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Korean J Urogenit Tract Infect Inflamm. 2015 Apr;10(1):1-6. English.
Published online April 30, 2015.  https://doi.org/10.14777/kjutii.2015.10.1.1
Copyright © 2015, Korean Association of Urogenital Tract Infection and Inflammation. All rights reserved.
Current Updates in Pharmacokinetics and Pharmacodynamics of Fluoroquinolones
Young Hwii Ko, and Phil Hyun Song
Department of Urology, Yeungnam University College of Medicine, Daegu, Korea.

Correspondence to: Phil Hyun Song. Department of Urology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 705-703, Korea. Tel: +82-53-620-3693, Fax: +82-53-627-5535, Email: sph04@hanmail.net
Received March 27, 2014; Revised April 13, 2014; Accepted April 13, 2014.

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Abstract

The ultimate goal of antimicrobial treatment is to decrease the morbidity and mortality related to infection. Maximizing these outcomes requires an understanding of the complex interactions between the drug administered, the host, and the infecting pathogen. Pharmacokinetics, which deals with the disposition of a drug in the body, focuses on such parameters as absorption, distribution, and elimination. Pharmacodynamics more specifically focuses on the interaction between the drug concentration at the site of action over time and the resulting antimicrobial effect. Use of quinolones has increased in vitro activity against several important pathogenic organisms as well as augmented pharmacokinetic parameters. These properties result in enhanced pharmacodynamic characteristics and should improve therapeutic outcomes against selected pathogens. In this article the pharmacokinetics and pharmacodynamic potential of these quinolones, particularly fluoroquinolones, is reviewed.

Keywords: Fluoroquinolones; Pharmacokinetics; Pharmacology

INTRODUCTION

Most decisions with regard to the selection of appropriate antimicrobial therapy were based on whether a drug would safely attain the necessary concentration in serum in order to inhibit or kill the infecting organism, and the following factors were usually considered: activity against the likely pathogen, resistance patterns, adverse effects and allergies, ease of dosing, cost, pharmacokinetics and pharmacodynamics.1, 2

This static parameter, referred to as the "minimum inhibitory concentration (MIC)" was the final arbiter of potential treatment success or failure.1 However, this in vitro measurement cannot provide information on either the rate of eradication of the organism or whether alterations in dosage or delivery of the drug would result in improved eradication, decreased emergence of resistance, or, ultimately, increased survival.2

This review will summarize the pharmacokinetics and pharmacodynamic principles of antimicrobial therapy and apply these principles to the currently available fluoroquinolone class of antimicrobials.

FLUOROQUINOLONES

Quinolones are unusual among antimicrobials in that they were not isolated from living organisms, but rather synthesized by chemists. The first quinolone, nalidixic acid, was derived from the antimalarial drug chloroquine.3 Subsequent agents were derived through side chain and nuclear manipulation.4 The development of the fluoroquinolone class may be described in generational terms, with each generation sharing similar features or antimicrobial spectra.3, 4, 5 First-generation agents possess activity against aerobic gram-negative bacteria, but little activity against aerobic gram-positive bacteria or anaerobes. Second-generation agents are the original fluoroquinolones, named for the addition of a fluorine atom at position C-6 (Fig. 1). These agents offer improved coverage against gram-negative bacteria and moderately improved gram-positive coverage. Third-generation agents achieve greater potency against gram-positive bacteria, particularly pneumococci, in combination with good activity against anaerobes. Fourth-generation fluoroquinolones have superior coverage against pneumococci and anaerobes.5

1. Structure-Activity Relationships

Decades of fluoroquinolone development provide considerable insight into the effects of structural modification upon the antimicrobial activity and pharmacologic properties of these agents. Fig. 1 depicts the core quinolone nucleus. Position 1 affects drug potency, pharmacokinetics, and the potential for interaction with theophylline. Positions 2, 3, and 4 determine antibacterial activity by influencing the affinity for bacterial enzymes. Additionally, positions 3 and 4 are involved in metal chelation and the resulting interaction with di- and trivalent cations. The presence of a methoxy side chain at position 5 enhances gram-positive activity and phototoxicity. The addition of a fluorine atom to position 6 transforms a quinolone into a fluoroquinolone, enhancing drug penetration into the bacterial cell and activity against gram-negative bacteria. Position 7, like position 1, is instrumental in drug potency, pharmacokinetics, and the interaction with theophylline. This position is also implicated in the central nervous system toxicity of some fluoroquinolones owing to their proclivity to bind to gammaaminobutyric acid. The addition of a piperazine moiety at position 7 augments activity against Pseudomonas aeruginosa, whereas a pyrrolidine group improves gram-positive activity. The presence of any halogen at position 8 can increase a drug's half-life, absorption, and anti-anaerobic activity; however, the resulting phototoxicity of di-halogenated compounds renders them unacceptable for clinical use. In contrast, superior pneumococcal activity is achieved by the addition of a methoxy group at position 8 without attendant phototoxicity.6, 7

