New Uses for New and Old Quinolones and the Challenge of Resistance

More than a decade ago ciprofloxacin, the first quinolone with broad indications, was released for clinical use in the United States. The release of ofloxacin, which also had broad applications, followed not long thereafter. Since that time there has been extensive use of these 2 agents and more limited use of other quinolones, such as norfloxacin, enoxacin, and lome-floxacin, which were limited to treatment of infections of the genitourinary tract. Applications of these quinolones largely employed their potent activities against gram-negative bacteria [1, 2]. This article focuses on information developed in the past 4 years on the 4 most recently released quinolones—levofloxacin, sparfloxacin, grepafloxacin, and trovafloxacin [3–8]—and their spectrum of activity, pharmacokinetics, tolerability, and clinical applications. It also focuses on new applications of the older quinolones. Issues of quinolone resistance related to expanding uses of quinolones will also be discussed. The newer fluoroquinolones have retained much of the activity of ciprofloxacin and ofloxacin against enteric gram-negative bacteria, but none is more potent than ciprofloxacin against these pathogens or against Pseudomonas aeruginosa. Levofloxacin is the active stereoisomer of the racemic mixture of the 2 stereoisomers that make up ofloxacin and thus is generally 2-fold more potent than ofloxacin [3]. Trovafloxacin [9] and, to a lesser extent, levofloxacin generally have gram-negative coverage similar to that of ciprofloxacin, but both may be less active against some strains of P. aeruginosa. There may also be gaps in trovafloxacin's coverage of some strains of Providencia species, Proteus species, and Serratia marcescens. There are also gaps in the gram-negative coverage of sparfloxacin and grepafloxacin. Sparfloxacin [10, 11] has only limited potency against P. aeruginosa, S. marcescens, Citrobacter freundii, and Proteus vulgaris; and grepafloxacin [12] lacks sufficient activity against P. aeruginosa, S. marcescens, Providencia stuartii, and Acinetobacter baumanii among gram-negative bacteria. Like ciprofloxacin and ofloxacin, the newer agents have excellent potency against genital pathogens, including Neisseria gonorrhoeae, Chlamydia trachomatis, and Mycoplasma hominis. Their clinical efficacy in the treatment of genital chlamydial infections may differ, however, as discussed below. Against respiratory pathogens, all of the newer quinolones, such as ciprofloxacin and ofloxacin, are highly potent against Haemophilus influenzae and Moraxella catarrhalis. However, these agents exhibit greater potency than ciprofloxacin and ofloxacin against Streptococcus pneumoniae, with MIC90 values of 1–2 µg/mL for levofloxacin [13], 0.25–0.5 µg/mL for sparfloxacin [14] and grepafloxacin [15], and 0.12–0.25 µg/mL for trovafloxacin [16]. For this reason, all have been developed for treatment of respiratory tract infections, as discussed below. Other respiratory pathogens, such as Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae, are also highly susceptible to all 4 newer quinolones. Although the newer quinolones all have greater potency than ciprofloxacin against gram-positive cocci in addition to S. pneumoniae, they will have a more limited role in treatment of staphylococcal and enterococcal infections because of marginal potency or acquired resistance. Among staphylococci, most methicillin-susceptible strains of Staphylococcus aureus are susceptible to levofloxacin (MIC90, 0.5–1 µg/mL) [17], sparfloxacin (MIC90, 0.06–0.125 µg/mL) [18], grepafloxacin (MIC90, 0.12 µg/mL) [12], and trovafloxacin (MIC90, 0.03–0.125 µg/mL) [19]. In contrast, many methicillin-resistant strains of S. aureus have acquired high-level resistance to ciprofloxacin that causes substantial cross-resistance to all of the newer agents. These same patterns of differing quinolone susceptibility have been seen with methicillin-susceptible and -resistant strains of coagulase-negative staphylococci. Activity against enterococci is marginal, with MIC90 values of 3.1 µg/mL for levofloxacin [20], 1–2 µg/mL for sparfloxacin [21], 2 to >4 µg/mL for grepafloxacin [12], and 1–32 µg/mL for trovafloxacin [9, 19]. Against vancomycin-resistant enterococci (which in the United States are often Enterococcus faecium), MICs often are at the high end of these ranges. Against Mycobacterium tuberculosis, levofloxacin appears to have good activity (MIC, 0.5–0.75 µg/mL) [22], as does sparfloxacin (MIC90, 0.5 µg/mL) [23]. Information is not available on grepafloxacin, and trovafloxacin has poor activity (MIC90, 32 µg/mL) [9]. Only trovafloxacin (of all available quinolones) has sufficient activity against anaerobic bacteria for clinical applicability [24]. Most species of anaerobic bacteria tested have been inhibited by ≤1 µg/mL, including Bacteroides fragilis, against which trovafloxacin was 32- to 64-fold more active than ciprofloxacin. Some strains of Bacteroides thetaiotaomicron had somewhat higher MICs of 2 µg/mL. The 4 newest fluoroquinolones vary in their pharmacokinetics (table 1). Levofloxacin and trovafloxacin both have oral