New Antibiotics in Pulmonary and Critical Care Medicine

†, * University of the Pacific, School of Pharmacy Stockton, California, and Kendle International, Inc.;   †Maine Medical Center, Portland, Maine, and University of Vermont, College of Medicine, Burlington, Vermont

Semin Respir Crit Care Med. 2000;21(1) 

In This Article

Classification Of Quinolones By Generation

The division of antibiotic classes into generations based on microbiological activity has always been controversial among academic infectious disease clinicians, but it has been extremely useful and practical to the practicing physician. For example, physicians usually know that when a cephalosporin is needed for gram-positive coverage, a first-generation agent should be selected, whereas the later-generation agents are more appropriate, with some exceptions, for situations in which gram-negative bacteria are the usual pathogens.

Unfortunately, quinolone classification systems based on chronology of development or structure are of little value to the practicing physician.[23,24] Moreover, classifying agents based solely on microbiological activity may lead to poor clinical or research decisions. An illustration of the fallacy associated with considering only microbiological activity involves grepafloxacin. This agent is highly active in vitro against S. pneumoniae and was studied for the treatment of community-acquired respiratory tract infections at a dose of 400 mg per day. Pharmacody-namically, an unacceptable number of treatment failures involving S. pneumoniae would be predictable based on unfavorable pharmacodynamic profile of this agent at the studied dose. Because these concepts were not well-understood, the 400 mg dosing regimen resulted in the predictable failure of grepafloxacin against the pneumococcus.[25] Interestingly, when the dose of grepafloxacin was increased to 600 mg per day, the resulting AUC:MIC ratio exceeded 30:1 and successful outcomes were predictably reported.

Our classification system, which was introduced a number of years ago, was the first to rely on the integration of both microbiological susceptibilities and pharmacokinetic data.[26,27,28] In other words, the unique pharmacodynamic profile displayed against S. pneumoniae and Bacteroides fragilis was used to characterize the clinical usefulness of each quinolone (Table 1). Such a classification system will likely prove useful, for the clinician is already being overwhelmed by the number of quinolones, potentially leading to unoptimized clinical decisions.

Nalidixic acid (Fig. 3B), introduced in the United States in 1963, was the first oral quinolone that gained any significant usage. Because of its reliable activity against most Enterobacteriaceae, it became a popular choice for the treatment of uncomplicated urinary tract infections. In fact, it was often referred to as an oral form of kanamycin. Unfortunately, its serum and tissue concentrations were so low that it could not be employed for infections in other body sites and its half-life was so short it had to be given on a four times a day schedule. Several other similar quinolones (e.g., oxolinic acid and cinoxacin) were developed that were essentially identical with nalidixic acid but could be given less frequently. None of these first-generation quinolones exhibited any activity against Pseudomonas aeruginosa, anaerobes, or gram-positive bacteria.

Structures of representative quinolones

Norfloxacin, the first second-generation quinolone, expanded quinolone bacterial coverage to include P. aeruginosa and staphylococci. This change was the result of the discovery that the placement of a fluorine into the C-6 position of the 4- quinolone molecule and the replacement of the C-7 methyl side chain of nalidixic acid with a piperazine group markedly enhanced microbiological activity (Fig. 3C).[29,30] As a result of the C-6 substitution, technically all compounds in this class should be referred to as fluoroquinolones. These quinolones have microbiological activity similar to that of the aminoglycosides, namely gentamicin, tobramycin, and amikacin. However, like the first-generation quinolones, the serum and tissue concentrations of these compounds are so low that they can only be used for the treatment of urinary tract infections.

