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Comparison of the Fluoroquinolones Based on Pharmacokinetic and Pharmacodynamic Parameters

Katherine E. Pickerill, Pharm.D., Joseph A. Paladino, Pharm.D., FCCP, and Jerome J. Schentag, Pharm.D., FCCP., The Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospitals, Buffalo, New York.

[Pharmacotherapy 20(4):417-428, 2000. © 2000 Pharmacotherapy Publications, Inc.]

Abstract

Introduction

Pharmacodynamics study the relationship between drug concentration and pharmacologic effect. For antimicrobials, pharmacodynamic activity can be described as concentration dependent or time dependent.^[1] As fluoroquinolones have concentration-dependent killing, the peak:MIC and/or area under the curve in 24 hours (AUC₂₄):MIC are pharmacodynamic values that best correlate with efficacy.^[2-4] Understanding these parameters can facilitate selection of effective antibiotics and optimal regimens to hasten response, prevent treatment failures, and minimize the development of resistance.^[5]

Spectrum of Activity

Data suggest that fluoroquinolones preferentially target DNA gyrase in gram-negative bacteria, whereas topoisomerase IV is the primary target in gram-positive bacteria.^[24-26] The preferential topoisomerase target within the cell also may be determined by fluoroquinolone structure.^[26] This implies that it is possible for some fluoroquinolones to have equal activity against both DNA gyrase and topoisomerase IV.^[26] Therefore, they would show activity against a broad range of gram-positive and -negative bacteria. A deficiency of ciprofloxacin, ofloxacin, levofloxacin, and other earlier fluoroquinolones is limited potency against gram-positive bacteria. The newer fluoroquinolones and others under development have improved activity against these organisms while retaining activity against gram-negative pathogens. Sparfloxacin, grepafloxacin, trovafloxacin, gatifloxacin, clinafloxacin, and moxifloxacin have greater in vitro activity than ciprofloxacin and ofloxacin against Staphylococcus aureus and Staphylococcus epidermidis (Table 2).^[7-13,23,27] However, staphylococcal strains that are methicillin resistant usually are resistant to fluoroquinolones.^[7-13,23,27] Gatifloxacin, clinafloxacin, and moxifloxacin have in vitro activity against methicillin-resistant strains of S. epidermidis, but clinical activity will depend on whether resistance develops during therapy.^[11,15,16] Most studies report MIC₉₀s of ciprofloxacin between 2 and 4 µg/ml for Enterococcus faecalis and greater than 4 µg/ml for Enterococcus faecium.^{[7,8,10,11,13-15,22,27]} Neither ofloxacin nor levofloxacin offers any advantage over ciprofloxacin for these bacterial strains.^[9] Grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, and moxifloxacin inhibit E. faecalis at concentrations of 0.5-1 µg/ml, but E. faecium tends to be more resistant.^{[7,8,10,11,13-15,22,27]} For S. pneumoniae, ciprofloxacin and ofloxacin MICs are 2 µg/ml or greater compared with the other fluoroquinolones, 0.06-1 µg/ml.^[16,21,28] Strains resistant to, or with decreased susceptibility to, penicillin remain susceptible to the agents.^{[16,21,28 ]} Sparfloxacin, grepafloxacin, trovafloxacin, gatifloxacin, clinafloxacin, and moxifloxacin show excellent in vitro activity against Streptococcus pyogenes and Streptococcus agalactiae.^[7,11,15,16]

All drugs in this class are highly active against Legionella sp, but other atypical microorganisms exhibit variable susceptibility patterns (Table 3).^{[11,23,29-39]} Several newer agents appear to be substantially more active than ciprofloxacin or ofloxacin against Mycoplasma pneumoniae and Chlamydia pneumoniae. The in vitro suscepti-bilities of 21 isolates of C. pneumoniae to grepafloxacin were 0.06-0.12 µg/ml, with an MIC₉₀ of 0.12 µg/ml.^[31] Gatifloxacin and moxifloxacin have the greatest in vitro activity against C. pneumoniae, followed by grepafloxacin and sparfloxacin.^{[11,31,34,35]} Gatifloxacin, moxifloxacin, trovafloxacin, and sparfloxacin show the best activity against M. pneumoniae. ^[36-38]