and iv formulations that allow direct estimates of oral bio-availability, with values >95% for levofloxacin [25] and 88% for trovafloxacin [26]. Maximum concentrations of drug in serum (Cmax) are highest for levofloxacin (5.7–6.4 µg/mL) and lowest for sparfloxacin (1.1 µg/mL) with usual dosing [27]. All of the newer quinolones have longer half-lives of elimination than the earlier agents and are given as single daily doses, with sparfloxacin having the longest half-life (20 h) [27] and levofloxacin the shortest (6–8 h) [25]. Although levofloxacin has only a slightly longer half-life than ofloxacin, it is given at a somewhat higher dose (with a 2-fold greater potency) once rather than twice a day. This dosage is based on pharmacodynamic modeling of quinolones that indicates concentration-dependent bacterial killing and post-antibiotic effects [28], similar to what is seen for aminoglycosides. The half-lives of sparfloxacin [27], grepafloxacin [29], and trovafloxacin [26, 30] all support once-daily dosing, and for sparfloxacin an initial, higher loading dose of 400 mg is recommended to reduce the time to attainment of steady-state con-centrations in serum. Routes of elimination differ among the newest quinolones. Levofloxacin, like ofloxacin, is largely excreted by renal routes, which include both glomerular filtration and tubular secretion. Nonrenal routes of elimination predominate for sparfloxacin, grepafloxacin, and trovafloxacin. For sparfloxacin, hepatic glucuronidation appears to be the main route of elimination, with glucuronide conjugates found in serum, urine, and bile [31]. Grepafloxacin is excreted largely in the feces by biliary excretion or transintestinal elimination, with only limited (<10%) formation of metabolites (glucuronide and sulfate conjugates and a metabolite with an oxidized piperazinyl ring) [29]. Trovafloxacin is eliminated primarily by biliary excretion, with additional hepatic metabolism by glucuronidation, N-acetylation, and N-sulfoconjugation, but minimal oxidative metabolism by hepatic cytochrome P450 enzymes [32]. Dosage adjustments in cases of renal and hepatic failure differ (table 2). No adjustments of dosages of grepafloxacin and trovafloxacin are necessary when renal failure occurs [33]. The doses of levofloxacin and sparfloxacin should be reduced for with use of sparfloxacin, the glucuronide in with renal In with hepatic failure renal adjustments in dosing of levofloxacin and sparfloxacin are generally use of grepafloxacin there are and in serum concentrations in with and in and the that the drug not be given to with hepatic failure For the that dosing be reduced in the of to hepatic In of the of trovafloxacin however, of trovafloxacin to such should be All of the newest quinolones, like the earlier of the with that their oral and other should not be given with dosing should be by at 2 not the of of sparfloxacin but does not the of oral trovafloxacin slightly but is not to the of other quinolones also the oral of trovafloxacin by by the 4 newest quinolones, only grepafloxacin has a with elimination and in of to in the in serum The of quinolones have been recently In most the of quinolones have not been in the same effects such as and generally are the most of effects of quinolones, with in the of of is grepafloxacin, which was with of of higher than with ciprofloxacin were more with the dose than with the as a in the was also by of grepafloxacin The most of effects has been related to the with and most have been for levofloxacin and sparfloxacin and similar for grepafloxacin and ciprofloxacin was more with use of trovafloxacin than with agents This was generally to with dosing, and to of the dosing for only of The that is reduced the single daily dose is given at are with grepafloxacin, and trovafloxacin. In contrast, sparfloxacin, which a at that is to be with was with higher of than were agents in were generally and a of No of in the which is with these is not by many which often only such as or and may some of the for the of the to the end of the on the has been with sparfloxacin and, to a lesser extent, grepafloxacin, but not with levofloxacin and trovafloxacin. sparfloxacin, this is at mg and at 400 mg and similar in to that with of the of in of in clinical was but have been with including some with in in of treatment in Grepafloxacin was recently by the because the drug have of sparfloxacin and grepafloxacin is for with of the or and for other to the have been for quinolones. This of was also in clinical of trovafloxacin. In contrast, in of with trovafloxacin given for was in of with in hepatic the of which 2 of in there have been to the and of hepatic in among for a of Among these were cases of failure in of which were to additional among the 4 of these the on a with that trovafloxacin be only for with or infections infections, and infections, and and infections that the of trovafloxacin the Although the of to be higher with of 2 failure was to in treatment for only 2 the of serum to reduce the The of this but have not been tract infections of ciprofloxacin and ofloxacin in are as are of their renal routes of elimination of of sparfloxacin, grepafloxacin, and