PHARMACOKINETICS

Fluoroquinolones have favorable pharmacokinetic properties that have encouraged their widespread use. They are well absorbed and have good tissue penetration, which facilitates their use for many clinical syndromes.6

1. Absorption

Fluoroquinolone antimicrobials normally exhibit rapid dissolution in the gastrointestinal tract and are absorbed in the duodenum and jejunum. Peak serum concentrations are usually attained 1-2 hours after dosing in healthy persons.7 The third-generation quinolones also exhibit maximal serum concentration (Cmax) in 1-2 hours, with the exception of sparfloxacin. Sparfloxacin is more slowly absorbed, and its Cmax is observed in 4-5 hours.8 This finding is most likely the result of the lower solubility of sparfloxacin in aqueous solution. Coingestion with food usually increases the time to peak serum concentration by 1 hour for these fluoroquinolones, but other pharmacokinetic values are unaltered.9, 10, 11

The Cmax varies significantly among these compounds. Following a 200-mg dose, peak levels in the range of 0.7 µg/ml (sparfloxacin) to 2.9 µg/ml (trovafloxacin) are attained. In dose-ranging studies it has been observed that an increase in dose will result in a linear increase in the Cmax for these fluoroquinolones.8, 9, 10, 12, 13 The area under the serum concentration-time curve (AUC) for these agents also increases linearly in proportion to dose. In contrast to its low Cmax, sparfloxacin has a large AUC due to its long elimination half-life (Table 1).


Table 1
Pharmacokinetic properties of fluoroquinolones
Click for larger imageClick for full tableDownload as Excel file

2. Distribution

The distribution volumes of the third-generation fluoroquinolones are large and may exceed those of secondgeneration compounds. For instance, the distribution volumes of grepafloxacin and sparfloxacin have been estimated to be 3.5 L/kg and 4.5 L/kg, respectively.14 These compounds, like their predecessors, exhibit low protein binding. Displacement of highly protein-bound drugs is unlikely with these fluoroquinolones, including trovafloxacin. 13 The penetration of third-generation quinolones into several different tissues and body fluids in humans has been demonstrated. Levofloxacin has been most extensively studied and has characteristics similar to those of ofloxacin.9 Levofloxacin concentrations in most tissues or fluids are generally higher or similar to those observed in plasma.15 Inflammatory fluid penetration of several of the newer fluoroquinolones has been studied.14, 16 In healthy volunteers, peak concentrations in chemically induced blisters ranged from 41-81% of those found in serum (Table 2).


Table 2
Inflammatory fluid penetration of fluoroquinolones
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High concentrations of these antimicrobials have also been observed in kidney parenchyma, gallbladder tissue and bile, and genital tract tissues.9, 17, 18 In a study of six surgical patients, mean grepafloxacin concentrations of 0.9 µg/ml, 5.6 mg/kg, and 51 µg/ml were attained in serum, gallbladder tissue, and bile, respectively, at 2-5 hours after oral administration of 300 mg.17

3. Elimination

The fluoroquinolones are removed from the body by both renal and nonrenal routes of elimination.7 High concentrations of unchanged drug can be found in the urine, bile, and feces. When analyzing the urinary excretion of the third-generation quinolones, one finds that these compounds fall into two distinct groups. Greater than 60% of unchanged drug can be recovered in urine following administration of levofloxacin and clinafloxacin.9, 12 In contrast, lower than 10% of unchanged drug is found in the urine after doses of grepafloxacin, sparfloxacin, and trovafloxacin.8, 13, 14

Changes in renal function can have a significant impact on the elimination of these drugs, including those that have low urinary recovery. For instance, the serum elimination half-life of sparfloxacin in patients with moderate or severe renal impairment (glomerular filtration rates of 22 ml/min and 7.7 ml/min, respectively) was found to be approximately two times higher than observed in healthy volunteers.19 The effect of renal impairment on the pharmacokinetics of levofloxacin has also been studied.9 The mean elimination half-lives in patients with creatinine clearances of 40-70 ml/min, 20-40 ml/min, and <20 ml/min were 6.4, 11, and 28 hours, respectively. The serum elimination half-life of the third-generation quinolones ranges from 4.6 to 21 hours in healthy adults (Table 1).

