College of Pharmacy, University of Minnesota, Minneapolis, MN and Clinical Pharmacy, Regions Hospital, 640 Jackson Street, St Paul, MN 55101, USA
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Abstract |
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Introduction |
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As a result of the lack of objective clinical information, the selection of an appropriate antimicrobial regimen is often difficult. Initial antibiotic therapy is, by definition, empirical and use of broad-spectrum agents, such as fluoroquinolones, or combination therapy is sometimes justified. Bacterial culture and antibiotic susceptibility testing are time consuming and cannot provide useful data at the initiation of antimicrobial therapy. Furthermore, there is considerable debate about whether the results of such studies represent accurately the clinical situation, since these data are obtained in a static in vitro setting. Meaningful outcome parameters that allow the prescriber to evaluate the clinical situation objectively and to determine whether monotherapy and/or standard dosing is adequate to treat the infection successfully do not currently exist. The prescribing of antibiotics therefore still remains as much an art as a science.
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The evolution of pharmacokinetics and pharmacodynamics |
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In the late 1960s and early 1970s, the science of pharmacokinetics evolved and was incorporated ultimately into the new drug development process. Pharmacokinetics provided the basis to study the physiological behaviour of drugs in vivo, allowing for mathematical modelling of the relationship between drug concentration and time. Drug absorption, distribution, metabolism and excretion can be characterized using standard pharmacokinetic mathematical models. Given these pharmacokinetic data, drug dose and dosage interval can be modified based on the patients underlying renal and/or hepatic function, thus avoiding concentration-related adverse drug reactions. Although pharmacokinetics defines the spatial relationship between drug concentration and time, it does not consider any effects changing drug concentrations might have on bacterial pathogens. This void was filled in the 1980s with the development of pharmacodynamics, i.e. the study of the relationship between drug, host and antimicrobial effect.1
After studying the relationship between antibiotic concentration and resultant bacterial killing, investigators have suggested that antibacterials can be classified by their pattern of bactericidal activity.24 Antibiotics exhibiting concentration-dependent (time-independent) effects are characterized by an increased rate and extent of bacterial killing over a wide range of concentrations. Additionally, persistent antibiotic effects [such as the post-antibiotic effect (PAE) and sub-MIC effects] tend to be prolonged and related to concentration for antibiotics characterized by concentration-dependent killing. For concentration-independent (time-dependent) antibiotics, once a threshold antibiotic concentration is achieved, the rate and extent of bacterial killing remain relatively constant over increasing antibiotic concentrations. This saturation of bactericidal activity typically occurs at low multiples (four to five times) of the MIC. Fluoroquinolones, aminoglycosides and metronidazole have concentration-dependent bactericidal activity while ß-lactams and vancomycin are concentration-independent. Understanding the interactions between bacteria and clinically relevant drug concentrations can provide critical insight into how to administer optimally a particular antibiotic against a specific pathogen.14
Pharmacodynamics is now emerging as an extremely important tool in deciding which antibiotic to use,5 enabling clinicians to make objective rather than subjective prescribing decisions. Clearly, such data are not yet completely available or accepted universally. This review will focus on the pharmacodynamics of fluoroquinolones. Our purpose is to review critically the presently available data, identify shortcomings that may exist in the understanding of fluoroquinolone pharmacodynamicsespecially as applied to Gram-positive bacteriaand evaluate the potential clinical use of these data.
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Pharmacodynamic strategies |
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Pharmacodynamic parameters integrate both pharmacokinetic and MIC data. Such parameters include: (i) the time for which antibiotic concentration remains above the MIC (t > MIC) for concentration-independent antibiotics; (ii) the ratio between the peak concentration and the MIC (peak/MIC) for concentration-dependent antibiotics; and (iii) the ratio between the area under the serum concentrationtime curve (AUC) and the MIC ratio (AUC/MIC) for concentration-dependent or -independent antibiotics.610
To optimize antibiotic performance, a basic understanding of whether the drug kills in a concentration-dependent or -independent fashion is necessary. For concentration-independent agents, there are several strategies for maximizing t > MIC: (i) for antibiotics with a short serum half-life, the dose can be divided into smaller units administered more frequently (continuous iv infusion is an extension of this concept); (ii) repository dosage forms such as procaine or benzathine penicillin G have been used to promote the continuous release of antibiotic into the serum; (iii) since the 1950s, concomitant administration of probenecid in order to inhibit renal tubular secretion has been used to maintain serum penicillin concentrations;11 and (iv) active metabolites with a lower MIC than the parent compound can make it easier to keep antibiotic concentrations above the MIC, as evident with clarithromycin.
