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 gram-negative 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 drug–cationic 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 1^{1,5–7,9,11–13,19} 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.

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).^{2–6,8,10,14,15,17,19}

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 gram-positive 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 mixture^12,21) 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 long-term 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 trimethoprim-sulfamethoxazole (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.