In the past 2 years, four new fluoroquinolones have been approved in the United States: sparfloxacin and levofloxacin in 1996 and grepafloxacin and trovafloxacin in late 1997 [3-5]. Levofloxacin is the active stereoisomer of the racemic mixture that constitutes ofloxacin; thus, levofloxacin has twofold greater activity. The newest fluoroquinolones are different from the earlier agents because they have increased activity against gram-positive bacteria and are administered once daily. Levofloxacin and trovafloxacin retain the most activity against gram-negative bacilli and have the broadest sets of indications. Trovafloxacin, in addition, is the first marketed quinolone with potent anaerobic activity. Grepafloxacin and sparfloxacin have indications limited to treatment of infections of the respiratory and genitourinary tracts.

All of these agents have been approved for treatment of community-acquired respiratory tract infections, including pneumonia and acute bacterial exacerbations of chronic bronchitis, which are most frequently caused by Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis. Atypical pathogens, such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species, are less frequently identified causes of community-acquired pneumonia. The newest fluoroquinolones have activity against all of these respiratory pathogens, but their increased potency against Streptococcus pneumoniae distinguishes them from the earlier quinolones.

Use of macrolides or fluoroquinolones for treatment of community-acquired respiratory tract infections has recently been recommended [6] because of increasing resistance of Streptococcus pneumoniae to penicillins and cephalosporins. Many strains of penicillin-resistant Streptococcus pneumoniae are also cross-resistant to other antibiotics that might be used in treatment. Because for some strains this cross-resistance includes macrolides, an appropriate fluoroquinolone may also be considered instead of a macrolide [7, 8]. The optimal regimen for treatment of respiratory tract infections caused by S. pneumoniae is uncertain; for some infections caused by relatively resistant strains of S. pneumoniae, higher doses of penicillins or third-generation cephalosporins may still be effective [9]. However, no definitive trials to date have compared penicillins, third-generation cephalosporins, and fluoroquinolones for treatment of respiratory tract infections caused by resistant pneumococci. Vancomycin has been added to a third-generation cephalosporin as initial empirical therapy for bacterial meningitis to account for the possible presence of a highly penicillin-resistant strain of Streptococcus pneumoniae; after the results of culture and susceptibility are known, vancomycin is withdrawn if it is not necessary.

Penicillin-resistant and penicillin-susceptible strains of Streptococcus pneumoniae have similar susceptibilities to quinolones. Thus, the use of fluoroquinolones to treat respiratory tract infections becomes more compelling as the prevalence and level of resistance to other antibiotics increase. In the United States, 25% to 30% of strains of Streptococcus pneumoniae have reduced susceptibility to penicillin; about half of these strains have high-level resistance [7]. The accumulating clinical data supporting the efficacy of the newest fluoroquinolones for treatment of respiratory tract infections (and Streptococcus pneumoniae infections in particular) suggest an efficacy for treating community-acquired pneumonia that is similar to that of comparator agents [10-12]. In most studies, Streptococcus pneumoniae isolates were susceptible to penicillin, and few or no patients with pneumonia and bacteremia were included.

Patients with bacteremic pneumococcal pneumonia represent a more rigorous test of antimicrobial efficacy for pneumococcal infection because they have both increased severity of illness and a greater certainty of microbiological diagnosis than could be inferred from cultures of expectorated sputum alone. The efficacy of the newest fluoroquinolones against other common respiratory pathogens, including atypical pathogens, also seems to be similar to that of conventional agents [11]. Although most studies included few or no patients with penicillin-resistant strains of Streptococcus pneumoniae, susceptibility to fluoroquinolones in vitro does not differ between penicillin-resistant and penicillin-susceptible strains; this finding suggests that clinical responses to fluoroquinolone therapy would be similar for both types of pneumococci.

Concentrations of quinolones in lung tissue exceed concentrations in serum, a difference that can be attributed partly to the accumulation of quinolones in phagocytes and alveolar macrophages [13]. Concentrations of quinolones in cerebrospinal fluid are, however, lower than those in serum [1], and data on use of quinolones for treating meningitis have been limited to small numbers of neurosurgical patients and one unpublished study of trovafloxacin treatment of meningococcal meningitis in children. Thus, whether the newest fluoroquinolones will have sufficient activity for treatment of meningitis caused by penicillin-resistant pneumococci remains unknown.