For concentration-dependent antimicrobials, the time of exposure may not be as important as its intensity. Options here are limited to the maximum tolerated level.
Another therapeutic option is the strategic combination of two antimicrobials in an attempt to generate a synergic effect. While this is often attempted, antibiotic synergy is a very specific situation that must be proven for each particular pathogen and the two selected antimicrobial agents. Even in vitro testing in the laboratory sometimes provides conflicting data when different measures of synergy are used.12 Although there are limited data defining optimal antibiotic combinations with fluoroquinolones, some general guidelines might be considered when attempting to produce synergy. Using antibiotics of the same chemical class should probably be avoided, as should use of two concentration-dependent antibiotics or two concentration-independent antibiotics.13
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The quinolone antibiotics |
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Fluoroquinolone pharmacodynamic investigations |
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In vitro model investigations
In vitro studies allow the researcher to examine the direct relationship between dosing regimens and bacteriological effect. These systems allow independent modification of drug concentration, dosing schedules, bacterial inoculum, simulated drug half-life and environmental conditions (e.g. aerobic compared with anaerobic). These in vitro modelling systems can provide detailed pharmacodynamic information on the direct quinoloneorganism interaction and assist in designing more effective animal models and clinical trials. However, caution should be used in extrapolating data from in vitro models to in vivo situations, as the former lack a functional immune system and other variables found in vivo, and generally are studied for only limited periods.
In 1987, Blaser and colleagues27 suggested that peak/ MIC ratios were important parameters in predicting the clinical use of quinolone antibiotics. Using an in vitro pharmacodynamic model, they examined netilmicin and enoxacin activity against Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Staphylococcus aureus. Bacterial regrowth was observed within 24 h unless the peak/MIC ratio exceeded 8. Furthermore, the regrowing bacteria had four- to eight-fold higher MICs, and little or no bactericidal effect occurred after subsequent antimicrobial dosing. The authors concluded that peak/MIC ratios may be an important indicator of both clinical success and the development of bacterial resistance.27 Similarly, the selection of resistant pathogens after quinolone dosing that produced peak/MIC ratios of <8 has also been noted in an in vitro investigation of ciprofloxacin against P. aeruginosa by Dudley and colleagues.28
Madaras-Kelly et al.29 investigated the utility of AUC/ MIC ratios to describe the antimicrobial activity of ciprofloxacin and ofloxacin against three strains of P. aeruginosa in vitro. Changing peak antibiotic concentrations and half-lives but maintaining equivalent AUC values allowed the investigators to determine whether AUC/MIC or peak/ MIC was more important in antibiotic performance. Both ciprofloxacin and ofloxacin demonstrated equivalent antibacterial activity at AUC/MIC ratios of 100, with ratios below this breakpoint resulting in poorer outcome. These data suggested that AUC/MIC may be the most useful measure of fluoroquinolone antibacterial activity against P. aeruginosa.29
Investigating further, Firsov and colleagues30 examined ciprofloxacin and trovafloxacin activity against E. coli, P. aeruginosa and K. pneumoniae in vitro. Individual pharmacodynamic parameters (AUC/MIC, peak/MIC and t > MIC) correlated equally well with antimicrobial effect for both ciprofloxacin and trovafloxacin; no advantage of one parameter over the others was supported by the data. The authors concluded that predictors of fluoroquinolone antimicrobial effects were of two types: intraquinolone (within regimens) and interquinolone (between regimens). AUC/MIC, peak/MIC and t > MIC were suggested as intraquinolone predictors, while t > MIC was suggested to be the only interquinolone predictor that might predict accurately the antimicrobial effect of one fluoroquinolone on the basis of data obtained from another.30
The role of t > MIC as an interquinolone predictor, however, was contradicted by further work from the same laboratory studying ciprofloxacin, gatifloxacin and trovafloxacin against S. aureus.31 The authors suggested that AUC/MIC was the best predictor of fluroquinolone effect based on their work with two strains of S. aureus, adding further confusion to the picture.