The replacement of norfloxacin's N-1 ethyl group with a cyclopropyl group resulted in compounds with greater bioavailability, such as ciprofloxacin (Fig. 3D).[29,30] Because to the summation of the C-6, C-7, and N-1 structural changes, compounds such as ciprofloxacin and ofloxacin can be used in many sites of infection outside of the uri-nary tract. Moreover, these quinolones exhibit high intracellular penetration, allowing for the therapy of the so-called atypical organisms, such as Chlamydia spp., Mycoplasma spp., and Legionella spp., which are also susceptible to these agents. The second-generation quinolones, therefore, can be divided into two subgroups. The first sub-group includes norfloxacin, lomefloxacin, and enoxacin, which are only useful for the treatment of urinary tract infections and are available only orally.

The second subgroup includes ciprofloxacin and ofloxacin, which in addition to urinary tract infections can be used to treat many systemic sites of infection and are available in both intravenous and oral formulations.

Unfortunately, none of the second-generation quinolones exhibit adequate pharmacodynamic profiles against streptococci or have sufficient clinical outcome data to rely upon to treat serious infections caused by these organisms. Although, for a short time there was a fluoroquinolone, temafloxacin, with appreciable streptococcal activity, it had to be with-drawn from the market because of the emergence of a syndrome of hemolysis and renal dysfunction (e.g., temafloxacin syndrome).[31] This represented a serious problem for the clinician because the leading cause of community-acquired pulmonary and sinus infections is S. pneumoniae, and the major cause of pharyngitis, soft tissue infections, and skin infections is Streptococcus pyogenes. This opened the door for the creation of quinolones that expanded the coverage for these bacteria: levofloxacin, sparfloxacin, grepafloxacin, and gatifloxacin.

The enhanced streptococcal activity of these compounds results from modifications to the piperazine group at C-7 of the quinolone nucleus. The addition of a sterically bulky methyl group(s) on this substituent not only improved both in vitro and in vivo activity against gram-positive organisms but also diminished the potential for adverse CNS events and drug interactions (Fig. 3E).[30] Pharmaco-dynamically, these agents possess AUC:MIC ratios that exceed 30, which as discussed earlier have been associated with successful treatment of infections caused by S. pneumoniae (WA Craig, personal communication).[12]

These new agents allow for single-agent therapy in community-acquired lung infection because they provide coverage for the leading bacterial and atypical causes of this infection. Levofloxacin and eventually gatifloxacin are particularly attractive choices because they are or will be available in both intravenous and oral formulations, have essentially 100% bioavailability, and have a low incidence of adverse events.[32,33] Sparfloxacin and grepafloxacin were only available as oral formulations. Moreover, as discussed later, the clinical usefulness of sparfoxacin is further limited because of poor adverse event profiles compared with other third-generation quinolones, and grepafloxacin has already been removed from the market due to QTc interval prolongation.

The fourth-generation quinolones, such as trovafloxacin, have appreciable activity against anaerobes, including B. fragilis.[34] This is associated with substituents attached to the C-8 position of the 4-quinolone nucleus. Although the C-8 methoxy group of moxifloxacin and gatifloxacin (Fig. 3E) confer some activity against anaerobes such as B. fragilis, a halogen substitution (e.g., clinafloxacin) at this position or N-8 substitution (trovafloxacin, tosufloxacin) provides for superior activity (Fig. 3F).[30,34,35,36] At the present time it remains unclear if 8-methoxy quinolone's anaerobic activity will translate into clinical efficacy against B. fragilis. We tentatively classified the 8-methoxy quinolones gatifloxacin and moxifloxacin as third- and fourth-generation agents, respectively.

It is important to recognize that the optimum pharmacodynamic parameters of quinolones and B. fragilis have not been well-elucidated. The generation classification is based solely on clinical outcome data and relative differences between trovafloxacin's AUC:MIC of 50 compared with other quinolones, which are generally lower than 15. However, the optimal AUC:MIC ratio may be significantly higher. In an in vitro model of infection, Peterson et al[37] reported that an AUC:MIC ratio of trovafloxacin and levofloxacin of 50 against B. fragilis was associated with regrowth and the development of resistance, whereas a ratio of 150 was not.


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