trovafloxacin in are than of other because their elimination is largely by routes of For in are available only for sparfloxacin, which when at doses dose and mg for a of was with ofloxacin mg given for similar clinical and These the high of susceptibility of the pathogens that in this Sparfloxacin given in a dose dose and mg however, was less than was ciprofloxacin mg for treatment of with No in the of of were but sparfloxacin was in other of the Pseudomonas aeruginosa, and enterococci that are more pathogens in with Levofloxacin has been for the treatment of with with infections Levofloxacin mg for was similar in clinical efficacy and to ciprofloxacin mg for at the of but were somewhat higher with levofloxacin of of the that higher doses or longer of should be for with No are available on the use of grepafloxacin and trovafloxacin for treatment of Their concentrations in and of sparfloxacin however, that sparfloxacin, grepafloxacin, and trovafloxacin ciprofloxacin or levofloxacin for by gram-negative bacteria. For treatment of sparfloxacin grepafloxacin and trovafloxacin have all been to be highly when given as single doses, in of and infections were also by grepafloxacin and trovafloxacin. The efficacy of sparfloxacin was to that of ciprofloxacin and the efficacy of trovafloxacin was similar to that of ofloxacin it is not the newer agents the older agents for treatment of Information on efficacy of the newer agents in with strains of with reduced susceptibility to ciprofloxacin be No are available on the use of levofloxacin for treatment of infections, but the high efficacy of ofloxacin that levofloxacin also be Against trachomatis, single doses of sparfloxacin and grepafloxacin, like single doses of other quinolones, were for for 2 of given single doses of sparfloxacin and of given single doses of grepafloxacin. More of both of these like a of ofloxacin however, were in genital For chlamydial in sparfloxacin mg on and mg given for was as as a of but a of sparfloxacin was somewhat less In with chlamydial of grepafloxacin mg and also had similar efficacy but only of in the for are on use of levofloxacin and trovafloxacin for genital chlamydial of treatment of infections with quinolones have been only with to ciprofloxacin and trovafloxacin. with was with and trovafloxacin was with followed by were of a In the there were 2 for this in which ciprofloxacin mg and mg were given and in which be iv to oral mg mg was given at a dosage of mg iv were similar in all with of for for and for with and and the were in the and in the not differ treatment with pathogens but were higher in all treatment among enterococci were than among enterococci were not It is not these limited efficacy of these agents against enterococcal or the of enterococci was a for with more In a similar trovafloxacin mg iv and mg trovafloxacin was with iv also with and were somewhat than in the ciprofloxacin for the trovafloxacin and for the the of with in the were with in both treatment not differ by and in the of was clinical with use of trovafloxacin for trovafloxacin for the anaerobic activity of trovafloxacin to be in this The of this that trovafloxacin may be for and anaerobic infections but efficacy in more similar of iv followed by trovafloxacin has also been with a of followed by for treatment of with infections, which were largely were similar for the 2 of of and also not differ in the of gram-negative gram-positive and were in at and Information is limited on the use of levofloxacin and trovafloxacin for treatment of with and In a single levofloxacin mg was with ciprofloxacin mg for treatment of a of in and with the of infections The was S. aureus of and were higher for levofloxacin than for ciprofloxacin of of S. among the of it was were also high of with levofloxacin of with of clinical were similar of with levofloxacin of with The role of levofloxacin in treatment of with and infections is not because the available are only and levofloxacin has not been by the for this For treatment of infections in the of in which anaerobic as as gram-positive and gram-negative bacteria may be pathogens, an additional active against anaerobic bacteria, such as or be which is active against a broad spectrum of pathogens, including anaerobic bacteria, was by the for treatment of infections, including in the of No clinical have been however, and are by the in the Sparfloxacin and grepafloxacin have not been developed for treatment of and tract All 4 of the newest quinolones were developed and in the United States for treatment of with respiratory tract In to pathogens in infections, their like that of ciprofloxacin and ofloxacin, is excellent for pathogens such as influenzae and and their potency is also generally high for pathogens, such as pneumoniae, pneumoniae, and Legionella species, with high concentrations of drug activity in against these S. was the which there had been with to the of the activity of earlier quinolones. of the newer agents potency against this clinical are available the use of sparfloxacin, grepafloxacin, and trovafloxacin for treatment of of respiratory tract No have been on the use of of these quinolones for treatment of and only