As an extension of these findings, Firsov and colleagues3235 have suggested a new approach to the comparison of quinolones based on the intensity of the antimicrobial effect (IE); this is defined as the difference between the areas under the control growth and bacterial killing/ regrowth curves. To measure IE accurately, experiments must be conducted until the bacterial regrowth curve reaches the control growth curve, which can easily take 4872 h for many of the newer quinolone agents. Each quinolone is then evaluated by the relationship between IE and the AUC/MIC ratio generated.3235 The utility of IE appears to be quinolone specific and independent of bacterial strain.35 The IE concept relies on bacterial regrowth regardless of clinical dosing schedules and, therefore, does not conform well to in vivo situations, limiting its clinical utility.
The applicability of using generic pharmacodynamic ratios as predictors of microbiological eradication of Gram-positive organisms and anaerobes was further examined in in vitro studies of levofloxacin, trovafloxacin and ciprofloxacin against strains of penicillin-resistant S. pneumoniae (PRSP), S. aureus, Bacteroides fragilis and Bacteroides thetaiotaomicron.3639 Data from these investigations indicated that, at clinically relevant concentrations, fluoroquinolones eradicate these Gram-positive aerobes and Gram-negative anaerobes in a concentration-independent fashion and an AUC/MIC breakpoint of 40 appears to be most appropriate for Gram-positive organisms and anaerobes.3639
Lacy and colleagues40 found that AUC/MIC ratios of 3055 were effective for ciprofloxacin and levofloxacin against four strains of PRSP. These were significantly lower than the suggested breakpoint of 100125 for P. aeruginosa,29 and suggests that fluoroquinolone pharmacodynamics are likely to be organism specific.
Lister & Sanders41 examined the pharmacodynamics of ciprofloxacin, ofloxacin and trovafloxacin against eight strains of S. pneumoniae using an in vitro model. In this investigation, an AUC/MIC ratio of 49 was sufficient for ofloxacin to eradicate all eight strains. With an AUC/MIC ratio of 44 and a peak/MIC ratio of 5, ciprofloxacin eradicated five of the strains.41 The authors suggested that the inability to eradicate three of the S. pneumoniae isolates with ciprofloxacin was a result of adaptive resistance or a reversible decrease in susceptibility after initial exposure to the antibiotic.
Hershberger & Rybak42 examined the bactericidal activities of six quinolones in an in vitro pharmacodynamic model of fibrin clots infected with PRSP.42 They found that trovafloxacin, gatifloxacin, clinafloxacin, sparfloxacin and levofloxacin had better activity than ciprofloxacin. Although no clear association between pharmacodynamic parameters and bacterial killing was identified, an AUC/MIC of 40 or a t > MIC of
55% was associated with decreased killing and significant bacterial regrowth.42
Coyle & Rybak43 came to similar conclusions when trovafloxacin, gatifloxacin, levofloxacin and ciprofloxacin were evaluated against two laboratory-derived ciprofloxacin-resistant S. pneumoniae isolates. During the experiment, MICs of ciprofloxacin increased from 4 and 8 mg/L to >32 mg/L, while trovafloxacin, gatifloxacin and levofloxacin MICs did not change. Bacterial regrowth and/ or resistance was associated with AUC/MIC ratios of 20 and peak/MIC ratios of
2.2.43
Further in vitro work was conducted with S. pneumoniae and levofloxacin by Ibrahim and colleagues.44 After infusing levofloxacin at a constant rate of 1, 2 or 10 x MIC for 15, 40, 65 and 100% of the dosing interval, the authors found no concentration-dependent killing and equal rates of kill with all dosing regimens. Regrowth was generally prevented, however, with AUC/MIC ratios of >30.44
Animal infection models
Animal studies are effective means of examining the relationship between pharmacodynamic parameters and in vivo efficacy. They can provide confusing results, however, owing to the effects of protein binding, variable pharmacokinetics and the animals immune system. Additionally, in vivo data tend to be analysed in terms of discrete endpoints (success or failure, death or survival, sensitive or resistant) that do not allow specific quantitative examination of antimicrobial activity. Furthermore, experimental models, such as S. pneumoniae thigh infections, may not be representative of typical human infections. An examination of the relationship between results from in vitro and in vivo studies, however, can lead to significant conclusions because of the complementary nature of the two experimental methods.