Ciprofloxacin and ofloxacin have relatively weak in vitro activity against most anaerobes. Whereas levofloxacin, grepafloxacin, and sparfloxacin have somewhat lower MIC₉₀s than ciprofloxacin to some anaerobic bacteria, they should not be considered clinically active against all anaerobes (Table 4).^{[7,9,10,13,27,40-42]} Of currently available fluoroquinolones, trovafloxacin has considerably better in vitro activity against these pathogens. Trovafloxacin inhibits 90% of Bacteroides fragilis and Clostridium sp at concentrations 0.5-2 µg/ml, and 90% of Peptostreptococcus sp at concentrations 0.5-1 µg/ml.^[7,10,11,40] Gatifloxacin and clinafloxacin have lower MIC levels than trovafloxacin against Peptostreptococcus, Clostridium perfringens, and other clostridia sp^[7,11,41,42] Moxifloxacin appears to have some anaerobic activity but less than trovafloxacin, clinafloxacin, or gatifloxacin.

Pharmacokinetics

Absorption and Distribution

Metabolism and Elimination

Fluoroquinolones are removed from the body by both renal and nonrenal mechanisms. Ofloxacin, levofloxacin, gatifloxacin, and clinafloxacin undergo limited metabolism in humans, with more than 60% of unchanged drug found in urine after administration.^[53,63-66] A dosage adjustment should be made for levofloxacin and ofloxacin when the patient's creatinine clearance is less than 50 ml/minute.^[52,53] It appears that the daily clinafloxacin dose should be halved in patients with creatinine clearances less than 40 ml/minute.^[66,70] Trovafloxacin, moxifloxacin, and grepafloxacin do not require a decrease in dosage in patients with impaired renal function. Trovafloxacin undergoes extensive hepatic metabolism to an inactive metabolite, and less than 10% of unchanged drug is renally eliminated^[73]; it is recommended that the dosage be decreased in patients with mild or moderate cirrhosis.^{[72 ]} Moxifloxacin undergoes conjugation to two metabolites that appear to have no major antimicrobial activity, and approximately 20% of the administered dose is excreted in urine.^[74] Grepafloxacin is eliminated primarily through hepatic metabolism and biliary excretion, and should be avoided in patients with hepatic failure as less than 10% is eliminated in urine as unchanged drug.^[57] Sparfloxacin and ciprofloxacin have two routes of elimination; nonetheless, a decrease in dosage is recommended for patients with creatinine clearances less than 50 and less than 30 ml/minute, respectively.^[45,71]

Pharmacodynamics

Studies in dynamic in vitro models of infection examined the relationship between dosage and bacterial killing. In these systems, bacteria are exposed to fluctuating concentrations of drug adjusted to simulate peak and trough serum concentrations observed in humans. The models suggest that a peak:MIC ratio of 10 or above and an AUIC ratio of 125 or above optimize rapid bacterial killing and prevent regrowth of resistant gram-negative bacterial subpopulations.^[75,76]

Animal studies confirmed these findings. In two murine models, total exposure or AUC was the variable most closely linked to outcome.^[77] An AUIC of 100 or greater, peak:MIC above 8, and serum levels above MIC 100% of the time predicted efficacy of fluoroquinolones in treating animal models of endocarditis; however, the AUIC showed the best linear correlation.^[78] In a study that examined how altering the dosage or treating a more susceptible organism influenced survival in a neutropenic rat model of P. aeruginosa sepsis, either the peak:MIC ratio or AUIC ratio of lomefloxacin correlated with efficacy.^[4] However, when the AUC was kept constant and the dosage was changed to increase the peak:MIC ratio (>= 20:1), outcomes improved significantly. The investigators hypothesized that the peak:MIC was an important parameter because, in vitro, ratios of 10 or more prevented emergence of resistant organisms.^[75] However, dose-related toxic side effects associated with fluoroquinolones prevent the attainment of these high peak concentrations in the clinical setting.

Relatively few studies were conducted in humans to confirm the hypothesis generated by in vitro and animal models. Treatment of respiratory, urinary, or skin and soft tissue infections with levofloxacin resulted in a high frequency of clinical and microbiologic cure when the peak:MIC ratio was greater than 12.2.³ It should be noted that the peak:MIC ratio and AUIC ratio were highly correlated, with a mean AUIC ratio below 65 in the group with unsuccessful outcome but greater than 100 in the group with successful outcome.