The availability of quinolones that have activity against resistant pneumococci and other respiratory pathogens represents both an opportunity and a challenge. The high oral bioavailability and long half-lives of the newest quinolones allow dosing as a single tablet once daily and thus make these drugs appealing to physicians and patients. In addition, coverage of the spectrum of usual pathogens in a time of increasing bacterial resistance and emphasis on empirical treatment of pneumonia gives physicians a valuable option. Tolerability of the newest agents is generally good, but some adverse effects seem to be more severe than those seen with ciprofloxacin and ofloxacin. In particular, sparfloxacin is more prone to phototoxicity and (like erythromycin) causes prolongation of the electrocardiographic QT interval, grepafloxacin has somewhat more dose-related gastrointestinal side effects, and trovafloxacin has a greater incidence of central nervous system side effects (especially dizziness). The newest quinolones may benefit some patients, but their ease of use may promote indiscriminate use. This possibility is particularly troublesome in treatment of patients with respiratory tract infections because recent findings suggest that many of these patients are treated with antibiotics but have conditions (such as viral infections) for which antibiotics are not indicated [14].

The newest quinolones (particularly trovafloxacin, which has a broad spectrum of activity, including activity against anaerobic organisms) will have other applications in patients with infections that often include mixtures of anaerobic organisms, gram-positive cocci, and gram-negative bacilli, such as intra-abdominal infections and infections of the diabetic foot. Data on the use of trovafloxacin for these indications have not yet been published, but data on the use of a combination of metronidazole and ciprofloxacin for treatment of intra-abdominal infections show that this regimen has clinical outcomes similar to those seen with imipenem [15].

Additional problems arise because of a substantial or increasing prevalence of antibiotic-resistant pathogens in hospitals. Most common among these are methicillin-resistant strains of Staphylococcus aureus, vancomycin-resistant enterococci, multidrug-resistant Pseudomonas aeruginosa, and enteric gram-negative bacteria expressing high levels of extended-spectrum ß-lactamases, which cause resistance to most or all penicillins and cephalosporins. Multidrug resistance is common for each of these types of nosocomial pathogens, leaving few or no antibiotics active against them. Fluoroquinolones may have only a limited role in the treatment of these multidrug-resistant pathogens, in part because of limited intrinsic potency or resistance already acquired in association with use of ciprofloxacin, ofloxacin, or other previously approved fluoroquinolones. Particularly noteworthy has been the prevalence (>90% in many medical centers [16]) of methicillin-resistant strains of Staphylococcus aureus that also have a high level of resistance to ciprofloxacin (often including cross-resistance to other, newer fluoroquinolones). Of interest, methicillin-susceptible strains of Staphylococcus aureus have remained generally susceptible to fluoroquinolones. In a similar fashion, epidemiologic cross-resistance to fluoroquinolones is seen more often in nosocomial bacteria that are resistant to many antibiotics. Further increments in potency of fluoroquinolones under development will be necessary if this class of agents is to provide reliable alternatives for treatment of methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and other organisms that have already acquired substantial levels of resistance to ciprofloxacin.

As the clinical applications of the fluoroquinolone class increase, new acquisition of bacterial fluoroquinolone resistance becomes a challenge. It is not surprising that a common risk factor for acquisition of fluoroquinolone resistance is patient exposure to the drugs [17]. The greater the therapeutic index (the ratio of drug concentration achieved at the site of infection and the drug concentration that inhibits growth), the lower the likelihood of selecting resistant mutants. In addition, therapeutic indices of 10 or more have been associated with less frequent development of resistance [18]. This relation can be understood in the context of general observations that single resistance mutations (which alter the drug target enzymes or enhance drug efflux) often confer increments of minimal inhibitory concentrations of fluoroquinolones of around 10-fold or less [19].

Highly resistant clinical isolates, however, have been shown to have multiple mutations, in some cases associated with intensive fluoroquinolone selective pressure and the likely presence of natural endogenous reservoirs in which organisms with intermediate levels of resistance may persist. In this context, it is predicted that choice of the fluoroquinolone with the highest therapeutic index for the targeted pathogen, use of full doses for brief periods, and avoidance of repetitive use in the same patient may reduce the risk for selection of endogenous resistant strains. Clinical studies to prove this prediction, however, are still lacking. In the case of Streptococcus pneumoniae, for which fluoroquinolone resistance is currently low, use of fluoroquinolones for treating respiratory tract infections in adults may have a slower effect on resistance because the principal reservoirs of pneumococci are in children, for whom fluoroquinolones do not yet have approved routine indications.

To preserve the therapeutic opportunities that the most recent generation of fluoroquinolones provides, the challenge will be to use these drugs thoughtfully. Most community-acquired respiratory infections in the United States are still caused by pathogens susceptible to ß-lactams and macrolides. Fluoroquinolones should be chosen for indications in which they offer a clear therapeutic advantage over other classes of antibiotics rather than as agents whose broad spectrum prompts routine empirical use. Use of fluoroquinolones should also be avoided in patients with respiratory syndromes for which antibiotics of any class may not be indicated [20].