In the late 1980s, the 24 h AUC/MIC (AUC24/MIC) ratio was shown to be the pharmacodynamic parameter that best correlates with efficacy for the aminoglycosides in animal models of infection.45,46 Much of the animal data regarding fluoroquinolone pharmacodynamics have been extrapolated from these aminoglycoside data, owing to their similar concentration-dependent activity. A brief examination of the landmark trials is warranted to give a better appreciation of the correlation between in vitro, animal and human pharmacodynamic data.
Craig and colleagues45,46 conducted studies of pneumonia, peritonitis and sepsis, caused by P. aeruginosa, E. coli, S. aureus and S. pneumoniae, in mice, rats and guinea pigs. The data from these investigations suggested that an AUC/ MIC ratio of c. 35 was necessary to achieve a bacteriostatic effect. This value appeared to be independent of the dosing interval or site of infection. Generally, AUC/MIC ratios of <30 were associated with >50% mortality and AUC/MIC ratios of 100 approached 100% survival.46 The authors suggested that fluoroquinolone serum concentrations need to average c. 4 x MIC for 24 h to result in 100% survival in experimental animal models.1,46
Craig and colleagues47 continued their investigations with tobramycin and pefloxacin against 15 Gram-negative bacilli from five different species in a murine thigh infection model. They demonstrated that the AUC/MIC ratio necessary to achieve a bacteriostatic effect in the animal models was not significantly different for pefloxacin and tobramycin, and that there was a strong linear relationship between the ratio and the results of in vitro susceptibility tests. The authors suggested that variations in antimicrobial potency could be explained by differences in pharmacokinetic and pharmacodynamic properties.
Drusano and colleagues48 investigated the in vivo utility of peak/MIC ratios with lomefloxacin in a neutropenic rat model of pseudomonal sepsis. Outcome was most likely to be successful when lomefloxacin was administered at a dose sufficient to achieve peak/MIC ratios of >10. At lower doses, producing peak/MIC ratios of <10, however, the AUC/MIC ratio appeared to be linked most closely to outcome.
In 1996, Vesga & Craig49 evaluated levofloxacin against six strains of PRSP in normal and neutropenic mice. Static-dose AUC/MIC ratios ranged from 22 to 59 in the animal models.50 A similar evaluation50 by Vesga and colleagues with sparfloxacin against multiple bacterial pathogens, including nine strains of S. pneumoniae, indicated that a mean AUC/MIC ratio of 29 was necessary to produce a net static effect.