The AUIC was the most significant variable for the probability of a clinical cure for seriously ill patients treated with ciprofloxacin.^[2] The probability of a clinical cure was 69% at an AUIC of 125 (log₁₀ = 2.1) and approximately 80% at an AUIC of 250 (log₁₀ = 2.4; Figure 1). In this trial, daily cultures were obtained to derive time to bacterial eradication. A statistically significant relationship was seen between time to bacterial eradication and the individual AUIC achieved in each patient (Figure 2). An AUIC of 125-250 resulted in effective bacterial killing, with eradication requiring approximately 7 days. When AUIC values were 250, bacterial killing was extremely rapid, with eradication averaging 2 days. However, increasing the AUIC beyond 250 did not increase the rate of eradication. The authors concluded that an AUIC of 125 or above is an effective threshold of antimicrobial activity for seriously ill hospitalized patients. Similar to an earlier study,^[3] the AUIC and peak:MIC ratio were highly correlated in these patients.

Figure 1. Percentage probability of a clinical cure versus AUIC fit to a modified Hill equation. The curve is the fitted relationship; each point represents three or four patients. A log₁₀AUIC of 2.1 is equivalent to an AUIC of 125, and log₁₀AUIC of 2.4 is equivalent to 250.^[2]

Figure 2. Time (days of therapy) to bacterial eradication versus AUIC illustrated by a time-to-event plot. Shown is the day of therapy versus patients remaining culture-positive on that day.^[2]

Figure 3. Relationship between the probability of developing resistance and treatment duration (days). When the AUIC ratio was 100 or greater, only 8% of organisms developed resistance, whereas only 7% remained susceptible when the AUIC ratio was less than 100. (Modified from reference 79.)

The killing rate of ciprofloxacin was examined against strains of S. pneumoniae, S. aureus, and P. aeruginosa for which MICs were similar.^[81] At clinically achievable concentrations (peak 3-6 times MIC), ciprofloxacin killed P. aeruginosa more rapidly than it did either S. aureus or S. pneumoniae. At higher concentrations of 15-18 times MIC, killing rates were similar for the three organisms. This implies some differences in interorganism susceptibility that cannot be discerned solely by measuring MIC.

A study of the impact of the dosing interval on the AUIC for six fluoroquinolones against various gram-negative and -positive organisms in thighs and lungs of neutropenic mice produced similar results.^[82,83] A 24-hour AUC:MIC ratio of 25 for gram-negative bacteria and 53 for gram-positive bacteria was required to achieve a bacteriostatic effect, suggesting that gram-positive bacteria are more difficult to eradicate than gram-negative. An AUIC breakpoint lower than 125 may be adequate for treating bacterial infections in immunocompetent patients, as suggested by the grepafloxacin outpatient study.^[80] However, an AUIC of 25-50 would be ineffective for seriously ill patients.^[2,3] Thus, when directly comparing fluoroquinolones, an AUIC break-point of 125 should be used as it predicts clinical efficacy in humans with serious infections and may prevent treatment failures.

Integrating Pharmacokinetics and Pharmacodynamics

Data required to determine these pharmaco-dynamic parameters are MICs, peak serum concentrations, and AUCs for typical dosages extracted from pharmacokinetic studies conducted at steady state in healthy volunteers (Table 5). Pharmacodynamic data in Table 6 indicate AUICs achieved at recommended dosages in patients with estimated creatinine clearances above 90 ml/minute. Creatinine clearance was chosen because it was the cut-off value frequently used in studies in healthy volunteers. The AUIC values of Legionella, M. pneumoniae, and C. pneumoniae were not included in this table as the pharmacodynamics of fluoroquinolones against intracellular-growing bacteria have yet to be examined.^[82]

When available, intravenous dosages were used to calculate AUICs. Fluoroquinolones do not achieve an effective AUIC against several bacterial species; however, in some instances they may be clinically effective even though pharmacodynamic data predict otherwise. One potential explanation is that AUCs in infected patients are larger than those in healthy volunteers. Second, AUCs of fluoroquinolones that are excreted renally may be increased in patients with mild renal insufficiency. Another explanation is that actual MICs of these organisms are less than median MIC₉₀s. To explore the implications of an MIC lower than the MIC₉₀, AUIC values can be recalculated using MIC₅₀ values; resulting AUIC values approach 125 for many fluoroquinolones against more organisms. However, this may not be clinically acceptable since only half of the pathogens are inhibited. The MIC₉₀ should be used as it is more conservative, but this may result in an overdose from an empiric standpoint if the goal is obtaining an AUIC of 125 for an organism with a lower than predicted MIC. Once sensitivity data are reported by the microbiology laboratory, the actual MIC should be used to determine dosage.