trovafloxacin has been by the for this bacterial of are often with of influenzae or with a lesser of S. and enteric or gram-negative bacteria. For treatment of with of clinical were similar for levofloxacin mg for with mg for and mg for for sparfloxacin or 400 mg on and or mg for with mg for and ofloxacin mg for for grepafloxacin mg or mg for with ciprofloxacin mg for and mg for and for trovafloxacin mg or mg for with mg and mg of of pathogens were also generally with the that sparfloxacin was than and trovafloxacin was than for of The to which resistance to the to the was not in In in a trovafloxacin dosage of mg was to a dosage of mg in S. in S. that quinolone was not in this or other of treatment of with of these has the of treatment on the time to the of as was in in which ciprofloxacin was to be to and with an of bacterial pathogens similar to in that S. is the most and pathogens also be in some The greater of in some with and in with in also more of the efficacy of quinolones than of with of resistance of to and other fluoroquinolones with activity against S. have been recommended as a for treatment of with of treatment of such with the newest quinolones have been some of which have also been in In of these clinical with the quinolones were similar or to with use of for for levofloxacin mg for iv or for mg for sparfloxacin mg on and mg mg for ofloxacin mg and for grepafloxacin mg mg and for trovafloxacin mg clinical were seen for levofloxacin of of and trovafloxacin of of than for their the had In the levofloxacin it was not to the of in the with or both In was in the for at the of the and was given to of in this treatment it was not to to what it was among found to have In the trovafloxacin is in for treatment of it may be less than against strains of There also as to be an in the of resistance to among higher of of influenzae were seen with grepafloxacin, and trovafloxacin than with their in with S. were similar with sparfloxacin and somewhat with grepafloxacin, and trovafloxacin than with their In the of with are of greater and for there is greater of the to clinical to levofloxacin of and trovafloxacin of have been Among quinolones, the of with have been with sparfloxacin, with a of of In to of and of were somewhat but the were to be There is less information on the use of quinolones for treatment of with of with to have had good clinical to levofloxacin of sparfloxacin of and trovafloxacin of limited support to in and that have to use of quinolones for with infections on efficacy of quinolones for treatment of with by and are to because of the substantial in the which agents not to have activity against these pathogens in This is by the of 2 In the of of clinical to levofloxacin were high for with of or of by However, were high in the of for infections and of for and not differ or not these also the clinical for trovafloxacin of for infections and of for were similar to for of for infections and of for in of these infections, clinical to or substantial of of and have to these to the time to of may be to there is clinical in the use of quinolones for treatment of these of acquired in the is often by a of pathogens similar to that and may be seen as a of respiratory bacteria are in only a of and are more to be is or with The use of to of the is an in addition to of agents. For treatment of with levofloxacin mg has been with mg and sparfloxacin mg on and mg has been with mg and mg to levofloxacin and were when of a to of In a that of by or to bacterial pathogens, a similar of levofloxacin of pathogens, which were influenzae S. S. aureus and sparfloxacin clinical that were to with use of or in were similar in the in which S. pneumoniae, and were the at the time of There are of the use of grepafloxacin or trovafloxacin for treatment of with Levofloxacin and trovafloxacin the for this but the of are trovafloxacin should not be for this levofloxacin may be an to but for treatment of treatment of in with that quinolones as of were in gram-negative but that with in of quinolones as for with and had only limited There however, been a in in of be for oral for because of the for and reduced have been of such oral in this a of oral ciprofloxacin and with iv in and with iv in the other the had and but were to oral and, in were to be at because of the of other of and a of of of treatment among given the oral and were similar in both the oral was with an higher of effects largely and in in an earlier of ciprofloxacin for treatment of a similar of was not seen in these oral also be for at however, to be Although 2 of ofloxacin that it may be to cases the the of these to in poor among such has been as was in a the most The of to the of resistance by a for bacteria that have acquired resistance or for bacteria in a that resistance resistance largely of resistance on or other resistance to rather than by may have the resistance have been the bacterial the resistance has this however, there is an not only for but also for additional among strains and species may In contrast, when resistance occurs largely by all of bacteria will of which may resistance in clinical appears to largely by the to which the recently