Further investigations with murine thigh and lung infection models have been conducted with gatifloxacin, sitafloxacin and gemifloxacin.5153 Mean AUC/MIC ratios needed to achieve clinical efficacy were <100 for Enterobacteriaceae, S. pneumoniae and S. aureus. Specifically, for S. pneumoniae mean AUC/MIC ratios of 37, 52 and 35 were necessary to achieve a net bacteriostatic effect for sitafloxacin, gatifloxacin and gemifloxacin, respectively.5153
Human clinical trials
Relatively few human trials have been conducted to confirm the hypotheses generated from the in vitro and animal investigations. One of the first reported studies, by Peloquin et al.,10 involved iv ciprofloxacin in patients with nosocomial pneumonia. The study involved 50 patients with Gram-negative lower respiratory tract infections, half of whom had failed previous antimicrobial therapy. Elevated peak/MIC ratios and AUC/MIC ratios and extended t > MIC were associated with successful bacterial eradication from the lower respiratory tract. Additionally, patients with trough concentrations exceeding the pathogen MIC were significantly more likely to show bacterial eradication.10
As a follow-up to the above work, Forrest et al.54 examined retrospectively the pharmacodynamics of iv ciprofloxacin in human patients with moderate to severe infections, chiefly of the lower respiratory tract. An AUC24/ MIC) of 125 was considered to be the minimally effective value, with values of 250 and 500 exhibiting an increased in vivo bactericidal rate and a shorter time to bactericidal eradication. Of the 74 patients evaluated, 82% had infections attributed to Gram-negative aerobic pathogens. Approximately 15% of the patients had S. aureus infections, with nearly half of those receiving concomitant rifampicin therapy.54
A year later, Hyatt and colleagues55 attempted to confirm the utility of AUC/MIC as a generic fluoroquinolone pharmacodynamic outcome parameter by assessing the bactericidal activity of ciprofloxacin serum ultrafiltrates from five healthy volunteers against strains of S. pneumoniae, S. aureus and P. aeruginosa. The killing rates were found to be considerably more rapid for P. aeruginosa than for the Gram-positive organisms at clinically achievable concentrations. The maximal effect of ciprofloxacin, however, was seen at 1540 x MIC for the tested Gram-positive organisms and 2050 x MIC for P. aeruginosa. These data appear to support the premise that MIC is a useful indicator of relative ciprofloxacin susceptibility for these three bacterial species, giving credence to the utility of AUC/MIC ratios as a generic predictor.55
A very small clinical study (n = 8) evaluated the pharmacodynamics of oral grepafloxacin in treatment of acute exacerbations of chronic bronchitis,56 and found an 87.5% bacteriological cure with AUC/MIC ratios ranging from 0 to 92 for S. pneumoniae isolates. The data suggest that the minimum AUC/MIC required for the treatment of pneumococcal infections may indeed be lower than the 125 suggested for Gram-negative bacteria.54,56
In the only prospective human study conducted to date, Preston and colleagues5 suggested peak/MIC as the optimal predictive parameter for successful clinical and microbiological outcome. The authors of this study reported that a peak/MIC ratio of 12.2 correlated with a successful clinical outcome and microbiological cure in patients treated with levofloxacin for urinary tract infections, pulmonary infections and skin and soft tissue infections. They noted that the AUC/MIC ratio was highly correlated with the peak/MIC ratio (r = 0.942), but concluded from previous animal studies48 that the peak/MIC ratio was linked more closely to clinical outcome.
In total, these studies evaluated 313 adult patients, 134 of whom had clinical outcome determinations and an identified microorganism with a measured MIC of levofloxacin. Five species accounted for 58% of the isolates recovered in the study: 15.7% of the patients had S. pneumoniae infections and 11.2% had S. aureus as the predominant pathogen.5 When the S. pneumoniae infections alone were examined, 19/20 were classified as clinically successful and all 20 were considered microbiologically cured. The single clinical failure was an anomaly since the MIC of levofloxacin for this pathogen was 0.15 mg/L, resulting in AUC/ MIC and peak/MIC ratios of 249 and 23, respectively. Overall, the AUC/MIC ratios were 50 in 17 of the 20 patients infected with pneumococci,
75 in 11 patients and >100 in nine patients. Therefore, even though only 45% of the cases had AUC/MIC ratios of >100, 95% clinical cure and 100% microbiological eradication rates were observed (G. L. Drusano, personal communication). As this was not a controlled in vitro investigation, the investigators were unable to take into account any effects of the host immune system, nor were they able to alter the serum concentration and half-life of levofloxacin for a rigorous evaluation of the individual contributions of peak/MIC and AUC/MIC. For these reasons, the authors chosen parameter, peak/MIC, may not be the optimal pharmacodynamic predictor for both Gram-positive and Gram-negative bacteria, especially when there is such covariance between AUC/MIC, peak/ MIC and t > MIC.