To achieve an AUIC of 125, MICs of sparfloxacin, trovafloxacin, gatifloxacin, and clinafloxacin should be 0.25 µg/ml or less, and MICs of ciprofloxacin and grepafloxacin should be 0.20 µg/ml or less. The MICs of levofloxacin and moxifloxacin should be 0.43 µg/ml or below and 0.38 µg/ml or below, respectively. These MIC breakpoints that result in an AUIC of 125 differ from National Committee for Clinical Laboratory Standards (NCCLS) breakpoints of susceptibility (Table 7).^[84] Using these breakpoints to calculate AUIC will result in values of 20-40, similar to the AUIC ratio necessary to produce a net bacteriostatic effect in animal models of infection, and may be adequate to treat outpatients.^{[80, 82]}

Pharmacodynamic data suggest that cipro-floxacin, ofloxacin, levofloxacin, moxifloxacin, gatifloxacin, and clinafloxacin would be effective in treating infections caused by gram-negative enteric pathogens as the AUIC threshold of 125 is achieved with recommended dosages. Grepafloxacin, sparfloxacin, and trovafloxacin have adequate pharmacodynamic activity against most Enterobacteriaceae but have decreased pharmacodynamic activity against several genera in that family.

The only fluoroquinolones that produce adequate peak:MIC ratios for treating susceptible strains of P. aeruginosa are ciprofloxacin and clinafloxacin, but dosages of 400 mg twice/day do not achieve an AUIC of 125 or greater in patients with normal renal function. Increasing the ciprofloxacin schedule from twice/day to 3 times/day has little benefit because the AUIC continues to be suboptimal. With normal renal function, ciprofloxacin 400 mg administered intravenously every 8 hours may not be sufficient to achieve a breakpoint of 125 in infections caused by bacteria for which MICs are 0.5 µg/ml or greater. Further studies are necessary to determine if higher dosages or combination therapy is the best strategy. The other fluoro-quinolones do not appear to be acceptable options for treatment of susceptible strains of P. aeruginosa due to defects in either pharmaco-kinetics (low AUC) or potency (high MIC).

Recommended dosages for ofloxacin, grepafloxacin, sparfloxacin, and trovafloxacin produce peak:MIC and AUIC ratios against methicillin-sensitive S. aureus that suggest efficacy of these agents against this micro-organism. Levofloxacin 500 mg/day does not result in an effective AUIC; however, this may change in patients with impaired renal function, as 85% of the drug is eliminated renally. For example, a patient with an estimated creatinine clearance of 50 ml/minute would have an AUIC of 192 secondary to an increase in the AUC.^[85] Dosage reductions of levofloxacin are recommended for patients with creatinine clearances less than 50 ml/minute, which may not produce an adequate AUIC. In patients with normal renal function, ciprofloxacin does not appear to be an option for treating staphylococcal infections unless the MIC is 0.20 µg/ml or below. Preliminary data imply that gatifloxacin, clinafloxacin, and moxifloxacin would be effective in treating methicillin-susceptible S. aureus.

Although MIC data for grepafloxacin, sparfloxacin, gatifloxacin, and clinafloxacin show good activity against groups A and B streptococci, pharmacodynamic data suggest otherwise. However, an AUIC of 125 or above for trovafloxacin and moxifloxacin indicates that these agents would be effective in eradicating the organisms. The favorable pharmacokinetic profiles, particularly high AUC, of ciprofloxacin, ofloxacin, and levofloxacin, are not sufficient to overcome the high MICs; thus they should not be given for empiric treatment of groups A and B streptococcal infections. Fluoroquinolones are not reliable choices for empiric treatment of suspected Enterococcus infection, as neither peak:MICs nor AUICs are at values that would predict acceptable clinical efficacy for this genus.

