. Of the second-generation agents, ofloxacin has the greatest activity against Chlamydia trachomatis. Ciprofloxacin and ofloxacin are the most widely used second-generation quinolones because of their availability in oral and intravenous formulations and their broad set of FDA-labeled indications. THIRD GENERATION The third-generation quinolones currently include levofloxacin, gatifloxacin, moxifloxacin and sparfloxacin. These agents are separated into a third class because of their expanded activity against gram-positive organisms, particularly penicillin-sensitive and penicillin-resistant S. pneumoniae, and atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae.6,12,19 Although the third-generation quinolones retain broad gram-negative coverage, they are less active than ciprofloxacin against Pseudomonas species. Because of their expanded antimicrobial spectrum, third-generation quinolones are useful in the treatment of community-acquired pneumonia, acute sinusitis and acute exacerbations of chronic

bronchitis, which are their primary FDA-labeled indications. Gatifloxacin also has FDA-labeled indications for urinary tract infections and gonorrhea.20 Levofloxacin (the more active component of the ofloxacin racemic mixture12,21) and gatifloxacin are available in oral and intravenous formulations. Sparfloxacin carries a significant risk of phototoxicity.21,23 Grepafloxacin, sparfloxacin and moxifloxacin have been reported to cause prolongation of the QT interval; gatifloxacin has not. However, 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.24 In contrast, levofloxacin does not affect the QT interval. FOURTH GENERATION Trovafloxacin, currently the only member of the fourth-generation class, adds significant antimicrobial activity against anaerobes while maintaining the gram-positive and gram-negative activity of the third-generation quinolones. It also retains activity against Pseudomonas species comparable to that of ciprofloxacin.17,18 Trovafloxacin is available in an oral tablet and as the prodrug alatrofloxacin (Trovan IV) in an intravenous formulation. Although the findings of few clinical trials on trovafloxacin have been published, the drug was originally labeled by the FDA for the treatment of a wide spectrum of infectious diseases.18 Because of concern about hepatotoxicity, trovafloxacin therapy should be reserved for life- or limb-threatening infections requiring inpatient treatment (hospital or longterm care facility), and the drug should be taken for no longer than 14 days.9

Final Comment
Fluoroquinolones are more expensive than first-line agents such as trimethoprimsulfamethoxazole (Bactrim, Septra) for the treatment of uncomplicated urinary tract infections or doxycycline (Vibramycin) for the treatment of acute exacerbations of chronic bronchitis. However, the use of orally administered fluoroquinolones (when indicated) instead of intravenously administered antibiotics may provide significant advantages in terms of reduced hospitalization or home health care costs. The average wholesale costs of orally and intravenously administered quinolones are provided in Table 4. TABLE 4 Cost of Fluoroquinolone Therapy Agent Norfloxacin (Noroxin) Lomefloxacin (Maxaquin) Enoxacin (Penetrex) Ofloxacin (Floxin) Ciprofloxacin (Cipro) Usual dosage Cost* 400 mg twice daily orally $ 68 400 mg per day orally 66 200 to 400 mg twice daily orally 62 to 65 200 to 400 mg twice daily orally 75 to 94 400 mg every 12 hours intravenously158 250 to 750 mg twice daily orally 68 to 80

Agent

Usual dosage Cost* 400 mg every 12 hours intravenously180 Levofloxacin (Levaquin) 250 to 500 mg per day orally 69 to 81 500 mg every 24 hours intravenously119 Sparfloxacin (Zagam) 200 mg per day orally 67 Gatifloxacin (Tequin) 400 mg per day orally 70 400 mg every 24 hours intravenously114 Moxifloxacin (Avelox) 400 mg per day orally 87 Trovafloxacin (Trovan) 100 to 200 mg per day orally 59 to 72 Alatrofloxacin (Trovan IV)200 mg every 24 hours intravenously111

*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.