Rather than relying on pharmacodynamic parameters to predict bacteriological or clinical response, Thomas and colleagues57 analysed the relationship of AUC/MIC and the development of bacterial resistance, similar to an earlier study.27 In a retrospective review of 107 acutely ill patients from four nosocomial lower respiratory tract infection clinical trials, the probability of developing bacterial resistance increased significantly when the AUC/MIC ratio was <100. Antimicrobials included in this analysis were cefmenoxime, imipenem, ceftazidime and ciprofloxacin. Approximately 86% of the isolates included in this analysis, however, were Gram-negative organisms. The authors note that the strongest relationship between AUC/MIC ratio and the development of bacterial resistance existed for P. aeruginosa treated with ciprofloxacin.57 These data indicate the utility of pharmacodynamic parameters in predicting the emergence of bacterial resistance rather than bacteriological or clinical cure.
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Limitations in the application of pharmacodynamic data |
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Clearly, AUC/MIC and peak/MIC ratios are applicable for the fluoroquinolones against Gram-negative bacteria, especially P. aeruginosa. There are limited and conflicting data, however, regarding the generic predictability of these pharmacodynamic parameters for fluoroquinolones.
Gram-negative bacteria are characterized by a complex outer cell wall of lipopolysaccharide, lipoprotein and phospholipid, whereas Gram-positive bacteria are relatively lipid-poor and possess a thick peptidoglycan cell wall with a layer of teichoic acid lying outside the peptidoglycan.60 Atypical pathogens have no formal cell wall structure and certain strains of bacteria can protect themselves by encapsulation, spore formation or glycocalyx production.60 When a fluoroquinolone enters a bacterial cell, various efflux proteins may be present and these can alter the amount of antibiotic that reaches the site of activity.60 Owing to these compositional and structural differences, as well as varying porin channel protein distribution, cellular uptake and affinity for DNA gyrase of fluoroquinolone antibiotics may vary considerably between species. Even with the newer fluoroquinolones, there are intrinsic differences in potency, based on MICs, between Gram-positive and Gram-negative bacteria. Accordingly, because of the large diversity among organisms, the lack of a universal pharmacodynamic predictor of antimicrobial efficacy among fluoroquinolones is unremarkable.
Environmental conditions at the site of infection may also affect the intrinsic activity of an antibiotic against various pathogens. The bactericidal activity of fluoroquinolones against S. aureus, for instance, differs in aerobic and anaerobic conditions,61 and clinical staphylococcal infections may occur in an anaerobic or microaerophilic environment. The bactericidal activity of five fluoroquinolones (ciprofloxacin, ofloxacin, temafloxacin, sparfloxacin and clinafloxacin) was delayed by anaerobiosis in an in vitro pharmacodynamic system. Data from these experiments indicated differing AUC/MIC ratios for staphylococci, despite similar kill curves.61
Another complication in the application of current pharmacodynamic data is the lack of consistent methods of analysis of in vitro pharmacodynamic studies. Investigators have employed different reductions in bacterial inoculum as endpoints to assess fluoroquinolone pharmacodynamic parameters. Craig and colleagues suggest that a 1 log10 reduction in the bacterial inoculum is sufficient (equating to a net bacteriostatic effect),4953 while others prefer a 3 log10, or 99.9%, reduction in bacterial inoculum, which equates to a bactericidal effect.3638 The role of bacterial regrowth remains unclear, as some investigators merely make passing commentary on the presence or absence of regrowth while Firsov and colleagues use the IE concept, which is highly dependent on the time taken for bacterial regrowth.3135
Universal consensus on methodology (e.g. in terms of log reduction endpoints, role of regrowth, length of experiments, number of pathogens necessary, inoculum size, lower counting limits, prevention of antibiotic carryover) would be beneficial. By creating consistent standards of operation and analysis, data from various studies might be pooled, enhancing their utility. The relationship between data from in vitro studies, animal models and clinical trials could also be defined more accurately.
Assuming that a pharmacodynamic ratio does prove to be a generic outcome parameter for all bacteria, the quantitative value of such a parameter might differ depending upon the organism, the intrinsic properties of the quinolone used and/or the environmental conditions at the site of infection. Defining values for pharmacodynamic outcome parameters based on the site of infection may necessary. Presently, however, the application of fluoroquinolone pharmacodynamics appears to be pathogen- and quinolone-specific.