Because of weak activity against S. pneumoniae, ofloxacin and ciprofloxacin usually are not considered first-line treatment for respiratory tract infections, but this is not true of newer fluoroquinolones. Based on the AUIC target of 125, drugs with the best activity against S. pneumoniae are clinafloxacin, moxifloxacin, sparfloxacin, and trovafloxacin. Grepafloxacin will be close to an AUIC of 125, but the AUIC of levofloxacin and gatifloxacin may be too low if the goal is covering the MIC₉₀ and preventing microbial resistance. Although pharmacodynamic parameters imply that grepafloxacin, levofloxacin, and gatifloxacin are not optimally active against S. pneumoniae, clinical data demonstrate efficacy of these agents.^[86-89] An explanation for this contradiction may be that an outpatient population may not require an AUIC threshold of 125 to achieve clinical response. They may have to achieve an AUIC of only 75, as suggested by one outpatient grepafloxacin study.^[80] These newer agents have close to an ideal spectrum of activity against respiratory pathogens, showing effective pharmacodynamic activity against S. pneumoniae, H. influenzae, M. catarrhalis, C. pneumoniae, M. pneumoniae, and Legionella sp. Levofloxacin, sparfloxacin, clinafloxacin, gatifloxacin, and moxifloxacin appear to be dependable for empiric treatment of community-acquired pneumonia. Trovafloxacin should not be given to treat outpatient community-acquired pneumonia since concerns of hepatic toxicity limit its application to hospitalized patients. Grepafloxacin is no longer a consideration as it has been withdrawn from the market.

Trovafloxacin is the first of the fluoroquinolones to be approved as monotherapy for intraabdominal infections caused by mixed aerobic and anaerobic flora, due in part to its in vitro activity against anaerobic organisms.^[60] It was effective in treating these infections in animal models and clinical trials.^[90-92] However, when MIC and pharmacokinetic data are both incorporated, trovafloxacin does not achieve an AUIC of 125 or above against anaerobic organisms. Unfortunately, none of the clinical trials evaluating pharmacodynamics of fluoroquinolones included infections caused by anaerobic bacteria, so it is unknown if a lower threshold of AUIC or peak:MIC would be sufficient.

Summary

Selection of the optimal fluoroquinolone and regimen requires careful consideration of both organism- and patient-specific factors, including spectrum of activity and pharmacokinetics. Using the above concepts, clinicians can design dosing regimens to optimize fluoroquinolone therapy and prevent emergence of resistant organisms and treatment failures.

Table 1. Median MIC₉₀s (µg/ml) of Gram-Negative Organisms to Fluoroquinolones^[6-22]

Organism	Cipro	Oflox	Levo	Grepa	Spar	Trova	Gati	Clina	Moxi
E. coli	0.03	0.12	0.06	0.12	0.10	0.25	0.016	0.008	0.008
Klebsiella sp	0.06	0.50	0.25	0.25	0.25	0.25	0.13	0.03	0.13
Enterobacter sp	0.06	0.25	0.06	0.25	0.12	0.12	0.06	0.03	0.06
Citrobacter sp	0.06	0.25	0.12	0.50	0.25	0.25	0.25	0.13	0.25
Proteus sp	0.06	0.50	0.25	0.50	0.50	0.50	0.25	0.03	0.25
M. morganii	0.06	0.25	0.06	0.50	0.50	0.50	0.25	0.06	0.25
Salmonella sp	0.03	0.12	0.06	0.10	0.06	0.06	0.06	0.008	0.13
Shigella sp	0.03	0.06	0.016	0.10	0.03	0.03	0.016	0.004	0.03
P. aeruginosa	2.0	6.0	4.0	8.0	4.0	4.0	6.0	2.0	8.0
S. maltophilia	8.0	8.0	8.0	2.0	8.0	2.0	3.13	2.0	2.0
H. influenzae	0.015	0.06	0.03	0.03	0.015	0.015	0.016	0.008	0.06
M. cattarhalis	0.06	0.12	0.06	0.03	0.015	0.03	0.03	0.008	0.06

Cipro = ciprofloxacin; Oflox = ofloxacin; Levo = levofloxacin; Grepa = grepafloxacin; Spar = sparfloxacin; Trova = trovafloxacin; Gati = gatifloxacin; Clina = clinafloxacin; Moxi = moxifloxacin.