quinolone resistance found in clinical of has is have been of 2 that the of the 2 quinolone and and that drug to these by of the gram-negative of in the to the and in gram-negative or both of of both in resistance that may vary among quinolones. For a in the of of causes a in the of but only a to in the of ciprofloxacin and other a that the of the of S. aureus resistance to ciprofloxacin by but has on the activity of For most of the newer quinolones, in single causes a in resistance. the of quinolone at the of to the for the for a quinolone this it is that the of resistance will be inhibited rather than by quinolone use of doses of quinolones or of pathogens at in which drug is poor may resistance by the may also when there are quinolone for that in that allow of the past decade of use of ciprofloxacin and ofloxacin, patterns of resistance in pathogens have Most has been the of a high of quinolone resistance among methicillin-resistant but not methicillin-susceptible strains of S. aureus in many of the This same in of quinolone resistance also methicillin-resistant and strains of coagulase-negative For these may have in The of drug in concentrations to and the of of staphylococci, and a for drug concentrations in serum for to of of strains by quinolone These however, have been to for methicillin-resistant and For methicillin-resistant additional were to the of quinolone including of strains and by to of because of the of the methicillin-resistant strains For with a P. aeruginosa, the of resistance has been substantial but more of these and for have to the more in resistance. Most however, has been the of resistance in pathogens that are highly susceptible to the quinolones, such that strains as by of the clinical generally have 2 and in some cases resistance These include gonorrhoeae, and In the of gonorrhoeae, of strains have been in of the United but resistance has highly in of the In in the United strains were and were less than susceptible strains to be by of to reduced and treatment was also The to which quinolone use and of strains by to the high of quinolone resistance in other of the is not For quinolone resistance has in in in both and and was with the use of quinolones in both of with has been but the to which of quinolones to and to resistance in these has been in the United States has an in acquired cases of in had not quinolone treatment This also substantial in the of and with of these with strains were with quinolones were to have than with susceptible has also been to have developed in a quinolone for by susceptible of The but were in of strains of have also in and have in with a not only because of the high susceptibility of the strains but also because of the high concentrations of many quinolones in urine, a of which should high that be to of resistance with quinolone for of resistance in such in have use of quinolones, infections, and use of resistance of has also developed in some in and in which quinolones were as of as as in in In these with has a and of the with have been with quinolone use as and were by not the in these were however, to have with quinolone or a more extensive of with in has an high of among as as for quinolones not be were the in the earlier of by In that of the with to were to an This like that to is a more of resistance of these had a of treatment with a rather than as the of the These in with earlier of high of of with in the that of the with may to high in of the with strains with high of an to have developed of and in it is that these of resistance are the of on of bacteria. strains may have the to the of have that have been to quinolones such are to quinolones for treatment of for for or for other indications, these may the which of highly It is that the with seen in have not in the United which has only recently more limited use of quinolones in the a the high of in and in is thus it will be to similar to with to a and as as to a in and the use of quinolones in resistance among respiratory pathogens has because only recently has treatment of respiratory tract infections a of quinolone use and because the of some pathogens such as S. is a in which quinolones have not been strains of S. pneumoniae, however, have been recently and as has an in older in to in No such in resistance was seen in a a quinolone use and the of resistance. was the of quinolone resistance with resistance in it is for infections to which are that the for agents is most quinolones more for treatment of respiratory tract infections, for resistance in respiratory pathogens will Since only a of S. strains in the United States are to it is to agents to many with and to the newest quinolones for not with use of other agents and for with more in in have clinical use of quinolones to the of other agents for treatment of respiratory tract infections will substantial to the for quinolones should be as of for treatment of bacterial respiratory tract infections and, like other should not be for respiratory to be of of of quinolones to will also be for in a will also be to the of the of quinolone as as dose and on the of resistance. of quinolones. Dosage adjustments of quinolones for with renal or hepatic