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Clinical application of fluoroquinolone pharmacodynamics |
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As is evident from Table II, quinolones typically have low protein binding (trovafloxacin is the exception) and excellent bioavailability (>70%). However, AUC and Cmax in healthy individuals are significantly different from those in sick patients, for both levofloxacin and gatifloxacin.5,62
Most investigators calculate pharmacodynamic ratios from pharmacokinetic data obtained in healthy volunteers. As AUCs for levofloxacin and gatifloxacin in patients with bacterial infections may be 33% higher than those seen in healthy individuals,5,62 this methodology may lead to an underestimation of the calculated AUC/MIC ratio. The increased AUCs observed in infected patients may result from diminished quinolone excretion, decreased protein binding or a heightened immune response. When available, pharmacokinetic data derived from patients with a bacterial infection should be used to calculate pharmacodynamic ratios.
The difference in protein binding between healthy volunteers and infected patients should also be considered when calculating pharmacodynamic ratios. In order to assess the AUC/MIC or peak/MIC ratio accurately, the free or unbound drug concentration, which represents the true antibiotic concentration available to cross biological membranes and interact with the bacterium, should be used. Otherwise the pharmacodynamic ratio may be overestimated.
Tissue penetration is another factor that might need to be considered when calculating pharmacodynamic ratios, since the AUC and maximum concentration at the site of infection are the relevant pharmacokinetic parameters needed to determine pharmacodynamic ratios. The ultimate role of tissue penetration in pharmacodynamic calculations, however, remains to be defined fully.
Tables IV and V illustrate the AUC/MIC and peak/MIC ratios generated with conventional single dose regimens for some of the newer quinolone agents. The AUCfree and Cmax,free values represent the values corrected for protein binding. Included in these tables are pharmacokinetic data for levofloxacin and gatifloxacin from patients with bacterial infections. These tables can assist the clinician in estimating AUC/MIC or peak/MIC ratios based on the MIC for a pathogen.
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The MIC represents the pathogen-specific variable in pharmacodynamic ratios. MICs can vary significantly depending on methodology and specimen source. The way in which MICs are measured (Etest, broth microdilution or disc diffusion) can affect the interpretation of the MIC,6365 and the type of broth, incubation time, incubation temperature and method of determining turbidity can all vary.66 The site of infection may also affect the true MIC for a given pathogen owing to the effects of pH on MIC.67
MIC errors of a single tube dilution can alter the corresponding pharmacodynamic ratio significantly. For example, if the AUC of levofloxacin is 72 and the MIC for an S. pneumoniae isolate is 0.5 mg/L, the corresponding AUC/MIC ratio is 144 (72/0.5). If the MIC is later found (perhaps by Etest) to be 1 mg/L, the AUC/MIC would then be 72 (72/1). We would suggest that, whenever possible, MICs of blood isolates, measured using NCCLS-approved methodology,68 should be used. The clinician should be aware that both patient- and pathogen-specific variation exists and the resulting pharmacodynamic ratio remains an estimate.
Gram-negative pathogens
Initial fluoroquinolone pharmacodynamic evaluations dealt primarily with P. aeruginosa.2729,48,54,55 As outlined above, breakpoint values of AUC/MIC for quinolones and pseudomonal sepsis have ranged from c. 10029 to 125.54 Similarly, peak/MIC ratios of 105,48 or 125 have been suggested for optimal bacteriological and clinical outcomes, respectively, in pseudomonal sepsis. Furthermore, peak/MIC ratios in excess of 812 have been associated with diminished development of bacterial resistance.5,27,28,57 Studies of ciprofloxacin in ventilator-dependent patients with lower respiratory tract infections10 did not identify a specific pharmacodynamic ratio, but development of bacterial resistance was associated with MICs > 0.25 mg/L. Retrospective analysis of these data suggest a peak/MIC ratio of c. 12.