Table 2. Median MIC₉₀s (µg/ml) of Gram-Positive Organisms to Fluoroquinolones^{[7-13,15,16,20,21,27]}

Organism	Cipro	Oflox	Levo	Grepa	Spar	Trova	Gati	Clina	Moxi
S. aureus, MS	1.0	0.5	0.5	0.12	0.13	0.06	0.13	0.06	0.06
S. aureus, MR	>16.0	>16.0	16.0	16.0	>16.0	4.0	6.25	8.0	4.0
S. epidermidis, MS	1.0	>4.0	0.5	0.12	0.25	0.13	0.25	0.25	0.13
S. epidermidis, MR	>16.0	>16.0	16.0	8.0	4.0	4.0	0.25	0.25	0.13
S. pyogenes	1.0	2.0	1.0	0.5	0.5	0.13	0.5	0.5	0.25
S. agalactiae	1.0	2.0	1.0	0.5	0.5	0.25	0.5	0.25	0.25
E. faecalis	2.0	4.0	2.0	0.5	0.5	1.0	2.0	0.5	0.5
E. faecium	4.0	>16.0	>16.0	8.0	1.0	2.0	4.0	2.0	2.0
S. pneumoniae
PCN susceptiblea	2.0	2.0	1.0	0.5	0.25	0.25	1.0	0.06	0.25
PCN intermediateb	2.0	2.0	1.0	0.25	0.25	0.25	0.5	0.06	0.25
PCN resistantc	2.0	2.0	1.0	0.25	0.25	0.25	0.5	0.06	0.12

MS = methicillin sensitive; MR = methicillin resistant; PCN = penicillin.
^aPenicillin susceptible is defined by an MIC of 0.06 µg/ml or less.
^bPenicillin intermediate is defined by an MIC of 0.12-1 µg/ml.
^cPenicillin resistant is defined by an MIC of 2 µg/ml or greater.

Table 3. Median MIC₉₀s (µg/ml) of Atypical Bacteria to Fluoroquinolones^[11,29-39]

Organism	Cipro	Oflox	Levo	Grepa	Spar	Trova	Gati	Clina	Moxi
L. pneumophila	0.03	0.03	0.03	0.015	0.03	0.015	0.016	0.03	0.06
M. pneumoniae	2.0	2.0	0.5	0.25	0.12	0.12	0.06	NA	0.12
C. pneumoniae	2.0	1.0	0.5	0.25	0.25	1.0	0.12	NA	0.06

NA = not available.

Table 4. Median MIC₉₀s (µg/ml) of Anaerobic Bacteria to Fluoroquinolones^{[7,9-11,13,21,40-42]}

Organism	Cipro	Oflox	Levo	Grepa	Spar	Trova	Gati	Clina	Moxi
B. fragilis	16.0	16.0	2.0	8.0	4.0	0.5	1.0	1.0	1.0
Bacteroides sp	32.0	NA	4.0	8.0	4.0	2.0	2.0	2.0	4.0
Peptostreptococcus sp	4.0	8.0	8.0	2.0	1.0	1.0	0.39	0.5	1.0
C. perfringens	0.5	0.5	NA	1.0	0.5	0.5	0.39	0.13	0.5
C. difficile	16.0	8.0	8.0	NA	NA	2.0	2.0	1.0	2.0
Clostridium sp	4.0	8.0	1.0	16.0	16.0	1.0	0.5	0.5	0.12

NA = not available.

Table 5. Pharmacokinetics of Fluoroquinolones in Healthy Volunteers (creatinine clearances > 90 ml/min)^[43-74]