DRUG INTERACTIONS

The absorption of quinolone antibiotics is significantly decreased by concomitant administration of compounds that contain multivalent metal cations such as aluminum, magnesium, zinc, iron, and calcium.20 This effect appears to be due to the formation of insoluble drug-cationic chelate complexes in the gastrointestinal tract.21 The bioavailability of third-generation quinolones has been shown to be decreased by 50% when they are administered with aluminum-magnesium antacids.22 It has been recommended that fluoroquinolones be given at least 2 hours prior to administration of these compounds.23

The clearance of other drugs can be altered by the coadministration of certain fluoroquinolones.20 For instance, ciprofloxacin and enoxacin have been shown to inhibit theophylline and caffeine metabolism, resulting in adverse effects such as nausea, vomiting, and central nerve system excitement. Pharmacokinetic studies of sparfloxacin, levofloxacin, and trovafloxacin have found that these fluoroquinolones do not significantly alter theophylline metabolism in healthy volunteers.9, 24 And additional investigations of potential drug interactions with third-generation quinolones are warranted, especially with regard to medications such as warfarin and cyclosporine.

PHARMACODYNAMICS

Almost 30 years ago, several investigators proposed that antibacterials can be divided into 2 major categories on the basis of their major mechanism of bacterial killing: time-dependent or concentration-dependent activity (Table 3).25


Table 3
Pharmacokinetic and pharmacodynamic parameters in antibiotic therapy
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1. Time-Dependent Antibacterials

The first group of antibacterials includes agents whose effect depends on the length of time that the drug is in contact with the bacteria at concentrations exceeding the MIC. Maximum killing is achieved at concentrations approaching 4-5 times the MIC,26 but any further increases in concentrations provide little to no additional benefits. Therefore, the length of time that the drug concentration is above the MIC (T>MIC) has been determined to be the most important parameter for determining clinical and microbiological success.25

For β-lactam antibacterials, when the T>MIC exceeds 40% to 50% of the dosing interval, clinical and bacteriological efficacy theoretically approaches >90% (Table 4). However, a few qualifying statements need to be made. Additionally, maximizing the T>MIC may improve outcomes for hospitalized patients infected with relatively resistant pathogens. Increasing the dosing frequency, total dose, or duration of infusion may maximize the T>MIC in select circumstances, thereby improving the outcome.26, 27 Further studies will be necessary before standard recommendations can be made.


Table 4
Pharmacodynamic parameters predictive of the outcome associated with various classes of antimicrobials
Click for larger imageClick for full tableDownload as Excel file

2. Concentration-Dependent Antibacterials

The second group of antibacterials includes agents whose effects depend on increasing concentrations of the antibacterial (Table 4). The parameters that most closely correlate with the success of these agents include the ratio of Cmax to the MIC (Cmax:MIC) and the ratio of the 24-h area under the plasma concentration curve (AUC24) to the MIC (AUC24:MIC).2 Most authors agree that only the concentration of free drug is important in making these calculations or for allowing accurate comparisons between drugs of the same class with different degrees of protein binding.28 Throughout the remaining discussion, "AUC:MIC" refers to free AUC:MIC, unless otherwise noted. Fluoroquinolones, aminoglycosides, and ketolides have been classified primarily as concentration-dependent antibiotics (Table 4). Many recently published studies in this field have focused on dissecting these parameters with regard to the fluoroquinolones. Overall, the AUC:MIC has had the greatest correlation with outcome in either in vitro or animal models of infection,28 but the greatest debate has focused on the magnitude of the AUC:MIC that is necessary to maximize outcome or prevent emergence of resistance.

The correlation of drug concentration and pharmacodynamics of an antibiotic class is based on the integration of microbiological activity and pharmacokinetics.29 The fluoroquinolones exert concentration-dependent killing, and both the AUC/MIC and Cmax/MIC ratios have been shown to be pharmacodynamic correlates of efficacy.30 In vitro models suggest that Cmax/MIC ratios of >8 and AUC24/MIC ratios of >125 are necessary for rapid bacterial eradication and prevention of regrowth with resistant subpopulations of certain bacteria.29, 30 Animal and patient studies have confinned these findings. In a neutropenic rat model of Pseudomonas aeruginosa sepsis, the serum peak/MIC ratio was linked to survivorship, particularly when high ratios (20:1) were obtained.31 In a study of acutely ill patients treated with ciprofloxacin, an AUC24/MIC ratio of >125 was highly predictive of a microbiological and clinical cure.30 These findings suggest that the clinical utility of this fluoroquinolone will depend on whether it can attain high Cmax/MIC (10:1) or AUC24/MIC (125:1) ratios against clinically important pathogens.

Conclusion

Fluoroquinolones have gained widespread use owing to their favorable pharmacokinetics, pharmacodynamics, and broad antimicrobial spectra. These quinolones are concentration-dependent killers, however, a new high dose and short course approach, while keeping pharmacodynamic principles in mind, may work faster, encourage better patient compliance, have similar toxicity, decrease cost, and prevent resistance development.

Notes

CONFLICT OF INTEREST:No potential conflict of interest relevant to this article was reported.

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