Assuming that an AUC/MIC ratio of 100 and peak/ MIC ratio of
10 are necessary for clinical and microbiological cure, an MIC
0.25 mg/L would be a necessary breakpoint for most fluoroquinolones, including ciprofloxacin. Most Gram-negative pathogens remain highly susceptible to the fluoroquinolones,6973 although a notable exception is P. aeruginosa, with MIC90s ranging from 0.25 to 8 mg/L.16
The pharmacokinetic data for the fluoroquinolones (Tables IV and V) suggest that, given the low MICs for Gram-negative bacilli, existing dosage regimens are sufficient to achieve AUC/MIC ratios of 100 and peak/MIC ratios of 10. With the exception of P. aeruginosa, the fluoroquinolones appear to have a high probability of clinical and microbiological efficacy against Gram-negative bacteria while minimizing the development of bacterial resistance. Importantly, the clinical experience with ciprofloxacin and levofloxacin correlates well with these pharmacodynamic predictions.
Streptococcus pneumoniae
As stated previously, the natural inclination is to extrapolate the data from Gram-negative organisms to other pathogens, such as Gram-positive pathogens, atypical pathogens and anaerobes. Within the past 3 years, however, a significant amount of data has emerged describing fluoroquinolone pharmacodynamics with the pneumococci. These data suggest that the breakpoint AUC/MIC ratio necessary to ensure successful outcome is c. 40.36,4044 Levofloxacin is the predominant fluoroquinolone evaluated, although these data correlate with conclusions from animal models by Andes & Craig for sitafloxacin, gatifloxacin and gemifloxacin,5153 as well as human clinical data by Preston and colleagues.5
Assuming that a minimal AUC/MIC ratio of 40 is necessary to achieve clinical and microbiological success in S. pneumoniae infections, the newer quinolone agents will generate an AUC/MIC 40 with isolates whose MICs are
1 mg/L. Such MICs are observed typically for most S. pneumoniae isolates and the newer quinolone agents.6468 The post-marketing clinical experience with levofloxacin in community-acquired pneumonia confirms these pharmacodynamic predictions. Recent data from the TRUST surveillance system indicate that the S. pneumoniae MIC90 of levofloxacin is 1 mg/L.17 According to the pharmacokinetic/pharmacodynamic data available for levofloxacin, typical AUC/MIC ratios generated by a 500 mg daily dose of levofloxacin range from 48 in healthy patients to 72 in patients with infections. As clinical treatment failures and reports of pneumococcal resistance remain rare for levofloxacin, a breakpoint AUC/MIC ratio of >40 correlates well with clinical experience. Interestingly, no apparent benefit is realized in terms of rate and extent of bactericidal activity with AUC/MIC ratios of >40. Further work characterizing the role of pharmacodynamics in the development of pneumococcal resistance is necessary.
Anaerobes
Trovafloxacin was the first fluoroquinolone with significant anaerobic activity and corresponding clinical indications. Moxifloxacin and gatifloxacin have demonstrated some activity against anaerobes although they are not approved for use in anaerobic infections.74,75 With more quinolone agents currently in development with enhanced anaerobic activity, the identification of pharmacodynamic parameters describing anaerobic activity is of importance. Initial data suggest that for B. fragilis and B. thetaiotaomicron, a breakpoint AUC/MIC ratio of between 10 and 50 appears to be appropriate and that AUC/MIC ratios of >50 and >15, respectively, were necessary to prevent the development of resistance in these two anaerobic species.37,39
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Conclusion |
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Given the recent evidence with Gram-positive bacteria and anaerobes, it seems unlikely that there will ever be a universal pharmacodynamic outcome parameter to predict clinical and microbiological success. It is possible that there is no single pharmacodynamic parameter that will be able to predict clinical and microbiological cure by extrapolation between quinolone agents or between bacterial species. Fluoroquinolone pharmacodynamics rather, appears to be both quinolone- and pathogen-specific.
Currently, the suggested pharmacodynamic breakpoints for the development of resistance correspond to those identified with clinical and microbiological outcome. Further studies of this important application of fluoroquinolone pharmacodynamics are warranted.
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Notes |
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References |
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Received 6 July 1999; returned 12 October 1999; revised 8 May 2000; accepted 20 July 2000