Drug	Dosage	Cmax (µg/ml)	Tmax (hrs)	Half-life (hrs)	AUC24 (µg/ml hr)	Vd (L/kg)	F (%)	Protein Binding (%)	Excretion
Ciprofloxacin	500 mg p.o. q12h	3.0	1.1	5-6	27.6-28.2	2.1-5	70-80	20-40	66% renal
	400 mg i.v. q12h	4.4			25.4				33% hepatic
	750 mg p.o. q12h	4.4			39.2-42.2
Ofloxacin	400 mg p.o. q12h	4.0	1.4	4.8	82.4-96.2	1.5	98	32	70% renal
	400 mg i.v. q12h	6.5		6.5	87.0
Levofloxacin	500 mg p.o. q24h	5.7	1.1	6-8	47.5	1.1-1.3	99	24-38	85% renal
	500 mg i.v. q24h	6.4			54.6
Grepafloxacin	400 mg p.o. q24h	1.4	2	12	14.4	5	70	50	10% renal
	600 mg p.o. q24h	1.9			24.6				90% hepatic
Sparfloxacin	200 mg p.o. q 24h	0.7-1.3	4-5	15-20	17.7-18.8	4.3-5.5	92	40	15% renal
	400 mg p.o. q24h	1.2-1.5			32.3-35.7				55% hepatic
Trovafloxacin	200 mg p.o. q24h	2.3	1.2	12	31.2	1.3	88	70	23% renal
	300 mg i.v. q24h	4.3			40.0				63% hepatic
Gatifloxacin	400 mg p.o. q24h	4.3	1.0	7-8	34.4	1.7-2.0	93	20	80% renal
	400 mg i.v. q24h	4.6			35.2
Clinafloxacin	200 mg i.v. q12h	2.6	1.5	5-7.6	22.0	1.9-2.5	90	2-7	50-70% renal
	400 mg i.v. q 12h	5.0			47.0
Moxifloxacin	400 mg p.o. q24h	4.5	1.2	12	48.0	1.8	95	55	20% renal
	400 mg i.v.a	4.6			36.9

F = bioavailability.
^aDerived from single-dose studies.

Table 6. AUICs of Fluoroquinolones for Selected Pathogens (numbers in italics indicate AUIC values of 75-125, numbers in bold indicate AUIC values < 75)

Organism	Cipro	Oflox	Levo	Grepa	Spar	Trova	Gati	Clina	Moxi
E. coli	847	725	910	205	340	160	2213	5875	6000
Klebsiella sp	423	174	218	98	136	160	272	1567	369
Enterobacter sp	423	348	910	98	283	333	590	1567	800
Citrobacter sp	423	348	455	49	136	160	142	362	192
Proteus sp	423	174	218	49	68	80	142	1567	192
M. morganii	423	348	910	49	68	80	142	783	192
Salmonella sp	847	725	910	246	567	667	590	5875	369
Shigella sp	847	1450	3640	246	1133	1333	2213	11750	1600
P. aeruginosa	13	15	14	3	9	10	6	24	6
S. maltophilia	3	11	7	12	4	20	11	24	24
H. influenzae	1693	1450	1820	820	2267	2667	2213	5875	800
M. cattarhalis	423	725	910	820	2267	1333	1180	5875	800
MSSA	25	174	109	205	262	667	272	783	800
MRSA	<2	5	3	2	<2	10	6	6	12
MSSE	25	22	109	205	136	308	142	188	369
MRSE	<2	5	3	3	9	10	142	188	369
S. pyogenes	25	44	55	49	68	308	71	94	192
S. agalactiae	25	44	55	49	68	160	71	188	192
E. faecalis	13	22	27	49	68	40	18	94	96
E. faecium	6	5	<3	3	34	20	9	24	24
S. pneumoniae	6	44	55	98	136	160	71	783	192
B. fragilis	2	5	27	3	9	80	35	47	48
Bacteroides sp	<1	--	14	3	9	20	18	24	12
Peptostreptococcus sp	6	11	7	12	34	40	90	94	48
C. perfringens	51	174	--	25	68	80	90	361	96
C. difficile	2	11	7	--	--	20	18	47	24
Clostridium sp	6	11	55	2	2	40	71	94	400

MSSA = methicillin-sensitive S. aureus; MRSA = methicillin resistant S. aureus; MSSE = methicillin-sensitive S. epidermidis; MRSE = methicillin-resistant S. epidermidis.

Table 7. Pharmacodynamics at NCCLS Breakpoints for Susceptibility^[84]

NCCLS
MIC
Drug	Dosage (mg/day)	Breakpoint (µg/ml)	Cmax:MIC	AUIC24
Ciprofloxacin	800	1	4:1	25
Ofloxacin	800	2	3:1	44
Levofloxacin	500	2	3:1	28
Grepafloxacin	600	1	2:1	25
Sparfloxacin	400	1	2:1	34
Trovafloxacin	300	2	2:1	20
Moxifloxacin	400	2	2:1	24

NCCLS = National Committee for Clinical Laboratory Standards.

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