The Authors DANA E. KING, M.D., is associate professor of family medicine at the Medical University of South Carolina, Charleston. Previously, he was associate professor at East Carolina University School of Medicine, Greenville, N.C. Dr. King received his medical degree from the University of Kentucky College of Medicine, Lexington. He completed a family practice residency at the University of Maryland School of Medicine, Baltimore, and a faculty development fellowship at the University of North Carolina (UNC) at Chapel Hill School of Medicine. ROBB MALONE, PHARM.D., is outpatient pharmacist and diabetes care specialist at UNC Hospitals, Chapel Hill, N.C. Previously, he was a pharmacotherapy resident in primary care in the Department of Family Medicine at East Carolina University School of Medicine. He received his doctor of pharmacy degree from the UNC at Chapel Hill School of Pharmacy. SANDRA H. LILLEY, PHARM.D., is associate professor of family medicine and head of the clinical pharmacy section of the Department of Family Medicine at East Carolina University School of Medicine. She is also a clinical associate professor at the UNC at Chapel Hill School of Pharmacy and associate director of pharmacy education for the Eastern Area Health Education Center, Greenville, N.C. Dr. Lilley received her pharmacy degree from the UNC at Chapel Hill School of Pharmacy and is a certified pharmacotherapy specialist. Address correspondence to Dana E. King, M.D., Department of Family Medicine, Medical University of South Carolina, 295 Calhoun St., Charleston, SC 29425. Reprints are not available from the authors. The authors thank Susan Loftin and Julie Calder for technical assistance in the preparation of the manuscript.

REFERENCES 1. Ambrose PG, Owens RC, Quintiliani R, Nightingale CH. New generations of quinolones: with particular attention to levofloxacin. Conn Med. 1997;61:26972. 2. Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev. 1989;2:378424. 3. Borcherding SM, Stevens R, Nicholas RA, Corley CR, Self T. Quinolones: a practical review of clinical uses, dosing considerations, and drug interactions. J Fam Pract. 1996;42:69 78. 4. Garey KW, Amsden GW. Trovafloxacin: an overview. Pharmacotherapy. 1999;19:2134. 5. Fitton A. The quinolones. An overview of their pharmacology. Clin Pharmacokinet. 1992;22(suppl 1):111. 6. Stein GE. Pharmacokinetics and pharmacodynamics of newer fluoroquinolones. Clin Infect Dis. 1996;23(suppl 1):S1924. 7. Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones. Drugs. 1993;45(suppl 3):5964. 8. Chysky V, Kapila K, Hullmann R, Arcieri G, Schacht P, Echols R. Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use. Emphasis on joint evaluation. Infection. 1991;19:28996. 9. Public health advisory, Food and Drug Administration, June 9, 1999. Trovan (trovafloxacin/alatrofloxacinmesylate). Retrieved March 22, 2000, from the World Wide Web: http://www.fda.gov/cder/news/trovan/trovanadvisory.htm. 10. Just PM. Overview of the fluoroquinolone antibiotics. Pharmacotherapy. 1993;13:4S17S. 11. Acar JF, Goldstein FW. Trends in bacterial resistance to fluoroquinolones. Clin Infect Dis. 1997;24(suppl 1):S6773. 12. Stein GE, Havlichek DH. Newer oral antimicrobials for resistant respiratory tract pathogens. Which show the most promise. Postgrad Med. 1998;103(6):6770. 13. Milkovich G, Reitan JF. Community-acquired pneumonia: is there a preferred therapy? Med/Pharm Forum. 1998; May:1722. 14. Ernst ME, Ernst EJ, Klepser ME. Levofloxacin and trovafloxacin: the next generation of fluoroquinolones? Am J Health Syst Pharm. 1997;54:256984.

15. Appelbaum PC. Quinolone activity against anaerobes: microbiological aspects. Drugs. 1995;49(suppl 2):7680. 16. Hecht DW, Wexler HM. In vitro susceptibility of anaerobes to quinolones in the United States. Clin Infect Dis. 1996;23(suppl 1):S28. 17. Brighty KE, Gootz TD. The chemistry and biological profile of trovafloxacin. J Antimicrob Chemother. 1997;39(suppl B):114. 18. Trovan (trovafloxacin) [Package insert]. New York, N.Y.: Pfizer Inc., 1998. 19. Gatifloxicin and moxifloxacin: two new fluoroquinolones. Med Lett Drugs Ther. 2000;42:157. 20. Drug facts and comparisons: loose-leaf information service. St. Louis: Facts and Comparisons, Wolters Kluwer Company, 2000:128093. 21. Sparfloxacin and levofloxacin. Med Lett Drugs Ther. 1997;39:414. 22. Stein GE, Ensberg M. Use of newer fluoroquinolones in the elderly. Clin Geriatr. 1998;6(8):538. 23. Lietman PS. Fluoroquinolone toxicities. An update. Drugs. 1995;49(suppl 2):15963. 24. Zagam (sparfloxacin) [Product information]. Collegeville, Pa.: Rhne-Poulenc Rorer Pharmaceuticals Inc., 1997. Copyright 2000 by the American Academy of Family Physicians. This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.